Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype accounting for approximately 10–20% of all cases. Due to a lack of actionable targets, chemotherapy has been for many decades the preferred, and often the only, available treatment option for this disease. There is now evidence, from several randomized controlled trials, that immune checkpoint inhibitors are effective as first-line treatment for advanced TNBC expressing PD-L1 and as neoadjuvant chemotherapy for high-risk early TNBC. Despite these encouraging results, there are still many open issues about the optimal use of immunotherapy in TNBC. This review summarizes the main results from clinical trials testing immunotherapy in TNBC and critically discusses some limitations of these study results. Finally, we present the challenges that need to be addressed soon in the evolving field of immune-oncology.Triple-negative breast cancer (TNBC) holds a poor prognosis compared to other breast cancer subtypes, and the development of new effective treatment strategies is an unmet medical need. TNBC has traditionally been considered not amenable to treatment with targeted agents due to a lack of actionable targets. Therefore, chemotherapy has remained the mainstay of systemic treatment for many decades. The advent of immunotherapy raised very hopeful expectations in TNBC, possibly due to higher levels of tumor-infiltrating lymphocytes, PD-L1 expression and tumor mutational burden compared to other breast cancer subtypes, that predict an effective anti-tumor immune-engagement. The results of clinical trials testing immunotherapy in TNBC led to the approval of the combination of immune checkpoint inhibitors and chemotherapy in both early and advanced settings. However, some open questions about the use of immunotherapy in TNBC still exist. These include a deeper understanding of the heterogeneity of the disease, identification of reliable predictive biomarkers of response, determination of the most appropriate chemotherapy backbone and appropriate management of potential long-term immune-related adverse events. In this review we aim to examine the available evidence on the use of immunotherapy strategies in both early and advanced TNBC, to critically discuss some of the limitations encountered in clinical research and to summarize data on novel promising immunotherapeutic strategies beyond PD-(L)1 blockade that have been investigated in the most recent trials. Triple-negative breast cancer (TNBC) accounts for 10 to 20% of newly diagnosed invasive breast cancers and is defined by the absence of immunostaining for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor-2 (HER2) . This poA deeper understanding of the molecular characteristics of TNBC unveiled different subtypes so that TNBC is no longer considered as a single entity ,7. BasedImmunotherapy has emerged as a significant advancement in oncology, but it took years before immune checkpoint inhibitors (ICIs) were investigated in TNBC. The discovery of higher genomic instability and a better understanding of the importance of tumour-infiltrating lymphocytes (TILs), programmed death ligand 1 (PD-L1) expression and tumor microenvironment (TME), paved the way for clinical trials testing ICIs in TNBC . The resIn this review, we aim to explore the available evidence supporting the use of immunotherapy in the treatment of TNBC in both early and advanced settings, discuss the limitations of the studies conducted so far, and critically analyze the open questions that require further investigation. Additionally, we provide insights into the most recent trials that are investigating the combination of immunotherapies with ICIs and conventional therapies, as well as other immunotherapeutic strategies.Primary investigations conducted with immunotherapy in TNBC evaluated the safety and efficacy of this strategy as monotherapy for patients with advanced disease. .The phase Ib KEYNOTE-012 trial  was the Unfortunately, the following phase III trial, the KEYNOTE-119 [The positive results of KEYNOTE-158 ,21 led tp = 0.0377). Additionally, an exploratory analysis of TNBC patients with PD-L1-positive disease (n = 32) revealed a lower hazard ratio (HR) of death compared to those with PD-L1-negative TNBC (n = 29) [Several clinical trials have tested the efficacy of other ICIs in monotherapy for the treatment of advanced TNBC. These include the phase I JAVELIN trial with avelumab , the pha(n = 29) . The resAs almost all previously reported studies suggested that ICIs as monotherapy might offer only limited survival benefit, subsequent studies focused on combining ICIs with chemotherapy to enhance immune response. The rationale behind this combination is to release antigens to stimulate immunogenicity and effector T-cells, as well as to reduce regulatory T-cells, increase MHC1 and IFN1 and make the microenvironment more favorable .Up to now, three randomized phase III trials investigated the role of immunotherapy plus chemotherapy versus chemotherapy alone in first-line metastatic TNBC .p = 0.002), but not in OS . Considering only patients with PD-L1 positive disease , the addition of atezolizumab was statistically significant in terms of PFS ; however, no statistical benefit was found in terms of median OS  [The first phase III trial testing immunotherapy combined with chemotherapy versus chemotherapy alone was the IMpassion130 . Patient53–0.86) ,30.Based on the primary results in the PD-L1 positive subgroup, atezolizumab received accelerated approval from the Food and Drug Administration (FDA) in March 2019 and from European Medicines Agency (EMA) in August 2019, making it the first immunotherapeutic agent to be approved in this setting.p = 0.20) [Due to different accessibility in the use of nab-paclitaxel as first-line therapy worldwide, the IMpassion131 trial tested the combination of atezolizumab and paclitaxel in the same setting of patients. Differently from IMpassion130, the primary endpoint of the study was investigator-based PFS tested in the PD-L1 positive population and, if significant, in the ITT. OS was a secondary endpoint to be tested only if the PFS was positive. Surprisingly, the study did not demonstrate improved PFS in the PD-L1 positive subgroup , may help clarify some doubts. In the experimental arm, atezolizumab is combined with different chemotherapy partners such as carboplatin and gemcitabine or capecitabine. This could help us clarify whether the main reason for the negative results of the IMpassion131 is atezolizumab itself or the chemotherapy backbone .p = 0.0012), regardless of the chemotherapy partner. No statistical differences were observed in the PD-L1 CPS > 1 and in the ITT, which was not formally tested. This result led to the approval of the drug by the FDA in November 2020 for patients with PD-L1 positive CPS > 10 tumor. Final OS results with longer follow-up demonstrated a 7-month improvement with pembrolizumab, from 16.1 months to 23.0 months . Subgroup analysis showed no benefit for patients with CPS < 10% and minimal incremental benefit for patients with tumor proportion score <20 compared with tumor proportion scores ≥10 [Besides the contradictory results with atezolizumab, pembrolizumab demonstrated more consistent data. The KEYNOTE-355 ,35 is a ores ≥10 . Since aWhile the initial discoveries came from studies conducted in the metastatic setting, in general, early-stage disease represents a more promising scenario for immunotherapy for several reasons. Most importantly, the tumor burden is more limited, the disease is therefore more homogeneous from a biological point of view, and the tumor microenvironment is less immunosuppressive and less impacted by previous systemic treatments . Moreovep < 0.001) with a delta of 13.6%, [p = 0.0003) [f 13.6%,  which, i 0.0003) ,41. The  0.0003) . Further 0.0003) ,41. Base 0.0003) .p = 0.0044). In contrast, the PD-L1 positive cohort achieved a higher rate of pCR compared with the PD-L1 negative cohort (68.8% vs. 49.3%) but this benefit did not cross the prespecified significance boundary and thus the study was not formally powered for testing EFS, disease-free survival (DFS) and OS analyses.The IMpassion031 trial  tested tp = 0.48). However, PD-L1 status was the greatest predictor of pCR regardless of the treatment received. High levels of PD-L1 were associated with the highest pCR rate. Stromal and intratumoral TILs were also predictive of pCR in both treatment arms. Continuing follow-up for the EFS is ongoing [The other phase III trial testing atezolizumab in the neoadjuvant setting is the NeoTRIP  which us ongoing .p = 0.287). However, a significantly improved 3-year iDFS  and OS  were reported, questioning the validity of pCR as a valid surrogate endpoint in the neoadjuvant immunotherapy trials [Another promising ICI tested in the early setting is durvalumab, which was evaluated in association with nab-paclitaxel followed by dose-dense epirubicin/cyclophosphamide in the phase II GeparNuevo trial . The stuy trials . InteresOther ongoing trials are evaluating the role of neoadjuvant with or without adjuvant immunotherapy in early-stage TNBC. The use of atezolizumab is currently being investigated in large trials, including the neoadjuvant to adjuvant NSABP-B59/GeparDouze trial (NCT03281954) and the adjuvant IMpassion030/ALEXANDRA trials . Trials The phase II NIMBUS study investigated the combination of nivolumab and ipilimumab in patients with hypermutated HER2-negative breast cancer. The ORR was 16.7% for patients with TMB ≥9 mut/Mb, which could reach 60% for those with TMB ≥14 mut/Mb. Durable responses of more than one year were observed with this strategy . RecentlThe BELLINI trial investigated the use of neoadjuvant nivolumab, with or without low-dose ipilimumab, in stage I-III TNBC patients with high levels of TILs. Results presented at ESMO 2022 showed that 23% of patients has partial radiological response (PR) after only 4 weeks of neoadjuvant nivolumab treatment. Immune activation was observed in 58% of patients and all patients with PR had TIL levels above 40%. These results suggest the potential for using ICIs without chemotherapy for early TNBC patients .The combination of tremelimumab, an anti-CTLA4, durvalumab and chemotherapy is being investigated in the phase I/II MOVIE trial, with moderate activity and a consistent safety profile  Table 4Table 4.Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated therapeutic efficacy in patients with germline BRCA1 or BRCA2 (gBRCA) mutations ,54,55. PMEDIOLA was a phase II trial testing the combination of durvalumab and Olaparib in patients with germline BRCA1 or BRCA2 mutations, reporting interesting results in terms of responses (ORR of 63.3%) . The comIn the randomized, non-comparative, phase II DORA trial, patients with TNBC were randomised to olaparib or olaparib plus durvalumab after a period of clinical benefit from platinum chemotherapy. The aim of the study was to test whether platinum sensitivity could serve as a sort of surrogate biomarker for patients with TNBC who might benefit from a maintenance strategy with PARP inhibitors with or without immunotherapy. The study showed that a subgroup of non-gBRCA-altered TNBC patients achieved durable DCR with a chemotherapy-free maintenance strategy of olaparib with or without durvalumab . The ongAnti-angiogenic drugs have been investigated in combination with immunotherapy due to their immunomodulatory properties. They are able to increase lymphocytic infiltration into the tumor and enhance antitumor immune responses . The FUTAntibody-drug conjugates (ADCs) represent a group of new drugs with an innovative mechanism of action. ADCs consist of a monoclonal antibody specific for proteins overexpressed on tumor cells, linked to a cytotoxic drug or payload through a linker. Metastatic breast cancer often exhibits elevated levels of Trop-2, a transmembrane calcium signal transducer, which contributes to tumor growth and advancement, providing the rationale for testing anti-Trop2 treatment strategies in these patients. Sacituzumab Govitecan (SG) is a novel ADC that combines an anti-Trop2 monoclonal antibody with SN-38, the active form of irinotecan, through a specialized hydrolyzable linker. This linker facilitates the intracellular and tumor microenvironment release of SN-38 .SG is approved for the treatment of metastatic TNBC based on the results of the phase III ASCENT trial, which showed both improved PFS and OS compared to the treatment of physician choice in heavily pre-treated patients . StudiesThe HER2-targeted ADC, trastuzumab deruxtecan (T-DXd), is approved for HER2-low metastatic breast cancer due to the improvement in PFS and OS . PreclinPrior studies have yielded conflicting results regarding the prognostic value of low HER2 expression, lacking robust evidence for its independent prognostic significance. Nevertheless, recent advances in both basic and clinical research have significantly transformed our understanding of HER2-low breast cancer . First, BEGONIA (NCT03742102) is an ongoing 2-part open-label platform study evaluating in first-line TNBC the safety and efficacy of durvalumab in combination with other novel therapies, such as the two novels ADC, dapotomab deruxtecan (Dato-DXd) and T-DXd. In the most recent updated analysis, the combination of durvalumab with Dato-DXd showed compelling high response rates (ORR 74%) with promising durability, irrespective of PD-L1 expression . SimilarNew strategies are currently under investigation. The IMPRIME-1 trial tested the efficacy of Imprime-PGG, an innate-immune activator, in combination with pembrolizumab for heavily pretreated metastatic TNBC patients. The trial showed an ORR of 15.9%, a DCR of 54.5%, and a median OS of 16.4 months, compared to 9 months for those receiving pembrolizumab alone .Another approach is to use purinergic pathway antagonists such as oleclumab, which was tested in a phase I/II SYNERGY trial. Results presented at ESMO 2022 showed that the addition of oleclumab to durvalumab with carboplatin/paclitaxel did not increase clinical benefit rate at week 24 in first-line advanced TNBC, although 9 long responder patients in both treatment arms are still under immunotherapy maintenance . Other cEarly-phase trials are also investigating the efficacy and safety of dendritic cell (DC) based antitumor vaccines. In HER2-negative patients, the addition of DC vaccines to standard NACT improved the rate of pCR from 2.8% to 23.1% in the PD-L1-negative population, although no significant differences were observed in 7-year EFS or in OS . CAR-T cSome important issues regarding the use of immunotherapy in clinical practice exist and need further investigation. These open questions are shown in While PD-L1 proved to be a predictive factor of immunotherapy in several studies in the metastatic setting, its predictive role was not confirmed in other trials.In addition, the development of different immunohistochemical assays, scoring systems, and cutoff values to determine PD-L1 status in the IMpassion130 and KEYNOTE-355 trials generates confusion about how to assess PD-L1 status in routine clinical practice; the various assays and scoring systems are not interchangeable and it is important that clinicians and pathologists are aware of this. The status of PD-L1 was defined differently among the studies: in the IMpassion trials, PD-L1 was considered positive if the immune cell score was 1% or greater, using the SP142 assay . In the KEYNOTE-355, the PD-L1 positivity was defined by the CPS using the 22C3 assay , with CPS cutoffs of 1% or greater and 10% or more. Despite attempts to harmonize scoring systems, agreement between tests remains low. Each test may miss about 20% of patients who are classified as positive by another test. It may not be practical for laboratories to perform multiple assays, and this problem has yet to be resolved.Although the expression of PD-L1 seems an established predictive biomarker in the advanced setting, it did not differentiate between responders and non-responders in the early setting. However, it is important to note that the PD-L1 threshold adopted in the subgroup analyses of KEYNOTE-522 (CPS ≥ 1) may not be the optimal one, since a threshold of CPS ≥ 10 is currently used to select patients in the metastatic setting, warranting this additional analysis in the future.p = 0.014), and among the metastatic sites, PD-L1 expression was lowest in the liver and highest in the lymph nodes [To make things worse, the temporal and spatial heterogeneity of PD-L1 should be taken into account. The levels of PD-L1 expression can vary between different stages of the disease, with higher levels observed in primary tumors than in metastatic lesions. Moreover, the expression levels may differ depending on the location of the metastatic site, with lung, soft tissues and lymph nodes metastases showing higher expression levels than liver, skin and bone metastases . In the ph nodes . These dIn clinical trials the response to ICIs is very heterogeneous and discovering new predictive biomarkers is un unmet need. However, to date, none of the translational research efforts have identified clinically useful biomarkers that can accurately predict the response to immunotherapy .Biomarkers currently under investigation include TILs, immune phenotype, tumor mutational burden, and BRCA1/2.It has been suggested that a high number of TILs in the pembrolizumab arm of the KEYNOTE-119 trial correlate favorably with clinical outcomes . In a biImmune phenotype refers to the immune cell composition and activation status of the tumor microenvironment, which can be assessed by gene expression profiling or immunohistochemistry. There is a plethora of biomarkers that identify “immune-enriched” tumors and are associated with a greater magnitude of benefit within the PD-L1 positive population. Immune-enriched profile is related to a basal-like immune-activated molecular subtype, compared with a basal-like immune-suppressed subtype. TMB reflects the number of somatic mutations in the tumor genome, which can be measured by next-generation sequencing. About 5% of metastatic breast cancer is associated with high TMB and has been shown to correlate with good response to immunotherapy . For theThe presence of BRCA 1/2 mutations provides higher genomic instability, leading to increased neoantigen load, making these tumors a very attractive target for immunotherapy. However, Emens et al. demonstrated that the presence of a germline BRCA1/2 mutation was not associated with PD-L1 expression and did not predict the benefit from atezolizumab in the IMpassion130 trial . CurrentThe low efficacy of immunotherapy as a monotherapy in TNBC, as well as the increased response rates seen with combination regimens comprising immunotherapy and chemotherapy, suggest that chemotherapy may influence the tumor microenvironment and the likelihood of response to ICI based regimens . Additionally, preliminary clinical findings indicate that the type of chemotherapy employed could influence both the tumor microenvironment and the probability of a response to immunotherapy-based regimens. For instance, in the TONIC trial, metastatic TNBC patients received a 2-week low-dose induction with various chemotherapy agents, including cyclophosphamide, cisplatin, doxorubicin, or irradiation, all followed by nivolumab. The cisplatin and doxorubicin cohorts demonstrated the highest ORR and also displayed an upregulation of immune-related genes implicated in PD-1/PD-L1 and T-cell cytotoxicity pathways .The NeoTRIP trial, which did not include anthracyclines in the neoadjuvant setting, failed to demonstrate an increased pCR. This contrasts with the positive result of IMpassion031 and thus suggests that anthracycline induction may lead to an upregulation of immune-related genes, thereby priming the tumor microenvironment for a more favorable response to immunotherapy .There is ongoing debate about how long immunotherapy treatment should be administered. Large, randomized trials have shown that immunotherapy can produce long-lasting responses, raising questions about whether it should be continued until disease progression or unacceptable toxicity in the metastatic setting. The appropriate duration of immunotherapy in the early setting is even more uncertain. Most trials do not differentiate the contributions of the neoadjuvant and adjuvant treatment phases, therefore it is not clear whether immunotherapy should be administered only in the neoadjuvant setting or also post-surgery and if so, for how long. While immunotherapy was continued after surgery in IMpassion031 and KEYNOTE-522 trials, GeparNuevo did not continue durvalumab postoperatively and still showed improvement EFS, suggesting that most of the benefit of ICI therapy is achieved in the neoadjuvant phase. Restricting treatment to the neoadjuvant phase could be associated with important benefits such as reducing treatment burden and lowering costs. Biomarkers are not yet able to accurately identify which patients will benefit from ICIs in the early setting. Ongoing trials are evaluating different possibilities of ICI timing, but final answers will only be available after future studies designed to directly compare these different approaches.The standard of care for patients with residual disease after neoadjuvant therapy was adding capecitabine according to the results of CREATEx trial , but wheThe use of immunotherapy in early-stage TNBC raises questions about what to do for patients who experience early relapse after (neo)adjuvant immunotherapy. It is unclear if patients can be rechallenged with immunotherapy and if disease-free interval matters. Trials in metastatic setting only enrolled immunotherapy-naïve patients and thus new clinical trials addressing this question are urgently needed. Patients with primary resistance who have a high residual cancer burden at the time of surgery, or early recurrences after surgery, are likely to have different disease biology and mechanism of resistance than patients who develop late recurrence. Whether retreatment with ICI is useful in patients with late relapse is unknown. Understanding the mechanisms of resistance is key to identifying novel treatment strategies for patients with recurrent or advanced TNBC after ICI therapy, like combining ICIs with other immunotherapeutic drugs or drugs with different mechanisms of action such as PARP-inhibitors. In the meantime, in the absence of such data, chemotherapy or new ADCs remain a possible option for patients resistant to immunotherapy. Most trials investigating ICIs in different tumor types have demonstrated a significant survival benefit, despite occasional disappointing results in terms of response rate, raising several questions about the appropriate endpoints to evaluate response to ICIs in clinical trials. ICIs work by enhancing the immune system’s response to cancer cells, leading to distinct tumor responses that may be more long-lasting than those produced by cytotoxic chemotherapy agents. Consequently, evaluating the effectiveness of ICIs requires different endpoints than those used for chemotherapy. While chemotherapy acts directly on tumor cells, ICIs restore T-cell infiltration in the tumor microenvironment, inducing a specific immune response against cancer cells . As a reThese results call into question the optimal endpoints for assessing ICI efficacy in clinical trials. For ICIs, pCR may not be the best measure of antitumor activity, and survival endpoints such as EFS may be more appropriate. However, survival endpoints require longer follow-up periods, more events, and larger sample sizes, making trial management more complex and costly.irAEs are autoimmune conditions that have the potential to impact any organ in the body, distinguishing them from adverse events typically associated with chemotherapy . Among pFatigue is also commonly observed, although usually in a mild form, with an estimated overall incidence of 16–24%. Although retreatment with ICIs can be considered for most grade 1–2 irAEs, ICIs are usually permanently discontinued for grade 3–4 events .The occurrence of irAEs is a serious issue especially when treating patients in a potentially curative setting, as some of these adverse effects may be permanent or life-threatening. In the KEYNOTE-522  irAEs ofFurthermore, considering that a large number of patients receiving early-stage ICI are younger, fertile women, it is imperative to also evaluate the potential impact of ICI on gynecological function. According to the evidence currently available, these compounds could potentially cause libido and sexual dysfunction as well as primary and secondary hypogonadism .Due to the existence of permanent and potentially life-threatening irAEs, the risk of developing these toxicities must be weighed against the absolute EFS benefit offered by neoadjuvant immunotherapy. Compared to clinical trials, in daily practice not all patients are sufficiently fit to receive immunotherapy. At ESMO 2022, results for the secondary endpoints assessing patient-reported outcomes (PROs) in KEYNOTE-522 were reported . The stuMoreover, appropriate reporting of irAEs in clinical trials is of paramount importance. Rare irAEs might be unrecognized if clinical trial publications report only AEs occurring above a specified incidence . This could favor underreporting of rare Aes, such as cardiac events, and could mask the real incidence of some rare toxicities .Another major problem is the economic challenge of using expensive drugs in the treatment of TNBC. The discovery of new strategies exacerbates inequalities in care and outcomes among cancer patients. In addition, clinical guidelines often do not take into account the context of different health systems and provide algorithms that are often incoherent with national cancer policies. Therefore, effective and integrated interventions need to be developed and implemented at multiple levels. Above all, the need to approve for clinical practice only drugs with demonstrated efficacy should be mandatory.ICIs in combination with chemotherapy are approved for treatment of both early and advanced TNBC. However, there are still grey areas in the use of immunotherapy in TNBC that require a deeper investigation.In the advanced setting, the KEYNOTE-355 has solidified the role of pembrolizumab in first-line metastatic TNBC, but some questions still remain due to the formally inconclusive data of IMpassion130 and the clinical failure of IMpassion131. Moreover, the initial faith in the predictive role of PD-L1 is now largely questioned by its dynamic heterogeneity , analytic inconsistency  and futility in early TNBC. Nonetheless, PD-L1 still remains the sole biomarker required for ICI recommendation in advanced TNBC, although it seems more able to exclude rather than select candidates for immunotherapy. Accordingly, further investigations are needed to identify useful biomarkers for chemo-immunotherapy, especially in the context of the evolving treatment scenario of metastatic TNBC. In the early setting, KEYNOTE-522 demonstrated significant pCR and EFS benefit for the addition of pembrolizumab to the (neo)adjuvant chemotherapy regardless of PD-L1 status. Nevertheless, the final benefit in pCR rate was not as pronounced as expected. As for EFS, it is not entirely clear the role of the anti-PD1 in the neoadjuvant versus adjuvant phase, since the trial design prevents to dissect the other contribution. In the adjuvant phase, the addition of pembrolizumab in patients who achieved pCR provided only marginal benefits, while it was more significant for those with residual disease, albeit in the context of a suboptimal control arm. As a consequence, uncertainties still exist in the adjuvant recommendation of ICI after achieving a pCR and new data from ongoing clinical trials are eagerly awaited.Over the last few years, significant steps forward have been made in the field of immunotherapy for TNBC. Nevertheless, it is crucial to recognize that the overall value of a drug is determined by the convergence of evidence from various clinical trials, rather than isolated yet relevant findings. Therefore, further insights are needed in the areas where data are limited and uncertainties persist.


In a time-to-event analysis female sex was associated with a decreased chance of reaching the reference HRQoL in the physical function, bodily pain and mental health dimensions. Higher body mass index was found in the physical functioning dimension and hypertension in the physical functioning, vitality and social functioning dimensions. Similar results were seen for diabetes mellitus in general health, vitality and mental health dimensions, as well as pulmonary illness in the physical role functioning dimension and psychiatric diagnosis in the social functioning dimension. Mechanical ventilation was associated with a decreased likelihood of achieving reference HRQoL in the bodily pain and physical functioning dimensions. Patients treated in an ICU because of COVID-19 had lower HRQoL 3–9 months after ICU discharge than 95% of the general population. Physical dimensions were more severely affected than mental dimensions. Female sex and several comorbidities were associated with a slower rate of recovery.In survivors of severe coronavirus disease 2019 (COVID-19) incomplete mental and physical recovery may considerably impact daily activities and health-related quality of life (HRQoL). HRQoL can be evaluated with the RAND-36 questionnaire, a multidimensional instrument that assesses physical and mental aspects of health in eight dimensions. The objective was to investigate HRQoL in intensive care patients previously treated for COVID-19 at three Nordic university hospitals, in a prospective multi-center cohort study. HRQoL was measured using RAND-36, 3–9 months after discharge from intensive care units (ICU). One hospital performed a second follow-up 12 months after discharge. A score under the lower limit of the 95% confidence interval in the reference cohorts was considered as significantly reduced HRQoL. We screened 542 and included 252 patients. There was more than twice as many male (174) as female (78) patients and the median age was 61  years. Hypertension was the most common comorbidity observed in 132 (52%) patients and 121 (48%) patients were mechanically ventilated for a median of 8 (IQR 4–14) days. In RAND-36 physical functioning, physical role functioning, general health (Study registration: clinicaltrials.gov: NCT04316884 registered on the 13th of March 2020, NCT04474249 registered on the 29th of June 2020 and NCT04864938 registered on the 4th of April 2021. In those surviving severe COVID-19 mental and physical recovery has been reported to occur at varying degrees and following different trajectories. Incomplete recovery, e.g. persistent dyspnea, fatigue and cognitive symptoms, may have considerable impact on daily activities and health-related quality of life (HRQoL)10 even affecting the families of intensive care unit (ICU) survivors11.During the coronavirus disease 2019 (COVID-19) pandemic, many patients presented with severe illness requiring hospitalization and intensive care. Over six million people died worldwide, in Finland there were close to nine thousand deaths and in Sweden almost twenty-four thousand in COVID-1915. The mechanisms of incomplete recovery in patients with mild to severe COVID-19 and post-intensive care are multifaceted19. One study20 suggested that invasive ventilation affects HRQoL at a 1-year follow-up compared to a mixed hospitalized cohort, including other patients treated at an ICU with diagnoses other than COVID-19. Moreover, in Sweden, the RAND-36 tool is widely used to assess HRQoL after intensive care as a standard in The Swedish Intensive Care Registry. Yet, large reports on HRQoL assessed with RAND-36, have been scarce in patients treated in an ICU with COVID-19.Studies have shown that COVID-19 and intensive care negatively impact short- and long-term HRQoLOur main hypothesis is that COVID-19 patients treated in ICU have decreased HRQoL compared to the normal range of the general population as a consequence of severe illness and the impact of intensive care. Thus, this study aimed to measure HRQoL in a large group of COVID-19 patients who received intensive care.21. We chose to measure the patients HRQoL with the generic instrument RAND-36 since it together with 36-Item Short form Survey22 (SF-36) a similar instrument, is the most widely used instruments used to measure HRQoL23. The availability of reference populations in both Sweden23 and Finland24 as well as the fact that it measures and separates different aspect of mental and physical health. As a secondary endpoint, we investigated how demographic factors, previous comorbidity and invasive ventilation, a proxy for more demanding intensive care, affected HRQoL in a time-to-event analysis.In this study we investigated patients treated in intensive care at three Nordic university hospitals and registered their HRQoL 3 to 6 months after discharge from ICU using the RAND-36We conducted a prospective multi-center cohort study on HRQoL in patients surviving intensive care for COVID-19 infection. Patients were included at tertiary care hospitals in Uppsala and Linköping in Sweden, and in Helsinki, Finland. Included patients were admitted to ICU 3rd of April 2020 to the 11th of August 2021 and followed up between 9th of July 2020 until December 8th, 2022.Patients ≥ 18 years of age treated at an ICU due to COVID-19 in any of the hospitals described above were eligible for inclusion with informed consent. Patients unable to complete the follow-up protocol or give informed consent were not included. See supplement for details concerning inclusion and exclusion of the different sites. The follow-up was planned for 3 to 6 months after ICU discharge. The Uppsala site performed a second follow-up 12 months after discharge.The follow-up was conducted by sending the RAND-36 questionnaires to the participants in advance. The questionnaires were collected when the participants visited an investigator or they were submitted by post after the visit. Some patients received and returned the questionnaires only through the post.We collected data on sex, age, body mass index (BMI) and clinical parameters  at intensive care admission. The medical records were screened for prior comorbidity for the following diagnosis groups: hypertension, other cardiovascular diagnoses, diabetes mellitus, pulmonary diagnoses, malignancy and psychiatric diagnoses. We did correlation analysis on preliminary data showing strong correlation between the factors concerning severity of disease. The correlations between the collected comorbidities, age and sex were weaker. Therefore, we only used presence of mechanical ventilation as the disease severity parameter, and included comorbidities, age and sex as covariates that are commonly used in intensive care studies.25. It has been translated and validated for the Swedish26 and Finnish populations24. A score in a dimension below the lower limit of the 95% confidence interval (CI) of the respective reference population was considered significantly below normal HRQoL.RAND-36 was used to assess physical, mental and social aspects of health. The instrument contains 36 items divided into eight subscales to measure health status: physical function, physical role function, bodily pain, general health, vitality, social function, mental health and emotional role function. The first four dimensions measure physical health and the last four mental and social health. The scores on all sub-scales are transformed to a scale from 0 (the worst score) to 100 (the best score). The RAND-36 was developed to reflect the part of the World Health Organization’s definition of health that pertains to self-reports of physical, mental and social well-being and functional abilityCohort size was not pre-determined, but the different sites aimed to include all patients receiving care at an ICU for COVID-19. Histogram inspection revealed that data were not normally distributed. Consequently, we used non-parametric methods to analyze the data. In the primary outcomes missing data was 2.4% at maximum. Missing data in the RAND-36 dimensions were imputed with the median of that dimension in the calculation of IQR. For other variables, missing values were omitted.23 for the Swedish observations, respective a Finnish reference cohort24 for the Finnish observations, in the specified dimension. The reference cohorts above were not exposed to COVID-19 since data were collected prior to the COVID-19 pandemic. We used a two-sided binomial test to determine whether HRQoL in our cohort was below the lower limit of the 95% CI of the relevant reference cohort.Reference level of quality of life (QoL) was defined as having a RAND-36 score within the 95% confidence interval (CI) of a Swedish reference cohortWe assumed HRQoL to be decreased during intensive care and defined recovery as a RAND-36 score above the lower limit of the 95% CI of the reference material at follow-up. Patients were called to follow-up at specific times but actual time to follow-up showed a substantial variation in time. This variation in follow-up times allows for a continuous analysis of recovery using time-to-event analysis assuming the variation in time to follow-up is not determined by the severity of symptoms. Thus, we analyzed the outcome predictors in a time-to-event analysis using a Cox proportional hazard model. Because there was multicollinearity between the length of stay in the ICU, mechanical ventilation and days mechanically ventilated, we chose to use treatment with mechanical ventilation as our variable for the severity of COVID-19 in this model. We also performed both the binominal test and the time to event analysis as a sensitivity analysis against the Swedish reference cohort see .https://www.r-project.org) was used for calculations with package ggplot2 3.3.5, survival 3.3–1, survminer 0.4.8 and survivalAnalysis 0.3.0. The level of statistical significance was set at p < 0.05.R version 4.1.2 , Linköping (2021-01283 and 2022-07064-02) and a local ethics board of the Helsinki University hospital district in Helsinki (HUS-1949–2020). The Declaration of Helsinki and its subsequent revisions were followed.Written informed consent was obtained from the patients.We screened 542 patients for participation. Of these, 143 declined, 4 withdrew consent and 143 did not answer, leaving a final sample of 252 (46%) participants in the first follow-up. One site conducted a second follow-up inviting 172 participants, of whom 118 (69%) returned the RAND-36 questionnaires , we assessed predictors of regaining HRQoL Fig.  in refer24, suggesting reduced physical capacity. One mental dimension was significantly reduced, implying that social and mental health are affected, but potentially less so than the physical dimensions. Other studies on HRQoL in the general population during the pandemic are scarce and we found none utilizing RAND-3625 or SF-3622 in the studied countries. However, one Swedish study with the less detailed instruments, Visual Analog Scale (VAS) and EQ-5D-5L27 reported also a reduction of HRQoL in the general Swedish population during the COVID-19 pandemic.We found that females had a numerically lower recovery rate in all dimensions, significant for physical functioning, bodily pain and mental health. Similar data have been reported in a previous study28 comparing sexes in a post-COVID-19 cohort and an ECMO survivor cohort29 where women perceived lower levels of HRQoL. However, women also perceived generally lower RAND-36 scores in all dimensions in the Swedish reference material23, suggesting that female sex affects HRQoL. In a previous study in post-COVID-19 patients30 an increased risk of onset of new pain after severe COVID-19 and decreased HRQoL were reported, although there were no sex differences. The skewed proportions between the sexes with double the number of males are in line with other studies describing patients admitted to the ICU for COVID-1931as well as proportions diagnosed with COVID-1920. It has been reported that males are struck harder by the disease 33 however not fully understood.The main finding of this study is that patients who received intensive care for COVID-19 perceived significantly lower levels of HRQoL in the physical dimensions of the RAND-36 (3 of 4 dimensions) compared to the previously collected reference populations31, and its negative impact on HRQoL has been shown in a population-based study in Sweden34. In the current study hypertension negatively affected the regaining of health in both the physical dimension; physical functioning as well as the mental dimensions; vitality and social functioning, which is consistent with the finding that hypertension is associated with more severe illness31. However, hypertension is closely related to age, which may bias this interpretation. Thus, more severe COVID-19 in hypertensive patients could reduce HRQoL and slow recovery.Hypertension has been reported to be a risk factor for ICU admission for COVID-1920. Unfortunately, our data cannot distinguish between the late effects of severe disease and intensive care treatment as such.In this study we report that mechanical ventilation was a negative factor in restoring HRQoL for both physical function and bodily pain in an ICU cohort. This finding suggests that the severity of illness affects the recovery in HRQoL even in critically ill patients, which may be mediated partly through mechanical ventilation or the associated treatment with sedatives and muscle relaxants. Similar findings were reported in a COVID-19 study where HRQoL, assessed by EQ-5D-3L, was higher at follow-up in patients not receiving oxygen vs. invasive ventilation35. Chronic respiratory illness is associated with an elevated risk of ICU admission in COVID-19 patients31. Data from a study on chronic obstructive pulmonary disease (COPD) patients treated in intensive care for exacerbation showed a decreased HRQoL compared to a reference population but not to a matched COPD cohort36 indicating that the lower HRQoL we see may be partly a preexisting problem caused by the underlying disease.The finding that patients with previous pulmonary diagnoses regained health slower for physical functioning and physical role functioning aligns with current knowledge and the risk of impaired lung function after a severe COVID-19 infection31. However, obesity has been associated with lower scores in all SF-36 dimensions, even in non-ICU patients, as recently reviewed37. The most marked effect of obesity is seen in physical functioning, which is consistent with our results.A similar argument can be made for the observation that higher BMI correlated with slower recovery in physical functioning, most likely because obesity is a risk factor for severe disease with ICU admission in COVID-1938.Patients with diabetes mellitus had a slower recovery in general health, vitality and mental health, highlighting that the disease affects different parts of the body and aspects of life. A study on people with diabetes showed an association between mortality over time and lower RAND-36 scores as a physical composite score  and two individual physical dimensions39, this effect could have been stronger, assuming that patients with psychiatric conditions were less likely to participate in the study. Additionally, these results may be affected by our exclusion criteria for mental illnesses.Finally, previous psychiatric diagnoses were associated with slower recovery in social functioning. Because anxiety disorders, including social phobia, specific phobias and generalized anxiety disorder, are the most common psychiatric conditionsTo the best of our knowledge, our study is the first to report a multidimensional assessment of long-term HRQoL in a COVID-19 cohort of this size treated in the ICU. Another strength of the study is that we used individual RAND-36 dimensions, identifying the specific areas of affected HRQoL. Moreover, the cohort is large and most patients have been followed up personally. Also, most of the patients submitted the RAND-36 tool at a patient visit with the option of asking questions. Finally, the multicenter design increases the external validity of the study.Because a number of potential participants died before the follow-up there is a risk of selection bias, where some more severely ill patients were not included. Similarly, bias in those not able to participate due to poor recovery or will of moving on in life is also a risk. However, the results identify risk factors of long-term reduction in HRQoL that are similar to those that are associated with more severe disease. Further, more severe disease in the form of mechanical ventilation is a risk factor for reduced HRQoL. Together this indicates that if anything this would tend to make the current analysis more conservative.The rate of recovery may be affected by rehabilitative interventions after ICU treatment. However, in the present study we lack detailed data on access to rehabilitation and the type of interventions whether in-hospital or after discharge. The different standard of reporting rehabilitation between the cohorts and incomplete data makes this question intractable to formal analysis.27 from the pandemic period we lack RAND-36 data on it. Finally, although all patients in this study were treated in intensive care , it is impossible to overlook the risk that patients during the pandemic may have received ICU care with lower standards, making a comparison with other non-COVID-19 ICU studies difficult. Ideally, the reference group would be collected simultaneously with the study in Finland and Sweden.Another limitation is that the time-to-event analysis is based on random variation in follow-up times rather than continuous follow-up which leaves it susceptible to reverse causation due to selection bias and survivor bias. However, the main contributor to variation in time to follow-up was the availability of time slots for follow-up on the investigator side rather than determined by the patients. Thus, we do not believe the time-to-event analysis was strongly biased by symptom severity. Further, the results from the non-time dependent analysis and previous studies are consistent with our results lending them additional credibility. Unfortunately, the reference populations were not collected during the pandemic and although there is data showing decreased HRQoL in general population in SwedenThe finding of a decreased HRQoL strongly suggests patients treated in the ICU for COVID-19 perceive reduced HRQoL compared to the general population long after discharge. Moreover, patients with female sex and certain comorbidities are more prone to slow recovery. These data suggest that ICU patients, especially those with risk factors identified in this study, should be followed up to evaluate whether they benefit from rehabilitation interventions.It would be useful to study a large cohort repeatedly over an extended period, given that the RAND-36 instrument is intended for longitudinal studies with a sequence of measurements and to study the long-term impact on HRQoL. Such a study would benefit from an ICU control cohort to explore different trajectories with different reasons for ICU admission. Future studies should also focus on the causes of diminished HRQoL and potential rehabilitation interventions in this group.In a cohort of patients treated in the ICU with COVID-19 HRQoL decreased compared to the general population during the first year after ICU discharge. Female sex and comorbidities were associated with a slower HRQoL recovery rate.Supplementary Information.


Understand whether and how the COVID-19 pandemic affects the risk of different types of conflict worldwide in the context of climate change.Based on the database of armed conflict, COVID-19, detailed climate, and non-climate data covering the period 2020–2021, we applied Structural Equation Modeling specifically to reorganize the links between climate, COVID-19, and conflict risk. Moreover, we used the Boosted Regression Tree method to simulate conflict risk under the influence of multiple factors.The transmission risk of COVID-19 seems to decrease as the temperature rises. Additionally, COVID-19 has a substantial worldwide impact on conflict risk, albeit regional and conflict risk variations exist. Moreover, when testing a one-month lagged effect, we find consistency across regions, indicating a positive influence of COVID-19 on demonstrations (protests and riots) and a negative relationship with non-state and violent conflict risk.COVID-19 has a complex effect on conflict risk worldwide under climate change.Laying the theoretical foundation of how COVID-19 affects conflict risk and providing some inspiration for the implementation of relevant policies. Exploring the effects of COVID-19 on conflict risk is essential to human health and safety. However, no clear conclusion has been drawn from previous studies regarding the causal link between COVID-19 and conflict risk, which limit the implementation of corresponding prevention policies. To address this knowledge gap, this study applies multiple approaches to understand if and how COVID-19 affects multiple types of conflict worldwide.1.1The adverse effect of COVID-19 on social stability has unfolded over recent years as the virus spread across the world, stemming from the drastic alteration of human lifestyles and the disservice this pandemic has done to the healthcare and economic systems . This huSince the COVID-19 induced recession has resulted in many individuals losing their jobs, the epidemic increased the likelihood that people may join violent groups because the groups pay their members . Further1.2Despite the increasing evidence for the view that the COVID-19 restrictions and their subsequent economic fallout might affect conflict dynamnics , this peHowever, given the complexity of the effect of COVID-19 on conflict, descriptive and limited statistical analysis using only conflict and COVID-19 data might be inadequate to yield persuasive results as they can omit critical information regarding, for example, the role of climate ,23. More1.3Conflict is a complex and dynamic social phenomenon whose onset, intensity, and duration are driven by various factors. To better explore the effects of COVID-19 on conflict, we must dig into previous research on the relationship between COVID-19 and conflict and their respective fields in general . We founThe climate-COVID-19-conflict nexus is complex that cannot be easily captured by statistical analyses. Reading through pertinent literature, we found that Structural Equation Modeling (SEM) is most appropriate for this study because it has been widely used in exploring the complex nexus between multiple variables . When pr1.4This study aimed to capture the underlying effect pattern of COVID-19 (deaths per month) on conflict risk  under climate change , detailed information on these datasets is provided in the Data and 22.1Structural Equation Modeling (SEM) is a widely used multivariate statistics method, which encompasses factor analysis and path analysis . Based oWe calculated the tolerance and variance inflation factor (VIF) of the data based on IBM SPSS Statistics 24 to assess the collinearity of the variables before fitting SEM . Results2.2Boosted Regression Tree (BRT) is an ensemble machine learning method for fitting statistical models . Unlike Based on RStudio Version 3.3.3 statistical programming environment, the ‘dismo’ and ‘gbm’ packages were adopted to deploy the BRT modeling framework. In this study, the main tuning parameter values were set as follows: . In addition, an ensemble of 50 BRT models was built to enhance the robustness of the modeling approach. A tenfold cross-validation area under the receiver operating characteristic curve (ROC-AUC) was adopted as an accuracy statistics index to avoid over-fitting.To assess the impact of COVID-19 on the conflict simulation, we set strategy A and strategy B in the BRT modeling. Specifically, we set COVID-19 as an independent variable in strategy A, while excluding it in strategy B to verify whether COVID-19 affects the predictive accuracy in conflict simulation.3To fully estimate the influence of COVID-19 on different conflict types worldwide, we used data acquired from UCDP GED version 21.1   and ACLEThe UCDP dataset is a joint project of the Center for the Study of Civil War at the Peace Research Institute Oslo. It is defined as an event where an organized actor used armed force against another organized actor or civilians, resulting in at least one direct death at a specific location on a specific date . AccordiThe ACLED data collected the dates, actors, locations, and fatalities of all reported violent and non-violent actions across most countries worldwide, which allowed the localized study of conflict within a country’s borders . The datTo generate monthly conflict data in 2020–2021 with a spatial resolution of 0.5°, we defined one month as the basic time unit to conduct statistics on conflict data before assigning every conflict event to the grid with a cell size of 0.5 × 0.5°. We converted the number of events in each grid cell to binary values of 0 and 1, where 1 indicated experienced conflict during this year, otherwise, 0 is assigned.Based on previous research, we collected data on climate, agriculture, disease, social, political, economic, and environment that may be associated with conflict ,38. WithFirst, we used the death toll as an index to measure the pandemic impact with the COVID-19 data obtained from the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University .Second, in recent years, the research linkages between climate and conflict have been intensively studied . ConsideEPR) [Third, we identified the environmental background variables (control variables) that may determine regional differences that lead to the inconsistency of conflict incidence across regions. Some studies suggested that water stress and food shortage may increase the chance of conflict .To measuEPR)  given thEPR)  , while in the second strategy, we excluded COVID-19 from the BRT model (strategy B). By comparing the simulation accuracy  of the two strategies, we were able to confirm whether our SEM results are reliably simulating COVID-19 impacts on conflict risk. Indeed, this independent approach corroborated the significant impact of COVID-19 on the three types of conflict worldwide .Fig. 3ROThe predictive performance of strategy A was significantly higher than that of strategy B for non-state violence, violent conflict, and demonstrations when analyzing data globally A–C. Howe5This study assessed the effect of COVID-19 on three types of conflict risk across the world and six regions. Our contribution to COVID-19-conflict nexus research was primarily manifested in three aspects: (1) By incorporating COVID-19 into methods derived from earlier conflict studies, we were able to separate the effect of COVID-19 on conflict risk from the effect of climate on COVID-19 and the indirect effect of climate on conflict caused by COVID-19. (2) Our results suggest that COVID-19 has a significant impact on conflict risk, showing consistency with some previous studies ,7. HowevWhile recognizing the non-negligible effect of COVID-19 on conflict risk at the global scale, our estimation showed variations in its effect across regions on different types of conflict risk. Such results are following previous studies showing that the effect of COVID-19 on conflict risk had heterogeneity at the country or city level ,8. HowevThe regional differences detected in our analysis are logical in the context of broader political trends and the results of other studies. In North America, for instance, where a populist movement spearheaded by Donald Trump resulted in strong political polarization of the pandemic management, the impact of the one-month-lagged COVID-19 measure has spurred the incidence of demonstrations (V = 0.01). In contrast, in South America, large social movements occurred in 2019 in countries like Chile, Ecuador, and Venezuela, but COVID-19 restrictions have been forbidding people to protest, leading to a decline in the incidence of demonstrations (V=−0.02) . LikewisIn addition, we confirmed the impact of COVID-19 on the simulation of conflict risk by including COVID-19 in the conflict risk simulation model. We found that COVID-19 could significantly improve the predictive accuracy of conflict simulations, indicating that the pandemic of COVID-19 has influenced the pattern of conflict to some extent. Thus, it is imperative to include the COVID-19 pandemic in post-2019 conflict simulations to increase precision in forecasting worldwide conflict ,59.6We built a large database and ran both SEM and BRT models to completely assess the influence of COVID-19 on conflict risk under climate change in order to determine if and how it affects various forms of conflict risk globally. The present findings confirmed that COVID-19 has a significant impact on conflict risk but with variation across regions and types of conflict risk. However, data indicated that when considering a one-month lag, COVID-19 consistently decreases the possibility of non-state and violent conflict risk while increasing the incidence of demonstrations across regions.Collectively, this study is one of the first to analyze the impact of COVID-19 on conflict risk at a detailed level by effectively combining a global dataset that covers multiple types of conflict risk and multiple intelligent cognition methods. The following are some advantages that this study has over earlier research. The impact of COVID-19 on conflict risk is first examined in this study on a grid scale, which has a finer data scale and a wider data coverage than earlier studies at regional or national dimensions. More importantly, this study explores the impact of COVID-19 on conflict risk from multiple perspectives by using a variety of intelligent cognitive methods, thus the results obtained from this study are more reliable than those obtained by simple statistical analysis of COVID-19 and conflict risk data.7Based on a theoretical understanding of how COVID-19 influences the incidence of conflict, our study provided compelling evidence that COVID-19 has a complicated and important impact on several forms of conflict risk both worldwide and regionally. On the one hand, it provides new insight into the field of conflict studies. For example, we should consider the driving effect of COVID-19 on conflict when studying conflict risk, to better analyze the driving mechanism of conflict risk. On the other hand, it provides some inspiration for the implementation of corresponding prevention policies. For instance, a reduction in hostilities one month after a large number of COVID-19 fatalities can open a window for ceasefires or peace talks. Authorities must simultaneously get ready to handle the dual problems of high COVID rates and rising societal unrest and dissent.8It is necessary to point out that there are several possible limitations of our analysis. First, regarding the dataset, this study used a relatively small sample size, and the COVID-19 data mostly relied on self-reported data, which may limit the generalizability and accuracy of the study results. Future research should include more comprehensive datasets with large samples to assess the impact of COVID-19 on conflict risk more accurately. Second, in terms of method, this study used convenience sampling methods and a cross-sectional design, which may introduce bias in the sample and limit the establishment of variable causality. Future studies could fruitfully explore this issue further by conducting random sampling of data to reduce random errors and incorporating more reasonable research methods to explore causal links between variables. Third, this study mainly discussed the conflict risk of COVID-19 in a specific cultural context with a specific theme, without investigating other potential factors that may influence the results, and the results may not be generalized to other cultures or contexts. Future research should consider the comparative analysis on different topics when exploring the impact of COVID-19 on conflict risk.10.13039/501100001809National Natural Science Foundation of China (42001238 and 42201497), the Strategic Priority Research Program of the 10.13039/501100002367Chinese Academy of Sciences (XDA19040305), 10.13039/501100012492Youth Innovation Promotion Association (2023000117), and the 10.13039/100010269Wellcome Trust (220211). This study contributes to the CLICCS Cluster of Excellence funded by the German Research Foundation (DFG). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.This research is supported and funded by the Xiaolan Xie, Mengmeng Hao, Fangyu Ding, Quansheng Ge, Dong Jiang: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Wrote the paper. Tobias Ide, David Helman, Jürgen Scheffran: Analyzed and interpreted the data; Wrote the paper. Qian Wang, Yushu Qian, Shuai Chen, Jiajie Wu, Tian Ma: Contributed analysis tools or data; Wrote the paper.https://github.com/Tina-Xi/Code-and-data.The code and data used in the present study are freely available online at 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


Telemental health (TMH) care has received increased attention, most recently due to the COVID-19 pandemic. Many treatment settings and clinicians were forced to rapidly shift to TMH modalities, including clinicians with limited exposure to and possibly negative attitudes toward alternative treatment delivery formats. With the shift to new modalities, effectiveness research is necessary to understand if patients are receiving the same quality of care as before the pandemic and their receipt of mostly in person services. This study compared the naturalistic treatment outcome trajectories for a cohort of patients who received in-person services prior to the pandemic and a distinct cohort of patients who received TMH services after the onset of the pandemic, in a community mental health setting with limited exposure to TMH prior to the COVID-19 pandemic.N = 958 patients in the Northeast United States. Treatment durations differed in the naturalistic treatment setting and we examined patient-reported outcomes up to a maximum of one year.We adopted a retrospective cohort design to examine treatment modality as a between-group moderator of symptom change trajectory on the self-report Patient Health Questionnaire (PHQ-9) in a sample of Statistically significant average decreases in symptom severity were found over the course of up to one year of treatment, yet the average outcome trajectory was not significantly different between two modality cohorts (in person delivery before the pandemic versus TMH delivery after pandemic onset).These findings suggest that even in a setting with limited exposure to or training in TMH, the average outcome trajectory for patients who received TMH was statistically similar to the outcome trajectory for patients in an earlier cohort who received in-person services prior to the pandemic onset. Overall, the results appear to support continued use of TMH services in community treatment settings. Although there is room for improvement, psychotherapy has demonstrated effectiveness in the treatment of a range of mental health and comorbid conditions in both controlled and naturalistic treatment settings . Most psSeveral factors have likely motivated increased attention toward the development, testing, and dissemination of TMH. One reason is the promise to mitigate mental health care access problems . Unmet tTo our knowledge, naturalistic TMH implementation has been examined most extensively in the United States (U.S.) in the context of the Veterans Administration . A recendid not use TMH prior to the COVID-19 pandemic. Among the most endorsed reasons for not using TMH prior to the pandemic were insufficient training, privacy issues, unclear reimbursement practices, efficacy concerns, and insufficient demand. Interestingly, a different survey of over 400 therapists with diverse training backgrounds indicated that most therapists reported having some degree of past TMH training/education , yet less than half reported using TMH prior to the COVID-19 pandemic  were included in the current study. Patients were excluded if they were missing any PHQ-9 score or if they had a baseline value yet no follow-up data. Additional demographic information was obtained from records kept by the facility. Demographic information is typically collected in the context of the initial intake appointment and is expected to be entered into an administrative database by the assigned clinician. Although the date of service when a PHQ-9 questionnaire was administered and a baseline PHQ-9 score was available for all patients included in the analyses, other demographic variables had significant missingness. Racial/ethnic identity was not recorded for most of the sample, and among those for whom racial/ethnic identity data were available (n = 206), racial/ethnic identity was coded as unknown for 18.4% of cases. Among the remaining (n = 168) patients with known racial/ethnic information, 60.7% were recorded as White, 32.2% as Black, 3.0% as another race or mixed races, 2.4% as Hispanic/Latinx, and 1.7% as Asian or Asian-American. Approximately half of those whose sex was available (n = 268) were recorded as male (55.2%) and the remainder were recorded as female. Patient age ranged from 19–77 .Data were derived from the routine data collection infrastructure of an outpatient community mental health clinic (CMHC) in the Northeastern United States. This CMHC provides treatment to adult county residents with serious mental illness and substance use disorder diagnoses. This setting collects routine data from patients to monitor treatment processes and outcomes and inform quality improvement. Adult patients at the CMHC between September 2017 and August 2021, and who completed the PHQ-9 at baseline and at least one follow-up timepoint (n = 236), the most common primary diagnoses were in the categories of mood disorders (44.5%) or psychotic disorders (42.4%). The remainder of patients had primary diagnoses of trauma-related disorders (8.1%), anxiety disorders (3.0%), substance use disorders (1.3%), or other disorders (0.8%). Notably, a relatively small percentage of patients in the study database were assigned a primary diagnosis of a substance use disorder. Patients with more severe and acute substance-related problems typically receive services in a different affiliated clinic.New patients are expected to be given a clinician-assigned primary diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders-5 . Like thThis study evaluated whether treatment modality (before versus after the onset of the COVID-19 pandemic cohort/use of TMH), race/ethnicity (White vs. non-White identifying), and/or their interaction moderated cohort trajectories of symptom change during routine outpatient treatment.n = 738). Patients who began treatment after 3/1/2020 were categorized and dummy-coded as post-pandemic onset/TMH cases (n = 220). This time demarcation reflected the full transition to offering psychotherapy via telehealth at the CMHC.Treatment modality (in-person services versus TMH) was nested within pre- versus post-COVID-19 pandemic onset, such that each case was coded 1 for pre- and 0 for post-COVID treatment. Patients who initiated and completed a course of treatment prior to 3/1/2020 were categorized and dummy-coded as pre-pandemic onset/in-person service cases . Diagnoses were assigned by clinicians upon patients’ first visit to the CMHC, and patients are administered the PHQ-9 at intake and then throughout treatment. Clinicians are expected to readminister the PHQ-9 on an approximately monthly basis; however, it is up to the clinician’s discretion regarding whether an assessment will be conducted at a particular visit . Given the naturalistic setting and the varied nature of the psychotherapies implemented, session frequencies and treatment durations vary among patients. Consequently, there was variability in PHQ-9 data collection.Furthermore, given the level of impairment of some patients in this setting, information can be collected verbally rather than in patient-completed written form, and regardless of format, PHQ-9 total scores are entered by the clinician in the administrative database. The standard in the setting is for patients to complete measures in a self-report format in the waiting area (pre-COVID-19). However, even prior to the pandemic, clinicians were allowed to administer questionnaires or forms verbally and record responses if deemed more appropriate. When the current treatment setting moved to TMH, the PHQ-9 was administered verbally by clinicians and the scores were recorded in the database. However, it was not the case that all pre-TMH PHQ-9 administrations were more “traditional” self-report administrations. Unfortunately, the precise format of each PHQ-9 administration was not recorded, neither before nor after the move to TMH.All patients received individual psychotherapy services from licensed psychotherapists through the CMHC. Patients were eligible to receive additional services including medication management, group psychotherapy, and treatment planning. Prior to COVID-19 onset, individual psychotherapy took place via in-person sessions and the clinic did not offer telepsychotherapy. In March of 2020, the clinic transitioned to TMH following public health guidance. Although details about the particular treatments delivered were not collected or available, setting staff describe the approach as largely supportive and problem-focused. In the current participant sample, all therapy providers were licensed Masters-level clinical social workers. Although information regarding a particular therapist’s theoretical orientation is/was not collected, the predominant orientation is best characterized as integrative, as staff are described as drawing from a mix of supportive, trauma-informed, solution-focused, and third-wave cognitive behavioral therapy approaches.observations past the one-year mark. This affected n = 348 cases. Notably, no cases were removed from the analysis; rather, we elected to remove outlying time points. This increased the consistency between the groups. As expected, cases with trimmed observations (due to a course of treatment exceeding one year) had significantly longer treatment durations than cases with untrimmed observations (p = 0.00). The average number of PHQ-9 observations in the post-COVID onset/TMH cohort was slightly higher  than the pre-COVID/in-person cohort .Analyses were conducted using SPSS version 25. Multivariate normality was inspected within groups of interest. The PHQ-9 total score was the longitudinal outcome variable of interest, and all included patients had a baseline and follow-up PHQ-9 score. Given the naturalistic variability in treatment duration and PHQ-9 observations, we examined these features and observed a large range in both domains. Based on this and input from setting administrators, we applied an additional inclusion/exclusion criterion: for cases with treatment courses that went beyond one year, we excluded PHQ-9 Given the multilevel data structure with PHQ-9 scores nested within patients, multilevel models MLM;  were useWe explored available demographic and clinical information in both modality cohorts. Group-level descriptives are reported in p = 0.868). In addition, the interaction effect between linear time and modality cohort was not statistically significant (p = 0.346), and the interaction between quadratic time and modality cohort was not statistically significant (p = 0.412).Model results are reported in Although evidence for the effectiveness of TMH is encouraging, and controlled research often demonstrates similar outcomes between in-person and TMH interventions, previous studies have typically involved trained and motivated telehealth clinicians and homogenous patient samples. Furthermore, quantitative and qualitative research demonstrates that many patients, therapists, and administrators remain skeptical of TMH. However, attitudes toward TMH may be shifting out of necessity, in the context of the COVID-19 pandemic that forced most service providers to rapidly adjust from in-person to TMH services. Some research has examined the experiences and “lessons learned” of stakeholders, yet less has been published on patient outcomes in routine service settings in the context of COVID-prompted practice changes.The current study explored the potential impact of the rapid shift to TMH in a CMHC setting that did not offer TMH services prior to the onset of the COVID-19 pandemic, with a comparison of average outcome trajectories between pre- and post-COVID-19 onset patient cohorts. On average, patients receiving psychotherapy in this CMHC demonstrated significant symptom improvement regardless of treatment modality. Average outcome trajectories were positive and did not systematically differ between modality cohorts in this context. The absence of a statistically significant difference is consistent with prior research demonstrating that TMH often yields similar effects to in-person mental health services .trajectories between the modality cohorts up to one year in treatment, patients in the pre-COVID cohort presented with somewhat higher baseline severity on the PHQ-9 relative to the post-COVID-19 onset cohort (d = 0.13). This result is somewhat counterintuitive given other reports of increasing levels of anxiety and depression in the context of the pandemic  are likely to be of most benefit.The raw data supporting the conclusions of this article will be made available by the authors upon reasonable request.The studies involving human participants were reviewed and approved by University at Albany Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.BH assisted with data collection and management, conducted the data analysis, and assisted in all aspects of the writing process. AS and SA participated in the writing process and contributed as experts. SA also assisted with data analysis. JB facilitated data collection, sharing, developed study objectives, and participated in the writing process. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To evaluate the implementation of new operational workflows for simultaneous screening of coronavirus disease 2019 (COVID-19) and tuberculosis at four high-volume COVID-19 testing centres located in tertiary hospitals in Mumbai, India.Each centre already offering antigen-detecting rapid diagnostic tests were equipped with a rapid molecular testing platform for COVID-19 and tuberculosis, sufficient laboratory staff, and reagents and consumables for screening. Using a verbal tuberculosis questionnaire, a patient follow-up agent screened individuals visiting the COVID-19 testing centres. Presumptive tuberculosis patients were asked to provide sputum samples for rapid molecular testing. Subsequently, we reversed our operational workflow to also screen patients visiting tuberculosis outpatient departments for COVID-19, using rapid diagnostic tests.From March to December 2021, we screened 14 588 presumptive COVID-19 patients for tuberculosis, of whom 475 (3.3%) were identified as having presumptive tuberculosis. Of these, 288 (60.6%) were tested and 32 individuals (11.1%) were identified as tuberculosis positive . Of the tuberculosis-positive individuals, three had rifampicin-resistant tuberculosis. Among the remaining 187 presumptive tuberculosis cases not tested, 174 reported no symptoms at follow-up and 13 individuals either refused testing or could not be traced. Of the 671 presumptive tuberculosis cases screened for COVID-19, 17 (2.5%) were positive by antigen rapid diagnostic tests, and five (0.7%) who tested negative, later tested positive on the molecular testing platform .Simultaneous screening for COVID-19 and tuberculosis in India is operationally feasible and can improve real-time on-site detection of COVID-19 and tuberculosis. The overwhelming need for health care generated by the coronavirus disease 2019 (COVID-19) pandemic had a catastrophic effect on health-care programmes, particularly outpatient tuberculosis screening and detection. Before the COVID-19 pandemic, India already accounted for the highest number of tuberculosis cases in the world, with an estimated 2.95 million people falling ill annually.Throughout the pandemic, Indian officials encouraged the use of antigen-detecting rapid diagnostic tests as the diagnostic tool of choice for COVID-19, primarily because of their ease of use and rapid on-site results. As these rapid tests are sensitive but not highly specific, the Indian Council of Medical Research also mandated confirmatory testing using real-time reverse transcription polymerase chain reaction (RT–PCR) for all individuals negative on rapid diagnostic tests but presenting with distinctive COVID-19 symptoms.Given the wide overlap in risk factors and symptoms in COVID-19 and tuberculosis, multiple stakeholders proposed simultaneous screening for COVID-19 and tuberculosis as a way to improve real time detection of these diseases, allowing for optimization of constrained health-care resources.In consideration of the above challenges to diagnosis, we launched this study to facilitate a new operational model for the screening of simultaneous COVID-19 and tuberculosis at four high-volume tertiary hospitals in Mumbai, India. In collaboration with the Brihanmumbai Municipal Corporation, FIND and the Indian nongovernmental organization Confluence for Health Action and Transformation Foundation led the project. Here we describe the operational model these groups used to facilitate simultaneous screening programmes in Mumbai, and lessons learned which can be useful for implementation of simultaneous COVID-19 and tuberculosis screening approaches elsewhere, especially settings with a high burden of tuberculosis.We designed this study as an implementation research study conducted at four high-volume COVID-19 rapid diagnostic testing centres in Mumbai from March to December 2021.Mumbai is one of the most populous cities in the world with 11.9 million inhabitants.The four tertiary hospitals selected offered walk-in COVID-19 testing using antigen-detecting rapid diagnostic tests, but also sent out samples for confirmatory molecular testing to referral laboratories. These hospitals primarily serve low-income residents of unregulated settlements (60–70%) and other mixed urban residents (30–40%).We included all people older than 18 years presenting themselves at either the COVID-19 testing centre or the tuberculosis outpatient department. To maintain uniformity in inclusion criteria, we excluded patients visiting other medical and general outpatient departments even if they subsequently tested positive for tuberculosis or COVID-19. All recruited participants were requested to provide verbal consent to participate in this screening. –We set up each study site in close proximity to the hospital’s COVID-19 rapid diagnostic testing centre to minimize potential challenges in sample collection and/or transportation of samples. We provided each centre with a Truenat™  machine – a rapid molecular multidisease testing platform that uses RT–PCR to detect tuberculosis and COVID-19. Truenat™ has been endorsed by the World Health Organization, India’s National Tuberculosis Elimination Programme and the Indian Council of Medical Research for diagnosis of both tuberculosis and COVID-19.We provided collaborating hospital laboratories with test chips, reagents and consumables for testing as well as one laboratory technician per laboratory. We recruited the laboratory staff using an advertised selection process and a technical interview with a FIND medical officer. A technical support team from Molbio Diagnostics trained all the recruited laboratory technicians and one technician from Brihanmumbai Municipal Corporation in rapid molecular sampling procedures. As required by the Indian government for all tuberculosis screening, the project team prepared a paper-based verbal questionnaireEach site received a patient follow-up agent, who we trained at the onset of the project, via a 3-hour online orientation, on administering the questionnaire and the workflow of the project. Two months into implementation (May 2021), we provided a 3-hour online refresher training to the agents where they could ask questions regarding any difficulties they had experienced.® machine was also used for tuberculosis testing due to high demand for Truenat™ tests. Presumptive tuberculosis participants unable to produce a sputum sample were referred to a Brihanmumbai Municipal Corporation-run facility for follow-up and linkage to specialized diagnostic and treatment services. The project staff also phoned presumptive tuberculosis patients who had not provided a sputum sample within 14 days to enquire about symptoms, and request that individuals with symptoms return to the outpatient departments. All patients testing positive for tuberculosis were linked to Brihanmumbai Municipal Corporation for treatment and follow-up.Beginning in mid-September 2021, we implemented a reversed operational workflow for simultaneous screening in three out of four sites via the process outlined in In this reversed workflow, the patient follow-up agent offered individuals visiting the tuberculosis outpatient departments COVID-19 testing. Subsequently Brihanmumbai Municipal Corporation personnel administered the antigen-detecting rapid diagnostic tests to those who accepted the offer. Consenting individuals who had symptoms of COVID-19 but tested negative by the rapid test had a second sample taken by a health-care worker for confirmatory rapid molecular testing on-site. All rapid molecular diagnostics performed with the Truenat™ platform for SARS-CoV-2 were conducted according to the Indian Council of Medical Research guidelines.This study was regularly monitored via progress review meetings, site visits and joint meetings through a steering committee that consisted of Brihanmumbai Municipal Corporation, the Bill & Melinda Gates Foundation, Confluence for Health Action and Transformation Foundation and FIND.The project provided one laboratory technician and one patient follow-up agent per site, related stationery, personal protective equipment, as well as Truenat™ cartridges. While the patient follow-up agent was dedicated to administering the tuberculosis questionnaire, about 3% of the laboratory technician’s time was allocated to conducting tuberculosis tests at each site for the duration of the study. We used a time estimation analysis to determine the time laboratory technicians required for each task . For botFor the reversed screening conducted in tuberculosis outpatient departments, the project only provided a patient follow-up agent to each site, as the Brihanmumbai Municipal Corporation provided the COVID-19 rapid tests as an extension of a larger COVID-19 programme. Hence, the cost of the reversed screening could not be calculated.Key variables included in this study are: the total number of participants; the number of participants who tested positive for tuberculosis and/or COVID-19; and the percentage of participants who tested positive for tuberculosis and/or COVID-19. For tuberculosis-positive samples, we also recorded the presence of rifampicin-resistance. The project coordinator digitized the paper-based tuberculosis questionnaire used for screening individuals presenting for COVID-19 testing, in Microsoft Word  before sending the information to the Brihanmumbai Municipal Corporation staff. Using Microsoft Excel, we analysed all tuberculosis testing data, which on-site project personnel had collected using Brihanmumbai Municipal Corporation laboratory registers. Data on COVID-19 screenings in tuberculosis departments were collected using the Brihanmumbai Municipal Corporation’s COVID-19 tracker form in Excel.Brihanmumbai Municipal Corporation staff cleaned all study data on-site and de-identified, meaning they only relayed anonymous patient data to the FIND team for final analysis. As the objective of the study was to screen and link patients for further evaluation per Brihanmumbai Municipal Corporation guidelines, de-identified individuals who tested positive under the intervention were reported via their case number to corporation teams at each testing site. Follow-up data on treatment or health outcomes post intervention were beyond the scope of this analysis.The study of simultaneous screening for COVID-19 and tuberculosis in Mumbai, India was approved as an intervention under the health department of Mumbai’s Brihanmumbai Municipal Corporation. We only initiated the study after receiving approval for collaboration from the Corporation. As simultaneous testing for COVID-19 and tuberculosis was recommended by the Indian Ministry of Health and Family Welfare and the Corporation as an intervention in all state hospitals, this study did not require specific ethical approval and was not conducted as a traditional research study, but rather as an evaluation of the implementation experience.From March to December 2021, we screened a total of 14 588 presumptive COVID-19 patients for tuberculosis, and we identified 475 (3.3%) presumptive tuberculosis patients . Of the Among the 14 588 individuals, rapid diagnostic tests were administered to 8118 (55.6%), and 523 (6.4%) were COVID-19 positive. Those not tested by rapid diagnostic tests may have received RT–PCR testing from the Brihanmumbai Municipal Corporation, and were not therefore included in participant follow-up exercises.Between September and December 2021, we offered screening to a total of 886 presumptive tuberculosis cases for COVID-19 . Of thesAmong the presumptive tuberculosis cases, 843 (95.1%) were tested for tuberculosis, with 175 (20.8%) identified as tuberculosis positive. Three tuberculosis-positive participants were diagnosed with rifampicin-resistant tuberculosis, and one participant was infected with both tuberculosis and COVID-19.In total, this study facilitated 1131 rapid molecular tuberculosis tests among presumptive COVID-19 cases, and diagnosed 207 individuals with tuberculosis, six of whom had rifampicin-resistant tuberculosis. The study also facilitated 712 rapid antigen and rapid molecular COVID-19 tests for presumptive tuberculosis patients, and subsequently diagnosed 22 presumptive tuberculosis patients with COVID-19.The total cost of simultaneous screening for COVID-19 and tuberculosis outpatient walk-ins between March and December 2021 was 19 792 United States dollars (US$) or US$ 1.4 per participant screened. This cost includes personnel, printing costs (for tuberculosis questionnaire forms), personal protective equipment and Truenat™ tuberculosis cartridges directly attributable to the study.This study of simultaneous COVID-19 and tuberculosis screening in outpatient facilities at tertiary hospitals in India demonstrates that this operational model can be successfully implemented across health facilities using simple verbal screening and inclusion procedures and rapid molecular testing on-site. This study was conducted in close collaboration with the Brihanmumbai Municipal Corporation and the steering committee that closely monitored progress with follow-up visits to implementation sites, made review phone calls and timely course corrections. This approach ensured smooth operations for the duration of the study, as well as an effective handover of the study intervention to Brihanmumbai Municipal Corporation after completion. We observed that although simultaneous screening could be facilitated in either direction, COVID-19 screening in tuberculosis outpatient departments was more streamlined than screening for tuberculosis at COVID-19 testing sites. Reasons include: a verbal questionnaire was not required for tuberculosis patients being screened for COVID-19; tuberculosis clinics were less crowded than COVID-19 testing sites ; and people presenting for tuberculosis testing were more open to being screened for co-morbid illnesses than those presenting for COVID-19 testing alone.This study also demonstrates that the operational workflows for tuberculosis and COVID-19 screening in India can be harmoniously combined, aided by the fact that the same local government manages the COVID-19 and tuberculosis departments. We also noted that closed rapid molecular testing platforms such as Truenat™ are well suited for deployment in outpatient laboratories, as they require minimal infrastructure for set-up and deployment while providing an affordable end-to-end solution for sample collection and results reporting in just a few hours.Although the overall study and its implementation were successful, we encountered some barriers along the way. First, availability of sufficient personnel was a challenge, especially during COVID-19 surges, as there were high rates of infection and sick leave across deployed staff, despite staff being vaccinated and following appropriate infection control measures. The reduced number of personnel available potentially affected the number of people that were recruited for screening. Second, many participants identified as presumptive tuberculosis patients and who were asked to return with their sample at a later date did not return. Additionally, recruited participants were confined to those who self-triaged for COVID-19 and presented at the various tertiary hospitals included in this study, potentially biasing the overall sample.We designed the project to be sustained beyond the initial implementation, with the project transitioned to Brihanmumbai Municipal Corporation staff after completion. However, we identified several factors as potential limitations towards the ongoing sustainability of the project. First, available personnel cross-trained to collect, analyse and report test results for more than one disease were lacking at the Brihanmumbai Municipal Corporation sites. To overcome this challenge, the study team provided Brihanmumbai Municipal Corporation with additional Truenat™ machines to test concurrently for COVID-19 and tuberculosis on-site. The study also built capacity among laboratory technicians for both testing protocols. A second limitation was the space constraints in hospitals, and the fear of patients releasing aerosols containing SARS-CoV-2 during sputum collection, which hindered us from setting up on-site sputum collection areas in three out of four hospitals. The Brihanmumbai Municipal Corporation and the study hospitals have noted the lessons from these challenges to better respond to future outbreaks.As the COVID-19 pandemic has now slowed to a near-endemic state, the study test sites have reverted to their original tuberculosis-related testing, with the supplied Truenat™ machines being used by the tuberculosis programme under Brihanmumbai Municipal Corporation supervision.While this article describes the implementation of simultaneous screening for COVID-19 and tuberculosis in tertiary hospitals in India, a similar approach has been used in several other countries. For example, in Kaduna State, Nigeria, the implementation of integrated community testing for tuberculosis and COVID-19 using a mobile diagnostic facility was found to be feasible and impactful.This study demonstrates that existing rapid molecular testing technology can be leveraged for future outbreak response, such as to provide flexible and temporary testing capacity in the event of an outbreak or pandemic. This study also highlights several measures that can potentially increase the feasibility and yield of future simultaneous screening efforts. These measures include ensuring adequate staffing levels; offering segregated on-site sputum collection areas; and more effective infection prevention and control measures for laboratory staff at sample collection sites. Additionally, simultaneous testing interventions can be streamlined in the laboratory by using a single sample type and test cartridge if possible, and offering dual patient screenings at a single touchpoint, instead of sequentially.COVID-19 and tuberculosis screening in India is operationally feasible and may improve the detection of COVID-19 and tuberculosis, particularly in settings where is a known high burden of both diseases. The experience gleaned from this study suggests that although operational workflows for tuberculosis and COVID-19 can be combined, COVID-19 screening using antigen-detecting rapid diagnostic tests at tuberculosis outpatient departments may be more practical and better received than attempting to screen for tuberculosis at COVID-19 testing sites.