Cancer patients display diminished viral RNA clearance and altered T cell responses during SARS-CoV-2 infection

Cancer patients display immunomodulation related to malignancy and anti-cancer therapies, but how these factors impact COVID-19 remains unknown. To investigate immune responses in cancer patients with COVID-19, we undertook a prospective case-control study, enrolling hospitalized solid tumor patients with acute COVID-19, as well as age-, gender-, and comorbidity-matched COVID-19 patients without cancer as controls. Using biospecimens collected during hospitalization, we performed virologic measurements as well as in-depth immunophenotyping of cellular, antibody and cytokine responses. We enrolled 17 cancer patients (cases) admitted to Yale-New Haven Hospital between March 15 and June 30, 2020 with COVID-19, as well as 17 matched non-cancer patients (controls) admitted with COVID-19. No significant differences were observed between cases and controls based on patient characteristics (age, gender, race, co-morbidities, smoking history, days from symptom onset to COVID-19 diagnosis) or outcomes (COVID-19 severity, length of hospital stay, rate of intubation or mortality). The most common primary tumor sites were lung (4/17) and gastrointestinal (4/17);all cases had received cancer-directed therapy within 6 months of COVID-19 diagnosis, with 13/17 receiving treatment less than 1 month prior to hospitalization. Three of 17 cases had received immune checkpoint inhibitor therapies. Despite having similar SARS-CoV-2 viral RNA loads at the time of COVID-19 diagnosis when compared with controls, cancer cases had increased viral RNA abundance during hospitalization, suggesting slower clearance. Antibody responses against SARS-CoV-2 were preserved in cancer cases, with cases displaying similar levels of IgM and IgG antibodies directed against SARS-CoV-2 epitopes compared to controls. Cytokine profiling revealed higher plasma levels of CCL3, IL1A and CXCL12 in cancer cases compared to controls. Using flow cytometric immunophenotyping, we found that innate immune and non-T cell adaptive immune parameters were similar between cases and controls hospitalized with COVID-19. However, among cancer cases on conventional therapies, T cell lymphopenia was more profound, and these cases demonstrated higher levels of CD8+ exhausted (CD8+CD45RA-PD1+TIM3+ ), CD8+GranzymeB+ and CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ activated T cells when compared with controls;interestingly, these differences were not observed in patients who had received immune checkpoint inhibition. Thus, we found reduced viral RNA clearance and specific alterations in T cell and cytokine responses in cancer patients hospitalized with COVID-19 compared with matched controls with COVID-19. This dysregulated T cell response in cancer patients, which may reflect immune modulation due to chronic antigen stimulation as well as cancer therapies, may lead to altered virologic and clinical outcomes in this population.

Detection of Pneumococcal Pneumonia during SARS-CoV-2 Infection

Background. Streptococcus pneumoniae (pneumococcus) is a common colonizer of the upper respiratory tract and can progress to cause invasive and mucosal disease. Additionally, infection with pneumococcus can complicate respiratory viral infections (influenza, respiratory syncytial virus, etc.) by exacerbating the initial disease. Limited data exist describing the potential relationship of SARS-CoV-2 infection with pneumococcus and the role of co-infection in influencing COVID-19 severity. Methods. Inpatients and healthcare workers testing positive for SARS-CoV-2 during March-August 2020 were tested for pneumococcus through culture-enrichment of saliva followed by RT-qPCR (to identify carriage) and for inpatients only, serotype-specific urine antigen detection (UAD) assays (to identify pneumococcal pneumonia). A multinomial multivariate regression model was used to examine the relationship between pneumococcal detection and COVID-19 severity. Results. Among the 126 subjects who tested positive for SARS-CoV-2, the median age was 62 years;54.9% of subjects were male;88.89% were inpatients;23.5% had an ICU stay;and 13.5% died. Pneumococcus was detected in 17 subjects (13.5%) by any method, including 5 subjects (4.0%) by RT-qPCR and 12 subjects (13.6%) by UAD. Little to no bacterial growth was observed on 21/235 culture plates. Detection by UAD was associated with both moderate and severe COVID-19 disease while RT-qPCR detection in saliva was not associated with severity. None of the 12 individuals who were UAD-positive died. Conclusion. Pneumococcal pneumonia (as determined by UAD) continues to occur during the ongoing pandemic and may be associated with more serious COVID-19 outcomes. Detection of pneumococcal carriage may be masked by high levels of antibiotic use. Future studies should better characterize the relationship between pneumococcus and SARS-CoV-2 across all disease severity levels.

Clinical and epidemiological features of healthcare workers detected with coronavirus disease

Background: Data early in the SARS-CoV-2 pandemic suggested frontline healthcare workers (HCW) may account for 10-20% of all infections. CDC estimated 600,000 infections in HCWs. Symptom screening is a strategy to prevent healthcare-associated transmission. This method may not identify asymptomatic or pre-symptomatic carriers. Methods: We conducted a prospective cohort study in asymptomatic or minimally symptomatic healthcare workers in a 1541-bed academic medical center. Although recruitment began in designated COVID-19 units, we expanded to all HCWs providing care to hospitalized patients during the pandemic. Data was gathered on demographics, work area in the hospital and daily questionnaires were sent listing symptoms of SARS-CoV-2. Protocol included twice weekly self-collected nasopharyngeal swab and saliva for SARS-CoV-2 N1 and N2.Those with positive PCR result, underwent telephone survey to assess symptomatology and severity of illness. Results: A total 525 HCWs began the study protocol and 16 were identified as PCR positive. Samples included concordant saliva and NP samples on 9 (56%), exclusively NP samples on 5 (31%) and 2 (12%) HCWs were positive by saliva PCR only. Majority were female, and all were nursing staff;with 19% reported not working in a designated COVID-19 unit. During the course of this active surveillance, universal masking was mandated in the institution. Rhinorrhea and headache were reported by 6 (38%), 5 (31%) reported cough and 3 (19%) developed myalgia. Changes in smell and taste preceded the positive PCR test in 2 (12%). One HCW reported developing a fever with acute illness. All were notified about their PCR positive status by institution's occupational health department and self-isolated to monitor for symptoms. Conclusion: The spectrum of disease in this HCW cohort is similar to mild disease in the community. Due to high incidence of asymptomatic or mildly symptomatic HCWs, active surveillance with routine testing proves be beneficial to prevent hospital transmission of SARS-CoV-2. Universal masking significantly decreased the HCW positive rate in our study, underscoring the need for universal efforts to mitigate healthcare-associated transmission with self-monitoring, face mask use, and other infection prevention behaviors like hand hygiene.

Implementing an at-home smell test for early assessment of COVID-19 in high-risk healthcare workers

Background: Smell loss has been recognized as an important, and potentially early, sign of COVID-19. However, to date smell loss has only been assessed in retrospective, COVID+ cohorts, and largely through self-report. The objective of this study was to implement a daily standardized behavioral test of smell sensitivity in healthcare workers (HCW) to capture changes in smell sensitivity over time and to assess whether these changes occur prior to positive COVID test. Methods: The study enrolled 500 high-risk COVID-negative HCW during the COVID-19 epidemic in Connecticut, beginning March 28, 2020 (80% F, mean age 38, 58% nurses). Initially, HCW received a daily symptom questionnaire with parosmia screening questions. On April 23 we introduced the “Jiffy”, a daily at-home psychophysical test of smell sensitivity, where olfactory stimuli are sampled and rated for perceived intensity. SARS-CoV-2 infection was tested every three days by PCR of nasopharyngeal swabs or saliva Results: Of the first 500 enrolled HCW, 376 HCW (75%) completed the Jiffy 4528 times (mean 12 times/HCW). 17/500 HCW (3.4%) had a COVID+ test, of which 9/17 (53%) reported smell loss through the Jiffy or the daily symptom survey. 6/9 (67%) reported smell loss that preceded or was concurrent with a COVID+ test. 8/17 COVID+ HCW completed the Jiffy, with 5/8 (63%) reporting reductions in smell versus 42/368 (11%) COVID- HCW (OR=13, 95% CI: 2.4-85, p=.001). COVID+ HCW rated their greatest reduction in smell sensitivity as slight (40%) and severe (60%), versus slight (88%) and moderate (12%) in COVID- HCW. 16/17 COVID+ HCW completed a daily symptom survey (mean 14 times/HCW), with 8/16 (50%) ever reporting parosmia versus 90/466 (19%) of COVID- HCW (OR=4.2, 95% CI: 1.3-13, p=.007). Overall, parosmia was the first reported symptom in 3/13 (23%) COVID+ HCW who reported symptoms. Conclusion: We conducted a prospective study of smell testing in a population at high risk for COVID-19 using two parallel approaches. Our results demonstrate the feasibility of at-home smell testing for assessing parosmia during COVID-19, in some cases even prior to a positive PCR result. Given the urgent need for widespread, lowcost, non-invasive testing for COVID-19, we are now developing an easy-to-use app to distribute this survey more widely to high-risk populations. (Table Presented).

Active monitoring of a healthcare worker cohort during the COVID-19 epidemic

Background: Initial CDC recommendations for passive monitoring of COVID-19 related symptoms among staff may not be sufficient in preventing the introduction and transmission of SARS-CoV-2 in healthcare settings. We therefore implemented active monitoring for SARS-CoV-2 infection in healthcare workers (HCWs) at an academic medical center during the COVID-19 epidemic in northeast US. Methods: We recruited a cohort of HCWs at Yale New Haven Hospital who worked in COVID-19 units and did not have COVID-19 related symptoms between March 28 and June 1, 2020. During follow-up, participants provided daily information on symptoms by responding to a web-based questionnaire, self-administered nasopharyngeal (NP) and saliva specimens every 3 days, and blood specimens every 14 days. We performed SARS-CoV-2 RT-PCR and an anti-spike protein IgM and IgG ELISA to identify virological and serological-confirmed infection, respectively. Results: We enrolled 525 (13%) amongst 4,136 HCW of whom daily information on symptoms and NP, saliva, and blood specimens were obtained for 66% (of 13208), 42% (or 1977), 44% (of 2071) and 65% (of 1099), respectively, of the follow-up measurement points. We identified 16 (3.0% of 525) HCWs with PCR-confirmed SARS-CoV-2 infection and an additional 12 (2.3% of 525) who were not tested by PCR or had negative PCR results but had serological evidence of infection. The overall cumulative incidence of SARS-CoV-2 infection was 5.3% (28 of 525) amongst HCWs. Cases were not identified by hospital protocols for passive staff self-monitoring for symptoms. Amongst 16 PCR-confirmed cases, 9 (56%) of the 16 PCR-confirmed HCW had symptoms during or after the date of initial detection. We did not identify an epidemiological link between the 28 confirmed cases. Conclusion: We found that a significant proportion (5.3%) of HCWs were infected with SARS-CoV-2 during the COVID-19 epidemic. In the setting of universal PPE use, infections were possibly acquired in the community rather than stemming from patient-HCW or HCW-HCW transmission. Passive monitoring of symptoms is inadequate in preventing introductions of SARS-CoV-2 into the healthcare setting due to asymptomatic and oligosymptomatic presentations.