To assess the prevalence of persistent functional impairment after coronavirus disease (COVID-19), we assessed 118 individuals 3-4 months after their initial COVID-19 diagnosis with a symptom survey, ...work productivity and activity index questionnaire, and 6-minute walk test. We found significant persistent symptoms and functional impairment, even in non-hospitalized patients with COVID-19.
COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms.
SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in ...both the lung and intestinal tissue.2, 3, 4 Although much is known about early fecal RNA shedding, little is known about long-term shedding, especially in those with mild COVID-19. Furthermore, most reports of fecal RNA shedding do not correlate these findings with GI symptoms.
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We analyzed the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. We also correlated shedding with disease symptoms.
Fecal SARS-CoV-2 RNA is detected in 49.2% 95% confidence interval, 38.2%-60.3% of participants within the first week after diagnosis. Whereas there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at 4 months, 12.7% 8.5%-18.4% of participants continued to shed SARS-CoV-2 RNA in the feces at 4 months after diagnosis and 3.8% 2.0%-7.3% shed at 7 months. Finally, we found that GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding of SARS-CoV-2 RNA.
The extended presence of viral RNA in feces, but not in respiratory samples, along with the association of fecal viral RNA shedding with GI symptoms suggest that SARS-CoV-2 infects the GI tract and that this infection can be prolonged in a subset of individuals with COVID-19.
This research was supported by a Stanford ChemH-IMA grant; fellowships from the AACR and NSF; and NIH R01-AI148623, R01-AI143757, and UL1TR003142.
Abstract
Background
Although mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines report >90% efficacy, breakthrough infections occur. Little is known about their ...effectiveness against SARS-CoV-2 variants, including the highly prevalent B.1.427/B.1.429 variant.
Methods
In this quality improvement project, we collected demographic and clinical information from post-vaccine SARS-CoV-2 cases (PVSCs), defined as healthcare personnel (HCP) with positive SARS-CoV-2 nucleic acid amplification test after receiving ≥1 vaccine dose. Available specimens were tested for L452R, N501Y, and E484K mutations using reverse-transcription polymerase chain reaction. Mutation prevalence was compared among unvaccinated, early post-vaccinated (≤14 days after dose 1), partially vaccinated (positive test >14 days after dose 1 and <14 days after dose 2), and fully vaccinated (>14 days after dose 2) PVSCs.
Results
From December 2020 to April 2021, ≥23 090 HCP received ≥1 dose of an mRNA-based SARS-CoV-2 vaccine, and 660 HCP cases of SARS-CoV-2 occurred, of which 189 were PVSCs. Among the PVSCs, 114 (60.3%), 49 (25.9%), and 26 (13.8%) were early post-vaccination, partially vaccinated, and fully vaccinated, respectively. Of 261 available samples from vaccinated and unvaccinated HCP, 103 (39.5%), including 42 PVSCs (36.5%), had the L452R mutation presumptive of B.1.427/B.1.429. When adjusted for community prevalence of B.1.427/B.1.429, PVSCs did not have significantly elevated risk of B.1.427/B.1.429 compared with unvaccinated HCP.
Conclusions
Most PVSCs occurred prior to expected onset of full, vaccine-derived immunity. Presumptive B.1.427/B.1.429 was not more prevalent in post-vaccine cases than in unvaccinated SARS-CoV-2 HCP. Continued infection control measures, particularly <14 days post-vaccination, and continued variant surveillance in PVSCs are imperative to control future SARS-CoV-2 surges.
In this retrospective report, 189 of 660 SARS-CoV-2 cases detected in healthcare personnel at an academic medical center occurred post-vaccination. Incidence of the L452R mutation, consistent with the B.1.427/B.1.429 variant of concern, did not vary by vaccination status.
HIV and tuberculosis (TB) coinfection remains a major public health threat in sub-Saharan Africa. Integration and decentralization of HIV and TB treatment services are being implemented, but data on ...outcomes of this strategy are lacking in rural, resource-limited settings. We evaluated TB treatment outcomes in TB/HIV coinfected patients in an integrated and decentralized system in rural KwaZulu-Natal, South Africa.
We retrospectively studied a cohort of HIV/TB coinfected patients initiating treatment for drug-susceptible TB at a district hospital HIV clinic from January 2012-June 2013. Patients were eligible for down-referral to primary health clinics(PHCs) for TB treatment completion if they met specific clinical criteria. Records were reviewed for patients' demographic, baseline clinical and laboratory information, past HIV and TB history, and TB treatment outcomes.
Of 657(88.7%) patients, 322(49.0%) were female, 558(84.9%) were new TB cases, and 572(87.1%) had pulmonary TB. After TB treatment initiation, 280(42.6%) were down-referred from the district level HIV clinic to PHCs for treatment completion; 377(57.4%) remained at the district hospital. Retained patients possessed characteristics indicative of more severe disease. In total, 540(82.2%) patients experienced treatment success, 69(10.5%) died, and 46(7.0%) defaulted. Down-referred patients experienced higher treatment success, and lower mortality, but were more likely to default, primarily at the time of transfer to PHC.
Decentralization of TB treatment to the primary care level is feasible in rural South Africa. Treatment outcomes are favorable when patients are carefully chosen for down-referral. Higher mortality in retained patients reflects increased baseline disease severity while higher default among down-referred patients reflects failed linkage of care. Better linkage mechanisms are needed including improved identification of potential defaulters, increased patient education, active communication between hospitals and PHCs, and tracing of patients lost to follow up. Decentralized and integrated care is successful for carefully selected TB/HIV coinfected patients and should be expanded.
This study followed treatment responders from a randomized controlled trial of adults with major depression. Patients treated with medication but withdrawn onto pill-placebo had more relapse through ...1 year of follow-up compared to patients who received prior behavioral activation, prior cognitive therapy, or continued medication. Prior psychotherapy was also superior to medication withdrawal in the prevention of recurrence across the 2nd year of follow-up. Specific comparisons indicated that patients previously exposed to cognitive therapy were significantly less likely to relapse following treatment termination than patients withdrawn from medication, and patients previously exposed to behavioral activation did almost as well relative to patients withdrawn from medication, although the difference was not significantly different. Differences between behavioral activation and cognitive therapy were small in magnitude and not significantly different across the full 2-year follow-up, and each therapy was at least as efficacious as the continuation of medication. These findings suggest that behavioral activation may be nearly as enduring as cognitive therapy and that both psychotherapies are less expensive and longer lasting alternatives to medication in the treatment of depression.
Antidepressant medication is considered the current standard for severe depression, and cognitive therapy is the most widely investigated psychosocial treatment for depression. However, not all ...patients want to take medication, and cognitive therapy has not demonstrated consistent efficacy across trials. Moreover, dismantling designs have suggested that behavioral components may account for the efficacy of cognitive therapy. The present study tested the efficacy of behavioral activation by comparing it with cognitive therapy and antidepressant medication in a randomized placebo-controlled design in adults with major depressive disorder (
N =
241). In addition, it examined the importance of initial severity as a moderator of treatment outcome. Among more severely depressed patients, behavioral activation was comparable to antidepressant medication, and both significantly outperformed cognitive therapy. The implications of these findings for the evaluation of current treatment guidelines and dissemination are discussed.
Abstract
Background
An immunodiagnostic assay that sensitively detects a cell-mediated immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed for epidemiological ...investigation and for clinical assessment of T- cell-mediated immune response to vaccines, particularly in the context of emerging variants that might escape antibody responses.
Methods
The performance of a whole blood interferon-gamma (IFN-γ) release assay (IGRA) for the detection of SARS-CoV-2 antigen-specific T cells was evaluated in coronavirus disease 2019 (COVID-19) convalescents tested serially up to 10 months post-infection and in healthy blood donors. SARS-CoV-2 IGRA was applied in contacts of households with index cases. Freshly collected blood in the lithium heparin tube was left unstimulated, stimulated with a SARS-CoV-2 peptide pool, and stimulated with mitogen.
Results
The overall sensitivity and specificity of IGRA were 84.5% (153/181; 95% confidence interval CI: 79.0–89.0) and 86.6% (123/142; 95% CI: 80.0–91.2), respectively. The sensitivity declined from 100% (16/16; 95% CI: 80.6–100) at 0.5-month post-infection to 79.5% (31/39; 95% CI: 64.4–89.2) at 10 months post-infection (P < .01). The IFN-γ response remained relatively robust at 10 months post-infection (3.8 vs 1.3 IU/mL, respectively). In 14 households, IGRA showed a positivity rate of 100% (12/12) and 65.2% (15/23), and IgG of 50.0% (6/12) and 43.5% (10/23) in index cases and contacts, respectively, exhibiting a difference of + 50% (95% CI: +25.4 to +74.6) and +21.7% (95% CI: +9.23 to +42.3), respectively. Either IGRA or IgG was positive in 100% (12/12) of index cases and 73.9% (17/23) of contacts.
Conclusions
The SARS-CoV-2 IGRA is a useful clinical diagnostic tool for assessing cell-mediated immune response to SARS-CoV-2.
SARS-CoV-2 immunodiagnostics are needed to identify infected individuals in order to understand the transmission dynamics of emerging variants and to assess vaccine response. Interferon-gamma release assay maintains sensitivity 10 months post-infection in convalescents and detects more household contacts than IgG.
Although the vast majority of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections are uncomplicated, our understanding of predictors of symptom resolution and viral shedding ...cessation remains limited. We characterized symptom trajectories and oropharyngeal viral shedding among 120 outpatients with uncomplicated Coronavirus Disease of 2019 (COVID-19) enrolled in a clinical trial of Peginterferon Lambda, which demonstrated no clinical or virologic benefit compared with placebo. In the combined trial cohort, objective fever was uncommon, inflammatory symptoms (myalgias, fatigue) peaked at 4 to 5 days postsymptom onset, and cough peaked at 9 days. The median time to symptom resolution from earliest symptom onset was 17 days (95% confidence interval 14–18). SARS-CoV-2 IgG seropositivity at enrollment was associated with hastened resolution of viral shedding (hazard ratio 1.80, 95% confidence interval 1.05–3.1, P = 0.03), but not with symptom resolution. Inflammatory symptoms were associated with a significantly greater odds of oropharyngeal SARS-CoV-2 RNA detection; respiratory symptoms were not. These findings have important implications for COVID-19 screening approaches and trial design.
Despite the recent rollout of Isoniazid Preventive Therapy (IPT) to prevent TB in people living with HIV in South Africa, adherence and completion rates are low. To explore barriers to IPT completion ...in rural KwaZulu-Natal, South Africa, we conducted individual semi-structured interviews among 30 HIV patients who had completed or defaulted IPT. Interview transcripts were analyzed according to the framework method of qualitative analysis. Facilitators of IPT completion included knowledge of TB and IPT, accepting one's HIV diagnosis, viewing IPT as similar to antiretroviral therapy, having social support in the community and the clinic, trust in the healthcare system, and desire for health preservation. Barriers included misunderstanding of IPT's preventive role in the absence of symptoms, inefficient health service delivery, ineffective communication with healthcare workers, financial burden of transport to clinic and lost wages, and competing priorities. HIV-related stigma was not identified as a significant barrier to IPT completion, and participants felt confident in their ability to manage stigma, for example by pretending their medications were for unrelated conditions. Completers were more comfortable communicating with health care workers than were defaulters. Efforts to facilitate successful IPT completion must include appropriate counseling and education for individual patients and addressing inefficiencies within the health care system in order to minimize patients' financial and logistical burden. These patient-level and structural changes are necessary for IPT to successfully reduce TB incidence in this resource-limited setting.
The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively ...develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients.
Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial.
We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.
Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models.
Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.
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