Long COVID after breakthrough SARS-CoV-2 infection

Authors: Ziyad Al-AlyBenjamin Bowe & Yan Xie 

Nature Medicine volume 28, pages1461–1467 (2022)

Abstract

The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.

Main

The post-acute sequelae of SARS-CoV-2 infection—also referred to as Long COVID—have been characterized1. Increasingly, vaccinated individuals are being diagnosed with COVID-19 as a result of breakthrough SARS-CoV-2 infection (BTI)2,3. Whether people with BTI experience post-acute sequelae is not clear. Addressing this knowledge gap is important to guide public health policy and post-acute COVID-19 care strategies.

Here we leverage the breadth and depth of the electronic healthcare databases of the US Department of Veterans Affairs to address the question of whether people with BTI develop post-acute sequelae. We characterize the risks and 6-month burdens of a panel of prespecified outcomes in a cohort of people who experienced BTI after completion of vaccination in the overall cohort and by care setting of the acute phase of the disease (that is, whether people were not hospitalized, hospitalized or admitted to an intensive care unit (ICU) during the first 30 days after a positive test). We then undertake a comparative evaluation of the magnitude of risk in people with BTI versus those with SARS-CoV-2 infection and no prior vaccination and, separately, hospitalized people with BTI versus those hospitalized with seasonal influenza.

Results

Post-acute sequelae in BTI versus controls without SARS-CoV-2 infection

There were 33,940 and 4,983,491 participants in the BTI group and a contemporary control group of users of the Veterans Health Administration from 1 January 2021 to 31 October 2021 with no record of a positive SARS-CoV-2 test, respectively. BTI participants had a positive SARS-CoV-2 test with prior record of a complete vaccination defined following Centers for Disease Control and Prevention (CDC) guidelines at 14 days after first Janssen (Johnson & Johnson)(Ad26.COV2.S) vaccination and 14 days after second Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) vaccination. The demographic and health characteristics of the BTI and the control groups before and after weighting are presented in Supplementary Tables 14. During the enrollment period, the overall rate of BTI within those fully vaccinated was 10.60 (95% CI: 10.52, 10.70) per 1,000 persons at 6 months; rates of breakthrough by vaccine type are presented in Supplementary Data Table 1.

For all analyses, we provide two measures of risk: (1) we estimated the adjusted HRs of a set of incident prespecified outcomes in people with BTI versus the control group; and (2) we estimated the adjusted excess burden of each outcome due to BTI per 1,000 persons 6 months after a positive SARS-CoV-2 test on the basis of the difference between the estimated incidence rate in individuals with BTI and the control group. Assessment of standardized mean differences of participant characteristics (from data domains including diagnoses, medications and laboratory test results) after application of weighting showed that they are well-balanced in each analysis of incident outcomes (Supplementary Fig. 1).

Compared to the contemporary control group, people who survived the first 30 days of BTI exhibited an increased risk of death (HR = 1.75, 95% CI: 1.59, 1.93) and excess burden of death estimated at 13.36 (95% CI: 11.36, 15.55) per 1,000 persons with BTI at 6 months; all burden estimates represent excess burden and are given per 1,000 persons with BTI at 6 months (Fig. 1). People with BTI also had an increased risk of having at least one post-acute sequela of SARS-CoV-2 (PASC) (HR = 1.50, 95% CI: 1.46, 1.54; burden of 122.22, 95% CI: 115.31, 129.24) (Supplementary Table 5).

figure 1
Fig. 1: Risk and 6-month excess burden of post-acute sequelae in people with BTI compared to the contemporary control group.

Compared to the control group, 30-day survivors of BTI exhibited increased risk of post-acute sequelae in the pulmonary (HR = 2.48 (2.33, 2.64); burden of 39.82 (36.83, 42.99)) and several extrapulmonary organ systems, including cardiovascular disorders (HR = 1.74 (1.66, 1.83); burden of 43.94 (39.72, 48.35)), coagulation and hematologic disorders (HR = 2.43 (2.18, 2.71); burden of 13.66 (11.95, 15.56)), fatigue (HR = 2.00 (1.82, 2.21); burden of 15.47 (13.21, 17.96)), gastrointestinal disorders (HR = 1.63 (1.54, 1.72); burden of 37.68 (33.76, 41.80)), kidney disorders (HR = 1.62 (1.47, 1.77); burden of 16.12 (13.72, 18.74)), mental health disorders (HR = 1.46 (1.39, 1.53); burden of 45.85 (40.97, 50.92)), metabolic disorders (HR = 1.46 (1.37, 1.56); burden of 30.70 (26.65, 35.00)), musculoskeletal disorders (HR = 1.53 (1.42, 1.64); burden of 19.81 (16.56, 23.31)) and neurologic disorders (HR = 1.69 (1.52, 1.88); burden of 11.60 (9.43, 14.01)). Risk and excess burden of each individual sequela and by organ system are provided in Extended Data Fig. 1 (Supplementary Table 6) and Fig. 1 (Supplementary Table 5), respectively.

The results were consistent in analyses considering a historical control group (n = 5,785,273) as the referent category (Extended Data Fig. 2 and Supplementary Table 7) and, separately, people who were vaccinated for SARS-CoV-2 and did not experience a BTI (n = 2,566,369) as another alternative control group (Extended Data Fig. 3 and Supplementary Table 8).

The risk of death was increased in the 30–90 days and also increased, but to a lesser extent, in the 90–180 days after a positive SARS-CoV-2 test (Supplementary Table 9). The risk of incident sequelae was increased in the 30–90 days after a positive SARS-CoV-2 test. In the period between 90 days and 180 days after testing positive, there was increased risk of both incident sequalae—albeit in lesser magnitude than the risk in days 30–90—and increased risk of recurrent or persistent sequalae (Supplementary Table 9).

Compared to the contemporary control group, there was increased risk of death, at least one PASC and organ involvement in people who were not immunocompromised before BTI (Extended Data Fig. 4a and Supplementary Table 10); the risks were generally higher in those who were immunocompromised before BTI (Extended Data Fig. 4a and Supplementary Table 10). Analyses of people with BTI showed that the risks of death, at least one PASC and organ system involvement were consistently higher in people who were immunocompromised versus those who were not before BTI (Extended Data Fig. 4b and Supplementary Table 10).

Of people with BTI, analyses by vaccine type suggested that there is no statistically significant difference in risk of post-acute death among the three SARS-CoV-2 vaccines (Pfizer-BioNTech (BNT162b2), Moderna (mRNA-1273) and Janssen (Johnson & Johnson) (Ad26.COV2.S)). Both BNT162b2 and mRNA-1273 were associated with decreased risk of at least one PASC: pulmonary and extrapulmonary organ involvement. There was no statistically significant difference in risk of any of these outcomes between BNT162b2 and mRNA-1273 (Supplementary Table 11).

Post-acute sequelae in BTI by care setting of the acute phase of the disease

The demographic and health characteristics of people with BTI who were not hospitalized, who were hospitalized and who were admitted to ICU during the acute phase of the disease before and after weighting are provided in Supplementary Tables 12 and 13. Evaluation of standardized mean differences of baseline participant characteristics after the application of the weighting suggested good balance (Supplementary Fig. 2).

Compared to the control group of people without evidence of SARS-CoV-2 infection, people who were not hospitalized during the first 30 days of BTI exhibited an increased risk of death (HR = 1.29 (1.12, 1.49); burden of 7.77 (5.62, 10.24)); the risk was further increased in those who were hospitalized (HR = 2.69 (2.33, 3.12); burden of 24.79 (20.39, 29.86)) and was highest in those who were admitted to ICU (HR = 5.68 (4.55, 7.09); burden of 60.02 (46.85, 76.19)). The risk of having at least one post-acute sequela was evident in non-hospitalized people (HR = 1.25 (1.20, 1.30); burden of 77.60 (68.40, 87.04)), was further increased in those who were hospitalized (HR = 2.95 (2.80, 3.10); burden of 334.10 (315.90, 352.53)) and was highest in those admitted to ICU (HR = 3.75 (3.38, 4.16); burden of 421.39 (383.37, 459.56)) (Fig. 2 and Supplementary Table 14).

figure 2
Fig. 2: Risk and 6-month excess burden of post-acute sequelae in those with BTI by acute phase care setting.

People who were not hospitalized exhibited small but significant increased risk of post-acute sequelae, including cardiovascular, coagulation and hematologic, gastrointestinal, mental health, metabolic, musculoskeletal and pulmonary disoders, as well as increased risk of fatigue (Fig. 2 and Supplementary Table 14). The risks were further increased in people who were hospitalized (Fig. 2 and Supplementary Table 14) and highest in those admitted to the ICU (Fig. 2 and Supplementary Table 14). Analyses of individual sequela are presented in Extended Data Fig. 5 and Supplementary Table 15.

Post-acute sequelae in BTI versus SARS-CoV-2 infection without prior vaccination

To place the magnitude of risk of post-acute sequelae in people with BTI in broad context of post-acute COVID-19 manifestations, we developed a comparative approach to evaluate the risk of organ system involvement in people with BTI (n = 33,940) versus people with SARS-CoV-2 infection and no prior history of vaccination (n = 113,474) (Supplementary Tables 1 and 16). Assessment of standardized mean differences of baseline characteristics in the weighted cohorts suggested good balance (Supplementary Figs. 3 and 4 and Supplementary Tables 4 and 17).

People with BTI exhibited lower risk of death (HR = 0.66 (0.58, 0.74); burden of −10.99 (−13.45, −8.22); negative values denote reduced burden in BTI relative to SARS-CoV-2 infection) and lower risk of post-acute sequelae (HR = 0.85 (0.82, 0.89); burden of −43.38 (−53.22, −33.31)) compared to those with SARS-CoV-2 infection and no prior history of vaccination (Fig. 3 and Supplementary Table 18). Comparatively, the risk of post-acute sequelae in all the examined organ systems was lower in people with BTI versus those with SARS-CoV-2 infection without prior vaccination. BTI was associated with lower risk of 24 of the 47 sequelae examined compared to those with SARS-CoV-2 infection without prior vaccination (Extended Data Fig. 6 and Supplementary Table 19). The reduced risk was evident (albeit weak) in those who were immunocompromised and in those who were not immunocompromised (Supplementary Table 20).

figure 3
Fig. 3: Risk and 6-month excess burden of post-acute sequelae in people with BTI compared to those with SARS-CoV-2 infection without prior vaccination.

Analyses within each care setting suggested that the risk reduction in BTI versus SARS-CoV-2 infection on both the relative (HR) and absolute (burden) scale generally becomes increasingly more pronounced as the acuity of the care setting increased (from non-hospitalized to admitted to ICU) (Fig. 4 and Supplementary Table 21). BTI was associated with less risk of death and at least one PASC in all care settings. There was also a consistently reduced risk of hematologic and coagulation disorders and pulmonary disorders in BTI versus SARS-CoV-2 infection without prior vaccination across all care settings.

figure 4
Fig. 4: Risk and 6-month excess burden of post-acute sequelae in those with BTI compared to those with SARS-CoV-2 infection without prior vaccination by acute phase care setting.

Post-acute sequelae in people hospitalized with BTI versus seasonal influenza

We developed a comparative analysis to better understand how people hospitalized with BTI (n = 3,667) fare relative to those who are hospitalized with seasonal influenza (n = 14,337). Demographic and health characteristics before and after weighting are provided in Supplementary Tables 22 and 23. Examination of standardized mean differences of baseline characteristics after application of overlap weighting demonstrated good balance (Supplementary Fig. 5).

Compared to people who were hospitalized with seasonal influenza, people with BTI who were hospitalized during the acute phase of the disease and survived the first 30 days exhibited an increased risk of death (HR = 2.43 (2.02, 2.93); burden of 43.58 (31.21, 58.26)) and increased risk of having at least one post-acute sequela (HR = 1.27 (1.19, 1.36); burden of 87.59 (63.83, 111.40)) (Extended Data Fig. 7 and Supplementary Table 24). People with BTI exhibited increased risk of sequelae in all the examined organ systems compared to those with seasonal influenza. Results of individual sequalae are presented in Supplementary Fig. 6 and Supplementary Table 25.

Positive and negative outcome controls

To assess whether our approach reproduces established knowledge, we tested the association between SARS-CoV-2 infection without prior vaccination and the risk of fatigue (a cardinal post-acute sequela of COVID-19, where, based on prior evidence, we would expect a positive association). The results showed that, compared to the contemporary control group, people with SARS-CoV-2 infection and without prior vaccination exhibited increased risk of fatigue (HR = 2.79 (2.57, 303)) (Extended Data Table 1a).

To assess the putative presence of spurious associations, we tested the association between BTI and several negative outcome controls where there was no biologic plausibility or epidemiologic evidence that an association is expected. We used the same data sources, cohort building process, covariate selection approach (including predefined and algorithmically selected high-dimensional covariates), weighting method and interpretation of results. The results suggested no significant association between BTI and risk of any of the negative outcome controls (Extended Data Table 1a).

To further test the rigor of our approach, we tested as a pair of negative exposure controls receipt of influenza vaccination in odd-numbered (n = 605,453) versus even-numbered (n = 571,291) calendar days between 1 March 2020 and 15 January 2021. Examination of the associations of receipt of influenza vaccine on odd-numbered versus even-numbered calendar days and each outcome yielded non-significant results, consistent with our a priori expectations for a successful application of negative exposure controls (Extended Data Table 1b).

Discussion

In this study of 33,940 people with BTI, 4,983,491 in the contemporary control, 5,785,273 in the historical control, 2,566,369 in the vaccinated control, 113,474 in the SARS-CoV-2 infection without prior vaccination group and 14,337 in the seasonal influenza group, we show that, compared to non-infected controls, people who survive the first 30 days of BTI exhibited increased risk of death and post-acute sequelae in the pulmonary and several extrapulmonary organ systems. The risks of death and post-acute sequelae were evident among non-hospitalized people, further increased among hospitalized people and highest among people who were admitted to ICU during the acute phase of the disease. Our comparative approach shows that risks of death and post-acute sequelae were lower in people with BTI versus people with SARS-CoV-2 infection without prior vaccination. Analyses of BTI versus SARS-CoV-2 infection without prior vaccination within the same care setting showed that this risk reduction was progressively more evident as care acuity of the acute phase of the disease increased from non-hospitalized to hospitalized and admitted to ICU and was consistently most pronounced for coagulation and pulmonary disorders. In comparative analyses among people who were hospitalized during the acute phase of the disease, those with BTI exhibited higher risks of death and post-acute sequelae than those with seasonal influenza. The constellation of findings shows that the burden of death and disease experienced by people with BTI is not trivial. Our comparative analyses provide a framework to better evaluate and contextually understand risks of the post-viral condition in people with BTI versus non-infected controls, versus SARS-CoV-2 infection without prior vaccination and versus seasonal influenza. The findings show that vaccination only partially reduces the risk of death and post-acute sequelae, suggesting that reliance on it as a sole mitigation strategy may not most optimally reduce the risk of the long-term health consequences of SARS-CoV-2 infection. Our results emphasize the need for continued optimization of primary prevention strategies of BTIs and will inform post-acute care approaches for people with BTI.

We examined the risk of death and post-acute sequelae in those with BTI versus several controls of people without evidence of SARS-CoV-2 infection, including (1) a contemporary control of people exposed to the same broader forces of the pandemic (lockdowns and economic, social and environmental stressors); (2) a historical control from a pre-pandemic era that represents a baseline unaffected by the disruptions of the pandemic; and (3) a vaccinated control group. The results show two key findings: (1) Long COVID, including increased risks of death and myriad post-acute sequelae in the pulmonary and extrapulmonary organ systems, also manifests in vaccinated individuals who experience a BTI; and (2) the range of post-acute sequelae in various organ systems in BTI does not appear to be different than COVID-19 without prior vaccination1,4,5,6,7,8,9,10,11,12. Our analyses of BTI versus SARS-CoV-2 infection without prior vaccination show that, comparatively, the magnitude of the risks of death and post-acute sequelae was lower in people with BTI versus those with SARS-CoV-2 infection who had not been previously vaccinated for it. These results show that, although vaccination may partially reduce the risks of post-acute death and disease, to most optimally reduce this burden requires continued emphasis on primary prevention of breakthrough SARS-CoV-2 infection as a goal of public health policy.

Although the absolute rates are smaller than in those with SARS-CoV-2 infection without prior vaccination, given the scale of the pandemic and the potential for breakthrough cases to continue to accumulate, the overall burden of death and disease after BTI will likely be substantial, will further add to the toll of this pandemic and will represent an additional strain on already overwhelmed health systems. In planning and development of health resources, governments and health systems should take into account the care needs of people with post-acute sequelae after BTI13.

Our analyses suggest that this risk reduction (of post-acute sequelae) was most pronounced in recipients of BNT162b2 and mRNA-1273 vaccines (compared to Ad26.COV2.S). Although these results recapitulate evidence of vaccine effectiveness in the acute phase of COVID-19, the mechanism or mechanisms underlying this carry-through effect of risk reduction from the acute to the post-acute phase of the disease is not entirely clear. One putative interpretation of these results is that vaccine-induced reduction in severity of the acute infection may then translate into less long-term risk of post-acute health outcomes. In other analyses, we also show that the reduced risk of post-acute sequelae in people with BTIs was partially eroded in people with immunocompromised status, suggesting a putative immune-related mechanism in the expression of post-acute sequelae that may be influenced by vaccination.

We also show that the risk of post-acute sequelae is higher in people with BTI than in people with seasonal influenza—a well-characterized respiratory viral illness. This extends previous evidence showing that the risk of post-acute sequelae in people with SARS-CoV-2 infection was higher than those with seasonal influenza and again emphasizes the importance of prevention of both SARS-CoV-2 infection and BTI1.

This study has several strengths. To our knowledge, it is the first large study to characterize the risks of post-acute sequelae of BTI at 6 months. We leveraged the vast national healthcare databases of the US Department of Veterans Affairs (the largest nationally integrated healthcare delivery system in the United States) to characterize the risk and 6-month burden of a comprehensive set of prespecified incident health outcomes in patients who survived the first 30 days of BTI versus several control groups (contemporary, historical and vaccinated controls). In addition to evaluating risk of BTI versus those with no evidence of SARS-CoV-2 infection in the overall cohort and by care setting of the acute phase of the disease (non-hospitalized, hospitalized and admitted to ICU), we also undertook a comparative evaluation of BTI versus SARS-CoV-2 infection in people who had not been previously vaccinated and, separately, BTI versus seasonal influenza. We used advanced statistical methodologies and adjusted through weighting for a battery of predefined covariates selected based on prior knowledge and algorithmically selected covariates from high-dimensional data domains, including diagnoses, prescription records and laboratory test results. We evaluated the rigor of our approach by testing positive and negative outcome controls to determine whether our approach would produce results consistent with pre-test expectations.

The study also has several limitations. The BTI and SARS-CoV-2 infection groups included only those who had a positive test for SARS-CoV-2 and did not include those who may have had an infection with SARS-CoV-2 but were not tested; however, if present, this will bias the estimates toward the null. Although the Veterans Affairs population is comprised of mostly men, it includes 8–10% women, which, across the groups in our study, included 1,300,744 female participants. Although we adjusted through the overlap weighting approach for a large battery of predefined and algorithmically selected covariates, and although our approach demonstrated good balance for more than 734 covariates (including all those that were available in the data but not included in the weighting process) from several data domains, including diagnoses, prescription medications and laboratory test results, and resulted in successful testing of positive outcome controls and negative outcome controls, we cannot completely rule out residual confounding. Our approach does not evaluate the severity of each outcome. Finally, the COVID-19 global pandemic is highly dynamic. As vaccine uptake continues to increase, as vaccine schedules continue to be optimized, as vaccine effectiveness wanes over time since vaccination, as booster vaccinations are deployed, as treatment strategies of the acute phase of COVID-19 continue to improve and as new variants of the virus emerge, it is likely that the epidemiology of BTI and its downstream sequelae may also change over time.

In sum, our findings provide evidence of increased risk of death and post-acute sequelae in people with BTI compared to controls with no evidence of SARS-CoV-2 infection; the risks were reduced in comparative analyses involving BTI versus SARS-CoV-2 infection without prior vaccination. Our results show that SARS-CoV-2 vaccination before infection only partially reduced the risk of death and post-acute sequelae. Measures for the prevention of breakthrough infections are needed to most optimally reduce the risk of the long-term health consequences of SARS-CoV-2 infection.

Methods

All participants who were eligible for this study were enrolled; no a priori sample size analyses were conducted to guide enrollment. All analyses were observational, and investigators were aware of participant exposure and outcome status. A summary of the major design elements is presented in Supplementary Table 26, and an analytic flowchart is provided in Supplementary Fig. 7.

Setting

Cohort participants were identified from the US Veterans Health Administration (VHA) electronic health databases. The VHA provides healthcare to discharged veterans of the US armed forces in a nationally integrated network of healthcare systems that includes more than 1,415 healthcare facilities. Veterans enrolled in the VHA have access to a comprehensive medical benefits package that includes outpatient services; preventive, primary and specialty care; mental health care; geriatric care; inpatient hospital care; extended long-term care; prescriptions; home healthcare; medical equipment; and prosthetics. The VHA healthcare databases are updated daily.

Cohorts

We first identified users of the VHA who were alive on 1 January 2021 (n = 5,430,912). Use of the VHA was defined as having record of use of outpatient or inpatient service, receipt of medication or use of laboratory service with the VHA healthcare system in the 2 years prior (Supplementary Fig. 8). Among these, 163,024 participants had a record of a first positive SARS-CoV-2 test from 1 January 2021 to 31 October 2021, and 5,140,387 had no record of any positive SARS-CoV-2 test between 1 January 2020 and 1 December 2021. Participants were followed until 1 December 2021.

To construct a group of people with BTI, we selected, from those with a positive SARS-CoV-2 test (n = 163,024), those with a record of completion of an Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination before the date of their first positive SARS-CoV-2 test (n = 34,863). Completion of vaccination was defined following CDC guidelines at the 14th day after the second shot of the mRNA-1273 or BNT162b2 vaccination series or the 14th day after the first shot of the Ad26.COV2.S vaccination. Setting the date of first positive SARS-CoV-2 test as time zero (T0), we then selected those alive 30 days after T0, resulting in a cohort of 33,940 participants in the BTI group.

We then constructed several control groups; the rationale for each of these control groups is provided in Supplementary Fig. 9. To build a contemporary control group of people with no evidence of SARS-CoV-2 infection, we then used the 5,140,387 users of the VHA who had no record of a SARS-CoV-2-positive test. Among these participants, we randomly assigned a T0 to each participant in the group on the basis of the distribution of the T0 dates in those with BTI. We finally selected those who were alive 30 days after their T0 (n = 4,983,491). The contemporary control group represents contemporaneous users of the VHA who were subject to the broader forces of the pandemic but did not contract SARS-CoV-2 infection. Of these, the 2,566,369 who had record of a SARS-CoV-2 vaccination before their T0 served as a vaccinated control group. The vaccinated control group represents contemporaneous users of the VHA who share the characteristic of being vaccinated with the breakthrough group and have a major distinction in that they did not contract SARS-CoV-2 infection subsequent to their vaccination.

To build an alternate control group during a period of time where participants were not subject to the influence of the pandemic, we identified users of the VHA who were alive on 1 January 2018 (n = 6,084,973) and who had no history of a positive SARS-CoV-2 test (n = 5,938,519). After randomly assigning a T0 in 2018 on the basis of the distribution of the calendar dates of T0 in those with BTI, 5,785,273 were alive 30 days after T0. Participants were followed until 1 December 2018. This group served as the historical control group.

To build the group of people with SARS-CoV-2 infection and without prior vaccination as a means of investigating the effect of prior vaccination on the risk of post-acute sequalae, we identified, from the 163,024 people with a first positive SARS-CoV-2 test from 1 January 2021 to 31 October 2021, 118,185 who had no record of any SARS-CoV-2 vaccination up through 30 days after first positive SARS-CoV-2 test (T0). We then selected the 113,474 who were alive 30 days after T0 to comprise the group of people with SARS-CoV-2 infection and no prior vaccination.

Finally, to compare post-acute sequelae of those hospitalized with BTI during the acute phase of the illness to those hospitalized with seasonal influenza, we separately identified 15,160 VHA users hospitalized with positive seasonal influenza test 5 days before or 30 days after the test between 1 October 2016 and 29 February 2020. We set the date of the positive seasonal influenza test as T0. To ensure no overlap with the BTI group, participants who had no record of a positive SARS-CoV-2 test were then selected (n = 14,431). From these, we selected 14,337 who were alive 30 days after their T0 to constitute the seasonal influenza group. Duration of follow-up was randomly assigned on the basis of follow-up in the BTI group.

Data sources

Data used in this study were obtained from the VHA Corporate Data Warehouse (CDW). Within CDW, the patient data domain provided information on demographic characteristics; the outpatient encounters domain and inpatient encounters domain provided information on health characteristics, including data on timing and location of interactions with the healthcare system, diagnoses and procedures; the pharmacy and barcode medication administration domains provided medication records; and the laboratory results domain provided laboratory test information in both outpatient and inpatient settings5,6. The COVID-19 Shared Data Resource provided information on SARS-CoV-2 test results and SARS-CoV-2 vaccination status. The 2019 Area Deprivation Index (ADI) at each cohort participant residential address was used as a contextual measure of socioeconomic disadvantage14.

Post-acute sequelae

We prespecified a set of outcomes based on prior evidence on the post-acute sequelae of SARS-CoV-2 infection—also referred to as Long COVID4,5,6,7,8,9,10,11,12. Outcomes were defined using validated definitions leveraging information from several data domains, including diagnoses, prescription medications and laboratory test results, at the time of first record of occurrence in the data5,6,15,16,17,18,19,20,21. Incident post-acute sequelae were examined in a cohort with no record of the health condition in the 2 years before T0. We additionally examined outcomes of death and having at least one of post-acute sequelae that was defined at the time of the first incident prespecified post-acute sequelae in each participant.

Additionally, we defined a set of outcomes where we aggregated the prespecified post-acute sequelae, where applicable, by organ system. These included cardiovascular disorders, coagulation and hematologic disorders, fatigue, gastrointestinal disorders, kidney disorders, mental health disorders, metabolic disorders, musculoskeletal disorders, neurologic disorders and pulmonary disorders. All outcomes were assessed starting from 30 days after T0.

Covariates

We included a set of predefined covariates based on prior knowledge4,5,6,7,8,9,10,11,12,19,22,23,24,25,26 and algorithmically selected covariates. Predefined covariates included demographic information (age, race and sex); contextual information (ADI); measures of the intensity of healthcare interaction in the 2 years before T0, including the number of outpatient visits, the number of inpatient visits, the number of unique medications the participant received a prescription for and the number of routine blood panels that were performed; and prior history of receiving an influenza vaccination. We also included smoking status as a covariate. Health characteristics included prior history of anxiety, cancer, cardiovascular disease, cerebrovascular disease, chronic kidney disease, peripheral artery disease, dementia, depression, type 2 diabetes mellitus and chronic obstructive pulmonary disease, and measures of estimated glomerular filtration rate, systolic and diastolic blood pressure, and body mass index (BMI). We also included, as measures of spatiotemporal differences, the calendar week of enrollment and geographic region of receipt of care defined by Veterans Integrated Services Networks (VISN).

In consideration of the dynamicity of the pandemic, for analyses that compared BTI, SARS-CoV-2 infection without prior vaccination and the contemporary control, additional covariates included SARS-CoV-2 testing capacity, SARS-CoV-2 positivity rates, hospital system capacity (the total number of inpatient hospital beds) and inpatient bed occupancy rates (the percentage of hospital beds that were occupied) as well as a measure of the proportions of SARS-CoV-2 variants by Health and Human Services region26. These measures were ascertained for each participant in the week before cohort enrollment at the location of the healthcare system at which they received care. In analyses of the vaccinated control, we additionally included calendar week of first vaccination shot. All continuous covariates were treated as natural cubic splines unless heavily skewed toward zero.

In addition to the predefined covariates, we leveraged the high dimensionality of VA data where we developed and deployed a high-dimensional variable selection algorithm to identify covariates that may potentially confound the examined associations27. Using classifications from the Clinical Classifications Software Refined version 2021.1, available from the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality, more than 70,000 ICD-10 diagnoses codes in the year before T0 for each participant were classified into 540 diagnostic categories28,29,30. Using the VA drug classification system, 3,425 different medications were classified into 543 medication classes31,32. Finally, laboratory results from 38 different laboratory measurements were classified into 62 laboratory test abnormalities, defined by being above or below the corresponding reference ranges, on the basis of the recorded Logical Observation Identifiers Names and Codes. Of the high-dimensional variables that occurred at least 100 times in participants in each group (up to 821), we selected the top 100 variables with the highest relative risk for differences in group membership for inclusion in models.

Statistical analysis

Mean (standard deviation) and frequency (percentage) of select characteristics are reported in the BTI group, SARS-CoV-2-infected group without prior vaccination, the contemporary control group, the historical control group, the vaccinated control group and the seasonal influenza group, where appropriate. Characteristics of those with BTI by hospitalization status are additionally presented. Vaccination characteristics for those with BTI are reported as well as BTI rates per 1,000 persons at 6 months for those vaccinated from 1 January to 31 October 2021.

To balance baseline characteristics, including predefined and high-dimensional variables across comparison groups, we applied an overlap weighting approach in our analyses. In brief, logistic regressions were constructed for probability of group membership of the groups being compared, using the predefined and high-dimensional covariates as independent variables, in separate subcohorts with no prior history of the outcome being examined, estimating propensity scores of the probability of group assignment33,34. In consideration of variability in duration of potential follow-up, calendar week of enrollment was included to balance length of follow-up between cohorts (uncensored duration of follow-up was included for comparison versus seasonal influenza). Propensity scores were then used in construction of the overlap weights whose application achieved similar baseline characteristic distributions across groups while providing higher weights to those with baseline characteristics more similar to those in other groups. Weights were then applied to Cox survival models to estimate HRs, where follow-up started 30 days after the date of testing positive. Standard errors were estimated by applying the robust sandwich variance estimator method. Covariate balance among all predefined and high-dimensional variables were assessed for each model through the standardized mean difference, where a difference <0.1 was taken as evidence of balance. We estimated the incidence rate difference (referred to as excess burden) between groups per 1,000 participants at 6 months after the start of follow-up based on the difference in survival probability in the relevant groups.

We first examined the risk and excess burden of individual post-acute sequelae, post-acute sequelae by organ system, at least one post-acute sequela and death between the BTI group, those with SARS-CoV-2 infection without prior vaccination and the contemporary control. We then compared risks of the BTI group with the historical control and, separately, with the vaccinated control.

Further analyses were conducted to better understand the risk in BTI versus the contemporary control. To investigate risk of post-acute sequalae before and after 90 days of follow-up, we conducted analyses that examined risk during the first 30–90 days, and during the 90–180 days, after T0. Examination of the risk from the 90–180 days was done overall, for incident outcomes during this period (where there was no record of the outcome during the 30–90-day period) and for recurrent or persistent outcomes during this period (where there was a prior record of the outcome during the 30–90-day period). We then comparatively evaluated the risks between the BTI and contemporary control based on their immunocompromised status, where immunocompromised status was defined (according to the CDC definition) by a history of organ transplantation, advanced kidney disease (an estimated glomerular filtration rate of less than 15 ml/min/1.73 m2 or end-stage renal disease), cancer, HIV or conditions with prescriptions of more than 30-day use of corticosteroids or immunosuppressants, including systemic lupus erythematosus and rheumatoid arthritis. We lastly compared the risks and burden of death, at least one PASC, pulmonary disorders and extrapulmonary disorders within those with BTI by type of vaccination received.

We then examined the risk and excess burden associated with BTI by care setting of the acute phase of the disease. Risks were estimated for individual sequelae and risks and excess burden of organ system involvement, at least one post-acute sequela and death in those with a BTI who were not hospitalized, who were hospitalized and who were admitted to ICU during the 5 days before and 30 days after their positive SARS-CoV-2 test compared to the contemporary control group.

We additionally examined differences in risk and burden between BTI and SARS-CoV-2 infection without prior vaccination by severity of the acute phase of the disease (non-hospitalized, hospitalized and admitted to ICU).

Finally, we compared the risks and excess burden of individual post-acute sequelae, post-acute sequelae by organ system, at least one post-acute sequela and death between those hospitalized with BTI and those hospitalized with seasonal influenza.

Positive and negative controls

We examined, as positive outcome controls, the risks of fatigue in those with SARS-CoV-2 infection without prior vaccination compared to the contemporary and historical control groups as a means of testing whether our approach would reproduce established knowledge8,9,10,11,12.

The application of negative outcome control may help detect both suspected and unsuspected sources of spurious biases. We, therefore, tested comparing BTI to the contemporary and historical controls, the risk of atopic dermatitis, accidental poisoning, accidental injury, fitting of a hearing aid or contact lenses, ingrown toenail and scarring as negative outcome controls—where no prior knowledge suggests that an association is expected. Additionally, we tested a pair of negative-exposure controls; we expected that receipt of the influenza vaccine on odd-numbered (n = 605,453) versus even-numbered (n = 571,291) calendar days between 1 March 2020 and 15 January 2021 would be associated with similar risks of the outcomes examined in our analyses. The successful testing of positive outcome controls, negative outcome controls and negative exposure controls may lessen concerns about biases related to study design, covariate selection, analytic approach, outcome ascertainment, unmeasured confounding and other potential sources of latent biases35,36.

All analyses were two-sided. In all analyses, a 95% CI that excluded unity was considered evidence of statistical significance. All analyses were conducted in SAS Enterprise Guide 8.2, and all figures were generated in R version 4.0.4. This study was approved by the VA St. Louis Health Care System Institutional Review Board (protocol no. 1606333).

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

The data that support the findings of this study are available from the US Department of Veterans Affairs. VA data are made freely available to researchers behind the VA firewall with an approved VA study protocol. For more information, visit https://www.virec.research.va.gov or contact the VA Information Resource Center at VIReC@va.gov.

Code availability

The analytic code is available at https://github.com/BcBowe3/Breakthrough.

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WHO report: 17 million in EU may have suffered long COVID-19

SEPTEMBER 13, 2022 Journal information:Nature Medicine

New research suggests at least 17 million people in the European Union may have experienced long COVID-19 symptoms during the first two years of the coronavirus pandemic, with women more likely than men to suffer from the condition, the World Health Organization said Tuesday.

The research, conducted for the WHO/Europe, was unclear on whether the symptoms that linger, recur or first appear at least one month after a coronavirus infection were more common in vaccinated or unvaccinated people. At least 17 million people met the WHO’s criteria of long COVID-19—with symptoms lasting at least three months in 2020 and 2021, the report said.

“Millions of people in our region, straddling Europe and Central Asia, are suffering debilitating symptoms many months after their initial COVID-19 infection,” said Hans Henri P. Kluge, WHO Regional Director for Europe, during a conference in Tel Aviv.

The modeling also suggests that women are twice as likely as men to experience long COVID-19, and the risk increases dramatically among severe infections needing hospitalization, the report said. One-in-three women and one-in-five men are likely to develop long COVID-19, according to the report.

“Knowing how many people are affected and for how long is important for health systems and government agencies to develop rehabilitative and support services,” said Christopher Murray, director of the Institute for Health Metrics and Evaluation, which conducted the research for the WHO.

The research, which represents estimates and not actual numbers of affected people, tracks with some other recent studies on the constellation of longer-term symptoms after coronavirus infections.

A U.S. study of veterans published in Nature Medicine in May provided fresh evidence that long COVID-19 can happen even after breakthrough infections in vaccinated people, and that older adults face higher risks for the long-term effects. The study showed that about one-third who had breakthrough infections exhibited signs of long COVID.

A separate report from the Centers for Disease Control and Prevention found that up to a year after an initial coronavirus infection, 1 in 4 adults aged 65 and older had at least one potential long COVID-19 health problem, compared with 1 in 5 younger adults.

Most people who have COVID-19 fully recover. But the WHO in Europe report on Tuesday estimated that 10% to 20% develop mid- and long-term symptoms such as fatigue, breathlessness and cognitive dysfunction.

Diabetes may increase long COVID risk; COVID while pregnant linked to baby brain development issues

Authors: Nancy Lapid Thu, June 9, 2022,

The following is a summary of some recent studies on COVID-19. They include research that warrants further study to corroborate the findings and that has yet to be certified by peer review.

Diabetes may increase the risk of long COVID, new analyses of seven previous studies suggest.

Researchers reviewed studies that tracked people for at least four weeks after COVID-19 recovery to see which individuals developed persistent symptoms associated with long COVID such as brain fog, skin conditions, depression, and shortness of breath. In three of the studies, people with diabetes were up to four times more likely to develop long COVID compared to people without diabetes, according to a presentation https://eppro02.ativ.me/web/page.php?page=IntHtml&project=ADA22&id=1683 on Sunday at the annual Scientific Sessions of the American Diabetes Association. The researchers said diabetes appears to be “a potent risk factor” for long COVID but their findings are preliminary because the studies used different methods, definitions of long COVID, and follow-up times, and some looked at hospitalized patients while others focused on people with milder cases of COVID-19.

“More high-quality studies across multiple populations and settings are needed to determine if diabetes is indeed a risk factor” for long COVID, the researchers said. “In the meantime, careful monitoring of people with diabetes… may be advised” after COVID-19.

COVID-19 in pregnancy linked with babies’ learning skills

Babies born to mothers who had COVID-19 while pregnant may be at higher than average risk for problems with brain development involved in learning, focusing, remembering, and developing social skills, researchers have found.

They studied 7,772 infants delivered in Massachusetts between March and September 2020, tracking the babies until age 12 months. During that time, 14.4% of the babies born to the 222 women with a positive coronavirus test during pregnancy were diagnosed with a neurodevelopmental disorder, compared to 8.7% of babies whose mothers avoided the virus while pregnant. After accounting for other neurodevelopmental risk factors, including preterm delivery, SARS-CoV-2 infection during pregnancy was linked with an 86% higher risk of a neurodevelopmental disorder diagnosis in offspring, the researchers reported on Thursday in JAMA Network Open https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2793178. The risk was more than doubled when the infection occurred in the third trimester.

The researchers point out that their study was brief and cannot rule out the possibility that additional neurodevelopmental effects will become apparent as the children grow up. On the other hand, they note, larger and more rigorous studies are needed to rule out other potential causes and prove that the coronavirus is to blame.

The rare but life-threatening inflammatory syndrome seen in some children after a coronavirus infection has become even more rare with the Omicron variant causing most infections and more kids vaccinated, according to a new study.

Researchers looked at data from Denmark on more than half a million children and adolescents infected after Omicron became dominant, about half of whom experienced breakthrough infections after vaccination. Overall, only one vaccinated child and 11 unvaccinated children developed Multisystem Inflammatory Syndrome in Children (MIS-C), which causes inflammation in the heart, lungs, kidneys and brain after a mild or asymptomatic SARS-CoV-2 infection. That translates to rates of 34.9 MIS-C cases per million unvaccinated children with COVID-19 and 3.7 cases per million vaccinated young COVID-19 patients, the researchers said on Wednesday in JAMA Pediatrics https://jamanetwork.com/journals/jamapediatrics/fullarticle/2793024. By comparison, rates of MIS-C cases when Delta was predominant were 290.7 per million unvaccinated infected kids and 101.5 per million among the vaccinated who had COVID, they said.

The fact that MIS-C risk was significantly lower in vaccinated children suggests the vaccine is helping to keep the immune system from causing the deadly inflammatory reaction that is an MIS-C hallmark, the researchers said.

CDC Director Issues Alert On Pfizer’s COVID-19 Pill

Authors: Jack Phillips via The Epoch Times, JUN 01, 2022 

Centers for Disease Control and Prevention Director Rochelle Walensky warned that Pfizer’s COVID-19 pill Paxlovid can lead to a rebound in symptoms.

“If you take Paxlovid, you might get symptoms again,” Walensky told CBS News on Tuesday.

“We haven’t yet seen anybody who has returned with symptoms needing to go to the hospital. So, generally, a milder course.”

Another researcher who is not affiliated with the CDC said that he has observed such a scenario.

“People who experience rebound are at risk of transmitting to other people, even though they’re outside what people accept as the usual window for being able to transmit,” Dr. Michael Charness of the Veterans Administration Medical Center in Boston told CNN on Tuesday.

After a patient recovers from COVID-19, the aforementioned rebound has occurred between two and eight days later, according to the CDC. The agency, however, told CBS that the benefits of taking Paxlovid outweigh the risks of COVID-19, namely among those who are at a high risk of developing severe symptoms from the virus.

A Pfizer technician handles the company’s COVID-19 pill, known as Paxlovid, in a file photograph. (Pfizer via AP)

About a week ago, the agency issued an alert to health care providers about the rebound, saying that patients who took Paxlovid either test positive for the virus after having tested negative or will experience COVID-19 symptoms.

“A brief return of symptoms may be part of the natural history of SARS-CoV-2 infection in some persons, independent of treatment with Paxlovid and regardless of vaccination status,” the federal health agency said at the time. SARS-CoV-2 is another name for the CCP (Chinese Communist Party) virus, which causes COVID-19.

“Limited information currently available from case reports suggests that persons treated with Paxlovid who experience COVID-19 rebound have had mild illness; there are no reports of severe disease. There is currently no evidence that additional treatment is needed with Paxlovid or other anti-SARS-CoV-2 therapies in cases where COVID-19 rebound is suspected,” the CDC added.

The Epoch Times has contacted Pfizer for comment. Pfizer told CBS that it is observing a rebound rate of approximately 2 percent and is continuing to monitor patients.

“We have not seen any [COVID-19] resistance emerge to date in patients treated with Paxlovid,” a spokesperson for the company told Reuters this week.

In recent weeks, doctors have increasingly prescribed Paxlovid, which has been authorized to treat at-risk people. But some health care workers told Reuters they are putting off prescribing the medication.

“I am shying away from giving it to people who are very low- risk, and are not terribly ill, particularly people who are vaccinated and boosted,” said Dr. Bruce Farber, chief of public health and epidemiology for Northwell Health, in an interview with the news agency. He will still prescribe the bill to people who have significant health conditions or are aged 75 and older.

Long COVID affects more older adults; shots don’t prevent it

Authors: LINDSEY TANNER AP Medical Writer MAY 26, 202

New U.S. research on long COVID-19 provides fresh evidence that it can happen even after breakthrough infections in vaccinated people, and that older adults face higher risks for the long-term effects.

In a study of veterans published Wednesday, about one-third who had breakthrough infections showed signs of long COVID.

A separate report from the Centers for Disease Control and Prevention found that up to a year after an initial coronavirus infection, 1 in 4 adults aged 65 and older had at least one potential long COVID health problem, compared with 1 in 5 younger adults.

Long COVID refers to any of more than two dozens symptoms that linger, recur or first appear at least one month after a coronavirus infection. These can affect all parts of the body and may include fatigue, shortness of breath, brain fog and blood clots.

Coronavirus vaccines that help prevent initial infections and serious illnesses provide some protection against long COVID but mounting research shows not as much as scientists had first hoped.

The veterans study published in Nature Medicine reviewed medical records of mostly white male veterans, aged 60, on average. Of the 13 million veterans, almost 3 million had been vaccinated last year, through October.

About 1%, or nearly 34,000, developed breakthrough infections. Lead author Dr. Ziyad Al-Aly noted that the study was done before the highly contagious omicron variant appeared at the end of the year and said the rate of breakthrough infections has likely increased.

Breakthrough infections and long COVID symptoms were more common among those who had received Johnson & Johnson’s single-dose shot compared with two doses of either Moderna or Pfizer vaccines. Whether any had received booster shots is not known; the first booster wasn’t OK’d in the U.S. until late September.

Overall, 32% had long COVID symptoms up to six months after breakthrough infections. That’s compared with 36% of unvaccinated veterans who had been infected and developed long COVID.

Vaccination reduced the chances for any long COVID symptoms by a “modest” 15%,” although it cut the risk in half for lingering respiratory or clotting problems, said Al-Aly, a researcher with Washington University and the Veterans Affairs health system in St. Louis. These symptoms included persistent shortness of breath or cough and blood clots in lungs or veins in the legs.

Infectious disease expert Dr. Kristin Englund, who runs a center for long COVID patients at the Cleveland Clinic, said the Nature Medicine study mirrors what she sees at her clinic. Long COVID patients there include people who were vaccinated and received boosters.

“We have no clear treatments for long COVID and encourage vaccination,”

However, others believe that vaccination has not been proven to be effective in preventing COVID infection nor has it been shown that the vaccines prevent long-haul illness, especially in the large majority of the elderly who have other chronic health conditions.

The CDC report, released Tuesday, used medical records for almost 2 million U.S. adults from the start of the pandemic in March 2020 to last November. They included 353,000 who had COVID-19. Patients were tracked for up to a year to determine if they developed any of 26 health conditions that have been attributed to long COVID.

Those who had COVID were much more likely than other adults without COVID to develop at least one of these conditions, and risks were greatest for those aged 65 and older. Information on vaccination, sex and race was not included.

Breathing problems and muscle aches were among the most common conditions.

Older adults’ risks were higher for certain conditions, including strokes, brain fog, kidney failure and mental health problems. The findings are worrisome because those conditions can hasten older adults’ needs for long-term care, the report authors said.

They stressed that routine assessment of all COVID patients “is critical to reduce the incidence” of long COVID.

Were fears about asymptomatic Covid spread overblown? 

Infected people without symptoms are TWO-THIRDS less likely to pass virus on, study finds

Authors: JOHN ELY MAILONLINE 26 May 2022 

Fears about silent spreaders of Covid — who suffer no symptoms but can pass the virus to others — may have been overblown. 

A study of nearly 30,000 people has found asymptomatic carriers are about 68 per cent less likely to pass the virus on than those who get sick.  

No10 used concerns about asymptomatic spread to justify forcing Britons to obey lockdowns and wear masks.  

They were thought to account for up to a third of all infections and many scientists claimed asymptomatic patients were just as infectious as the sick.

But a new global study spanning 42 countries, including the UK and US, found they were only responsible for as little as 14 per cent of cases. 

They also estimate that their overall risk of passing the virus to someone else ‘about two-thirds lower’. 

Scientists claimed Covid’s ability to spread asymptomatically was one of the reasons for harsh social curbs.

During one of the national lockdowns in January 2021, the Government said about a third of people with Covid had no symptoms and urged people to ‘act like you’ve got it’.

Experts analysed data from 130 studies from 42 countries.

They involved 28,426 people who caught Covid between April 2020 and July 2021. 

Of these patients, nearly 12,000 had an asymptomatic infection, having tested positive on a PCR but having suffered no symptoms. 

All of the studies included the results of community screening programmes, contact tracing, and investigations into specific outbreaks like on cruise ships. 

They found the ‘secondary attack rate’, how likely people infected with Covid are to pass the virus to others, was 68 per cent lower for asymptomatic cases, compared to those with symptoms. 

Scientists also estimated between 14-to-50 per cent of the Covid infections were asymptomatic. 

They said the range was so high due to the differences in the methodologies of the studies they drew the data from. 

But lead author, Diana Buitrago-Garcia, from the University of Bern in Switzerland, suggested their role in overall Covid transmission was minor.  

‘If both the proportion and transmissibility of asymptomatic infection are relatively low, people with asymptomatic SARS-CoV-2 infection should account for a smaller proportion of overall transmission than presymptomatic individuals,’ she said. 

Co-author, Professor Nicola Low, an expert in social and preventative medicine at Bern, said while it was clear asymptomatic cases were less infectious, the true scale of these cases in the pandemic was difficult to calculate. 

‘The true proportion of SARS-CoV-2 infection is still not known, and it would be misleading to rely on a single number because the 130 studies that we reviewed were so different,’ she said. 

‘People with truly asymptomatic infection are, however, less infectious than those with symptomatic infection.’ 

Another limitation of the study, which is ongoing as more data becomes available, is that it only includes studies up to July 2021.

This, as the authors highlight, means it will not include any data on more recent Covid variants like Omicron, which only emerged in November last year and is milder than earlier versions of the virus. 

It also means the sample size includes data from both before and when vaccines were starting to be rolled out in various countries, which could influence the results. 

Most of the studies included in the research, which has been published in the journal PLOS Medicine, were from Europe and the Americas, with 45 from each.  

The authors also highlighted reduced routine testing as countries, like the UK, wind down their routine pandemic testing will also impact future research into asymptomatic cases.

Fears about asymptomatic Covid cases unwittingly spreading the virus were part of a Government rationale for urging people at the start of 2021 to take a test twice a week.

At the time then-Health Secretary Matt Hancock said regular testing was one the best ways to catch asymptomatic cases and keep people safe. 

‘Around 1 in 3 people have coronavirus without any symptoms, so getting tested regularly is one of the simplest and easiest ways we can keep ourselves and our loved ones safe,’ he said. 

‘I’d encourage everyone to take up the offer and test twice a week.’ 

Covid symptoms themselves have undergone several changes over the course of the pandemic.

In the beginning UK health officials only accepted three symptoms: a high temperature, a cough and a loss or change to taste or smell as signs someone had the virus, despite other countries including up to 14.

But in April this year the NHS quietly expanded the list to 12, including a loss of appetite, feeling or being sick and a headache, shortness of breath, feeling tired, an aching body, a sore throat, a blocked or runny nose and diarrhea. 

WHAT IS THE FULL LIST OF COVID SYMPTOMS? 

According to the NHS, symptoms of Covid in adults can include: 

  • a high temperature or shivering (chills) – a high temperature means you feel hot to touch on your chest or back (you do not need to measure your temperature) 
  • a new, continuous cough – this means coughing a lot for more than an hour, or 3 or more coughing episodes in 24 hours 
  • a loss or change to your sense of smell or taste 
  • shortness of breath 
  • feeling tired or exhausted
  • an aching body 
  • a headache 
  • a sore throat 
  • a blocked or runny nose 
  • loss of appetite 
  • diarrhea 
  • feeling sick or being sick

Vaccines may not prevent many symptoms of long covid, study suggests

Veterans Affairs analyzed records from nearly 34,000 people in U.S. who experienced breakthrough infections

Image without a caption

 Authors: Ariana Eunjung Cha May 25, 2022

A large U.S. study looking at whether vaccination protects against long covid showed the shots have only a slight protective effect: Being vaccinated appeared to reduce the risk of lung and blood clot disorders, but did little to protect against most other symptoms.

The new paper, publishedWednesdayin Nature Medicine, is part of a series of studies by the Department of Veterans Affairs on the impact of the coronavirus, and was based on 33,940 people who experienced breakthrough infections after vaccination.

The data confirms the large body of research that shows vaccination greatly reduces the risk of death or serious illness. But there was more ambiguity regarding long covid.

Six months after their initial diagnosis of covid, people in the study who were vaccinated had only a slightly reduced risk of getting long covid — 15 percent overall. The greatest benefit appeared to be in reducing blood clotting and lung complications. But there was no difference between the vaccinated and unvaccinated when it came to longer-term risks of neurological issues, gastrointestinal symptoms, kidney failure and other conditions.

“This was disappointing,” said Ziyad Al-Aly, lead author and chief of research and development service at VA Saint Louis Health Care System. “I was hoping to see that vaccines offer more protection, especially given that vaccines are our only line of defense nowadays.”

“Long covid” refers to the constellation of symptoms that many people have reported months after their initial infections. Early in the pandemic, some patients who complained of lingering symptoms were dismissed by physicians who thought the manifestations might be psychological. But the condition has since become a major concern for the medical community.

The World Health Organization has defined post-covid syndrome as symptoms that last for at least two months and cannot be explained by alternate diagnoses. It cited evidence suggesting that as many as 20 percent of the half-billion people worldwide estimated to be infected with coronavirus may experience mid- and long-term effects.

This week, the Centers for Disease Control and Prevention released new estimates of the syndrome’s toll in the United States, suggesting it affects one in five adults younger than 65 who had covid, and one in four of those aged 65 and older. People in both age groups had twice the risk of uninfected people of developing respiratory symptoms and lung problems, including pulmonary embolism, the CDC found. Those in the older age group were at greater risk of developing kidney failure, Type 2 diabetes, neurological conditions and mental health issues.

The Veterans Affairs study, believed to be the largest peer-reviewed analysis in the United States on long covid based on medical records, looked at patients who either had two doses of the Moderna or Pfizer—BioNTech vaccines, or one dose of the Johnson & Johnson vaccine. It did not assess the impact of booster shots. While the study population contained a wide range of ages and racial and ethnic backgrounds, it did skew older, Whiter and more male than the United States as a whole.

The VA study also had no way to tell how different variants may change the risk of long covid. These breakthrough infections, for example, took place at a time when alpha, delta and prior variants were at high levels in the United States. It does not cover the period when the omicron variant and its subvariants began circulating in late 2021.

The findings add to the debate surrounding similar analyses trickling out from the United KingdomIsrael and other countries that have shown conflicting results in terms of whether vaccines protect against long covid.

One British study published in the medical journal Lancet, for example, based on self-reported data from an app, showed a 50 percent reduction in risk among those who were vaccinated. On the other hand, a paper by University of Oxford researchers based on electronic records from the United States found that vaccination did not appear to reduce the risk of long covid for most symptoms.

The question of vaccines and long covid has been a critical one for doctors. Some patients have claimed a vaccine has cured them, while others have avoided the shots for fear of triggering symptoms.

Igor Koralnik, chief of neuro-infectious diseases at Northwestern Medicine, said recent research suggests neither is true. In a paper published in the Annals of Clinical and Translational Neurology on Tuesday,Koralnik and his colleagues found that 77 percent of the 52 long-covid patients they are following had been vaccinated against the coronavirus, but the shots did not appear to have a positive or negative impact on cognitive function or fatigue.

“There is a neutral effect of vaccination. It didn’t cure long covid. It didn’t make long covid worse,” Koralnik said.

At the Dartmouth Hitchcock Medical Center’s Post-Acute COVID Syndrome Clinic, Christina Martin, an advance practice nurse, said that since November, her staff has noticed a “worrying trend” of vaccinated people having breakthrough infections and developing long covid.

When the clinic was founded a year ago, she said, they anticipated seeing fewer new patients by this time as more people became vaccinated. Unfortunately, they’ve seen the opposite, with patient numbers going up.

“We now feel that long covid is here to stay. … This will have profound implications on our health-care system and resources,” Martin said.

David Putrino, a long-covid researcher who serves as director of rehabilitation innovation at the Mount Sinai Health System in New York, shares those concerns. He worries that public health leaders are not taking the current surge seriously enough because they are discounting the risks of long covid.

Putrino said that demand for appointments at his medical center’s long covid clinic continues to increase and he does not anticipate a slowdown any time soon. The clinic has seen about 2,500 patients since opening in May, 2020.

“We failed in our health messaging that death is not the only serious outcome of a covid-19 infection,” Putrino said. “. . . I’m very concerned that what this is going to do is lead us into a continuation of this mass-disabling event we are seeing with long covid.”

More of the vaccinated and boosted landing in hospital with COVID-19

Authors: By Ariel Hart Zachary Hansen May 19. 2022 – The Atlanta Journal-Constitution

Doctors say it’s caused by a combination of a variant that can escape the vaccine’s effects and the most vulnerable also being the most vaccinated

As summer once again brings signs of a coming COVID-19 wave, an unusual trend has emerged: The Georgians who are fully vaccinated and boosted are increasingly winding up in the hospital with serious COVID-19 symptoms.

The phenomenon points to two changes in the unpredictable pandemic battleground more than two years in. The circulating omicron variant has become better at evading the vaccine, which was designed on the first version of coronavirus to appear in China. And the people most likely to get boosted are those who were most vulnerable to begin with: the elderly, or patients with pre-existing conditions. Despite the extra vaccine protection, those people remain the most vulnerable.

Even in light of the unexpected hospitalizations of those vaccinated and boosted, doctors say it’s still true that boosted groups are the least likely to die.

“I’ve had several older patients who have been boosted and had the vaccine,” said Dr. William Cleveland, a nephrologist in southwest Atlanta. “They get hospitalized, and they had to have some significant medical attention, but they get discharged. And I know that just because of their frailty, without having had the vaccine they would not have survived.”

The rate of hospitalizations for boosted Georgians fell again this week, but still remains higher than the rate of hospitalizations for those with only the primary vaccine series (2 shots). The fact that boosted patients’ hospitalizations nearly outstripped all others even for one week was an unprecedent moment in the pandemic. In the past, hospitalization rates for unvaccinated groups have drastically outnumbered those who have taken the vaccine — sometimes tenfold.

The trend emerged at the tail-end of the omicron variant outbreak and has accelerated over the past two months, setting off alarm bells for state public health experts already expecting a surge in cases this summer.

Dr. Eva Lee, director of the Center for Operations Research in Medicine and Healthcare at Georgia Tech, agreed that the rate of hospitalizations among boosted people was on track to outpace other populations. However, she said it’s not a sign of vaccines losing all effectiveness — it has to do with who is choosing to get boosted.

“A big part of the people that are boosted are also the ones that are really at high risk already to begin with, right?” Lee said. “But what has remained and hasn’t changed is the following: The people that are at risk remain at risk. That means the people that are immune-compromised and the people that are like the elderly people, and people who have coexisting conditions, their risk is still higher.”

Growing number of breakthroughs

Overall, the number of people hospitalized with COVID remains at or near the lowest rate since the beginning of the pandemic. But state data shows that the most protected and least protected groups are starting to find themselves fighting for their lives in Georgia hospitals at nearly the same levels.

According to Georgia Department of Public Health data, unvaccinated groups were being hospitalized due to COVID at twice the rate of other populations at the beginning of March. By the end of April, there were 1.3 hospitalizations per 100,000 vaccinated and boosted Georgians compared to 1.6 hospitalizations for every 100,000 unvaccinated Georgians.https://datawrapper.dwcdn.net/qtaSR/1/

In addition to at-risk groups being more likely to get every shot available to them, omicron and its subvariants have presented a challenge for the U.S.’s current vaccines. Breakthrough cases of less serious illness are now common, and health experts warn they are a sign of the vaccines’ waning immunity.

“Prior to Omicron we could, with a booster, assume there was well over 90-95% vaccine effectiveness vs severe disease,” Eric Topol, founder and director of the Scripps Research Translational Institute in New York, wrote in a recent column sounding the alarm for a summer surge in COVID-19 infections. “It is clear, however, from multiple reports … that this level of protection has declined to approximately 80%, particularly taking account the more rapid waning than previously seen. That represents a substantial drop-off.”

The growing number of breakthrough cases has prompted national health officials to discuss reformulating the current vaccines to specifically target omicron and its subvariants. The U.S. Food and Drug Administration has a meeting scheduled for June 28 to evaluate vaccine efficiency and composition.

Georgia hasn’t seen any noticeable uptick in COVID-19 deaths, but death reports often lag behind increasing hospitalization rates by several weeks.

While health experts are troubled by the rising hospitalization rates, they emphasize that COVID’s death toll would already be on the rise if the most at-risk Georgians weren’t vaccinated and boosted.

Surprised to still be alive

Raymond Fain knew he couldn’t risk getting COVID-19. Given he has kidney disease, the 58-year-old made sure to not only get fully vaccinated but he took a Pfizer booster shot to boot.

Just two months later, during the onslaught of the omicron variant this winter, he was shocked to be told that in spite of his vaccinations he caught COVID. What followed was a bad sickness and two rounds of hospitalization that totaled nearly a month. But at the end of it, came another surprise: He lived.

“I was sort of shocked that that disease that I caught didn’t overcome me with, the failed kidneys. You know what I’m saying?” Fain said.

Cleveland works with Fain’s doctor, both of whom have pleaded with their kidney patients to get vaccinated. Cleveland is all too familiar with kidney patients who get COVID and don’t make it. He’s heard all the excuses, and he’s ready to counter them.

“I’ve seen so much of that (kidney patients succumbing to COVID) that I do not hesitate to try to explain to my patients that I’ve just seen this too many times to to be comfortable with them saying that they are afraid,” Cleveland said.

The percentage of Georgia residents who’ve been vaccinated is among the lowest in the country — the peach state currently ranks 45th. The state’s booster adoption rate is even worse, with less than half of all fully vaccinated people choosing to get one booster dose.

There’s also a large age disparity among those getting boosted. Nearly 60% of all Georgia seniors, people 65 and older, have gotten a booster dose, but there’s a stark drop-off for younger populations. Only about 15% of 25- to 34-year-old Georgians are boosted.

The low booster adoption rate for younger people, who are less likely to be at a high risk of life-threatening infections, is an explanation for why boosted groups seem to be hospitalized at higher rates, health experts said.https://datawrapper.dwcdn.net/KYHdI/1/

“All such people need to have vaccination and booster coverage but our (Centers for Disease Control and Prevention) has failed to convey their life-saving impact from the get go…” Topol wrote in his column. “That’s why we have 31% of Americans who had had 1 booster shot whereas most peer countries are double that proportion.”

For Fain, he’s surprised he was able to pull through his severe bout with COVID and get back on his feet, but his friends and loved ones haven’t let him forget how close he was to death.

“Everybody’s going to talk to me now, they say, ‘Boy when you started, we thought you was going to get gone. You sounded so bad,’” Fain said. “Yeah, but everything is okay now. I’m strong.”

New Omicron BA.4 and BA.5 Sublineages May Evade Vaccines, Natural Immunity. What Experts Say

Authors: Mint Newsletters April 29, 2022

  • The BA.4 and BA.5 sublineages appear to be more infectious than the earlier BA.2 lineage
  • The sub-lineages have been detected in seven of South Africa’s nine provinces and 20 countries worldwide

New omicron sublineages, discovered by South African scientists this month, are likely able to evade vaccines and natural immunity from prior infections, the head of gene sequencing units that produced a study on the strains said, according to Bloomberg report.

It is important to note that the BA.4 and BA.5 sublineages appear to be more infectious than the earlier BA.2 lineage, which itself was more infectious than the original omicron variant, Tulio de Oliveira, the head of the institutes, said.

Omicron sublineages  mutated to evade immunity

  • As almost all South Africans either having been vaccinated against the coronavirus or having had a prior infection the current surge in cases means that the strains are more likely to be capable of evading the body’s defenses rather than simply being more transmissible, de Oliveira said.
  • There are “mutations in the lineages that allow the virus to evade immunity,” he said in a response to queries. “We expect that it can cause reinfections and it can break through some vaccines, because that’s the only way something can grow in South Africa where we estimate that more than 90% of the population has a level of immune protection.”
  • South Africa is seen as a key harbinger of how the omicron variant and its sublineages are likely to play out in the rest of the world. South African and Botswanan scientists discovered omicron in November and South Africa was the first country to experience a major surge of infections as a result of the variant.
  • The new sublineages account for about 70% of new coronavirus cases in South Africa, de Oliveira said in a series of Twitter postings. 
  • “Our main scenario for Omicron BA.4 and BA.5 is that it increases infections but that does not translate into large hospitalizations and deaths,” he said.
  • So far, the sublineages have been detected in seven of South Africa’s nine provinces and 20 countries worldwide. 

Another rare virus puzzle: They got sick, got treated, got covid again

Authors: Carolyn Y. Johnson  April 27, 2022 The Washington Post

Shortly after he served on a jury in March, Gregg Crumley developed a sore throat and congestion. The retired molecular biologist took a rapid test on a Saturday and saw a dark, thick line materialize — “wildly positive” for the coronavirus.

Crumley, 71, contacted his doctor two days later. By the afternoon, friends had dropped off a course of Paxlovid, a five-day regimen of antiviral pills that aims to keep people from becoming seriously ill.

The day he took his last dose, his symptoms were abating. He tested each of the next three days: all negative.

Then, in the middle of a community Zoom meeting, he started feeling sick again. Crumley, who is vaccinated and boosted, thought it might be residual effects of his immune response to the virus. But the chills were more prolonged and unpleasant. He tested. Positive. Again.

Crumley, like other patients who have experienced relapses after taking Paxlovid, is puzzled — and concerned. On Twitter, physicians and patients alike are engaged in a real-time group brainstorm about what might be happening, with scant evidence to work with.

It is the latest twist — and newest riddle — in the pandemic, a reminder that two years in, the world is still on a learning curve with the coronavirus.

Infectious-disease experts agree that this phenomenon of the virus rebounding after some patients take the drug appears to be real but rare. Exactly how often it occurs, why it happens and what — if anything — to do about it remain matters of debate.

What’s clear is that patients should be warned it is possible so they don’t panic — and so that they know to test again if they start feeling ill. More data is needed to understand what is going on. Paxlovid, made by the drug giant Pfizer, remains a useful drug, even though it has sparked a new mystery.Biden administration boosts access to antivirals as covid cases rise

“I’m not negative on Paxlovid,” said Crumley, who lives in Philadelphia and whose last positive test was a week after his second wave of illness began. “I don’t know whether it’s just stopping [viral] replication for that five-day period of time, and it comes back.”

One of the top worries accompanying antiviral drugs is the threat of resistance, when the virus evolves to evade the treatment. A Food and Drug Administration analysis of Pfizer’s clinical trial of the drug showed the virus rebounded in several subjects about 10 to 14 days after their initial symptoms but found no reason and no evidence that their infections were resistant to the treatment.

Michael E. Charness, chief of staff at the VA Boston Healthcare System, published a detailed case study of one 71-year-old patient who had a relapse. The man, who was vaccinated and boosted, received Paxlovid and quickly felt better. When he developed cold symptoms a week after his case of covid had resolved, researchers sequenced the virus’s genetic code and found it was the same virus surging back. That ruled out a reinfection, the emergence of a variant or the virus becoming resistant.

Charness would like to see more data and other questions answered. Should antivirals be given longer, to assure the virus is cleared? Should people be treated a second time? What are the implications for people returning to their normal lives?

“If you have a resurgence of viral load, and that happens on day 10, when CDC says you’re back to work, no mask, what are you supposed to do about isolation? Is that a moment when you’re contagious again?” Charness said. “The person we studied, we advised to isolate until their viral load was gone the second time.”

Pfizer is collecting data, in clinical trials and in real-world monitoring of the drug’s use. The company’s trial data indicates there is a late uptick in viral load in “a small number” of people who take the drug, but the rates appear to be similar among study participants given a placebo, according to company spokesman Kit Longley. The people who experienced such increases also did not develop severe disease the second time around.

Those findings suggest that Paxlovid isn’t the reason people are relapsing, because that’s happening in untreated people, too.

If that turns out to be true, it raises the concern that some people — whether they have taken the drug or not — could be infectious long after they think they are in the clear, and after guidelines suggest they can stop taking precautions.

“Although it is too early to determine the cause, this suggests the observed increase in viral load is unlikely to be related to Paxlovid,” Longley wrote in an email. “We have not seen any resistance to Paxlovid, and remain very confident in its clinical effectiveness.”

The limited evidence leaves most physicians favoring the idea that Paxlovid knocks the virus down but doesn’t knock it out completely. It’s possible that by holding the virus in check, the immune response doesn’t fully ramp up, because it doesn’t see enough virus. Once the treatment ends, the virus can start multiplying again in some people.

Philip Bretsky, a primary care doctor in Santa Monica, Calif., said he has encountered two cases among patients, both of whom were vaccinated and boosted at least once.

A double-boosted 72-year-old who had chronic medical conditions that raised his risk for severe illness started to feel unwell at the end of March. He tested positive and began a course of Paxlovid. He felt better and tested negative. Then, 12 days later, he started feeling crummy again — and tested positive.

Reinfection seemed improbable, and Bretsky thought resistance was unlikely with a five-day course of treatment.

In well-vaccinated people, being reinfected so quickly would be “like getting struck by lightning or winning the lottery,” Bretsky said. “I don’t think this is reinfection. I think this is recrudescence of the original infection.”

Experts don’t know how common this phenomenon is. Many people may not test if they get sick again after their initial infection has receded, making it hard to track.

That almost happened to Holly Teliska, 42, of San Francisco. Teliska got sick shortly after returning home from a trip to New York. She has a risk factor for severe illness and got access to Paxlovid right away. When she finished her treatment course, she took a home PCR test that was negative and felt much better, though remained fatigued.

Four days later, she came down with a runny nose and cough. She assumed she had caught her daughter’s cold and powered through. Five days later, with plans to visit an immunocompromised friend, she took a test.

Teliska almost felt silly testing herself. She had been vaccinated and boosted, then infected.

“We’ve been saying I’m her safest friend now, now that I’ve had covid, so for three months, I can go spend time with her pretty safely,” Teliska said. “That really threw that narrative out the window. … This entire experience has been a real reminder there is still so much to learn.”

Paxlovid is new. It only began to be used in December, so reports people share on social media of resurgent illness may be the tip of the iceberg — or might simply reflect the eagerness to learn more about a rare, intriguing outcome.

If such cases turn out to be exceedingly rare, then these case reports may be a sporadic curiosity — something to warn patients could happen. If more common, it could lead to tweaks in treatment regimens.

The mounting anecdotes are compelling to many physicians, but it’s also possible the virus might rarely rebound. Yonatan Grad, an associate professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, has studied the viral loads of NBA players and staff during the course of an infection. That data, he said, shows that viral loads can bounce around.

What’s “exceptionally uncommon,” Grad said, is for the viral load to plunge for a few days to a level that suggests they are negative and then go up again.

Paul Sax, an infectious-diseases specialist at Brigham and Women’s Hospital in Boston, recently shared the story of a patient who became infected and then relapsed after taking Paxlovid. He has heard from lots of colleagues with similar stories. But the anecdotes raise more questions than they answer.

Even if the virus has not been shown to develop resistance to the treatment during a resurgence, that’s doesn’t mean it won’t happen, he points out. Does the treatment knock the virus down so successfully that people aren’t generating a robust immune response? That could have implications for understanding whether being infected acts as a potent booster.

The phenomenon is so new that many doctors aren’t aware of it. Jennifer Charness, a 31-year-old nurse who lives in Brookline, Mass., had the benefit of knowing about her father’s work at the Boston VA.

Charness started sneezing in early April and got a blaringly positive coronavirus test. She has a history of asthma and was prescribed Paxlovid. As she took the drug, she saw her positive test line grow fainter and her symptoms resolve. She swabbed to make sure she was negative before going back to work, as a precaution. Then, two days later, she felt the symptoms come back and tested positive — again.

“I’m so frustrated,” Charness said. “I don’t think I’m going to get very sick. It’s the concern of what does this mean for my viral load, and how contagious am I? And when will I not be contagious? I’m stuck back in my home again.”

Charness’s primary concern is that she doesn’t pose a risk to anyone else. She consulted a doctor via telemedicine Friday. The practice hadn’t heard of any cases like hers and decided to treat it as a reinfection and reset the isolation clock.

“I’m Day 4,” she said. “Or am I Day 13?”