Tuberculosis service disruptions and adaptations during the first year of the COVID-19 pandemic in the private health sector of two urban settings in Nigeria-A mixed methods study.

Nigeria has the second largest share of undiagnosed TB cases in the world and a large private health sector estimated to be the point of initial care-seeking for 67% of TB patients. There is evidence that COVID-19 restrictions disrupted private healthcare provision, but insufficient data on how private healthcare provision changed as a result of the pandemic. We conducted qualitative interviews and a survey to assess the impact of the pandemic, and government response on private healthcare provision, and the disruptions providers experienced, particularly for TB services. Using mixed methods, we targeted policymakers, and a network of clinical facilities, laboratories, community pharmacies, and medicine vendors in Kano and Lagos, Nigeria. We interviewed 11 policymakers, surveyed participants in 2,412 private facilities. Most (n = 1,676, 70%) facilities remained open during the initial lockdown period, and most (n = 1,667, 69%) offered TB screening. TB notifications dipped during the lockdown periods but quickly recovered. Clinical facilities reported disruptions in availability of medical supplies, staff, required renovations, patient volume and income. Few private providers (n = 119, 11% in Kano; n = 323, 25% in Lagos) offered any COVID-19 screening up to the time of the survey, as these were only available in designated facilities. These findings aligned with the interviews as policymakers reported a gradual return to pre-COVID services after initial disruptions and diversion of resources to the pandemic response. Our results show that COVID-19 and control measures had a temporary impact on private sector TB care. Although some facilities saw decreases in TB notifications, private facilities continued to provide care for individuals with TB who otherwise might have been unable to seek care in the public sector. Our findings highlight resilience in the private sector as they recovered fairly quickly from pandemic-related disruptions, and the important role private providers can play in supporting TB control efforts.

Lipidomic signatures align with inflammatory patterns and outcomes in critical illness.

Alterations in lipid metabolism have the potential to be markers as well as drivers of pathobiology of acute critical illness. Here, we took advantage of the temporal precision offered by trauma as a common cause of critical illness to identify the dynamic patterns in the circulating lipidome in critically ill humans. The major findings include an early loss of all classes of circulating lipids followed by a delayed and selective lipogenesis in patients destined to remain critically ill. The previously reported survival benefit of early thawed plasma administration was associated with preserved lipid levels that related to favorable changes in coagulation and inflammation biomarkers in causal modelling. Phosphatidylethanolamines (PE) were elevated in patients with persistent critical illness and PE levels were prognostic for worse outcomes not only in trauma but also severe COVID-19 patients. Here we show selective rise in systemic PE as a common prognostic feature of critical illness.

Adaptations to the first wave of the COVID-19 pandemic by private sector tuberculosis care providers in India.

Background: India's dominant private healthcare sector is the destination for 60-85% of initial tuberculosis care-seeking. The COVID-19 pandemic in India drastically affected TB case notifications in the first half of 2020. In this survey, we assessed the impact of the first wave of COVID-19 in India on private providers, and changes they adopted in their practice due to the pandemic. Methods: The Joint Effort for Elimination of TB (JEET) is a nationwide Global Fund project implemented across 406 districts in 23 states to extend quality TB services to patients seeking care in private sector. We conducted a rapid survey of 11% (2,750) of active providers engaged under JEET's intense Patient Provider Support Agency (PPSA) model across 15 Indian states in Q1 (February-March) of 2021. Providers were contacted in person or telephonically, and consenting participants were interviewed using a web-based survey tool. Responses from participants were elicited on their practice before COVID-19, during the 2020 lockdowns (March-April 2020) and currently (Q1 2021). Data were adjusted for survey design and non-response, and results were summarised using descriptive statistics and logistic regression. Results: Of the 2,750 providers sampled, 2,011 consented and were surveyed (73 % response). Nearly 50 % were between 30 and 45 years of age, and 51 % were from Uttar Pradesh, Maharashtra and Gujarat. Seventy percent of providers reported reduced daily out-patient numbers in Q1 2021 compared to pre-COVID times. During the lockdown, 898 (40 %) of providers said their facilities were closed, while 323 (11 %) offered limited services including teleconsultation. In Q1 2021, 88 % of provider facilities were fully open, with 10 % providing adjusted services, and 4 % using teleconsultation. Only 2 % remained completely closed. Majority of the providers (92 %) reported not experiencing any delays in TB testing in Q1 2021 compared to pre-COVID times. Only 6 % reported raising costs at their clinic, mostly to cover personal protective equipment (PPE) and other infection control measures, although 60-90 % implemented various infection control measures. Thirty-three percent of TB providers were ordering COVID-19 testing, in addition to TB testing.To adapt, 82% of survey providers implemented social distancing and increased timing between appointments and 83% started conducting temperature checks, with variation by state and provider type, while 89% adopted additional sanitation measures in their facilities. Furthermore, 62% of providers started using PPE, and 13% made physical changes (air filters, isolation of patient areas) to their clinic to prevent infection. Seventy percent of providers stated that infection control measures could decrease TB transmission. Conclusion: Although COVID-19 restrictions resulted in significant declines in patient turn-out at private facilities, our analysis showed that most providers were open and costs for TB care remained mostly the same in Q1 2021. As result of the COVID-19 pandemic, several positive strategies have been adapted by the private sector TB care providers. Since the subsequent COVID-19 waves were more severe or widespread, additional work is needed to assess the impact of the pandemic on the private health sector.

Antibodies targeting conserved non-canonical antigens and endemic coronaviruses associate with favorable outcomes in severe COVID-19.

While there have been extensive analyses characterizing cellular and humoral responses across the severity spectrum in COVID-19, outcome predictors within severe COVID-19 remain less comprehensively elucidated. Furthermore, properties of antibodies (Abs) directed against viral antigens beyond spike and their associations with disease outcomes remain poorly defined. We perform deep molecular profiling of Abs directed against a wide range of antigenic specificities in severe COVID-19 patients. The profiles included canonical (spike [S], receptor-binding domain [RBD], and nucleocapsid [N]) and non-canonical (orf3a, orf8, nsp3, nsp13, and membrane [M]) antigenic specificities. Notably, multivariate Ab profiles directed against canonical or non-canonical antigens are equally discriminative of survival in severe COVID-19. Intriguingly, pre-pandemic healthy controls have cross-reactive Abs directed against nsp13, a protein conserved across coronaviruses. Consistent with these findings, a model built on Ab profiles for endemic coronavirus antigens also predicts COVID-19 outcome. Our results suggest the importance of studying Abs targeting non-canonical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and endemic coronavirus antigens in COVID-19.

Functional reprogramming of monocytes in patients with acute and convalescent severe COVID-19.

Severe COVID-19 disease is associated with dysregulation of the myeloid compartment during acute infection. Survivors frequently experience long-lasting sequelae, but little is known about the eventual persistence of this immune alteration. Herein, we evaluated TLR-induced cytokine responses in a cohort of mild to critical patients during acute or convalescent phases (n = 97). In the acute phase, we observed impaired cytokine production by monocytes in the patients with the most severe COVID-19. This capacity was globally restored in convalescent patients. However, we observed increased responsiveness to TLR1/2 ligation in patients who recovered from severe disease, indicating that these cells display distinct functional properties at the different stages of the disease. In patients with acute severe COVID-19, we identified a specific transcriptomic and epigenomic state in monocytes that can account for their functional refractoriness. The molecular profile of monocytes from recovering patients was distinct and characterized by increased chromatin accessibility at activating protein 1 (AP1) and MAF loci. These results demonstrate that severe COVID-19 infection has a profound impact on the differentiation status and function of circulating monocytes, during both the acute and the convalescent phases, in a completely distinct manner. This could have important implications for our understanding of short- and long-term COVID-19-related morbidity.

People critically ill with COVID-19 exhibit peripheral immune profiles predictive of mortality and reflective of SARS-CoV-2 lung viral burden.

Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in people critically ill with COVID-19. Here, we present high-dimensional profiling of blood and respiratory samples from people with severe COVID-19 to examine the association between cell-linked molecular features and mortality outcomes. Peripheral transcriptional profiles by single-cell RNA sequencing (RNA-seq)-based deconvolution of immune states are associated with COVID-19 mortality. Further, persistently high levels of an interferon signaling module in monocytes over time lead to subsequent concerted upregulation of inflammatory cytokines. SARS-CoV-2-infected myeloid cells in the lower respiratory tract upregulate CXCL10, leading to a higher risk of death. Our analysis suggests a pivotal role for viral-infected myeloid cells and protracted interferon signaling in severe COVID-19.

Quantifying heterogeneity in SARS-CoV-2 transmission during the lockdown in India.

The novel SARS-CoV-2 virus, as it manifested in India in April 2020, showed marked heterogeneity in its transmission. Here, we used data collected from contact tracing during the lockdown in response to the first wave of COVID-19 in Punjab, a major state in India, to quantify this heterogeneity, and to examine implications for transmission dynamics. We found evidence of heterogeneity acting at multiple levels: in the number of potentially infectious contacts per index case, and in the per-contact risk of infection. Incorporating these findings in simple mathematical models of disease transmission reveals that these heterogeneities act in combination to strongly influence transmission dynamics. Standard approaches, such as representing heterogeneity through secondary case distributions, could be biased by neglecting these underlying interactions between heterogeneities. We discuss implications for policy, and for more efficient contact tracing in resource-constrained settings such as India. Our results highlight how contact tracing, an important public health measure, can also provide important insights into epidemic spread and control.