India’s Fight against the COVID-19 Pandemic: Lessons and the Way Forward

In early 2020, when the COVID-19 pandemic was indiscriminately spreading around the world, the seeming ability of India, the world’s second most populous country (with over 1.3 billion people), to contain the virus within its borders and keep COVID-19 infection and mortality rates low relative to population size was seen as miraculous. However, the miracle ended when ‘second-wave’ hit India in April 2021. On 1 May 2021, India became the first country in the world to record more than 400,000 coronavirus infections in a single day. This exponential rise in COVID-19 cases started on 28 April 2021 when India recorded 379,459 new COVID-19 cases and 3,647 deaths. This marked the eighth straight day of more than 300,000 cases a day—making India the second-highest COVID-19 case count in the world (over 20 million) with over 25 per cent of the global deaths from COVID. The following examines India’s fight against the pandemic, the failure to contain the second wave, the lessons learned and the way forward.

Activation of the MKK3-p38-MK2-ZFP36 axis by coronavirus infection restricts the upregulation of AU-rich element-containing transcripts in proinflammatory response

Coronavirus infections induce the expression of multiple proinflammatory cytokines and chemokines. We have previously shown that in cells infected with gammacoronavirus infectious bronchitis virus (IBV), interleukin 6 (IL-6) and IL-8 were drastically upregulated, and the MAP kinase p38 and the integrated stress response pathways were implicated in this process. In this study, we report that coronavirus infection activates a negative regulatory loop that restricts the upregulation of a number of proinflammatory genes. As revealed by the initial transcriptomic and subsequent validation analyses, the anti-inflammatory adenine-uridine (AU)-rich element (ARE)-binding protein, Zinc finger protein 36 (ZFP36) and its related family members were upregulated in cells infected with IBV and three other coronaviruses, alphacoronaviruses porcine epidemic diarrhea virus (PEDV) and human coronavirus 229E (HCoV-229E), and betacoronavirus HCoV-OC43, respectively. Characterization of the functional roles of ZFP36 during IBV infection demonstrated that ZFP36 promoted the degradation of transcripts coding for IL-6, IL-8, dual-specificity phosphatase 1 (DUSP1), prostaglandin-endoperoxide synthase 2 (PTGS2) and TNF-α-induced protein 3 (TNFAIP3), through binding to AREs in these transcripts. Consistently, knockdown and inhibition of JNK and p38 kinase activities reduced the expression of ZFP36, as well as the expression of IL-6 and IL-8. On the contrary, overexpression of mitogen-activated protein kinase kinase 3 (MKK3) and MAPKAP kinase-2 (MK2), the upstream and downstream kinases of p38, respectively, increased the expression of ZFP36 and decreased the expression of IL-8. Taken together, this study reveals an important regulatory role of the MKK3-p38-MK2-ZFP36 axis in coronavirus infection-induced proinflammatory response. Importance Excessive and uncontrolled induction and release of proinflammatory cytokines and chemokines, the so-called cytokine release syndrome (CRS), would cause life-threatening complications and multiple organ failure in severe coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and COVID-19. This study reveals that coronavirus infection also induces the expression of ZFP36, an anti-inflammatory ARE-binding protein, promoting the degradation of ARE-containing transcripts coding for IL-6 and IL-8 as well as a number of other proteins related to inflammatory response. Furthermore, the p38 MAP kinase, its upstream kinase MKK3 and downstream kinase MK2 were shown to play a regulatory role in upregulation of ZFP36 during coronavirus infection cycles. This MKK3-p38-MK2-ZFP36 axis would constitute a potential therapeutic target for severe coronavirus infections.

Tratamiento farmacológico en pacientes con COVID-19: una revisión integradora

Introducción: La salud hoy más que nunca ha sido vulnerada, la humanidad está sufriendo por la invasión del coronavirus SARS-CoV-2, que ha expuesto al mundo a la peor emergencia sanitaria en este siglo. La comunidad científica y los sistemas de salud global conjuntan esfuerzos en la búsqueda de un tratamiento definitivo, a la fecha se reconoce que la terapia está dirigida a mitigar los síntomas. Objetivo: Identificar las evidencias científicas sobre el tratamiento farmacológico en los pacientes con COVID-19. Metodología: Se realizó una revisión integradora de la literatura publicada de diciembre 2019 a octubre 2020, en los sistemas de información Clinical Key, Dialnet, EBSCO Host y Scopus, mediante los descriptores Coronavirus Infections, COVID-19, Drug therapy, tratamiento farmacológico. Los criterios de selección fueron artículos de investigación cuantitativa de cualquier tipo de diseño, en inglés y español disponibles a texto completo, obteniéndose una muestra de 24 artículos. Resultados: La mayoría de los estudios fueron revisiones integrativas con 66.6% y ensayos clínicos o in vitro con 12.5%. Se identificaron en la terapia farmacológica nueve medicamentos de mayor uso en COVID-19: Hidroxicloroquina/cloroquina, lopinavir/ritonavir, remdesivir, azitromicina, ivermectina, tocilizumab y dexametasona, no obstante, solo cuatro fármacos mostraron efectividad significativa según la evidencia científica. Conclusiones: remdesivir demostró mayor efectividad y seguridad en el tratamiento, tocilizumab y dexametasona mostraron resultados favorables, sin embargo, los resultados no son contundentes. Los autores señalan que aún no es posible afirmar que se dispone de tratamientos que combata la COVID-19 efectivamente.

Osteopathic status in patients with new coronavirus infection COVID-19

Introduction. The appearance of COVID-19 has set tasks for healthcare professionals related to the rapid diagnosis and provision of medical care to patients. Currently, intensive study of the clinical and epidemiological features of the disease continues, and of the development of new means of its prevention and treatment. At the same time, it is necessary not only to provide medical care in the acute period of the disease, but also to carry out rehabilitation measures for the consequences of a coronavirus infection. In accordance with the approved clinical recommendations, osteopathic correction in the acute period of an infectious disease is contraindicated. However, there is a potential interest of the possibility of osteopathic correction methods use during the period of convalescence, as well as within the framework of rehabilitation measures after a new coronavirus infection.At the same time, for objective reasons, there is no data on the structure of somatic dysfunctions in this group of patients in the literature. All of the above has predetermined the purpose of the research.The aim of the study is to draw up a map of the most common somatic dysfunctions and analyze their relationship with other subjective and objective manifestations of the disease based on the data of the osteopathic status assessing of patients who have undergone a new coronavirus infection COVID-19.Materials and methods. A cross-sectional study was conducted on the basis of Samara medical and sanitary unit № 2 and on the basis of the Saint-Petersburg «City Mariinsky Hospital» in the period from May 2020 to March 2021. There were 70 patients under observation in the rehabilitation department who had undergone a new coronavirus infection COVID-19. There were assessed the osteopathic status of all patients (by an osteopathic doctor with using personal protective equipment) and the level of anxiety; the data was copied from medical documentation.Results. Somatic dysfunctions of all three levels of manifestation are revealed in patients with the new coronavirus infections during the convalescence period. The global and regional somatic dysfunctions were distributed almost equally (45,7 and 54,3 %, respectively) in the structure of dominant somatic dysfunctions in patients with new coronavirus infections during the convalescence period. Patients with new coronavirus infections during the convalescence period are characterized by medium and high levels of both situational and personal anxiety. In the course of the work, a moderate positive relationship was established between a global rhythmogenic disorder (violation of the production of a thoracic rhythmic pulse) and a large volume of lung tissue damage (CT-2) according to the multispiral computed tomography of the thoracic cavity, as well as between a global psychoviscerosomatic disorder and a high level of situational anxiety.Conclusion. Somatic dysfunctions of all three levels of manifestation are revealed in patients with new coronavirus infections during the convalescence period. In addition, this group of patients is characterized by an average and high level of both situational and personal anxiety.The revealed correlations suggest that the inclusion of osteopathic correction in comprehensive rehabilitation programs for this group of patients may be pathogenetically reasonable.

Echinacea as a Potential Force against Coronavirus Infections? A Mini-Review of Randomized Controlled Trials in Adults and Children

Echinacea purpurea was shown to broadly inhibit coronaviruses and SARS-CoV-2 in vitro. This review discusses the available clinical evidence from randomized, blinded and controlled human studies. Two RCTs with results on enveloped viruses, respectively coronavirus infections during prevention treatment were detected. Incidence and/or viral loads were measured by RT-PCR and symptom severity was recorded. Jawad et al. (2012) collected nasopharyngeal swabs from adults (N=755) over 4 months of continuous prevention. Overall, 24 and 47 enveloped virus infections occurred, including 21 and 33 coronavirus detections [229E; HKU1; OC43] with Echinaforce extract [2400mg daily] and placebo, respectively (p=0.0114). Ogal et al. (2021) administered the same extract [1200mg] or control for 4 months to children (4-12 years) (N=203). Echinacea reduced the incidence of enveloped virus infections from 47 to 29 (p=0.0038) whereas 11 and 13 coronavirus detections [229E, OC43, NL63] were counted (p>0.05). Respiratory symptoms during coronavirus infections were significantly lower with area-under-curve AUC=75.8 (+/-50.24) versus 27.1 (+/-21.27) score points (p=0.0036). Importantly, viral loads in nasal secretions were significantly reduced by 98.5%, with Ct-values 31.1 [95% CI 26.3; 35.9] versus 25.0 [95% CI 20.5; 29.5] (p = 0.0479). Results from clinical studies confirm the antiviral activity found for Echinacea in vitro, embracing enveloped respiratory pathogens and therefore coronaviruses as well. Substantiating results from a new completed study seems to extrapolate these effects to the prevention of SARS-CoV-2 infection. As hypothesized, the testified broad antiviral activity of Echinacea extract appears to be inclusive for SARS-CoV-2.

SARS-CoV-2 and endemic coronaviruses: Comparing symptom presentation and severity of symptomatic illness among Nicaraguan Children

It has been proposed that as SARS-CoV-2 transitions to endemicity, children will represent the greatest proportion of SARS-Co-V-2 infections as they currently do with endemic coronavirus infections. While SARS-CoV-2 infection severity is low for children, it is unclear if SARS-CoV-2 infections are distinct in symptom presentation, duration, and severity from endemic coronavirus infections in children. We compared symptom risk and duration of endemic coronavirus infections from 2011-2016 with SARS-CoV-2 infections from March 2020-September 2021 in a Nicaraguan pediatric cohort. Respiratory samples were collected from participants that met testing criteria and blood samples were collected annually. Respiratory samples were tested for each of the endemic coronaviruses from 2011-2016 and for SARS-CoV-2 from 2020-2021 via rt-PCR. 2021 blood samples were tested for SARS-CoV-2 antibodies and a subset of 2011-2016 blood samples from four-years-old participants were tested for endemic coronavirus antibodies. By April 2021, 854 (49%) active participants were ELISA positive for SARS-CoV-2 antibodies. Most participants had antibodies against one alpha and one beta coronavirus by age four. We observed 595 symptomatic endemic coronavirus infections from 2011-2016 and 121 symptomatic with SARS-CoV-2 infections from March 2020-September 2021. Symptom presentation of SARS-CoV-2 infection and endemic coronavirus infections were very similar, and SARS-CoV-2 symptomatic infections were as or less severe on average than endemic coronavirus infections. This suggests that, for children, SARS-CoV-2 may be just another endemic coronavirus. However, questions about the impact of variants and the long-term effects of SARS-CoV-2 remain.