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La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario

Ponencia presentada por el Dr. Bonaventura Clotet Sala en el directo online ‘COVID 360’, realizado el 9 de julio de 2020

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La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario

  1. 1. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Update on COVID19 (SARS-CoV-2) Dr.B. Clotet Infectious Diseases Service Hospital “Germans Trias i Pujol. Badalona. Barcelona (Spain) E-mail address: bclotet@irsicaixa.es
  2. 2. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Seven Human Coronaviruses (HCoVs) ▪ Common HCoVs (lower pathogenicity): – HCoV-229E (alpha) – HCoV-NL63 (alpha) – HCoV-OC43 (beta) – HCoV-HKU1 (beta) ▪ XXI Century HCoVs (higher pathogenicity): – SARS-CoV (beta) – MERS-CoV (beta) – SARS-CoV-2* (beta) The illness COVID-19 is caused by SARS-CoV-2, which is more like SARS CoV (79% genetic similarity) thanMERS-Co. Among all known coronavirus sequences SARS-CoV-2 is most similar to bat coronavirus RaTG13, with 98% similarity and coronavirus sequences in the pangolín also share high similarity. (Tay MZ et al. Nature Reviews 20;363-374:2020) https://www.who.int/emergencies/diseases/novel‐coronavirus‐2019/technical‐guidancenaming‐the‐coronavirus‐disease‐(covid‐2019)‐and‐the‐virus‐that‐causes‐it
  3. 3. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala SARS-CoV & MERS-CoV Emergence in XXI Century www.who.int access on 2020 Jan 21st China R0 ≈1.8-2.5 Middle East R0 ≈0.3-1.3
  4. 4. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala A seafood market in Wuhan, China the probably source of an outbreak of a novel Coronavirus (COVID-19) in Dec. 2019 Normile D. Science. Jan. 3, 2020; Deslandes A et al. IJAA. 2020. doi: https://doi.org/10.1016/j.ijantimicag.2020.106006 SARS-COV-2 was already spreading in France in late December 2019 and in Barcelona in samples stored of residual water was identified in March 2019
  5. 5. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Widespread rapid dissemination in our hyper-connected world creates real-time challenges to prediction analyses
  6. 6. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Incubation period 5 days (range 2-14 days) We estimated that fewer than 2.5% of infected personswill display symptoms within 2.2 days (CI, 1.8 to 2.9 days) o exposure, whereas symptom onset will occur within 11.5 days (CI, 8.2 to 15.6 days) for 97.5% of infectedpersons Lauer SA et al. Ann Intern Med. 2020.doi:10.7326/M20-0504.
  7. 7. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Spike mutation (D614G) reveals the emergence of a more transmissible form of SARS-CoV-2 Phylogenetic Trees based on 4,535 trimmed full genome SARS C0V02 alignments from Global Initiative for Sharing All Influenza Data (GISAID) . Korber B et al. bioRxiv preprint doi: https://doi.org/10.1101/2020.04.29.069054. This version posted May 5, 2020 • Todate we have identified 13 mutations in Spike that are accumulating. • The mutation Spike D614G is of urgent concern; it began spreading in Europe in early February, and when introduced to new regions it rapidly becomes the dominant form. • With the mutation, the tripod breaks much less frequently, meaning more of its spikes are fully functional. • Encouragingly, immune factors from the serum of infected people work equally well against engineered viruses both with and without the D614G mutation. That’s a hopeful sign that vaccine candidates in development will work against variants with or without that mutation
  8. 8. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala SARS-CoV-2 Pathogenesis: ACE2 receptor & TMPRSS2 are primarily expressed in bronchial transient secretory cells Transient secretory cells display a transient cell state between goblet and ciliated cells in HBECs Lukassen S et al. The EMBO Journal; 2020: e105114
  9. 9. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala • Virus shedding is Highest Early in the Course of Disease • Virus shedding can occur several days prior to symptom onset (pre- symptomatic period) • Virus can be isolated from stool but there is no epidemiologic evidence of fecal-oral transmission • Virus shedding usually lasts for 10-14 days in mild/moderate cases, and for more than 4 weeks in severe and critical cases • Patients who recover can be PCR positive after symptoms resolve Zou et al., N Engl J Med, 2020; Wang W et al. JAMA 2020; Aylward B et al, WHO-China Mission, 2020 Virology of SARS-CoV-2
  10. 10. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Viral Shedding Greatest At Time Symptoms Start ▪ SARS-CoV-2 viral loads in 17 symptomatic patients ▪ No data regarding duration of replication-competent virus shedding (e.g., culture) Zou et al., N Engl J Med, 2020; DOI: 0.1056/NEJMc2001737
  11. 11. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala
  12. 12. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala SARS.CoV-2 specific CD8 and CD4 T cells identified in 70% and 100% Covid 19 convalescent patients, respectively. CD4 T cell responses to Spike were robust and correlated with the magnitude of anti-SARS-CoV-2 IgG and IgA titers. CD8 T cells recognized Spike and M with at least 8 SARS-CoV-2 ORFs targeted SARS-CoV-2 reactive CD4 T cells in 40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating “common cold” coronaviruses and SARS-CoV-2
  13. 13. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala
  14. 14. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala
  15. 15. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala
  16. 16. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala
  17. 17. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Signs/Symptoms of COVID-19 ▪ The majority set of signs or symptoms can not reliably discriminate SARS-CoV-2 from other respiratory viral illnesses such as influenza – Subacute to acute onset – Fever > 37,5ºC – Non-productive cough – Fatigue – Headache – Muscular and articular pain – Dispnea – Olfactory and taste disorders precede the onset of symptoms in 1/3 of patients*. Might be long-lasting (>>6 weeks) – Chills, repeated shaking with chills, muscle pain, headache and sorethroat – Diarrhoea (some reports of diarrhea alone preceding cough and fever) – Cutaneous lesions in 20% (skin rashes-rash and hives, purple toe lesions due to vasculitis) ▪ Complications include pneumonia, respiratory failure, multiorgan system failure, thromboembolic events (Pulmonary embolism & Stroke), myocardial infactation, myocarditis, arrhytmias, hepatitis, acute kidney injury ▪ Most people will recover spontaneously with supportive care ▪ Children tend to have milder disease than adults (unusual cases of Kawasaki disease). Liu Chinese Med J; 2020; Wang, JAMA; 2020;. Guan N Engl J Med; 2020. Chen 2020, Lancet; 2020; *Giacomelli A et al. Clin Infect Dis,2020.
  18. 18. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Extrapulmonary Complications of COVID-19 Madjid M et al. JAMA Cardiol, March 27, 2020; Mao L et al. JAMA Neurol. April 10, 2020; Toscano G et al. NEJM, April 17, 2020; Fan Z et al. Clin Gastroenterol Hepatol. April 3 2020; Cheng Y et al. Kidney Intern. March 20 2020; Lala A et al. medRxiv preprint doi: https://doi.org/10.1101/2020.04.20.20072702; Galvan-Casas C et al. Br J Dermatol. Apr 29 2020. • Cardiovascular • Neurological • Digestive • Others Myocarditis and myocardial injury Myocardial Infarction Heart Failure Arrhythmias Thromboembolic Disease Stroke Guillain–Barré Syndrome Hepatitis Acute kidney injury; Skin manifestations
  19. 19. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Skin Manifestations in Patients Hospitalized with COVID-19 • Nationwide case collection survey of images and clinical data from 429 cases • Clinical patterns - Acral areas of erythema with vesicles or pustules (pseudo-chilblain)(19%) - Other vesicular eruptions (9%) - Urticarial lesions (19%) - Maculopapular eruptions (47%) - Livedo or necrosis (6%). • Timing - Vesicular eruptions appear early in the course of the disease (15% before other symptoms) - The pseudo-chilblain pattern frequently appears late in the evolution of the COVID-1 disease (59% after other symptoms) - The rest tend to appear with other symptoms of COVID-19. Galvan-Casas C et al. Br J Dermatol. Apr 29 2020. doi: 10.1111/bjd.19163.
  20. 20. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Skin Manifestations in Patients Hospitalized with COVID-19 Galvan-Casas C et al. Br J Dermatol. Apr 29 2020. doi: 10.1111/bjd.19163. Urticarial lesions Livedoid areas Monomorphic disseminated vesicles
  21. 21. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Chest X-ray and CT findings in SARS-CoV-2 Guang W et al. NEJM 2020; DOI: 10.1056/NEJMoa2002032
  22. 22. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Chest X-ray and CT findings in SARS-CoV-2 March 4th 2020 March 7th 2020
  23. 23. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala In-hospital Mortality Prognostic factors Age (per yr.): 1.10 (1.03-1.17) SOFA score: 5.65 (2,61-12,23) D-dimer >1 µg/mL: 18.42 (2.64-128) Zhou F et al. Lancet, March 9, 2020https://doi.org/10.1016/ Temporal changes in laboratory markers from illness onset in hospitalizedpatients D-dimer Lymphocyte IL-6 Ferritin LDHhsTroponin
  24. 24. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala In-hospital Mortality Prognostic factors Clinical variables Williamson E et al. medRxiv preprint May 7, 2020. doi:https://doi.org/10.1101/2020.05.06.20092999. - Age (above 50 yr.) - Comorbidities including Obesity Laboratory variables - Neutrophils/Lymphocytes ratio - IL-6, CRP, LDH, Ferritin - D-dimer - NT-proBNP; us-Troponin - Degree of respiratory insufficiency - SPO2 ≤93% (ambient air) - PaO2/FiO2 <300 mmHg Chest-X ray / CT scan - Bilateral involvement - Radiological progression (>50%) Evolutive variables - SOFA score - ICU admission - Mechanical ventilation CALL score* - NPV (≤6 p): 99% - PPV (≥9 p): 78% Pericas JM & Hernandez-Meneses M et al. Eur Heart J. 2020, in press; * Ji D et al. Clin Infect Dis. 2020
  25. 25. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala El estudio identificó una mayor frecuencia de 26 variantes genéticas en los pacientes afectados por insuficiencia respiratoria, en comparación con el grupo control no infectado, y dos de ellas, en particular localizadas en los cromosomas 3 y 9 “mostraron una potente asociación con la gravedad”. Los datos mostraron que “tener el grupo sanguíneo A se asocia con un 50% más de riesgo de necesidad de apoyo respiratorio en caso de infección por el coronavirus. Por el contrario, poseer el grupo sanguíneo O confiere un efecto protector frente al desarrollo de insuficiencia respiratoria (35% menos de riesgo)”.
  26. 26. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Ware LB et al. NEJM, 2000. Tse GMK et al. J Clin Pathol 2004; Shi Y et al. Cell Death & Differentiation. 2020. SARS-CoV-2 (COVID19) Pathogenesis: ARDS ACE2 0 Acute Respiratory Distress Sydrome (ARDS) pathology Acute diffuse alveolar damage, with pulmonary edema and formation of a hyaline membrane in a SARS-CoVpatient The airspaces are indicated by asterisks and some of the hyaline membranes lining the alveolar spaces are highlighted by arrows (hematoxylin and eosin stain; original magnification,x100). Cytokine Storm → ARDS
  27. 27. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Objectives COVID-19 Treatment: Treat Early & Hard Siddiqu HK, Mehra MR. J Heart Lung Transplant. March 25th 2020 doi:10.1016/j.healun.2020.03.012 1.- Antivirals 2.- Anti-inflammatory drugs Remdesivir, Baricitinib, Aplidina? IL-6/IL-1/JAK inhibitors High dose Igs Hiperimmune serum Monoclonal Abs Dexametasone
  28. 28. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Vaccine development Vaccine-mediated disease enhancement (VMDE) syndrome occurred in the 1960s with inactivated RSV and measles vaccines. VMDE results in increased disease severity if the subject is later infected by the natural virus. Pathogenesis of RSV VMDE is distinct from antibody disease enhancement (ADE) which occurs for macrophage tropic viruses (Dengue in humans and feline infectious peritonitis in cats) and is directly caused by non-neutralizing or sub neutralizing Abs leading to more efficient viral uptake via Fcy receptor binding. VMDE and ADE has been demonstrated for some SARS-CoV-1 vaccine candidates in the animal models. Preserve neutralization sensitive epitopes present in protein S in their prefusion conformation through stabilization (2 proline residues to the top of the central helix) is very important in any vaccine design.
  29. 29. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala
  30. 30. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala PANCORONAVIRUS VACCINES
  31. 31. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Take-home Messages SARS-CoV-2 is a new coronavirus with high infectivity (R0=3). Cause severe respiratory infection in 20% of cases, mainly in elderly and in patients with comorbidities. Overall mortality is high, ≈10%. Antiviral and anti-inflammatory drugs must be started early in order to avoid the development of ARDS and mechanical ventilation, with 50% mortality.  Antiviral activity of HCQ, lopinavir/ritonavir is very poor. Remdesivir is the first antiviral that has shown clinical benefit in severe COVID-19 pneumonia and has recently been approved by the FDA.  IL-1 and IL-6 inhibitors are showing promising results in observational studies, but clinical trials to demonstrate their efficacy are lacking Case isolation, contact tracing and personal and population prevention measures should contain the epidemic. Vaccine studies are already started.
  32. 32. La crisis sanitaria por la infección y la necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala Acknowledgements Dr JMa Miró Dra Nuria Izquierdo Dr Julià Blanco Dr Jorge Carrillo Dr Roger Paredes To all my front-line colleagues To our patients

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