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

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. La crisis sanitaria por la infección y la
necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala

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. La crisis sanitaria por la infección y la
necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala

14. La crisis sanitaria por la infección y la
necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala

15. La crisis sanitaria por la infección y la
necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala

16. La crisis sanitaria por la infección y la
necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. La crisis sanitaria por la infección y la
necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala

30. La crisis sanitaria por la infección y la
necesaria adaptación del sistema sanitario Dr. Bonaventura Clotet Sala
PANCORONAVIRUS VACCINES

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. 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