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COVID-19: state of art at 30.03.2020

For more information: https://emcrit.org/ibcc/covid19/ ;
https://emedicine.medscape.com/article/2500114-overview

ORIGIN
SARS-CoV-2 is the seventh coronavirus known to infect humans; SARS-CoV, MERSCoV and SARS-CoV-2 can
cause severe disease, whereas HKU1, NL63, OC43 and 229E are associated with mild symptoms (1).
The virus has a natural and zoonotic origin: two scenarios that can plausibly explain the origin of SARS-CoV-
2: (i) natural selection in an animal host before zoonotic transfer; and (ii) natural selection in humans
following zoonotic transfer (2,3).
Estimates of the timing of the most recent common ancestor of SARS-CoV-2 made with current sequence
data point to emergence of the virus in late November 2019 to early December 2019 (4).

PHYSIOPATHOGENESIS
Two notable genomic features of SARS-CoV-2: (5,6)
- based on structural studies and biochemical experiments, SARS-CoV-2 appears to be optimized for
binding to the human receptor ACE2;
- the spike protein of SARS-CoV-2 has a functional polybasic (furin) cleavage site at the S1–S2 boundary
through the insertion of 12 nucleotides, which additionally led to the predicted acquisition of three O-
linked glycans around the site
Hypotheses about the pathogenesis of SARS-CoV-2 infection: the virus might pass through the mucous
membranes, especially nasal and larynx mucosa, then enters the lungs through the respiratory tract. The
virus may enter the peripheral blood from the lungs, causing viremia. Then the virus would attack the
targeting organs that express ACE2, such as the lungs, heart, renal, gastrointestinal tract. The virus begins a
second attack, causing the patient’s condition to aggravate around 7 to 14 days after onset. B lymphocyte
reduction may occur early in the disease, which may affect antibody production in the patient. Besides, the
inflammatory factors associated with diseases mainly containing IL-6 were significantly increased, which also
contributed to the aggravation of the disease around 7 to 14 days after onset (7).

EPIDEMIOLOGY
- Case definition (ECDC): https://www.ecdc.europa.eu/en/case-definition-and-european-surveillance-
human-infection-novel-coronavirus-2019-ncov
- Johns Hopkins map: https://coronavirus.jhu.edu/map.html
- Chinese data updated to 11 February 2020 - total cases 72 314 (8):
Age distribution (N = 44 672)
≥80 years: 3% (1408 cases)
30-79 years: 87% (38 680 cases)
20-29 years: 8% (3619 cases)
10-19 years: 1% (549 cases)

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<10 years: 1% (416 cases)

Spectrum of disease (N = 44 415)
Mild: 81% (36 160 cases)
Severe: 14% (6168 cases)
Critical: 5% (2087 cases)
- European data (ECDC): https://www.ecdc.europa.eu/en/novel-coronavirus-china
- Italian data (ISS): https://www.epicentro.iss.it/coronavirus/sars-cov-2-italia;
https://www.epicentro.iss.it/coronavirus/bollettino/Infografica_28marzo%20ENG.pdf
- Italian data (sole24ore): https://lab24.ilsole24ore.com/coronavirus/
- Italian data (summaries): https://www.francescofurno.com/emergenza-covid
- Survey sul contagio da COVID-19 nelle RSA: https://www.epicentro.iss.it/coronavirus/sars-cov-2-
survey-rsa
R0 from SARS-CoV-2 is 2.2 in China (9) but 2.3-3.1 in Lombardy (10)
Mathematical model created from data from the Diamond Princess: Estimated case and infection fatality
ratios (CFR, IFR) for COVID-19 on the ship was 2.3% (0.75%–5.3%) and 1.2% (0.38–2.7%). Comparing deaths
onboard with expected deaths based on naive CFR estimates using China data, we estimate IFR and CFR in
China to be 0.5% (95% CI: 0.2–1.2%) and 1.1% (95% CI: 0.3–2.4%) respectively (11).
New analysis provides some rough initial estimates for the % of symptomatic COVID-19 cases that might
have been detected/reported in different countries (focusing on those with >10 deaths) (12).
Lauer S (13) (181 symptomatic patients China): The median incubation period was estimated to be 5.1 days,
and 97.5% of those who develop symptoms will do so within 11.5 days of infection. These estimates imply
that, under conservative assumptions, 101 out of every 10 000 cases (99th per- centile, 482) will develop
symptoms after 14 days of active monitoring or quarantine.
IN-HOSPITAL TRANSMISSION: hospital-associated transmission was suspected as the presumed mechanism
of infection for affected health professionals (29%) and hospitalized patients (12.3%) (9).
LONG-TERM CARE FACILITIES: a study performed in Washington reported 167 confirmed cases of Covid-19
among residents, personnel, and visitors in a long-term care facility. Most cases among residents included
respiratory illness consistent with Covid-19; however, in 7 residents no symptoms were documented.
Hospitalization rates for facility residents, visitors, and staff were 54.5%, 50.0%, and 6.0%, respectively. The
case fatality rate for residents was 33.7% (14).

VIRAL SHEDDING and ROLE OF ASYMPTOMATICS

Respiratory droplet transmission is the main route of transmission [see Infection Control paragraph for more
details about discussion on this topic]. Person-to-person transmission also by asymptomatic carriers (15,16).
In 8.9% of the patients, SARS-CoV-2 was detected before the development of viral pneumonia (17)
He X (18) (94 confirmed cases): the contagiousness begins about two and a half days before the onset of
symptoms and reaches its climax fifteen hours before
Median duration of viral shedding in nasopharyngeal swab was 12 days and 15 patients (83%) had viral
shedding from the nasopharynx detected for 7 days or longer (19)
Duration of viral shedding ranged between 8 and 37 days. The median duration of viral shedding was 20
days in survivors but continued until death in fatal cases (20)
Zou L (21) (18 patients – serial swabs): Higher viral loads were detected soon after symptom onset, with
higher viral loads detected in the nose than in the throat. The viral load that was detected in the
asymptomatic patient was similar to that in the symptomatic patients

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Li R (22): analyzed the trend of the epidemic in 375 Chinese cities between January 10 and January 23, when
containment measures such as the travel ban were imposed. 86 % of cases were "undocumented", that is
asymptomatic or with very mild symptoms. Although the asymptomatic were only 55 % likely to infect others
compared to the symptomatic, they were found to be the cause of 79 % of the additional infections, both
because they were very numerous and because they could move more.
Cereda D (10) (Italian data – the first 5,830 laboratory-confirmed cases): not observed significantly different
viral loads in nasal swabs between symptomatic and asymptomatic
Wolfel R (18) (9 patients): shedding of viral RNA from sputum outlasted the end of symptoms.
Seroconversion occurred after 6-12 days, but was not followed by a rapid decline of viral loads. High VL in
the stool (sign of active replication in the GI tract).
Hu Z (23) (24 asymptomatic patients): some close contactors presented symptoms and causing transmission
after de-isolation. The median communicable period, defined as the interval from the first day of positive
nucleic acid tests to the first day of continuous negative tests, was 9.5 days.

DIAGNOSIS
The current diagnostic of COVID-19 includes detection of virus by genomic techniques using either PCR-
based method or deep sequencing. However, these detection methods heavily rely on the presence of viral
genome in sufficient amounts at the site of sample collection that can be amplified. Missing the time-
window of viral replication can provide false negative results. Similarly, an incorrect sample collection can
limit the usefulness of qPCR-based assay (3,24)
Collect specimens from the upper respiratory tract (URT; nasopharyngeal and oropharyngeal) AND, where
clinical suspicion remains and URT specimens are negative, collect specimens from the lower respiratory
tract when readily available (LRT; expectorated sputum, endotracheal aspirate, or bronchoalveolar lavage
in ventilated patient) for COVID-19 virus testing by RT-PCR and bacterial stains/cultures (25)
Wang W (26) (205 patients): of 1070 total samples tested, types with the highest rates of positive results
included BAL fluid (14/15; 93%), sputum (75/104; 72%), nasal swabs (5/8; 63%), brush biopsy (6/13; 46%),
pharyngeal swabs (126/398; 32%), feces (44/153; 29%), blood (3/307; 1%), and urine (0/72; 0%). Nasal swabs
were found to contain the most virus.

CLINIC
The clinical phase is divided into three: the viremia phase, the acute phase (pneumonia phase) and the
recovery phase. If the immune function of patients in the acute phase is effective, the virus can be effectively
suppressed, then enter the recovery phase. If the patient is older, or in an immune impaired state, combined
with other basic diseases such as hypertension and diabetes, the immune system cannot effectively control
the virus in the acute phase, the patient will become severe or critical type. As we mentioned in our

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hypothesis, T cells, B cells were further reduced, while inflammatory cytokines and D-Dimer continued to
increase in severe type patients (7).
Huang C (27) (41 patients with pneumonia): 99% had fever, 70% reported fatigue, 59% had dry cough, 40%
had anorexia, 35% experienced myalgias, 31% had dyspnea, and 27% had sputum production.
Guan W (17) (1099 patients, multicenter): median age 47 years; 41.9% female. 3.5% were health care
workers. The great part was from or had contacts with people from Wuhan. S/S: fever (43.8% on admission
and 88.7% during hospitalization), cough (67.8%), diarrhea (3.8%). The median incubation period was 4 days
(2-7). On admission, ground-glass opacity was the most common radiologic finding on chest CT (56.4%). No
radiographic or CT abnormality was found in 17.9% with non-severe disease and in 5 of 173 patients (2.9%)
with severe disease. Lymphocytopenia 83.2% on admission. A primary composite end-point event occurred
in 67 patients (6.1%). Interesting table with cf. COVID-19, SARS, MERS and influence (supplementary
material).
Wu J (28): compared to those aged 30–59 years, those aged below 30 and above 59 years were 0.6 (0.3–
1.1) and 5.1 (4.2–6.1) times more likely to die after developing symptoms. The risk of symptomatic infection
increased with age (for example, at ~4% per year among adults aged 30–60 years).
Yang X (29) (single-centered, retrospective study, 52 critically ill patients): among the critical patients 11%
did not experienced fever until 2–8 days after the onset of symptoms related to SARS-CoV-2 infection. The
median duration from onset of symptoms to radiological confirmation of pneumonia was 5 (3–7) days. The
median duration from onset of symptoms to ICU admission was 9·5 (7·0–12·5) days.
Wang D (9) (single-center case series, 138 patients): median age 56 years, 54.3% men. Hypertension
(31.2%), diabetes (10.1%), cardiovascular disease (14.5%), and malignancy (7.2%). Hospital-associated
transmission was suspected as the presumed mechanism of infection for affected health professionals (29%)
and hospitalized patients (12.3%). S/S: fever, fatigue and dry cough. Lymphopenia (70.3%), elevated LDH
(39.9%). Chest CT showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. 26.1%
in ICU because of ARDS (61.1%), arrhythmia (44.4%), and shock (30.6%). The median time from first
symptom to dyspnea was 5 days, to hospital admission was 7 days, and to ARDS was 8 days. Interesting
laboratory tests trend (see image):

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Zhou F (20) (retrospective cohort, 191 patients): median age 56 yers, male++, comorbidity (~ 50%):
hypertension ++, diabetes and coronary artery disease. S/S fever and cough, asthenia. Lymphopenia 40%.
The median time from illness onset to invasive mechanical ventilation was 14·5 days. Sepsis was the most
frequently observed complication, followed by respiratory failure, ARDS, heart failure, and septic shock. 50%
of non-survivors experienced a secondary infection, and VAP occurred 31%. 181 (95%) patients received
antibiotics and 41 (21%) received antivirals (lopinavir/ritonavir). Time from illness onset to dyspnea 7 days.
Time from illness onset to ARDS 10-12 days. In univariable analysis, odds of in-hospital death were higher in
patients with diabetes or coronary heart disease. Age, lymphopenia, leucocytosis, and elevated ALT, lactate
dehydrogenase, high-sensitivity cardiac troponin I, creatine kinase, d-dimer, serum ferritin, IL-6,
prothrombin time, creatinine, and procalcitonin were also associated with death. Interesting clinical course
(see image):

Cereda D (10) (Italian data - the first 5,830 laboratory-confirmed cases): median age 69 years; >50% in the
over 65 (34% in the 75+); 62% males. 47% hospitalized and 18% ICUs.
Arentz M (30) (21 patients with severe COVID-19 admitted to the IC): 33% had cardiomyopathy.
Anosmia has been reported as a potential history finding in patients diagnosed with COVID-19, but this has
not been a distinguishing feature in published studies, so its clinical importance is questionable (26).
Wu C (53) (cohort study, 201 patients): 84 patients (41.8%) developed ARDS, and of those, 44 (52.4%) died.
The risk factors related to the development of ARDS and progression from ARDS to death included older
age, neutrophilia, and organ and coagulation dysfunction.

CLINICAL PHENOTYPES AND MANAGEMENT IN ER – SIMEU

https://www.simeu.it/w/articoli/leggiArticolo/3963/leggi
1. Fever without respiratory failure (normal BG and normal walking test) and normal chest x-ray -->
discharge with indication for self-quarantine pending the outcome of the swab
2. Fever with pathological chest x-ray and BG indicative of moderate respiratory failure (PO2> 60
mmHg in aa) --> O2 therapy - OBI or hospitalization in ordinary hospital stay
3. Fever with moderate-severe respiratory failure documented by BG in triage (PO2 < 60 mmHg in
aa) --> O2 therapy / CPAP - hospitalization in ordinary hospitalization or subintensive-care therapy
4. Respiratory failure with suspected initial ARDS or complicated pneumonia --> O2 therapy / CPAP /
OTI and invasive ventilation - hospitalization in subintensive-care therapy or ICU

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5. ARDS free onset --> CPAP / OTI and invasive ventilation - hospitalization in ICU

PATHOLOGICAL ANATOMY
Xu Z (31) (case report): 50-year-old man. LUNGS – bilateral diffuse alveolar damage with cellular fibromyxoid
exudates; desquamation of pneumocytes and hyaline membrane formation, indicating ARDS; interstitial
mononuclear inflammatory infiltrates, dominated by lymphocytes; syncytial cells with atypical enlarged
pneumocytes were identified in the intra-alveolar spaces, showing viral cytopathic-like changes. No obvious
intranuclear or intracytoplasmic viral inclusions were identified. LIVER – moderate microvesicular steatosis
and mild lobular and portal activity. HEART – a few interstitial mononuclear inflammatory infiltrates.

CYTOKINIC STORM
Higher mortality in patients with COVID19 and high IL-6 levels at hospitalization (20)
Well-known role of the inflammatory storm in infectious diseases, especially in viral infections (CMV, EBV,
influenza, SARS) (32)
Review 2017: strongly suggest a crucial role for virus-induced immunopathological events in causing fatal
pneumonia after hCoV infections (33)
Role of age in the different expression of pro-inflammatory cytokines: aging in itself unbalances the body
towards a pro-inflammatory state, then just one more external stimulus is enough to trigger the
inflammatory storm (34)
Screen all patients with severe COVID-19 for hyperinflammation using laboratory trends (35)

MORTALITY
Chinese data updated to 11 February 2020 - total cases 72 314 (8):
Case-fatality rate
2.3% (1023 of 44 672 confirmed cases)
14.8% in patients aged ≥80 years (208 of 1408)
8.0% in patients aged 70-79 years (312 of 3918)
49.0% in critical cases (1023 of 2087)
CFR was elevated among those with preexisting comorbid conditions: 10.5% for cardiovascular disease,
7.3% for diabetes, 6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer.
Wu J (28): 1.4% of symptomatic patients died in Wuhan.
Characteristics of patients who died positive for COVID-19 in Italy (ISS):
https://www.epicentro.iss.it/coronavirus/sars-cov-2-decessi-italia
Sample of 268 who died "during" the epidemic (ISS data 13 March): 76.5% of the subjects had arterial
hypertension, a huge deviation from what was recorded by ISTAT among the causes of death in 2014, by age,
among these 268 , the percentage of subjects with dementia, cancer or stroke is substantially in line with
what was observed in 2014 -> therefore we have a selective agent at work, which increases the risk of death
of certain specific patients, not all (36)
RISK FACTORS: men, elderly, comorbidity
- Yang X (10) (52 critically ill patients): 61·5% patients had died at 28 days. Compared with survivors, non
survivors were more likely to develop ARDS (81% vs 45%), were more likely to receive mechanical
ventilation (94% vs 35%), were older and were more likely to have chronic medical illnesses. Neither the

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median duration from onset of symptoms to radiological confirmation of pneumonia or from onset of
symptoms to ICU admission were different between survivors and non-survivors. The ratio of partial
pressure of oxygen (PaO2) to FiO2 was significantly lower in non-survivors. Based on APACHE II score
and SOFA score at ICU admission, non-survivors were in a more critical condition than survivors.
- Zhou F (20) (retrospective cohort study of 191 patients): older age, elevated d-dimer levels, and high
SOFA score could help clinicians to identify at an early stage those patients with COVID-19 who have
poor prognosis
- Ruan Q (37) (retrospective multicenter study of 68 death cases): predictors of a fatal outcome in COVID-
19 cases included age, the presence of underlying diseases (cardiovascular ++), the presence of
secondary infection and elevated inflammatory indicators in the blood. Suggest that COVID-19 mortality
might be due to virus-activated “cytokine storm syndrome” or fulminant myocarditis.

PHARMACOLOGICAL THERAPY
Retrospective data from SARS suggests that earlier treatment (e.g. within 1-2 days of admission) may be
more effective than reserving therapy until severe organ failures occur (38)
The vast majority of patients will do fine without any therapy, so in most cases there's no need for antiviral
therapy. However, waiting until patients are severely ill before initiating therapy could cause us to miss an
early treatment window, during which the disease course is more modifiable. Predictors of adverse outcome
might be useful in predicting who will do poorly and thus who might benefit most from early anti-viral
therapy?
An array of drugs approved for other indications as well as several investigational drugs are being studied in
several hundred clinical trials that are underway across the globe (https://clinicaltrials.gov/)

H YDROXYCHLOROQUINE AND C HLOROQUINE

Chloroquine and hydroxychloroquine have anti-viral activity in vitro, as well as anti-inflammatory activities.
Both agents seem to have reasonable side-effect profiles, although hydroxychloroquine is safer (chloroquine
has a narrower therapeutic window with regard to cardiotoxicity and arrhythmia).
Mechanism of action:
- Interference with the cellular receptor ACE2
- Impairment of acidification of endosomes
- Activity against many pro-inflammatory cytokines (e.g., IL-1 and IL-6)
In vitro & animal data:
1. Chloroquine:
- In vitro data using cell lines shows that chloroquine can inhibit COVID-19 with a 50% inhibitory
concentration of 1 uM, implying that therapeutic levels could be achieved in humans (39)
2. Hydroxychloroquine:
- Yao X (40) found that the hydroxychloroquine was much more potent than chloroquine at
inhibition of COVID-19 in cell lines (EC50 of 0.7 uM vs. 5 uM, respectively). They recommended
a regimen of 400 mg BID for the first day followed by 200 mg BID for the following four days.
Human data:
Gautret P (41): Hydroxychloroquine and azithromycin (Marseille study)
- Non-randomized, open label study evaluating the use of chloroquine (200 mg TID) with or without
azithromycin (500 mg once, followed by 250 mg daily for four days).
- Hydroxychloroquine-treated patients were older than control patients.

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- The primary endpoint was reduction in viral load: at day6 post-inclusion, 100% of patients treated with
hydroxychloroquine and azithromycin combination were virologicaly cured comparing with 57.1% in
patients treated with hydroxychloroquine only, and 12.5% in the control group (p<0.001).

- No significant difference was observed between hydroxychloroquine-treated patients and control

patients with regard to gender, clinical status and duration of symptoms prior to inclusion
- Study limitations include withdrawal of some patients from the hydroxychloroquine group.
- Emerging reports from China suggest that chloroquine has been studied with favorable results, but data
is currently not available (42). Hopefully, clinical data with chloroquine will be published shortly.
Dosing:
1. Hydroxychloroquine
i) Loading dose of 400 mg PO BID on day #1.
ii) Maintenance dose of 200 mg q12 hours for 5-10 days, preferably with food (43,44). A higher
maintenance dose (200 mg TID) was described in the Marseille study (41). This higher maintenance
dose could be reasonable in patients with a concern for poor oral absorption.
No dosing adjustment for renal or hepatic dysfunction, or for obesity.
2. Azithromycin: 500mg on day1 followed by 250mg per day, the next four days (41)
3. Chloroquine: generally considered a second-line agent, due to increased toxicity compared to
hydroxychloroquine; (500 mg chloroquine phosphate contains 300 mg of chloroquine itself). 500 mg
chloroquine phosphate PO twice daily for 10 days is the regimen recommended by a group in China for
patients without contraindications. May require dose adjustment in renal or hepatic dysfunction.
Indications: Strong consideration for hydroxychloroquine in hypoxemic patients who aren't candidates for
RCTs.
Contraindications/cautions for hydroxychloroquine:
1. Contraindications:
- QT prolongation (if baseline QTc 450-500 ms, consider daily ECG; control Mg and K levels)
- Epilepsy (reduces seizure threshold)
- Porphyria
- Myasthenia gravis
- Retinal pathology
- G6PD deficiency
2. Serious adverse events generally result from prolonged use. Complications may include:
- Torsade de pointes
- Cardiomyopathy
- Bone marrow suppression (thrombocytopenia, leukopenia)
- Hypoglycemia – use with caution in diabetic patients.

R EMDESIVIR

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Remdesivir is an investigational intravenous drug with broad antiviral activity that inhibits viral replication
through premature termination of RNA transcription and has in-vitro activity against SARS-CoV-2 and in-vitro
and in-vivo activity against related betacoronaviruses (39,45–47).
For now, it is not on the market but is supplied by Gilead as part of two RCTs (a. Double-blinded, placebo-
controlled trial of remdesivir versus placebo and b. Phase 3 randomized open-label trials 5-days versus 10-
days versus standard of care) or for compassionate use.

L OPINAVIR / RITONAVIR ( LPV / R )

Further considerations (https://emcrit.org/squirt/lopinavir-in-covid-19/): studied mainly for SARS where it
demonstrated clinical efficacy and viral load reduction in 2 works in combination with ribavirin (31,41). Also
studied (always + ribavirin) as PEP in the MERS with promising results (48).
Lopinavir-ritonavir did not show promise for treatment of hospitalized COVID-19 patients with pneumonia in
a recent clinical trial in China. This trial was underpowered, and lopinavir-ritonavir is under investigation in
a World Health Organization study. In addition, lopinavir-ritonavir is in a severe shortage.
Young BE (19) (cohort study 16 patients): among six patients with hypoxemia, five were treated with
lopinavir/ritonavir (200 mg/100 mg BID). Among them, two patients deteriorated and had persistent
nasopharyngeal virus carriage. Possible reasons for these underwhelming results might include statistical
underpowering, low dose of lopinavir/ritonavir, lack of synergistic ribavirin, and/or late initiation of therapy.
Cao B (49) (open-label randomized controlled trial of 199 patients): patients with COVID-19 were
randomized to 14 days of lopinavir-ritonavir plus standard of care vs. standard of care alone. The median
interval time between symptom onset and randomization was 13 days. No statistically significant difference
was seen between the two groups with regards to time to clinical improvement or mortality. Gastrointestinal
adverse events were more common with lopinavir-ritonavir, and 13.8% discontinued lopinavir-ritonavir early
due to adverse events.
Considerations: monotherapy only and 13 days after the onset of symptoms
Alternatively: Darunavir/ritonavir or darunavir/cobicistat (50)

F AVIPIRAVIR
RNA-dependent RNA-polymerase inhibitor. Developed and approved in Japan as an anti-flu. There appears
to be a Chinese clinical trial with 320 patients in which Favipiravir gave 91% of radiological responses (against
62% of the untreated) and a more rapid negative test of viral tests (median of 4 days versus 11) [cf. Zhang
Xinmin, director of the National Center for Biotechnology Development, press release of March 17, 2020].

T OCILIZUMAB
Tocilizumab is a recombinant humanized monoclonal antibody which binds to the interleukin-6 (IL-6)
receptor and blocks it from functioning.
No high-level evidence is currently available: ongoing trial in Italy and case series from China.
Xu X (51) (21 patients): 21 hypoxemic patients were treated with tocilizumab 400 mg as an intravenous
infusion (most patients received a single dose, but 3 patients received two doses). Patients appeared to
improve clinically, with rapid reduction in inflammatory markers. No adverse effects were noted.
TOCIVID19 - ongoing study in Italy with SIMIT patronage (below the specifications).
a) Inclusion criteria
- End of the initial phase of high viral load of COVID-19 (e.g. apyretic> 72h and / or at least 7 days
after the onset of symptoms)
- Worsening of respiratory exchanges such as to require non-invasive or invasive support for
ventilation (BCRSS score ≥3)

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- High levels of IL-6 (> 40 pg / ml); alternatively high levels of d-dimer and / or PCR and / or ferritin
and / or fibrinogen increasing progressively
b) Exclusion criteria
- Age <18 years
- AST / ALT values higher than 5 times the normal levels
- Neutrophil value lower than 500 cells / mmc
- PLT value lower than 50,000 cells / mmc
- Documented sepsis by other pathogens than COVID-19
- Presence of comorbidities related, according to clinical judgment, to an unfavorable outcome
- Complicated diverticulitis or intestinal perforation
- Skin infection in progress (e.g. dermohypodermatitis not controlled by antibiotic therapy)
- Immunosuppressive anti-rejection therapy
c) Proposed therapeutic scheme:
- 8 mg / kg IV - maximum of 800mg per dose (same dose recorded by the FDA for the treatment
of the "cytokine storm" following treatment with CAR-T cells)
- A second administration (same dose) can be administered after 12 hours if the respiratory
function has not restored, at the discretion of the investigator
After 24 hours from the last administration, repeat the plasma dosage of IL-6 and / or D-dimer.
Treatment must be accompanied by antiviral treatment (lopinavir / ritonavir or remdesivir + chloroquine /
hydroxychloroquine) and / or steroidal (dexamethasone).
Adverse events:
- Elevated AST, ALT commonly seen.
- Infusion reaction (~10% of patients), which can include anaphylaxis.
- Increased risk of certain opportunistic infections (e.g. tuberculosis or invasive fungal infections).
- Spontaneous gastrointestinal perforation.

B ARATICINIB
NAK inhibitor, with a particularly high affinity for AAK1, a pivotal regulator of clathrin-mediated endocytosis,
-> JAK inhibitor (52).

A NAKINRA
Anti IL-1, used in some UTI settings in Lombardy (data not known).

C ONVALESCENT P LASMA
Shen C (53) (uncontrolled case series of 5 critically ill patients with ARDS): administration of convalescent
plasma containing neutralizing antibody was followed by an improvement in clinical status: body
temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased, and PAO2/FIO2 increased
within 12 days. Viral loads also decreased and became negative within 12 days after the transfusion, and
SARS-CoV-2–specific ELISA and neutralizing antibody titers increased following the transfusion. ARDS
resolved in 4 patients at 12 days after transfusion, and 3 patients were weaned from mechanical ventilation
within 2 weeks of treatment. It is unclear if these patients would have improved without transfusion of
convalescent plasma and all patients were treated with multiple other agents.

O THERS
For investigational therapies see: https://emedicine.medscape.com/article/2500114-treatment

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SUPPORT THERAPY
O XYGEN THERAPY
High-flow nasal oxygen (HFNO) should be used only in selected patients with hypoxemic respiratory failure
-> adult HFNO systems can deliver 60 L/min of gas flow and FiO2 up to 1.0. Use airborne precautions.
Compared with standard oxygen therapy, HFNO reduces the need for intubation. Patients with hypercapnia,
hemodynamic instability, multiorgan failure, or abnormal mental status should generally not receive HFNO,
although emerging data suggest that HFNO may be safe in patients with mild-moderate and non-worsening
hypercapnia. Patients receiving HFNO should be in a monitored setting and cared for by experienced
personnel capable of performing endotracheal intubation in case the patient acutely deteriorates or does
not improve after a short trial (about 1 hour) (54)
Non-invasive ventilation (NIV)
Patients treated with either HFNO or NIV should be closely monitored for clinical deterioration
Mechanical ventilation is the main supportive treatment for critically ill patients (29)

S TEROID THERAPY
Do not routinely give systemic corticosteroids for treatment of viral pneumonia outside clinical trials.
A systematic review of observational studies of corticosteroids administered to patients with SARS reported
no survival benefit and possible harms (avascular necrosis, psychosis, diabetes, and delayed viral clearance).
A systematic review of observational studies in influenza found a higher risk of mortality and secondary
infections with corticosteroids; the evidence was judged as very low to low quality owing to confounding by
indication. A subsequent study that addressed this limitation by adjusting for time-varying confounders
found no effect on mortality. Finally, a recent study of patients receiving corticosteroids for MERS used a
similar statistical approach and found no effect of corticosteroids on mortality but delayed LRT clearance of
MERS-CoV. Given the lack of effectiveness and possible harm, routine corticosteroids should be avoided
unless they are indicated for another reason. Other reasons may include exacerbation of asthma or COPD,
septic shock, and risk/benefit analysis needs to be conducted for individual patients.
Early guidelines for management of critically ill adults with COVID-19 specify when to use low-dose
corticosteroids and when to refrain from using corticosteroids. The recommendations depend on the precise
clinical situation (eg, refractory shock, mechanically ventilated patients with ARDS); however, these particular
recommendations are based on evidence listed as weak -> use low-dose corticosteroids (methylprednisolone
at 1-2mg/kg/day for 5 to 7 days was) in ARDS (55).
Wu C (56) (cohort study, 201 patients): 84 patients (41.8%) developed ARDS, and of those, 44 (52.4%) died.
Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95%
CI, 0.20-0.72). Patients who received methylprednisolone treatment were much more likely to develop ARDS
likely owing to confounding by indication; specifically, sicker patients were more likely to be given
methylprednisolone. However, administration of methylprednisolone appeared to reduce the risk of death
in patients with ARDS. These findings suggest that for patients with COVID-19 pneumonia,
methylprednisolone treatment may be beneficial for those who have developed ARDS on disease
progression.

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A NTI - THROMBOTIC PROPHYLAXIS

Use pharmacological prophylaxis (low molecular-weight heparin [preferred if available] or heparin 5000 units
subcutaneously twice daily) in adolescents and adults without contraindications. For those with
contraindications, use mechanical prophylaxis (intermittent pneumatic compression devices) (25).
Anticoagulation therapy is recommended for COVID-19 patients when the D-Dimer value is 4 times higher
than the normal upper limit, except for patients with anticoagulant contraindications. 100U per kg weight
per 12 hours by subcutaneous injection for 3-5 days (7).

P ARACETAMOL OR IBUPROFENE
The French Medicines Agency on its official page (here) warns of the possible harmful effects of NSAIDs. The
EMA, for its part, undertakes to carry out an investigation in this regard and collect data but is not reluctant
to advise against its use, however, it is advisable to prudently take paracetamol in the first instance (57).

ACE- INHIBITORS /ARB

Hypothesis of the link between ACE inhibitors and Covid-19: SARS-CoV-2 uses ACE receptor 2 for entry into
target and in animal experiments both lisinopril and losartan can significantly increase mRNA expression of
cardiac ACE2. Is the expression of ACE2 receptor in the virus targeted cells increased by the use of ACE-I/ARB
and is the patient therefore more at risk for a severe course? We need rapid epidemiological and preclinical
studies to clarify this relationship. If this were the case, we might be able to reduce the risk of fatal Covid-19
courses in many patients by temporarily replacing these drugs (58). ESC highlights the lack of any and strongly
recommend that physicians and patients should continue treatment with their usual anti-hypertensive
therapy (59) -> in healthy patients continue therapy, in hospitalized patients modify ACE-I/ARB with other
therapy (calcium channel blockers) (50).

IMAGING
Performer CT imaging (strong recommendation). The imaging findings vary with the patient’s age, immunity
status, disease stage at the time of scanning, underlying diseases, and drug interventions. The imaging
features of lesions show: (1) dominant distribution (mainly subpleural, along the bronchial vascular bundles);
(2) quantity (often more than three or more lesions, occasional single or double lesions); (3) shape (patchy,
large block, nodular, lumpy, honeycomblike or grid-like, cord-like, etc.); (4) density (mostly uneven, a paving
stones-like change mixed with ground glass density and interlobular septal thickening, consolidation and
thickened bronchial wall, etc.); and (5) concomitant signs vary (air-bronchogram, rare pleural effusion and
mediastinal lymph nodes enlargement, etc.). The CT imaging demonstrates 5 stages according to the time of
onset and the response of body to the virus (see ref.) (60).

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Evolution of chest CT findings: Several studies have reported on short-term CT follow up of patients with
COVID-19 infection. Early-stage CT findings (0-4 days after symptom onset) from 24 CT scans were no lung
opacities (17%), focal ground-glass opacity or consolidation (42%), or multifocal lung opacity (42%).
Approximately 50% of patients had peripheral predominant lung opacities. Serial CT scans during middle
stages (5–13 days) of illness showed progression of lung opacities. Peak lung involvement was characterized
by development of crazy paving (19%), new or increasing lung consolidation and higher rates of bilateral and
multilobar involvement (86%). Late-stage CT findings (14 days or longer) showed varying degrees of clearing
but no resolution up to at least 26 days (61).

IMMUNITY
As far as we know about other coronaviruses, at least a temporary natural immunity should develop for a
period of at least 6-12 months (Ralph Baric, interview on "The Week in Virology podcast").
Studies of MERS survivors showed that MERS-CoV-specific antibody responses tended to be lower and
transient in patients with mild or subclinical disease when compared with patients with severe disease, in
whom MERS-CoV-specific antibody responses were detected for at least 2 years (62).
Guo L (63) (208 plasma samples collected from 82 confirmed and 58 probable cases): The median duration
of IgM and IgA antibody detection were 5 days (IQR 3-6), while IgG was detected on 14 days (IQR 10-18)
after symptom onset, with a positive rate of 85.4%, 92.7% and 77.9% respectively. The positive detection
rate is significantly increased (98.6%) when combined IgM ELISA assay with PCR for each patient compare
with a single qPCR test (51.9%). No cross-reactivity of SARS-CoV-2 rNP with human plasma positive for IgG
antibodies against NL63, 229E, OC43, and HKU1, but strong cross-reactivity with SARS-CoV.
Wolfel R (18) (9 patients): shedding of viral RNA from sputum outlasted the end of symptoms.
Seroconversion occurred after 6-12 days but was not followed by a rapid decline of viral loads.
Lou B (64) (80 patients): near all (98.8%, 79/80) patients converted to be seropositive during the illness
course. Seroconversion was first observed on 7d.p.e (2d.p.o). The first detectible antibody is total Ab and
followed by IgM and IgG, with a median seroconversion time of 15d.p.e (9d.p.o), 18d.p.e (10d.p.o) and
20d.p.e (12d.p.o). The rising of antibody levels accompanied with the decline of viral load. The performance
of ELISAs (compared with LFIA and CMIA) seems the best, although the differences are generally not
significant. For patients in the early stage of illness (0-7d.p.o), Ab showed the highest sensitivity (64.1%)
compared to the IgM and IgG (33.3% for both, p<0.001). The sensitivities of Ab, IgM and IgG detection
increased to 100%, 96.7% and 93.3% two weeks later, respectively. The median seroconversion time was
shorter for the short incubation period group than for the long incubation period group (13d.p.e vs 21d.p.e,
p<0.001).

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VACCINE
At March 21, just over two and a half months after the outbreak began, WHO has surveyed 50 vaccine
candidates worldwide, 2 of which are already in the clinical evaluation phase and 48 in the pre-clinical phase.
Getting a vaccine available will take from one year to eighteen months.
For investigational vaccines see: https://emedicine.medscape.com/article/2500114-treatment

POST EXPOSURE PROPHYLAXIS

Hydroxychloroquine is an option, there are no data but only ongoing trails (65)

INFECTION CONTROL
V IRUS ON SURFACES
Study of virus concentration on different surfaces indicates that SARS-CoV-2 lives up to three days on certain
surfaces such as plastic and steel, and only for a few hours on surfaces such as cardboard and copper. The
virus appears to survive for a short time, a few hours at most, as an aerosol (66)
Study on rooms of 3 patients: significant environmental contamination by patients with SARS-CoV-2 through
respiratory droplets and fecal shedding suggesting the environment as a potential medium of transmission
and supports the need for strict adherence to environmental and hand hygiene. Post-cleaning samples were
negative, suggesting that current decontamination measures are sufficient. Air samples were negative
despite the extent of environmental contamination (67)

DPI USE - WHO

“Standard precautions should be applied at all times. Additional contact and droplet precautions should
continue until the patient is asymptomatic. More comprehensive information about the mode of virus
transmission is required to define the duration of additional precautions” -> see the complete document for
more details (68)

T URBULENT GAS CLOUDS AND RESPIRATORY PATHOGEN EMISSIONS

A recent work has called into question the school difference in airborne transmission of infectious diseases
between aerosols and droplets (69).

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This work starts from the observation that exhalations, sneezes, and coughs not only consist of muco-salivary
droplets following short-range semiballistic emission trajectories but, importantly, are primarily made of a
multiphase turbulent gas (a puff) cloud that entrains ambient air and traps and carries within it clusters of
droplets with a continuum of droplet sizes. Given various combinations of an individual patient’s physiology
and environmental conditions, such as humidity and temperature, the gas cloud and its payload of pathogen-
bearing droplets of all sizes can travel 7-8 m. There is a need to understand the biophysics of host-to-host
respiratory disease transmission accounting for in-host physiology, pathogenesis, and epidemiological spread
of disease (70).

DISCHARGE and DPI USE

For hospital discharge, in a clinically recovered patient, two negative tests, at least 24 hours apart, is
recommended (71)
The decision to discontinue transmission-based precautions should be made using:
- Test-based strategy
i. Resolution of fever without the use of fever-reducing medications and
ii. Improvement in respiratory symptoms (e.g., cough, shortness of breath), and
iii. Negative results of a standardized molecular assay for detection of SARS-CoV-2 RNA from at least
two consecutive nasopharyngeal swab specimens collected ≥24 hours apart (total of two negative
specimens)
- Non-test-based strategy
i. At least 3 days (72 hours) have passed since recovery defined as resolution of fever without the
use of fever-reducing medications and improvement in respiratory symptoms (e.g., cough,
shortness of breath); and,
ii. At least 7 days have passed since symptoms first appeared
Testing-based strategy is preferred in hospitalized, severely immunocompromised patients (these groups
may be contagious for longer than others) and those being transferred to a long-term care or assisted living
facility (72)

SPECIAL POPULATIONS
C HILDREN
Dong Y (73) (2145 bambini cinesi): oltre il 90% erano asintomatici, lievi o moderati, con un solo decesso
riscontrato, per una letalità pari a <0.05%
Two neonatal cases of COVID-19 infection have been confirmed so far, with one case confirmed at 17 days
after birth and having a close contact history with two confirmed cases (the baby’s mother and maternity
matron) and the other case confirmed at 36 h after birth and for whom the possibility of close contact history
cannot be excluded (74)

P REGNANT WOMEN
Chen H (75) (9 pregnant women 3° trimester): clinical characteristics of COVID-19 pneumonia in pregnant
women were similar to those of non-pregnant adult patients. No evidence of vertical transmission in
pregnant women who develop COVID-19 pneumonia in the third trimester (no SARS-CoV-2 in amniotic fluid,
cord blood, breastmilk, and neonatal throat swab)
The risk of vertical transmission of COVID-19 might be as low as that of SARS-CoV-1, but pregnant women
are susceptible to respiratory pathogens and to development of severe pneumonia, which possibly makes
them more susceptible to COVID-19 infection than the general population (74)

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Is it possible that SARS-CoV-2 can be transmitted in utero? Yes, especially because virus nucleic acid has
been detected in blood samples: the suggestion of in utero transmission rests on IgM detection in 3
neonates, and IgM is a challenging way to diagnose many congenital infections. No infant specimen had a
positive reverse transcriptase–polymerase chain reaction test result, so there is not virologic evidence for
congenital infection (76,77).
Relative safety of hydroxychloroquine in pregnancy, maternal fetal medicine recommends considering
hydroxychloroquine as treatment for SARS-CoV-2 in pregnancy.

D IALYZED PATIENTS
Document reference CDC: https://www.cdc.gov/coronavirus/2019-ncov/healthcare-facilities/dialysis.html

OTHER TOPICS:
1. COVID19 - Social Science Research:
https://docs.google.com/document/d/1Ehuw_W8aYPThH33um_mLLZ9dKx4W0LXIxxX2-
g9pjH4/mobilebasic
2. Società Italiana Andrologia:
https://it.surveymonkey.com/r/QuestionarioQuarantenaSIA?fbclid=IwAR04wqX7eCNAJMyZelfXbvt
Y8dlARAyY-eQD7lgjpQ9Z8qBC34DaAiMUB8Q

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