INTRODUCTION
In December 2019, the first case of coronavirus disease 2019 (COVID-19), was reported
from China. An emerging infectious disease caused by a new strain of coronavirus,
namely severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) led to a global
health problem and pandemic (1).
By 28 May 2020, the total number of laboratory-confirmed cases of COVID-19 surpassed
5,701,337, with 357,688 reported deaths worldwide (2). Iran reported its first confirmed
cases of COVID-19 on the 19 February 2020 in Qom, Qom Province (3), and by 29 May
2020, a total of 143,849 confirmed cases and 7627 deaths were reported (2).
More than 300 active clinical trials concerning agents and therapeutic measures potentiality
effective in the treatment of COVID-19 are underway. However, no proven effective
therapies for this virus are supported by any currently existing randomized clinical
trials (RCTs) (4).
Scope of this protocol and ethical issues
The guideline released by the National Research Institute of Tuberculosis and Lung
Diseases (NRITLD), Masih Daneshvari Hospital COVID-19 Expert Group, may help the clinicians
caring for patients admitted to hospitals with confirmed or suspected SARS-CoV-2 infection.
Care of mild and outpatient cases and interventions for infection control are beyond
the scope of the present paper.
Due to the emerging aspect of COVID-19 and its evolving knowledge, any recommendation
may change in the future. Therefore, clinicians should update their information in
short periods. On the other hand, adherence to national and local guidelines is mandatory,
and prescription of any drug out of national protocols should be done just under clinical
trials that obtained informed consent from patients and were approved by an ethics
committee.
Classification of severity
The severity of respiratory problems in COVID-19 is defined as follows:
Mild: Symptomatic patients without pulmonary infiltration and peripheral capillary
oxygen saturation (SpO2) of >93% in ambient air.
Moderate: Patients with pulmonary infiltration and SpO2 of >93% in ambient air.
Severe: Patients with the respiratory rate (RR) of ≥30 breath/minute, SpO2 ≤93% in
ambient air, or pulmonary infiltrates in more than 50% of the lung field, not in a
critical state.
Critical: Patients admitted to the intensive care unit (ICU); patients who need high
flow oxygen with a nasal cannula, noninvasive ventilation, or mechanical ventilation;
the ones with acute respiratory distress syndrome (ARDS) or shock (5,6).
Indications of a virologic assay
Virologic assay by reverse transcriptase polymerase chain reaction (RT-PCR) is recommended
for any patient with an indication of hospital admission. It is also necessary for
symptomatic health care workers taking care of suspected or confirmed cases of COVID-19.
The highest accuracy for the detection of SARS-CoV-2 can be obtained by using the
lower respiratory tract specimens. However, the collection of sputum and bronchoalveolar
lavage puts the healthcare workers at a higher risk due to aerosols formation. Nasopharyngeal
or oropharyngeal swab/wash is the routine method to obtain a specimen for testing.
It is reported that the detection of the COVID-19 virus with oropharyngeal swabs was
less frequent than nasopharyngeal ones (7).
In Iran, due to restrictions on obtaining nasopharyngeal swabs, the oropharyngeal
swabs or washing comprise the majority of respiratory tract specimens. Clinicians
should consider that a single negative RT-PCR is not sufficient to exclude COVID-19,
especially if the clinical suspicion is high. Therefore, they should consider test
repetition and eventually rely on compatible symptoms, exposure history, and typical
CT imaging features for the diagnosis of COVID-19 (8).
At present, based on the current evidence, the world health organization (WHO) recommends
the utilization of serologic tests only in research settings and not for clinical
decision-making (9).
Indications of imaging study
Normal host symptomatic cases with SpO2 of ≤93% in ambient air
Immunocompromised patients with any symptom (mainly, but not limited to, fever and
hypoxemia) suspected of COVID-19
Any febrile patients with the risk factors of severe disease (BMI ≥40 kg/m2
, hypertension, chronic pulmonary/cardiovascular disease, and diabetes mellitus) suspected
of COVID-19
Although the most sensitive modality is the lung CT-scan (10), plain chest x-ray (CXR)
may be adequate in normal hosts. For immunocompromised patients, a CT-scan of the
lung is highly recommended. Routine use of CT-scan, as a screening measure, among
asymptomatic cases should highly be deferred (11).
Indications of admission
Indications of in-hospital management are: RR ≥30 breath/minute; SpO2 ≤93% in ambient
air, any abnormalities in CXR, considerable infiltration in the lung CT-scan, decreased
level of consciousness, shock, and clinicians’ judgment (e g, in the case of alone
patients or oral intolerance).
Admission to hospital is not necessary for patients with small and tiny pulmonary
infiltration in the lung CT-scan unless other indications exist.
Mild cases should be managed as an outpatient, but patient education is necessary
to come back in the case of deterioration.
Protocol of treatment
Moderate cases
- Chloroquine
Chloroquine (in our setting, hydroxychloroquine sulfate), as monotherapy, is recommended
for outpatient therapy. It can be prescribed for symptomatic high-risk groups without
pneumonia; two tablets b.i.d for the first day and then one tablet b.i.d for 5–10
days (12). In the hospital, when lopinavir/ritonavir is the basic regimen, (13) it
is recommended to prescribe hydroxychloroquine just on the first day with a dosage
of two tablets b.i.d in order to prevent serious interactions.
In a recent observational study, the administration of hydroxychloroquine was not
associated with the decrease of intubation or mortality rates (14). Therefore, recommendations
for the prescription of this drug to treat COVID-19 may change in the future.
- Lopinavir/ritonavir
Lopinavir/ritonavir, sold as Kaletra®, is the basic regimen for the cases admitted
to hospitals, recommended by the Iranian National COVID-19 Scientific Program. Its
efficacy is controversial (4), and in a recent study, no benefit was observed with
lopinavir-ritonavir treatment beyond the standard care in hospitalized adult patients
with severe COVID-19 (15). It is prescribed as two 200/50 mg tablets b.i.d. Kaletra®
causes critical adverse effects and interacts with other drugs. The most serious one
is the QT interval prolongation and life-threatening arrhythmia (4). Concomitant administration
of drugs with the QT prolongation effects, such as fluoroquinolones, methadon, ondansetron,
and metoclopramide, should be avoided in order to prevent arrhythmia. Concomitant
administration of Kaletra® with rivaroxaban, lovastatin, simvastatin, colchicine,
cisapride, and sildenafil to treat pulmonary artery hypertension is contraindicated
(16). It is necessary to get the baseline ECG, and if the corrected QT interval is
longer than 500 msec, the drug should be discontinued. For the QT intervals between
450 and 500 msec, the daily repetition of ECG is recommended. Correction of serum
electrolytes, such as potassium >4 mEq/L and magnesium >3 mEq/L, is recommended to
decrease the chance of arrhythmia (16).
The most frequent problem with Kaletra® is gastrointestinal upset. Taking tablets
with food may decrease the chance of this problem (17).
Kaletra® should be prescribed for minimally seven days, but this period can be extended
to 14 days (4).
- Remdesivir (as a clinical trial) (IRCT20171122037571N2)
The preliminary findings support the administration of remdesivir to treat hospitalized
patients with COVID-19, especially before the disease progression leading patients
to require mechanical ventilation (18). Remdesivir is administered intravenously as
a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose administered
daily for of 5 to 10 days (19,20).
The efficacy of remdesivir is under investigation by the WHO in the Solidarity Trial.
The Solidarity Trial (an international trial conducted by WHO) compares four treatment
options (remdesivir, lopinavir/ritonavir, lopinavir/ritonavir with interferon beta-1a,
and hydroxychloroquine) against the standard of care to assess their relative effectiveness
against COVID-19 (21).
- Favipiravir (as a clinical trial) (IRCT20151227025726N14)
Favipiravir, sold as Avigan®, is an antiviral agent administered to treat influenza
before COVID-19 pandemic (22) and is a promising agent to treat COVID-19 (23). Multiple
clinical trials are ongoing in the world to evaluate its efficacy among patients with
COVID-19 (4).
Favipiravir can be used as the first-line antiviral agent (alternative to Kaletra®)
or the secondary agent when Kaletra® fails, and the patient condition worsens (both
of them as clinical trials).
Different dosages of favipiravir are used in various trials. The dose of 1600 mg b.i.d
on the first day, followed by 600 mg b.i.d for seven days is recommended (23).
Favipiravir is a teratogen; therefore, its administration is contraindicated in pregnancy.
Limited data are available about its administration in renal insufficiency, but it
seems that the dose adjustment is not necessary. Increased exposures are observed
in Child-Pugh class A to C, and dose adjustment should be considered in Child-Pugh
C (4).
- Umifenovir (as a clinical trial) (IRCT20151227025726N15)
Umifenovir, sold as Arbidol®, can be used as an alternative to Kaletra® (24), but
its prescription should be limited to approved clinical trials. Arbidol® is available
as 100 mg capsules, and the dosage is 200 mg TDS for seven days. No dose adjustment
is necessary in renal failure, and there is no specific recommendation in the case
of hepatic impairment (4).
- Oseltamivir and Ribavirin
As the recommendation of the National Scientific Committee of COVID-19, and termination
of seasonal influenza circulation in the community, oseltamivir is no longer prescribed.
Also, ribavirin is withdrawn from the COVID-19 drug regimen in Iran.
Severe cases
- Interferon beta 1-a (as a clinical trial) (IRCT 20151227025726N12)
Interferon beta 1-a can be added to the basic regimen in the context of an approved
clinical trial (4,21,25–27). Inclusion criteria are:
- Bilateral pulmonary involvement
- At rest SpO2 of <90% in ambient air
Exclusion criterion is:
- Intubation
The recommended dose is 12 million units subcutaneous, every other day for three to
five doses (28).
- Steroid
A recent preliminary report of the RECOVERY Trial shows that a low dose of dexamethasone
reduces the risk of death in patients with COVID-19 requiring supplemental oxygen
(29). We recommend 4 mg dexamethasone b.i.d for 10 days if SpO2 remains less than
90%.
- IVIG (as a clinical trial)
Intravenous immunoglobulin (IVIG) preparation can be added to the basic regimen based
on an approved clinical trial (4,30).
Inclusion criteria:
- Bilateral pulmonary infiltration
- At rest SpO2 of <90% with fraction of inspired oxygen (FiO2) >30%–40%
IVIG dosage is 25 g/day for three days.
- Tocilizumab (as a clinical trial) (IRCT 20151227025726N13)
For patients under 65 years old with positive PCR results and SpO2 <90%, the quantification
of plasma interleukin 6 (IL-6) level is recommended. If the IL-6 level is higher than
7 pg/mL, the prescription of tocilizumab, sold as Actemra®, should be considered in
the context of an approved clinical trial. For this purpose, an expert team should
discuss the case and decide.
Inclusion criteria for tocilizumab administration are:
- Age between 18 and 65 years
- Confirmation of COVID-19 by PCR
- Critical or severe cases with minimally one of the following conditions:
Admission to ICU
At rest RR of ≥30 breath/minute
SpO2 of <90% in ambient air
PaO2/FiO2 of <300
Serum IL-6 level of ≥7 pg/mL
Exclusion criteria are:
- Acute or chronic renal failure
- Rise of liver enzymes more than 5x upper limit of normal (ULN); or more than 3x
ULN and symptomatic; or severe liver insufficiency with class C Child-Pugh score.
- Pregnancy or nursing mother
- Any active infection other than COVID-19
- Active peptic ulcer disease
- Intubation
Before the administration of the drug, latent TB and viral hepatitis should be evaluated.
Also, informed patient consent is necessary. Tocilizumab is prescribed as a single
dose of 400 mg drug diluted in 100 mL normal saline via IV infusion within one hour.
Close monitoring is essential during the infusion (4,31–
33).
- Convalescent plasma therapy (as a collaborative center in a multi-institutional
trial) (IRCT20200325046860N1)
Convalescent plasma prepared by plasmapheresis from recovered cases of COVID-19 is
used to treat severe cases unresponsive to other measures (34). Although promising,
its safety is a concern and should be administered under strict monitoring (35). RCTs
to evaluate convalescent plasma for the treatment of COVID-19 are underway. The process
of donation, collection, preparation, and testing is very complex and should be performed
just by an authorized organization (in Iran, the Iranian Blood Transfusion Organization).
Candidates for plasma therapy are confirmed or highly suspected cases of COVID-19
who are hypoxemic (SpO2 <90% in ambient air) with no improvement after minimally 48
hours of conventional treatment. Transfusion of one unit of plasma (500 to 650 mL)
is performed within four hours under careful monitoring for transfusion reactions.
In the case of the clinician request, one more unit can be transfused after 24 hours
for unresponsive cases (34,36, 37).
ICU Care
Criteria for the ICU admission of patients with COVID-19 are:
SpO2 of ≤85% or partial pressure of arterial oxygen (PaO2) of ≤60 mmHg unresponsive
to appropriate oxygen therapy
Severe respiratory distress
Hemodynamic instability
Acid-base disturbance
Other ICU admission criteria (38).
- Respiratory support strategy
There are two types of hypoxic patients with COVID-19 pneumonia and different mechanisms
and pathophysiology, clearly distinguishable by the lung CT-scan. In the first group,
lung compliance is nearly normal, without ARDS, and in the second, the compliance
is low with ARDS. In type 2 patients, in addition to viral pneumonia, they likely
have self-induced lung injury due to vigorous inspiratory efforts leading to highly
negative intrathoracic pressures and increased edema. Therefore, early intubation
and subsequent invasive mechanical ventilation in rapidly progressing respiratory
distress can diminish the change from type 1 to type 2 and decrease the risk of self-induced
lung injury (39,40).
- Noninvasive ventilation and high flow nasal therapy
We recommend NIV versus early intubation in selected patients with COVID-19 that can
tolerate masks, are cooperative, and have no signs of severe respiratory distress.
Whenever any intolerance or disadvantages of NIV are suspected, the strategy is changed
to the early invasive ventilation protocol.
The main concern about NIV is the aerosol formation and hazard for health care staff
(41). Ideally, NIV should be performed in the ICU setting with a negative pressure
system, the air passing through the high-efficiency particulate air filters, and exhaust
directly to the exterior.
NIV needs an ICU team capable of working with noninvasive machines and familiar with
mask technologies, such as helmet and full-face masks and new modes of noninvasive
ventilation.
- Invasive mechanical ventilation
If severe respiratory distress is present, or when the hypoxemia is nonresponsive
to NIV, endotracheal intubation should be considered to prevent self-induced lung
injury. We recommend the application of the low tidal volume strategy to reduce ventilator-induced
lung injury (40); PEEP levels 8–10 cm H2O in type 1 patients and 14–15 cm H2O in type
2 cases, and plateau airway pressure maximally 30 cm H2O. Then the RR is increased
to maximally 30 breath/minute if necessary, which is the mainstay of the lung-protective
ventilation.
Also, ventilation in the prone position is recommended as a rescue maneuver in type
1 and as a long-term treatment in type 2 patients (39). An early tracheostomy with
preferred the mini-surgical percutaneous dilatational tracheostomy method is recommended
(42).
- Steroid
For the patients admitted to ICU with any stage of ARDS, the prescription of corticosteroids
is recommended to decrease the inflammation. The recommended dose is 20 mg dexamethasone
daily from day 1 to 5, then 10 mg daily from day 6 to 10. This approach is applied
based on the study by Villar et al., (43) in the rapid progression of ARDS in patients
with COVID-19 in order not to lose the time.
- Extracorporeal membrane oxygenation
In patients under mechanical ventilation, with PaO2/FiO2 <80 for six hours or PaO2/FiO2
<50 for three hours, despite having high positive end-expiratory pressure and neuromuscular
blockage, it is planned for ECMO. Transthoracic echocardiography is performed; if
left ventricular ejection fraction is >50% the veno-venous ECMO, and if <50% or in
case of hemodynamic instability, the veno-arterial ECMO are planned.
The drainage cannula is inserted by the close Seldinger maneuver in the left or right
femoral vein, and the return cannula by the same technique in the right internal jugular
vein. The position of the cannula is checked by CXR, and the efficacy of the system
is evaluated by increasing arterial oxygen saturation and PaO2. All patients receive
a continuous dose of intravenous heparin with the activated partial thromboplastin
time (aPTT) of 50–70 seconds. The aPTT is checked every six hours daily.
Other strategies
Rehydration and appropriate nutritional support is recommended.
Also, a standard dose of venous thromboembolism prophylaxis with low molecular weight
or unfractionated heparin is recommended for all the patients with COVID-19 admitted
to hospitals. For ARDS cases and patients admitted to ICU, an escalated dose of heparin
(half of a therapeutic dosage) is preferred (44).
Indication of stress ulcer prophylaxis is similar to those of other patients admitted
to hospitals.
Hospital discharge planning
The decision to discharge patients is clinical-based. Overall admission duration of
minimally seven days is recommended.
The following criteria are recommended for discharge planning:
- Being afebrile for 72 hours without receiving antipyretic drugs
- A significant improvement in imaging studies (CT-scan or CXR as the physician preference)
- SpO2 of ≥93% in ambient air
- Stability of vital signs (blood pressure, RR, and pulse rate)
- Tolerance of oral intake
PCR testing before discharge is necessary, but the negative result PCR is not mandatory
for patient discharge, although it is preferable.
The patient has to be isolated in his or her house for minimally two weeks. Doctors
and nurses should train any patient before discharge from the hospital both verbally
and by providing pamphlets, especially in the infection control measures.
Follow-up
If follow-up imaging is necessary, it recommends 6–8 weeks after discharge. The selection
of the modality is on the basis of extension of involvement in the previous imaging
studies.
Prophylaxis
Currently, there is no evidence of any clinical trial supporting any prophylactic
regimen (4). We do not recommend the use of any drug for the prevention of COVID-19
by health care workers or others.
Table 1.
Drug dosage and schedule
Drugs
Dosage
Duration
Comments
Hydroxychloroquine sulfate
400 mg/PO/bid 1st day then 200 mg/PO/bid
7–14 days
In concomitant usage with Kaletra, just loading dose (1st day) is recommended.
Lopinavir/ritonavir (Kaletra)
200/50 mg II/PO/bid
7–14 days
The basic regimen as Iranian protocol.
Favipiravir (Avigan)
*
1600 mg/po/bid 1st day then 600 mg/bid
7 days
Umifenovir (Arbidol)
*
200 mg t.i.d
7 days
Remdesivir
*
200 mg 1st day then 100 mg daily
5–10 days
Interferon β 1 a
12 MU/SC/every other day
5 doses
In severe cases
Dexamethason
4 mg / IV / b.i.d
10 days
In severe cases
IVIG
*
25 gr / IV infusion / daily
3 days
In severe cases
Tocilizumab (Actemra)
*
8 mg/kg (400 mg) / slow IV infusion
Single dose
Can be repeated after 12 – 24 hours
*
Just to be used as approved clinical trials