Introduction
The world is plagued by the COVID-19 pandemic. This is an unprecedented situation
in the modern era wherein we do not know our enemy in detail. In fact, we hardly know
anything. We have just started to learn about COVID-19; the management guidelines
are evolving and are mostly consensus based at present, rather than randomized data.
In this article, we will briefly review some important updates and evolving research
in the management of COVID-19.
Testing
Diagnostic testing
Nasopharyngeal swab by real-time reverse transcription- polymerase chain reaction
(rRT-PCR) is the recommended testing method for COVID-19.[1] RT-PCR has a high specificity and does not cross-react with other human coronaviruses
and respiratory pathogens.[2]
Antibody-based rapid testing in the blood is not recommended by the World Health Organization
as results are dependent on age, nutritional status, the severity of illness, concurrent
medications, and immunosuppression like human immunodeficiency virus (HIV).
Indications for testing (Indian Council of Medical Research Guidelines)
-
All symptomatic individuals who have undertaken international travel in the past 14
days
-
All symptomatic contacts of laboratory COVID-19 confirmed cases
-
All symptomatic health-care workersAll patients with severe acute respiratory illness
(fever and cough and/or shortness of breath)
-
Asymptomatic direct and high-risk contacts of a confirmed case should be tested once
between day 5 and day 14 of coming in his/her contact
-
All symptomatic influenza-like illness with fever, cough, sore throat, and/or runny
nose (in hotspots/cluster and large migration gatherings/evacuees canters):
-
Within 7 days of illness – rRT-PCR
-
After 7 days of illness – Antibody test (if negative, confirmed by rRT-PCR).[3]
Treatment
The current standard of care for COVID-19 infection is symptomatic supportive care.
The potential investigational therapies include antivirals, antibodies, cell-based
therapy, ribonucleic acid (RNA)-based therapy, and others. Surviving sepsis management
guidelines in mentioned in [Table 1].
Table 1
Surviving sepsis guidelines: management of critically ill adults with COVID-19[19]
|
Recommendation
|
Level of evidence
|
|
MAP: Mean arterial pressure, SPO2: Oxygen saturation, ARDS: Acute respiratory distress
syndrome, PEEP: Positive end-expiratory pressure, ECMO: Extracorporeal membrane oxygenation,
HFNC: High-flow nasal cannula, NIPPV: Noninvasive positive-pressure ventilation
|
|
Health-care workers performing aerosol-generating procedures should use N95 respirators
in addition to other personal protective equipment (gloves, gown, and face shield/goggles)
in a negative pressure room
|
Best practice
|
|
The most experienced person with airway management should intubate and use video-guided
laryngoscopy (if available) to minimize the number of attempts and risk of transmission
|
Best practice
|
|
Supplemental oxygen should be started if the peripheral SPO2 is <92%
|
Weak
|
|
For patients with acute hypoxemic respiratory failure on oxygen, SpO2 be maintained not higher than 96%
|
Strong
|
|
For patients with hypoxemia despite conventional oxygen, HFNC/NIPPV can be used with
close monitoring of the respiratory status. If worsening is suspected, early intubation
in a controlled environment is advised
|
Best practice
|
|
For intubated patients with suspicion of COVID-19 infection, the endotracheal aspirate
is the preferred specimen for COVID-19 testing
|
Weak
|
|
In mechanically ventilated patients with ARDS, low tidal volume ventilation (4-8 mL/kg
of predicted body weight) and targeting plateau pressures of <30 cm H2O
|
Strong
|
|
For patients with moderate-to-severe ARDS, target a higher PEEP >10 cm H20 with monitoring for barotrauma
|
Strong
|
|
For patients with moderate-to-severe ARDS, prone ventilation for 12-16 h with judicious
use of neuromuscular blocking agents (intermittent bolus or continuous infusion) can
be done
|
Weak
|
|
For patients with refractory hypoxemia, venovenous ECMO can be done
|
Weak
|
|
For mechanically ventilated patients with ARDS, systemic corticosteroid (methylprednisolone
1-2 mg/kg/day for 5-7 days) can be used
|
Weak
|
|
In mechanically ventilated patients with respiratory failure, empiric antibacterial
agents can be used
|
Weak
|
|
For patients with shock, initial resuscitation should be a conservative fluid strategy
with a buffered/balanced crystalloid solution. Avoid starches, dextrans, gelatins,
and albumin
|
Weak
|
|
For patients with shock, norepinephrine is the preferred first-line vasoactive agent
and vasopressin the second-line agent
|
Weak
|
|
For patients with cardiogenic shock, dobutamine is the preferred first-line vasoactive
agent
|
Weak
|
|
For patients with shock on vasopressor support, a MAP of 60-65 mmHg should be targeted
|
Weak
|
|
For critically ill patients, paracetamol can be used to control fever
|
Weak
|
|
For critically ill patients, treatment options including lopinavir/ritonavir, convalescent
plasma, immunoglobulins, interferons, chloroquine/hydroxychloroquine, and tocilizumab
are not recommended[19]
|
Weak
|
Investigational therapies
Remdesivir
Remdesivir, a nucleotide analog prodrug that inhibits viral RNA polymerases and has
shown in vitro activity against severe acute respiratory syndrome coronavirus 2.[4]
In a study of 53 patients with severe COVID-19 (oxygen saturation of <94% in room
air or who receiving oxygen support), the patients received remdesivir on a compassionate
basis for 10 days (200 mg intravenously on day 1, followed by 100 mg daily for 9 days).
At baseline, 57% patients received mechanical ventilation and 8% received extracorporeal
membrane oxygenation. This study showed that 68% had an improvement in oxygen support,
57% of ventilated patients were extubated, 47% discharged, and 13% died. The limitations
of this study are small numbers, short duration of follow-up (18 days), nonrandomized
design, late initiation of treatment (remdesivir was started 12 days from the start
of symptoms), different duration of remdesivir treatment, and no data on viral load.[5]
Lopinavir-Ritonavir
Lopinavir/ritonavir combination showed in vitro activity against other novel coronaviruses through inhibition of 3-chymotrypsin-like
protease.[4] It is Food and Drug Administration (FDA) approved for the treatment for HIV.
A randomized controlled, open-label trial was done in adult hospitalized Chinese patients
with severe COVID-19 (oxygen saturation of <94% in room air or a ratio of the partial
pressure of oxygen to the fraction of inspired oxygen of <300 mmHg). Patients were
randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and
100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard
care alone. A total of 199 patients were randomized, and mortality at 28 days was
similar in the lopinavir–ritonavir group and the standard care group (19.2% vs. 25.0%;
difference: −5.8% points; 95% confidence interval [CI]: −17.3–5.7). This study showed
that there was no benefit (clinical improvement, reduction in mortality, or reduction
in viral RNA load) when treated with antiviral drugs (lopinavir–ritonavir combination)
as compared to standard of care treatment.[6] Currently, this is the only published phase 3 randomized controlled trial (RCT)
for the management of COVID-19 infection.
Hydroxychloroquine/chloroquine and azithromycin
Chloroquine and hydroxychloroquine are used in the treatment of malaria, discoid/systemic
lupus erythematosus, and rheumatoid arthritis. These drugs have immunomodulatory effects
and block the viral entry into cells by inhibiting glycosylation of host receptors,
proteolytic processing, and endosomal acidification.[4]
A French study included twenty patients with COVID-19 infection who were treated with
oral hydroxychloroquine sulfate 200 mg, 3 times/day with or without azithromycin for
10 days and were compared to controls. There was a reduction in viral loads on day
6 as compared to the controls. The limitations of this study are small sample size,
nonrandomized design, and mortality not being the endpoint.[7] Another French study with 11 patients with severe COVID-19 infection treated with
hydroxychloroquine (600 mg/day for 10 days) and azithromycin (500 mg on day 1 and
250 mg from day 2 to day 5) showed no evidence of rapid antiviral clearance or clinical
benefit.[8] Moreover, severe side effects of chloroquine can include psychiatric manifestations,
arrhythmias, and sudden death.[9]
Inhalational plasminogen therapy
Plasminogen is a key regulator in fibrin degradation, wound healing, and infection.[10]
A study from China with 13 patients who had moderate-to- severe COVID-19 infection
were treated with atomization inhalation of free-dried plasminogen (10 mg OD for moderate
and 10 mg BD for severe infection). Six patients with severe infection had improvement
in oxygen saturation, five patients with moderate infection had radiological improvement
of pneumonia, and two critical patients with hypoxemia had improvement in saturation
within an hour.[10] The limitations of this study are the small sample size, nonrandomized design, and
mortality not being evaluated as an endpoint.
Convalescent plasma therapy
Passive immunization for the treatment of human infectious diseases can be traced
back to the 20th century when antibodies were used from the serum of stimulated animals,
especially rabbits and horses.[11]
A study has been reported from China, in which ten patients who had severe COVID-19
infection received one dose of 200 mL of convalescent plasma (CP) derived from recently
recovered donors with the neutralizing antibody titers above 1:640 in addition to
supportive care, antiviral agents, and steroids. The clinical symptoms were significantly
improved along with an increase in oxygen saturation within 3 days. Radiological examinations
showed varying degrees of resolution of lung lesions within 7 days. The viral load
was undetectable after transfusion in seven patients who had previous viremia. The
limitations of this study are a small number, nonrandomized design, confounding use
of antiviral therapy and steroids, and nonassessment of cytokine changes. This study
also does not answer the question of an optimal concentration of neutralizing antibodies
and treatment schedule.[12] In another uncontrolled case series of five critically ill patients with COVID-19
and acute respiratory distress syndrome (ARDS) from China, the administration of CP
containing neutralizing antibody was followed by an improvement in clinical status.[13]
The Indian Council of Medical Research (ICMR) is planning to do a randomized controlled,
open-label trial of CP therapy versus conventional therapy in COVID-19-infected patients.[14]
Tocilizumab
Tocilizumab is a novel monoclonal antibody that competitively inhibits the binding
of interleukin-6 (IL-6) to its receptor. It is FDA approved for the treatment of rheumatoid
arthritis and cytokine release syndrome.[4]
A study from China reported 15 moderate-to-seriously ill COVID-19-infected patients
treated with injection tocilizumab (80–600 mg) with or without methylprednisolone.
This study showed a reduction of C-reactive protein and IL-6 in patients who received
tocilizumab. The limitations of this study are small sample size, nonrandomized design,
and again, mortality was not an endpoint.[15]
Methylprednisolone
A retrospective cohort study from China evaluated 201 COVID-19-infected patients with
ARDS who were treated with methylprednisolone and reported a lower risk of death (hazard
ratio: 0.38; 95% CI: 0.20–0.72).[16] The Chinese thoracic society recommends methylprednisolone 0.5–1 mg/kg for <7 days
in selected patients after assessing the risks and benefits.[17] The limitations include the retrospective study design and the potential adverse
effects of steroids.
Low-molecular-weight heparin
A study from China evaluated the use of low-molecular-weight heparin in patients with
severe COVID-19. This study enrolled 449 patients, and among them, 99 patients received
heparin for 7 or more days. There was no difference in mortality between patients
who used heparin and those who did not (30.3% vs. 29.7%, P = 0.910). However, the
mortality was reduced in patients who used heparin with sepsis-induced coagulopathy
score >4 (40.0% vs. 64.2%, P = 0.029) or D-dimer >6-fold of upper limit of normal
(32.8% vs. 52.4%, P = 0.017).[18] The limitations of this study are retrospective design and the influence of confounding
variables (other therapies).
Infectious Disease Society of America Guidelines
The Infectious Disease Society of America does not recommend the use of hydroxychloroquine/chloroquine
± azithromycin, lopinavir/ritonavir, corticosteroids, tocilizumab, and CP as a treatment
for COVID-19 infection outside the context of a clinical trial.
Prophylaxis (Indian Council of Medical Research National Taskforce Recommendation)
-
Asymptomatic health-care workers involved in the care of suspected or confirmed cases
of COVID-19:
tablet hydroxychloroquine 400 mg twice a day on day 1, followed by 400 mg once weekly
for the next 7 weeks
-
Asymptomatic household contacts of laboratory-confirmed cases:
tablet hydroxychloroquine 400 mg twice a day on day 1, followed by 400 mg once weekly
for the next 3 weeks[20]
Contraindications
Hydroxychloroquine is contraindicated in children below 6 years and patients with
preexisting retinopathy.
Monitoring
A baseline electrocardiogram should be done to rule out congenital/acquired long QT
syndrome and second- or third-degree atrioventricular blocks. Electrolyte imbalances
(hypokalemia/hypomagnesemia/hypocalcemia) must be corrected before starting hydroxychloroquine.
Side effects
Hydroxychloroquine can cause hypoglycemia,[21] QTc prolongation, and torsades de pointes that can lead to fatal ventricular arrhythmia[22] or cardiomyopathy.[23]
Is there evidence to support hydroxychloroquine prophylaxis?
Anin vitro study showed hydroxychloroquine to be more potent than chloroquine in inhibiting
COVID-19 infection.[24] A phase 3 RCT from Columbia University comparing hydroxychloroquine prophylaxis
with placebo for household contacts of index cases with an estimated sample size of
1600 is planned.[25] The hydroxychloroquine prophylaxis is debatable given the inadequate evidence to
support, potentially fatal side effects due to QTc prolongation, risk of hemolytic
anemia in patients with glucose-6-phosphate dehydrogenase deficiency, and a possible
shortage of hydroxychloroquine for patients with malaria, rheumatoid arthritis, and
systemic lupus erythematosus.[26]
Prevention
Vaccine
Vaccines are a crucial component for COVID-19 prevention as there is rapid clinical
deterioration and no effective treatment. Currently, m-RNA and nucleic acid-based
vaccine clinical trials against COVID-19 infection are ongoing.[27]
World Health Organization – Solidarity trial
This trial randomizes patients with COVID-19 infection to either local standard of
care or local standard of care plus one of the four experimental therapies (remdesivir,
chloroquine or hydroxychloroquine, lopinavir + ritonavir, lopinavir + ritonavir +
interferon beta-1a). Currently, the Canadian arm is recruiting patients for the treatment
with lopinavir + ritonavir, and Norwegian arm is recruiting patients for the treatment
with remdesivir or hydroxychloroquine.
Conclusion
Currently, the appropriate prevention, prophylaxis, and treatment of COVID-19 infection
are largely unknown. Symptomatic supportive care with active participation in clinical
trials is encouraged. We await the results of many ongoing RCTs to guide us in the
prevention and management of COVID-19 infection [Table 2] and [Table 3].
Table 2
Ongoing phase 3 clinical trials
|
Type
|
Mechanism
|
Developer/researcher
|
Sample size
|
|
Sarilumab
|
Interleukin-6 antagonist
|
Sanofi/Regeneron
|
400
|
|
Remdesivir
|
Antiviral
|
Gilead
|
2400
|
|
CD24Fc
|
Nonviral immunomodulator
|
|
230
|
|
Tocilizumab
|
Humanized anti-interleukin-6 receptor monoclonal antibody
|
Roche
|
330
|
|
Chloroquine/Hydroxychloroquine
|
Antimalarial
Antirheumatic
|
Washington University School of Medicine
|
55000
|
|
BCG vaccine
|
Antituberculosis
|
Murdoch Children’s Research Institute
|
4170
|
|
Enoxaparin
|
Anticoagulant
|
University hospital, Geneva
|
200
|
|
Hydroxychloroquine/oseltamivir/azithromycin
|
Antirheumatic
Antiviral against H1N1
Antibiotic
|
Shehnoor Azhar, Lahore
|
500
|
|
Anakinra, Siltuximab, Tocilizumab
|
Anti-interleukin
|
University hospital, Ghent
|
342
|
|
Hyperbaric oxygen
|
Free radical
|
Karolinska University Hospital
|
200
|
|
Colchicine
|
Inhibits microtubules
|
Montreal Heart Institute
|
6000
|
|
Naproxen
|
Anti-inflammatory
|
Assistance Publique - Hôpitaux de Paris
|
584
|
|
Hydroxychloroquine
Ritonavir/lopinavir
|
Antirheumatic
Antiviral
|
Centre Hospitalier Universitaire de Saint Etienne
|
1200
|
|
Darunavir/cobicistat + chloroquine
|
Antiretroviral
Antimalarial
|
Fundacio Lluita Contra la Sida
|
3040
|
|
Nitazoxanide
|
Antiprotozoal
|
Romark
|
330
|
|
Natural honey
|
Anti-inflammatory, Immunomodulatory
|
Misr University for Science and Technology
|
1000
|
|
Convalescent plasma
Sarilumab
Baricitinib
Hydroxychloroquine
|
Artificially acquired passive immunization
Interleukin-6 antagonist
Janus kinase inhibitor
Antirheumatic
|
Thomas Benfield
|
1500
|
|
Cholecalciferol
|
Vitamin D3
|
University hospital, Angers
|
260
|
|
Pyridostigmine bromide
|
Acetylcholinesterase inhibitor
|
Salvador Zubiran
|
436
|
Table 3
Anticancer clinical trials for COVID-19 infection
|
Type
|
Mechanism
|
Developer/researcher
|
Sample size
|
|
Bevacizumab
|
Vascular endothelial growth factor antagonist
|
Qilu Hospital of Shandong University
|
140
|
|
Imatinib
|
Tyrosine kinase inhibitor
|
Hospital Universitario de Fuenlabrada
|
165
|
