|Year : 2020 | Volume
| Issue : 7 | Page : 42-48
Pharmacological management of COVID-19
Veena Raghunathan, Maninder Singh Dhaliwal
Department of Pediatric Critical Care, Medanta - The Medicity, Gurgaon, Haryana, India
|Date of Submission||20-Apr-2020|
|Date of Decision||25-Apr-2020|
|Date of Acceptance||29-Apr-2020|
|Date of Web Publication||29-May-2020|
Dr. Maninder Singh Dhaliwal
Medanta - The Medicity, Gurgaon - 122 001, Haryana
Source of Support: None, Conflict of Interest: None
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic has brought the world to a standstill and is the largest public health crisis in the world in the present generation. As the cases continue to increase globally, and more patients are developing severe disease, large volumes of clinical data collection and aggressive research is being carried out to find effective medical therapies for this disease. No definitive proven treatment option exists till date. Various immunomodulatory and anti-viral drugs have shown potential, and are being studied extensively through randomized trials. The most available literature is based on the adult study population, with few/no children being included. This review attempts to summarize the pharmacotherapeutic options presently in consideration in children in the treatment of SARS-CoV2.
Keywords: COVID 19, drugs, hydroxychloroquine/chloroquine, lopinavir/ritonavir
|How to cite this article:|
Raghunathan V, Dhaliwal MS. Pharmacological management of COVID-19. J Pediatr Crit Care 2020;7, Suppl S1:42-8
| Introduction|| |
The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has assumed the alarming proportions of a global pandemic affecting around 2 million people so far with over a lakh deaths worldwide. It was declared as a Public Health Emergency of International Concern on January 30, 2020 and subsequently recognized as a pandemic by the World Health Organization on March 11, 2020. Due to the rapidity of the spread and increasing number of sick cases, critical care physicians have been faced with a challenging situation: Where not much is known about therapeutic options, and yet quick decisions need to be taken to save lives. At present, there is no globally accepted standard of care in the pharmacological management of SARS-CoV2. Various therapies are undergoing clinical trials or being compassionately used. Although SARS-CoV2 seems to affect children to a lesser extent than adults, infants and young children, especially with comorbidities, are at risk for developing severe disease and require aggressive treatment. This review aims to summarize the pharmacotherapeutic options and the practical aspects in the treatment of SARS-CoV2, to equip the intensivist/treating, pediatrician, to battle against this deadly disease.
| Severe Acute Respiratory Syndrome Corona Virus 2: Understanding the Virus and Rationale for Therapy|| |
SARS-CoV2 is a single-stranded RNA-enveloped beta coronavirus and belongs to the same subgroup as the viruses that caused SARS outbreak in 2002 and Middle East Respiratory Syndrome (MERS) outbreak in 2012. Thus it is a reasonable approach to initially consider similar therapies as were used during the SARS and MERS outbreaks. SARS-CoV virus targets cells through its structural S protein that binds to the angiotensin-converting enzyme 2 receptor. The structural components of SARS-CoV2 share some similarities to other viruses such as HIV, Hepatitis B, C. It replicates using proteins such as 3 chymotrypsin-like protease and RNA polymerase. Hence, nucleoside analogs used in HIV and other respiratory viruses and HIV protease inhibitors may be useful in SARS-Co V2. Alternatively, other approaches apart from hindering viral replication include immune modulation (e.g., use of monoclonal antibodies like tocilizumab, convalescent plasma therapy) and agents that inhibiting viral entry (chloroquine/hydroxychoroquine). These pharmacological options will be discussed in detail below.
| General and Supportive Treatment|| |
Patients with respiratory distress/severe acute respiratory illness should receive oxygen. Target is sPO2 >90%; during resuscitation it is higher around 94%. Use of low flow devices like nasal prongs is preferred: They are tolerated better and reduce droplet spread of infection, unlike high flow nasal cannula (HFNC). If hypoxic on low flow, HFNC, or noninvasive ventilation can be tried, provided patient is continually monitored for signs of fatigue/worsening. Respiratory failure needs intubation, with all appropriate barrier precautions.
Wheeze is uncommon in children with SARS-CoV2, as lung involvement is mainly in alveoli rather than small airways. Hence, bronchodilators are not needed routinely and may cause harm due to pro-inflammatory effects on alveoli, worsening of ventilation-perfusion mismatch and increased tachycardia. If there is clinical evidence of wheeze/asthmatic child, bronchodilation with use of MDI/spacer rather than nebulization if preferred, as this minimizes droplet spread.
The preferred antipyretic is paracetamol. Ibuprofen should be avoided. It can worsen/cause acute kidney injury (AKI), especially in a child with poor oral intake. Furthermore, there are unsubstantiated reports of ibuprofen being linked to severe clinical manifestations of SARS-CoV2, possibly due to the upregulation of ACE receptors in the lung.
In the case of comorbid underlying conditions, it should be determined which need to be continued or stopped. It is important to consider drug–drug interactions and monitor for the same.
Although the patient may be suspected to have SARS-CoV2, it is important to administer empiric antimicrobial in patients with sepsis/severe acute respiratory infection within 1 h of identification. There is no evidence around which antibiotic to use. The choice of antibiotic is should be based on whether it is a community-acquired or health care-associated pneumonia and local antibiogram as applicable. The frequency of bacterial co-infection in children with SARS-CoV2 is unclear. One study from China found that 20% of children had coinfection with Mycoplasma pneumonia. A retrospective systematic review of studies of rates of bacterial coinfection during the H1N1 pandemic evaluated that 15% of patients had co-infection; however, the incidence was lower in children. Bacterial coinfection is highly likely if: There is severe disease at presentation, discolored sputum production, high white blood cell count/C reactive protein on investigation, nonimprovement by day 3 of treatment. Bacterial coinfection is likely to be associated morbidity and in adults with mortality. In children with comorbidities, there should be a lower threshold to start antibiotics. If there is the ongoing local circulation of seasonal influenza, empiric therapy with a neuraminidase inhibitor can also should be considered.
Conservative fluid strategy is recommended by the Surviving Sepsis Campaign guidelines for COVID 19. It must be remembered that tissue hypoperfusion should be avoided. Most children do not require fluid restriction to below maintenance values. AKI can occur in viral infections in children, unnecessary fluid restriction will worsen it. Children with fever or respiratory distress tend to have increased insensible losses. Also, oral intake due to illness may be decreased, so when they present, dehydration may be present, which would need to be appropriately corrected. Hence close monitoring of fluid balance and daily weight recording may help to guide fluid plan. There is no routine indication for diuretic therapy unless there is evidence of pulmonary edema.
Resuscitation strategy in septic shock
For resuscitation, 10–20 ml/kg crystalloid bolus) should be used in the first 30–60 min with continuous reassessment after each bolus. Among the crystalloids, balanced/buffered solutions (Ringer Lactate, Plasmalyte) may be preferred over normal saline. If signs of volume overload (crepts in the chest, hepatomegaly), then discontinue fluid boluses. Perfusion targets are age-appropriate mean arterial pressure, urine output >1 ml/kg/h, improvement in the capillary refill, mottling, decrease in heart rate, lactate, and better sensorium; dynamic indices of volume responsiveness can also be used to guide fluid therapy. Hypotonic crystalloids, starches, or gelatins should not be used for resuscitation. Albumin could be used for resuscitation when the patient is requiring substantial amounts of crystalloids.
If signs of shock persist after two fluid boluses, or signs of volume overload occur during resuscitation, vasopressors should be administered. Vasopressors (epinephrine, norepinephrine, vasopressin, or dopamine) are most safely given through the central line. Vasopressors (i.e., norepinephrine, epinephrine, vasopressin, and dopamine) are most safely and accurately given through a central venous catheter. However, if central lines are not available, they can be safely administered through peripheral lines, preferably in more diluted concentrations and in a larger vein. Peripheral access should be closely monitored for signs of extravasation and/or local necrosis and converted to the central line as soon as feasible. Intraosseous access can also be used for vasopressor administration. Epinephrine is considered first-line treatment in children. If signs of poor perfusion and cardiac dysfunction persist despite achieving targeted blood pressure with fluids and vasopressors, inotrope such as dobutamine should be considered.
Sedation and analgesia
Benzodiazapine and opiods (morphine) can be used in patients with severe disease, who are receiving mechanical ventilation. Opioids also have anti-tussive properties, and benzodiazepines may help to allay anxiety and reduce oxygen demand in patients who are severely tachypneic (NOT for mild/moderate respiratory distress). However, the decision to administer these drugs in a nonventilated patient is a clinical bedside call to be taken by the senior intensivists, with complete preparedness for intubation/securing airway if needed.
Continuous neuromuscular blockade should not be used routinely in patients with ARDS, except in situ ations of ventilator dyssynchrony despite sedation or refractory hypoxemia.
There is no recommendation for the routine use of systemic steroids in the treatment of SARS-CoV pneumonia. There is no evidence of significant lung inflammation in children with SARS-CoV2; hence, they are unlikely to be beneficial. Furthermore, the administration of steroids may harm by causing immunosuppressive effects, prolonged viral shedding, psychosis, and diabetes. A metanalysis of 10 observational studies in influenza with 6548 patients stated increased mortality and secondary infections with the use of steroids. The efficacy of steroids in ARDS/septic shock generally remains debated, and probably those most likely to benefit from steroids are those with bacterial rather than viral infections. The surviving sepsis guidelines in children mention considering intravenous hydrocortisone to treat children with septic shock if fluid resuscitation and vasopressor therapy can restore hemodynamic stability. Clinicians considering steroids in SARS-CoV2 patients must balance potential small mortality benefits and risk of prolonged viral shedding. If steroids are administered, one must monitor for hyperglycemia, hypernatremia, and hypokalemia.
Patients with severe SARS-CoV2 have disseminated intravascular coagulation. Microthrombi formation in lungs probably plays a role in the impaired gas exchange in patients with pneumonia. Studies from China have shown that anticoagulation reduced mortality in severe SARS-CoV2 patients with coagulopathy. Prophylactic low molecular weight heparin should be given to all cases of SARS-CoV2 requiring ICU admission, unless there is a contraindication to the same. Therapeutic dosage should be considered for those on CRRT/ ECMO or showing evidence of severe microthrombi induced organ dysfunction or documented/suspected macrothromboembolism.
| Specific Therapies|| |
No definitive therapy till date has proven benefit on SARS-CoV2. However, based on the similarity of viral proteins, various antiviral and immunomodulatory agents have been tried. Some drugs have demonstratedin vitro activity against SARS-CoV2 or potential benefits in small, mostly observational clinical studies. Yet, when dealing with severe disease, the following drugs may be considered as discussed below:
Both chloroquine and hydroxychloroquine may have antiviral activity. Possible mechanisms for these include interference with ACE2, a receptor for SARS-CoV2, thus blocking viral entry into cells along with other factors like proteolytic processing and endosomal acidification to hinder virus-cell fusion. They also have immunomodulatory effects through attenuation of cytokine production. No high-quality evidence exists for the efficacy of chloroquine/hydroxychloroquine treatment of SARS or MERS. China has reported that chloroquine has been successfully used to treat over a 100 SARS-CoV2 patients resulting in improved radiologic findings, and enhanced viral clearance, and reduced disease progression., Hydroxychloroquine has been shown to have 3 fold higher cytotoxicity against SARS-CoV2 inin vitro studies compared to chloroquine. A recent open labeled nonrandomized study of 36 patients in France, concluded improved virologic clearance with hydroxychloroquine compared to controls receiving standard supportive care. This study though promising, had a small sample size, and it not evaluate the safety profile of the drug. There are randomized control trials going on to evaluate the efficacy of these drugs. So, in children, there is probably no benefit for routine cases, but it may be considered in case of severe illness requiring PICU admission. It is suggested that hydroxychloroquine will be a recommended drug in adults with COVID-19. In children, it is unlikely to have clinically significant benefit when given routinely but may be considered in the rare event of PICU admission.
The dosage for hydroxychloroquine suggested in adults with SARS-CoV2 is loading dose of 400 mg twice daily for 1 day followed by 200 mg twice daily. In children, loading with 13 mg/kg followed by 6.5 mg/kg twice daily is proposed.
The most common are gastrointestinal side effects and include nausea, vomiting, metallic taste, and cramping. Others include photosensitivity, drug eruptions, and hypoglycemia. Cardiomyopathy, neuropathy and myopathy are reported with very high doses. Retinopathy, a hallmark of chloroquine toxicity is associated with high dose prolonged administration, hence less relevant in the setting of SARS-CoV2 treatment. Caution is recommended in use in G6PD deficient patients, although clinically significant hemolytic anemia has not been reported so far. It should be avoided though in patients with preexisting cardiac disorders due to risk of QT prolongation and torsades pointes. Baseline blood sugar and electrocardiogram are recommended before chloroquine therapy.
To decrease nausea and vomiting, it is recommended to administer the drug along with meals. Administration of antacids within 4 h of chloroquine should be avoided due to chelation effects and reduced bioavailability. No dose adjustments are needed if CrCl >10 mL/min; however 50% dose should be administered if CrCl <10 mL/min or patient is on hemodialysis/peritoneal dialysis. Patients on CRRT should receive full dose. There is no alternative intravenous form of chloroquine or its analogs available.
Hydroxychloroquine + azithromycin: There are around four small observational studies which have compared the combination therapy of hydroxychloroquine and azithromycin to supportive care/hydroxychloroquine alone. While it is unclear whether the efficacy of the combination is better, cardiac side effects (QT prolongation, torsades de pointes, and ventricular tachycardia) are a concern. As both medications have QT-prolonging effects, a combination is likely to increase the risk of harmful effects.
It should be noted that lopinavir/ritonavir, along with chloroquine, should be avoided in combination.
Hydroxychloroquine for prophylaxis
ICMR has recommended hydroxychoroquine for prophylaxis asymptomatic healthcare workers involved in the care of suspected or confirmed cases and asymptomatic contacts (older than 15 years) of SARS-CoV2: 400 mg twice a day on Day 1, followed by 400 mg once weekly for next 7 or 3 weeks respectively, to be taken with meals.
These drugs are proved and in use for the treatment of HIV and are thought to be advantageous in SARS-CoV due to inhibitory action on 3 chymotrypsin-like protease. Clinical studies in the previous SARS pandemic reported decreased mortality and intubation rates with lopinavir/ritonavir. However due to the retrospective, observational nature, definite conclusions could not be drawn. An adult randomized controlled trial of 199 patients with severe SARS-CoV2 has failed to show any benefit beyond standard care. Based on scattered case studies, lopinavir/ritonavir is being used in critically ill adults. It must be started early in the course of illness; delayed initiation is ineffective. The Indian Ministry of Health and Family Welfare guidelines for the management of COVID-19 warns of severe adverse effects with prolonged therapy with Lopinavir/ritonavir and advises its use ONLY after informed expressed consent on a case to case basis for severe cases (in the presence of hypoxia, hypotension, new-onset organ dysfunction or high-risk factors like diabetes/immunocompromised patients). No trial of antiviral medications has been conducted in children. The British Pediatric Respiratory Societies and other likewise, pediatric guidelines worldwide do not recommend antivirals in children at present. Emerging evidence is awaited.
The widely used regimen for SARS-CoV2 is 400 mg/100 mg twice daily for up to 14 days in adults. In children, the dosage generally used in pediatrics is 300 mg/75 mg/m2 of body surface area per dose twice daily (maximum being 400/100 mg).
Lopinavir/ritonavir tablets can be administered without regard to food; however with or after meals may enhance GI tolerability. The tablets must be administered whole; not crushed/split. The oral solution of the drug should be administered with food because a high-fat meal increases absorption. The drug has poor palatability, which is difficult to mask with flavoring/food. The poor palatability of LPV/r oral solution is difficult to mask with flavorings or foods (see Formulations).
Gastrointestinal intolerance (nausea, diarrhea) are common. Hepatotoxicity may occur and maybe particularly marked when combination therapy is used or in the presence of viral infection, similar to the SARS-CoV2 scenario, where approximately 20%–30% of patients at presentation have elevated transaminases. In the above mentioned randomized trial, 14% of patients needed to discontinue therapy due to adverse effects. Other adverse effects include hypersensitivity, pancreatitis, prolonged Qt and cardiac conduction abnormalities. It must be kept in mind that it is a CYP3A4 inhibitor and substrate, and hence may alter other drug levels.
It is a neuraminidase inhibitor used in the treatment of influenza. It has noin vitro action against SARSCoV2. As the SARS-CoV2 outbreak occurred in China during the peak influenza season, empirical oseltamivir was used rampantly until SARS-CoV2 was discovered. Hence this drug has no role once influenza has been excluded.
Interferon therapy has been studied in the past for novel coronaviruses, especially as combined therapy with anti-viral agents. Due to conflicting data, it is not presently worth a recommendation in the treatment of SARS-CoV2. At present, though, Chinese guidelines suggest the use of interferons as an alternative for combination therapy.
Is a research monophosphate prodrug which in activated form inhibits viral RNA dependent RNA polymerase. This investigational drug showed activity against Ebola when studied during its outbreak. It is probably the most promising therapy against SARS-CoV2. It hasin vitro activity against many novel coronaviruses, including SARS-CoV2, and currently, phase 3 randomized clinical trials are underway. In murine models, its use results in decreased viral lung titers, and it prevented pulmonary hemorrhage. Its safety profile is also attractive: Its propensity for liver or kidney toxicity is low compared to other antivirals. There are case reports of successful use in SARS-CoV2. The presently used dose in adults is 200 mg loading following by 100 mg daily infusion. For weight <40 kg, the dosage recommended is 5 mg/kg loading followed by 2.5 mg/kg once daily for 5–10 days, or till improvement in respiratory symptoms. It is administered in intravenous form, hence it can be used if enteral drug administration is not possible and needs no hepatic/renal dose adjustment.
Play a role in decreasing inflammatory cytokine response and is a potential adjunct therapy in SARS-CoV2. Interleukin-6 (IL-6) appears to be key to the dysregulated immune response in SARS-CoV2. Tocilizumab, a monoclonal IL-6 receptor antagonist, could thus dampen the cytokine release and cause clinical improvement. It has been used in a small series of severe SARS-CoV2 patients with improvement in lung function and rapid defervescence. Its use is probably best reserved for patients with severe disease who have failed other therapies. Randomized controlled trials are underway to evaluate tocilizumab alone or in combination in patients with severe SARS-CoV2 pneumonia. Dosage is 4–8 mg/kg for a single dose to be diluted in normal saline and administered slowly >1 h. A second dose may be considered 8–12 h after the first one if inadequate response. Adverse effects include: Increased upper respiratory tract infections, reactivation of tuberculosis, hypertension, hepatotoxicity, hypersensitivity reactions and gastrointestinal perforations
Convalescent plasma therapy/immunoglobulin
Another potential adjunctive therapy for SARS-CoV2 is the use of convalescent plasma, which contains antibodies from recovered patients, which may help suppress viremia by the transfer of passive immunity. A previous metanalysis of studies, including 714 patients with SARS or severe influenza, showed that treatment with convalescent plasma and immunoglobulins helped to decrease mortality. Intravenous immunoglobulin has been tried in a few patients in China at a dose of 0.3–0.5 g/kg/day. Preliminary data suggest convalescent plasma is advantageous, without serious adverse effects in the present SARS-CoV2 pandemic. The US FDA has approved the use of convalescent plasma to treat critical patients. Efforts are also on to use convalescent plasma to extract specific SARS-CoV2 antibodies for targeted therapy.
Nitazoxanide is a traditional antihelminthic drug. It has demonstratedin vitro activity against MERS and other corona viruses, which aroused interest in its role as a potential drug for SARS-CoV2. Human data of its efficacy against coronavirus is lacking, but given its safety profile, tolerance and immunomodulatory effects, it should be studied further as a treatment option for SARS-CoV2. It is a well-tolerated drug, with no major side effects. Dosage of 300 mg twice daily in patients >12 years, 200 mg twice daily for 4–11 years age group, 100 mg twice daily for 1–3 years age group.
Role of ACE inhibitors and angiotensin receptor blockers
SARS-CoV2 uses the ACE 2 receptor to enter into the human cell. This mechanism has generated a controversy on whether ACE inhibitors/angiotensin receptor blockers would worsen or antagonize the disease. As ACE inhibitors upregulate ACE 2 receptors, this may increase virus entry into cells. Angiotensin receptor blockers by the same theory would block the ACE 2 receptors hence inhibit virus entry. Till there is further clarity on this, practice guidelines world over advise continuation of these drugs for patients on chronic therapy.
There are inconclusive data and questionable efficacy with ribavirin against novel coronaviruses. Furthermore, given its considerable toxicity, it does not have much value in the treatment of SARS-CoV2.
Some of the main drugs presently in focus in the treatment of SARS-CoV2 have been summarized in [Table 1].
| Conclusion|| |
Due to the serious nature of this disease and rapid, devastating effects throughout the world, various therapeutic options are being potentially considered; however, research is far limited and inadequate. These include: Vitamin C, zinc, ivermectin, indomethacin, tissue plasminogen activator, monoclonal antibodies like Ecluzumab, Bevacizumab, Sarilumab and antivirals like Umifenovir (Arbidol), Darunavir, etc., Ongoing randomized trials and experience gathered from the cured cases will help to illuminate us in future. To conclude, the treatment of SARs-CoV2 remains largely supportive considering our present knowledge of the disease and lack of current strong evidence favouring the use of specific therapies. Hopefully, definitive treatment options will be clearer in near future, given the dynamics of the situation.
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Conflicts of interest
There are no conflicts of interest.
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