COVID-19: Treatment

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For more information, please refer to the body of World Health Organization articles about COVID-19 to date.

Patients with COVID-19 who demonstrate very mild illness may not require hospitalization (refer here for criteria on which patients should be screened for COVID-19).  Determining which patients may be screened and treated as outpatients as opposed to which patients should present for in-person screening is individualized, but those who are elderly or have chronic, underlying lung disease are part of a higher risk population group.  

COVID-19 has been associated with profound cytokine storm leading to a hyperinflammatory state. A component of immune dysregulation is also suspected, and the virus may have a potential for attacking specifically T lymphocytes. In the most severe cases, this can progress to fulminant ARDS, multisystem organ failure, and fatal dysrhythmias.  While much is to be learned about this disease, interleukin-6 (IL6) is at least one of the mediators of cytokine storm-related organ dysfunction. Additional clinical manifestations of this cytokine storm syndrome include capillary leak syndrome, hypotension, renal disease, myocarditis with heart failure, and renal failure. A markedly elevated serum ferritin is an early marker of cytokine storm. Cytokine storm related myocarditis and heart failure is the cause of at least some COVID-19 related mortality. 

This post will focus on treatments for COVID-19. The treatments for COVID-19 are largely supportive and include management complications such as hypoxia and shock.

The SCCM guidelines recommend that high flow nasal cannula (HFNC) be used over conventional oxygen therapy for management of hypoxia in patients with COVID-19.  Some data suggests that patients may be less likely to require intubation as compared to those managed with traditional oxygen therapy. The SCCM reports data is lacking for the concern that HFNC increases the risk for aerosolization of COVID-19.  The SCCM further recommends that HFNC be used over non-invasive positive pressure ventilation (NIPPV) for the management of hypoxic respiratory failure in patients with COVID-19 as NIPPV is showing a high failure rate in COVID-19 and also a much higher risk of transmitting the virus to health-care providers due to aerosolization of particles.  The SCCM guidelines note certain situations in which NIPPV may be beneficial, and also note that patients on either HFNC or NIPPV should be monitored carefully as they are at risk for very rapid decline and early intubation should be considered.

In contrast to viral pneumonia, which is often complicated by superimposed bacterial pneumonia, some severely ill patients are progressing directly to acute respiratory distress syndrome (ARDS).  For those patients that require intubation, the SCCM guidelines recommend ARDS volume ventilation strategies, with low tidal volume, high PEEP, lung protective ventilation with target plateau pressures of <30 cm H20.  They also recommend recruitment maneuvers if patients experience hypoxia despite optimizing mechanical ventilation.  They recommend against the utilization of staircase recruitment maneuvers. The SCCM guidelines recommend proning strategies in patients with moderate to severe ARDS with neuromuscular blockage for up to 28 hours. 

While the routine use of nitric oxide is not recommended, a trial of an inhaled pulmonary vasodilator can be used per the SCCM guidelines in those patients with severe ARDS.  If no improvement is seen, it should be tapered off.

While there are no clinical trials that have reported data on the outcomes of venovenous ECMO in patients with COVID-19, the SCCM guidelines do recommend this as a rescue therapy for patients who experience refractory hypoxia despite proning, paralysis and maximum optimization via mechanical ventilation.

The SCCM guidelines do not recommend steroids for treatment of mechanically ventilated patients without ARDS.  They do recommend systemic corticosteroids in patients with COVID-19 and ARDS, though issued a statement that this is a weak recommendation with low quality evidence and not all board members agreed, that some wished not to issue a recommendation without further evidence.

The SCCM Guidelines recommends for adults with COVID-19 and shock, that crystalloids be used as fluid resuscitation of choice.  They recommend that norepinephrine be the first line pressor, with vasopressin be added as the second line vasopressor.  If norepinephrine is not available, vasopressin or epinephrine should be used as the first line vasopressor agent to target a MAP goal of 60-65 mm Hg. The SCCM recommends that dobutamine be added if there is evidence of continued cardiac dysfunction with hypoperfusion despite adequate fluid resuscitation despite norepinephrine.

For patients with refractory shock, the SCCM guidelines recommend low-dose corticosteroid therapy as opposed to high-dose corticosteroid therapy (200mg hydrocortisone/day) typically utilized in septic shock used to combat acute, secondary adrenal insufficiency.

The SCCM guidelines recommend empiric antimicrobial therapy for mechanically ventilated patients with COVID-19 with daily reassessment of need and potential for de-escalation.

The SCCM guidelines recommend the use of acetaminophen for fever control, noting that it may increase patient comfort and does not increase the rate of mortality.  They note that enough evidence is not available to recommend the use of non-steroidal anti-inflammatory drugs.

The SCCM guidelines recommends against routine use of lopinavir/ritonavir for management of patients with COVID-19 and says there is insufficient evidence to provide a recommendation on any other antivirals for treatment of patients with COVID-19 at this time.  Lopinavir/Ritonavir has been shown to be ineffective in the treatment of COVID-19 in a 199 person randomized trial. All patients were hospitalized and had a PO2 of <94%.  There was no difference in time to clinical improvement.  There was no difference in 28-day mortality (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7) or detectable viral RNA. (NEJM. https://www.nejm.org/doi/full/...) DOI: 10.1056/NEJMoa2001282

Remdesivir, an investigational antiviral, reported to have in-vitro activity against SARS-CoV-2 is being studied in clinical trials. The CDC reports that multiple clinical trials of investigational therapeutics have been implemented in China, including two clinical trials of remdesivir.  Some patients with COVID-19 have received IV remdesivir for compassionate use outside of a clinical trial setting. An NIH adaptive randomized controlled clinical trial of investigational therapeutics for hospitalized COVID-19 patients in the United States was approved by the Food and Drug Administration; the first investigational therapeutic to be studied is remdesivir. Other remdesivir trials for COVID-19 patients in the U.S. are available for patients with moderate and severe COVID-19.  Some COVID-19 patients have received uncontrolled treatment with other investigational antivirals. For information on specific clinical trials underway for treatment of patients with COVID-19, see clinicaltrials.gov, and www.chictr.org.

Tocilizumab (anti-IL 6) is a humanized immunoglobulin that blocks receptor binding to IL-6. Randomized controlled trials are underway exploring the use of in efforts to suppress the hyperinflammatory syndrome associated with COVID-19.  Secondary hemophagocytic lymphohistiocytosis (sHLH) has been seen to develop in this patient population and is characterized by fulminant and fatal hypercytokinaemia with multiorgan failure.  This mechanism is also an important component by which patients are developing fulminant myocarditis, an often fatal consequence of COVID-19 in very severe cases. SCCM guidelines state that there is insufficient data to issue a recommendation for or against use of tocilizumab (anti-IL 6) in the treatment of COVID-19 in critically ill adults.

Interferon beta-1a showed no benefit in a well done randomized, controlled trial of ARDS (not specific to COVID-19) (JAMA. 2020;323(8):725-733. doi:10.1001/jama.2019.22525). The SCCM guidelines state that there is insufficient data to issue a recommendation for or against use of interferon in the treatment of COVID-19 in critically ill adults.

Hydroxychloroquine (200mg TID) has been suggested as a treatment for COVID-19 (Gautret et al).  However, the study used a surrogate outcome (viral shedding).  Additionally, the patients who deteriorated clinically were all in the hydroxychloroquine group. Finally, although length of stay and mortality were secondary outcomes, they do not report this data. The SCCM guidelines state there is insufficient data to recommend for or against the use of chloroquine or hydroxychloroquine, though many centers are using this in combination with azithromycin for treatment of COVID-19 

ACE-I and Angiotensin-II receptor antagonists (ARBs) have been tried.  The primary route of virus entry into cells seems to be ACE2 receptors which are blocked by ARBs.   However, ARBs upregulate the ACE2 receptor. There is no data suggesting that ARBS or ACE-I worsen outcomes in COVID-19. These medications are not mentioned in the SCCM guidelines.  It is not recommended that patients stop their ACE-I and ARBs.  See European Society of Cardiology statement here.  The American Heart Association, American College of Cardiology and Heart Failure Society of America also recommend against stopping ACE-I and ARBs. https://www.hfsa.org/patients-...

Convalescent serum: A study of five patients with severe disease showed improvement after the use of convalescent serum.  This shows promise but data is very limited.  It is being used on protocol at some hospitals. (JAMA. Published online March 27, 2020. doi:10.1001/jama.2020.4783)

NSAIDS:  There is no evidence that NSAIDS worsen the course or outcome of COVID-19.

References

Chen N, Zhou M, Dong X, Qu J, Gong F. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Jan 30. [Epub ahead of print]

Chen, C., Zhou, Y. & Wang, D.W. SARS-CoV-2: a potential novel etiology of fulminant myocarditis. Herz (2020). https://doi.org/10.1007/s00059...

Chuan Qin, MD, PhD, Luoqi Zhou, MD, Ziwei Hu, MD, Shuoqi Zhang, MD, PhD, Sheng Yang, MD, Yu Tao, MD, PhD, Cuihong Xie, MD, PhD, Ke Ma, MD, PhD, Ke Shang, MD, PhD, Wei Wang, MD, PhD, Dai-Shi Tian, MD, PhD, Dysregulation of immune response in patients with COVID-19 in Wuhan, China, Clinical Infectious Diseases, , ciaa248, https://doi.org/10.1093/cid/ciaa248

Garcia Borrega J, Gödel P, Rüger MA, Onur ÖA, Shimabukuro-Vornhagen A, Kochanek M, Böll B. In the Eye of the Storm: Immune-mediatedToxicities Associated With CAR-T Cell Therapy. HemaSphere, 2019;3:2. http://dx.doi.org/10.1097/HS9....

Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949

Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020; 395:473

Shakoory B, Carcillo J, Chatham; Amdur R, Zhao H; Dinarello C; Cron, R; Opal S. Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial*. Publication Date: February 2016. Issn Print: 0090-3493. PMID: 26584195. Critical Care Medicine. 44(2):275–281, FEBRUARY 2016. DOI: 10.1097/CCM.0000000000001402.

Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Feb 4. doi: 1038/s41422-020-0282-0. [Epub ahead of print] PubMed PMID: 32020029.

Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, Li SB, Wang HY, Zhang S, Gao HN, Sheng JF, Cai HL, Qiu YQ, Li LJ. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020 Feb 19;368:m606. doi:10.1136/bmj.m606.

Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, Ng OT, Marimuthu K, Ang LW, Mak TM, Lau SK, Anderson DE, Chan KS, Tan TY, Ng TY, Cui L, Said Z, Kurupatham L, Chen MI, Chan M, Vasoo S, Wang LF, Tan BH, Lin RTP, Lee VJM, Leo YS, Lye DC; Singapore 2019 Novel Coronavirus Outbreak Research Team. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA. 2020 Mar 3. doi: 10.1001/jama.2020.3204. [Epub ahead of print]

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HASAN BAYRAMER 7 days ago

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best wishes