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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 17  |  Issue : 3  |  Page : 144-148

Practical approach to manage patients with moderate and severe COVID infection


Bariatric Medicine, Academics and Clinical Training-Apollo Hospital, Navi Mumbai, Maharashtra, India

Date of Submission22-Aug-2020
Date of Decision02-Sep-2020
Date of Acceptance03-Sep-2020
Date of Web Publication16-Sep-2020

Correspondence Address:
Sanjay P Khare
Apollo Hospital, Navi Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_108_20

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  Abstract 


COVID-19 infection has hit humanity with a ferocious velocity that's left 7.8 billion humans across 195 countries in seven continents absolutely stunned. Never have we seen life brought to such an absolute standstill by a biological agent. The WHO declared the COVID-19 outbreak a global health emergency and subsequently a global pandemic. The hospitals and intensive care units have been packed to capacity. Most of the modalities of treatment are intuitive and based on a short experience of 6 months (three in our country). This article presents a practical approach to the management of patients with moderate and severe infection COVID-19. The patients in these two groups are separated on the basis of clinical and laboratory parameters. Adequate management of moderately severe patients may prevent the progression of the disease. The role of various specific agents used in the treatment is briefly discussed.

Keywords: COVID-19, cytokine storm, noninvasive ventilation, oxygen, pharmacotherapy, plasma therapy, ventilator


How to cite this article:
Khare SP. Practical approach to manage patients with moderate and severe COVID infection. Apollo Med 2020;17:144-8

How to cite this URL:
Khare SP. Practical approach to manage patients with moderate and severe COVID infection. Apollo Med [serial online] 2020 [cited 2020 Oct 31];17:144-8. Available from: https://www.apollomedicine.org/text.asp?2020/17/3/144/295209




  Introduction Top


Never has mankind been hit by such a vicious onslaught of infection. Within a short span of 6–7 months, 21,641,369 cases have been registered. It is likely that many more are subclinically infected and not registered. A count of 769,481 deaths is truly alarming. India has the dubious distinction of being the third highest infected country after the USA and Brazil.[1] Fortunately, India has the lowest fatality rates in the world (1.94%–2.41% as per different sources) and is definitely waning further.[2] Since it is a new infection, hitherto not encountered, there is no standardized approach to manage COVID infections. At present treatment, efforts are concentrated on securing oxygenation, reducing inflammation, averting or subduing the incipient cytokine storm, and trying antiviral medications.

This article presents the practical aspects of approach toward both moderate and severe cases of COVID-19 infection. Physicians simply have not had the opportunity of consensus building, planned studies, knowledge sharing, review of therapeutics, laying down impeccable guidelines, etc. Hence, current modalities of treatment are an amalgamation of theoretical knowledge, practical sensibilities, and intuitive wisdom.

The modalities described here in this article are a sum total of all that are being practiced in most leading institutions of the world in general and at Apollo Hospitals, Navi Mumbai, in particular.

This article restricts itself to the management of patients having moderate and severe affliction.


  Approach Top


One would assume that medications such as azithromycin (500 mg OD for 5 days) and/or hydroxychloroquine sulfate (HCQS, 400 mg BD for the 1st day and then 200 mg BD for 5 days) have already been given to the patients. It must be mentioned that HCQS has emerged to be one of the most disputed, acrimoniously argued, and controversial agents for usage in COVID-19.[3] HCQS cannot be considered a safe drug. Electrocardiogram aberrations, neuropsychiatric side effects, and hematological toxicities have been reported. This author does not recommend HCQS. Vitamin B complex, Vitamin C, and zinc are routinely given, although their beneficial role is unproven.

When a moderate/severe case of COVID case is seen, he/she is immediately “triaged.” Important parameters are:

  1. Subjective symptoms of fever, breathlessness, and discomfort
  2. Objective evidence of tachypnea, SpO2 levels, radiological findings, and laboratory parameters. A 6-min walk test helps by “unmasking” a potentially hypoxic patient so that attending doctor is not unpleasantly surprised later on.


“Moderate” and “severe” cases are discerned/segregated quickly and accurately, as a further line of treatment rests on this staging. These two categories may be differentiated as per [Table 1].{Table 1}


  Management Top


Moderate COVID-19 infection

This is a condition which is dealt best in intensive care unit (ICU) settings, since the situation is likely to spiral rapidly downward, if not handled urgently and properly. Adequate management at this stage would avoid progression to the next (severe) stage, where mortality is quite high. A three-pronged attack is usually adhered to: (1) maintenance of adequate oxygen levels, (2) antivirals to reduce viral load, and (3) agents to reduce inflammation and to preempt impending cytokine storm.

The following is usually done.

1. Adequate oxygenation is mandatory. Nasal oxygen to ensure saturation of 95% and above is started. Usual requirements can be anything from 2 to 6 L/M. Requirements may go up to as much as 10–15 L/M. Higher needs in the face of rising respiratory rate and subjective feeling of worsening breathlessness mandates escalating patient's status in the “severe” category. Usual facial masks may be used initially.

If requirements cross 10–15 L/M of oxygen, a special “high-flow nasal cannula” (AIRVO) is used. The AIRVO 2 is a humidifier with an integrated flow generator that delivers high-flow warmed and humidified respiratory gasses to spontaneously breathing patients through a variety of interfaces. Increase in Peak Expiratory End Pressure generated is similar to airway pressure achieved by nCPAP.[4],[5] This affords a Fio2 of as much as 0.5–0.6 along with humidifier advantage. Hence, the usual high-flow complications such as dryness of airways, crusting, and nasal trauma can be avoided. Besides, with this device, the patient gets to be fully mobile and feed properly and can even lie down prone.

Pharmacotherapy

  1. Favipiravir is an oral antiviral, which works by selectively inhibiting RNA polymerase, which is necessary for viral replication. Each tablet has 200 mg. 1800 mg twice daily is given on the 1st day (9 tablets twice daily) on day 1, followed by 800 mg twice daily (4 tablets twice daily) up to day 14. Hence, pill burden is quite high. Each tablet costs around 103 Rs. Hence, the total cost comes to around 12,000–15,000 Rupees. It is contraindicated in pregnancy as it has a high teratogenic potential. Side effects include vomiting, slight reduction in subjective desire of voluntary movements, slight fall in red blood cell count, and mild alterations of liver enzymes
  2. Inhaled steroids may be tried at this stage, rationale being to reduce inflammation at alveolar level. Ciclesonide-2 puffs thrice daily through a spacer may work
  3. Radiological and laboratory parameters are reassessed, to categorize and prognosticate further possibilities. High-resolution computed tomography chest (either first time or repeat) with CORAD scores is considered. Levels of interleukin (IL)-6, ferritin, and lactate dehydrogenase are heeded to.


If patient is improving, its well and good. However, if there is further tachypnoea, rise in Oxygen requirements and worsening of lab parameters, it is justifiable to upgrade the patient's status to “severe” and deal with it in following manner.

Severe COVID infection

Oxygenation

It is of paramount importance here. A quick decision needs to be taken about modality of oxygen delivery. In case SpO2 levels are not in the ideal zone despite full-fledged nasal cannula/face mask/AirGo approach, ventilation emerges as a necessary modality. Noninvasive ventilation (NIV) may be tried initially, though it has been an observation here that this is rather cumbersome for the patient. The “blast” of air may be perceived as grossly uncomfortable by the already distressed patient. Eating/drinking necessitates temporary removal, causing fall in SpO2. Change in position too is difficult. Lying prone is almost impossible. Hence, faced with this dilemma and a falling oxygen saturation, prospects of invasive ventilation (IV) loom large.

Invasive ventilation

IV is considered a necessary evil. Although inevitable in certain scenarios, it can cause a lot of complications including hypotension, ventilator-related infection, volume imbalance, and sedation-related delirium. It is a clinical call whether to intubate a patient or not. It is feared that NIV might be associated with dispersion of aerosol, thus increasing the risk of transmission to health-care workers. This could be one of the reasons that encourage physicians to choose IV over NIV along with a clinical scenario. Be it as it may, COVID patients going on a ventilator is never a good sign. Some of the factors that herald a poor outcome in an IV patient are higher white blood cell count, lower lymphocyte and platelet counts, higher C-reactive protein (CRP), aspartate aminotransferase, alanine aminotransferase, and total bilirubin.[6] Sequential organ failure assessment scores in the IV and NIV groups were also significantly higher than the NV group. Mortality and/or morbidity is significant.[7] However, with increasing experience with IV in COVID, better outcomes are being observed. Ventilating patients in prone position can decrease mortality when performed right from the initial hours of presentation. The minimum suggested duration of prone position is 12 h a day.[8],[9]

Pharmacotherapy

Methylprednisolone[10]

Corticosteroids may be effectively beneficial by inhibiting the inflammatory storm via suppression of cytokine levels and pro-inflammatory gene expression.[11] This gets translated into diminished serous exudate at the site of inflammation, reduced tissue edema, and diminished inflammatory injury. 500 mg IV OD is given for the next 3–5 days, with the prime aim of reducing inflammation and cytokine storm. Some authorities have advocated methylprednisolone infusion as well[12] (methylprednisolone 80 mg/kg IV bolus, followed by infusion of 80 mg/day in 240 mL normal saline at 10 mL/h). The infusion is continued for at least 8 days and until achieving either a PaO2:FiO2>350 mmHg or a CRP <20 mg/L. Treatment is then switched to oral administration of methylprednisolone 16 mg or 20 mg IV twice daily until CRP returns to <20% of normal range and/or PaO2:FiO2>400 or SatHbO2 ≥95%.

Low-molecular-weight heparin

Elevated baseline D-dimer levels indicate an inflammatory procoagulant condition and are associated with higher mortality.[13] Its rise is in proportion to other biomarkers. This needs to be interpreted correctly, and accordingly, low-molecular-weight heparin is started. Enoxaparin is administered subcutaneously at 1 mg/kg, BD.

Convalescent plasma

Patients who have recovered from COVID infection are expected to have antibodies that they have made naturally during their successful fight against COVID. It is postulated that these antibodies might offer beneficial effects for the patient who is currently down with active and severe COVID infection. Hence, 28 days after recovery, these recovered patients are invited to donate plasma. 500 ml of plasma is collected over 30–40 min and is stored in 2 bags of 250 ml each at minus 80°. In severe cases of COVID, after ABO compatibility is established, one bag is transfused over 2–2.5 h and the other is given the next day. The cost would be in the range of 14,000–15,000 Rupees for the total therapy. Patients selected for this therapy need to be COVID antibody negative. Those patients with a duration of more than 7 days are preferred.

Remdesivir[14]

Remdesivir is an adenosine analog, having activity against the single-stranded RNA viruses. A research paper published on April 13, 2020, in the Science Daily, by the University of Alberta Faculty of Medicine and Dentistry, showed that remdesivir is highly effective in stopping the replication mechanism of the coronavirus that causes COVID-19. Remdesivir is to be considered even if favipiravir has been given initially, as the mechanism of action/efficacy/benefits of these two antivirals is slightly different.

Remdesivir treatment was associated with significantly improved clinical recovery and a 62% reduction in the risk of mortality. 74.4% of remdesivir-treated patients recovered by day 14 versus 59% of patients receiving usual line of treatment. The mortality rate in patients treated with remdesivir was 7.6% at day 14 compared with 12.5% among patients not taking remdesivir. Five days of remdesivir treatment was 65% more likely to yield clinical improvement at day 11 than standard of care. Early intervention with a 5-day treatment course can significantly improve outcomes.[14]

This benefit was also noted in pediatric and pregnant patients.

200 mg IV bolus is given followed by 100 mg IV BD for 5 days.

The total cost would be around 35,000–50,000 Rupees.

Cytokine storm

Severe infection may trigger a “cytokine storm” with release of IL-6, IL-1, IL-12, and IL-18, along with tumor necrosis factor-alpha and other inflammatory mediators. The increased pulmonary inflammatory response makes oxygenation difficult. As a marker for this, IL-6 levels are considered. Normal levels are 4–5 ng/ml. 30–50 may be seen in severe cases. In really bad cases, levels of as much as 1000 have been seen. (Our center has reported 5500 pg/ml in a case who obviously succumbed later.) If IL-6 levels are grossly elevated along with significant (and treatment resistant) hypoxia, tocilizumab is to be considered. It must be noted that at this stage, radiological inputs will be difficult to obtain and interpret. Hence, decision should be chiefly clinical/biochemical.

Tocilizumab[15]

Tocilizumab is a monoclonal antibody that competitively inhibits the binding of interleukin-6 (IL-6) to its receptor (IL-6R). Inhibiting the entire receptor complex prevents IL-6 signal transduction to inflammatory mediators that summon B and T cells.

Treatment with tocilizumab (IL-6 inhibitor) might reduce the risk of invasive mechanical ventilation or death in patients with severe COVID-19 pneumonia.

A 400 mg dose is given as a single intravenous drip infusion over 60 min. The cost is around 40,000–50,000 Rupees.

Difficulties faced by the managing staff

  1. It is a tedious task to wear the personal protective equipment (PPE) suits and work for long shifts. Suffocation, fogging of vision, headaches, irritability, fatigue, and restlessness have been frequently encountered by doctors caring for COVID patients. It is, in fact, being spoken about as being a “post PPE syndrome”
  2. ”Donning” (wearing the PPE) and “doffing” (removing it at the end of duty) is quite a time-consuming task and needs to be properly adhered to, especially doffing because this is where there are maximum chances of infection to the doctor
  3. It is not even possible to drink water or go to the toilet once the PPE is donned. The usage of mobiles has to be curtailed, making communication outside the ICU, etc., cumbersome. Handwriting gets affected with all those gloves, making documentation uneasy.



  Postrecovery Outcomes Top


Continued observation is necessary following initial recovery.

  1. Even after an apparent initial recovery for the first few days, there might be a sudden deterioration. This is especially true if the initial ferritin and IL-6 have been very high. This is probably due to a delayed cytokine storm
  2. A sudden and unexpected spontaneous pneumothorax has been observed
  3. Prognosis is grave right from the beginning, in the following conditions:


    • Oncology and hematological malignancies
    • Chronic renal failure
    • Posttransplant cases
    • Poorly controlled diabetes
    • Smokers
    • Patients having chronic obstructive pulmonary disease
    • Age group of 70–80 years, followed by age group 60–70 years.


  4. A number of patients in moderate-to-severe category have high blood sugar levels for which insulin infusions are needed. Possible mechanisms include stress-induced hyperglycemia, usage of steroids, and altered cellular mechanism following monoclonal antibodies.
  5. In spite of an apparently successful recovery and subsequent discharge, there may be a lingering malaise, feeling of being unwell, vague body aches and pains, and being unable to resume usual (preillness) activities. This may be akin to a “chronic fatigue syndrome”
  6. Severe psychological/psychiatric maladies have been observed and reported. Posttraumatic stress disorder is quite common, as is depression and anxiety. Being cooped up in isolation reduces productivity and harms self-esteem
  7. Even after a successful recovery, some patients have been breathless and may go on to develop pulmonary fibrosis.



  Conclusion Top


This unheard-of virus, first described from Wuhan in China, has succeeded in radically changing life, as we know it, for humans. The sheer virulence and transmissibility of this virus is astounding. Rumors abound about it being a genetically mutated, man-made agent, thereby making it even more difficult to contain. Vaccine is on the horizon and seems promising. Till then, Treatment is evolving along with the experience garnered.

However, this isn't really the first time in recorded history that mankind has faced such a challenge. We've had some similarly scary situations in the past as well, some of them being (a)various Plague epidemics from 165 AD to 1750 in which millions of humans have perished (b) Influenza epidemic of 1889 and then 1918 and 1957 (c) AIDS epidemic-1981 (d) H1N1 Swine Flu epidemic-2009-2010 (e) West African Ebolla epidemic-2014 (f) Zica Virus epidemic-2015.

All these epidemics had seemed terrifying at that point of time, but not only did mankind survive, it in fact emerged stronger and evolved with a better innate resistance and immunity. Similarly, this too shall pass.

Judicious observation, perfect interpretation and sensible application should help mankind surpass this biological challenge as well.

Development of an effective and safe vaccine and its administration to entire population should be a phenomenal achievement for humans.

But lessons should be learnt. Our environment is the ultimate force that this universe has created and needs to be respected, nurtured and tended to, if future complications are to be avoided.

Acknowledgment

We gratefully acknowledge Dr. Gunadhar Padhi (Consultant Intensivist, Apollo Navi Mumbai) for his valuable inputs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sagar K. “India becomes third worst affected country by coronavirus, overtakes Russia”. Deccan Herald. New Delhi: The Printers (Mysore) Private Limited; 2020.  Back to cited text no. 1
    
2.
”CoVID news by MIB”. Twitter. Ministry of information and Broadcasting-India; 2020.  Back to cited text no. 2
    
3.
Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: A multinational registry analysis. Lancet 2020;395:1820.  Back to cited text no. 3
    
4.
Sarkar M, Sinha R, Roychowdhoury R, et al. “Comparative Study between Noninvasive Continuous Positive Airway Pressure and Hot Humidified High-flow Nasal Canulae as a Mode of Respiratory Support in Infants with Acute Bronchiolitis in Pediatric Intensive Care Unit of a Tertiary Care Hospital”. Indian Journal of Critical Care Medicine 2018;22:85-90.  Back to cited text no. 4
    
5.
Stéphan F, Barrucand B, Petit P, Rézaiguia-Delclaux S, Médard A, Delannoy B, et al. High-Flow Nasal Oxygen vs Noninvasive Positive Airway Pressure in Hypoxemic Patients After Cardiothoracic Surgery: A Randomized Clinical Trial. JAMA 2015;313:2331-9. doi: 10.1001/jama.2015.5213  Back to cited text no. 5
    
6.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. Hlh Across Specialty Collaboration UK. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4.  Back to cited text no. 6
    
7.
Hua J, Qian C, Luo Z, et al. Invasive mechanical ventilation in COVID-19 patient management: Experience with 469 patients in Wuhan. Crit Care 24:348(2020). Available form: https://doi.org/10.1186/s13054-020-03044. DOI: https://doi.org/10.1186/s13054-020-03044-9.  Back to cited text no. 7
    
8.
Mora-Arteaga JA, Bernal-Ramírez OJ, Rodríguez SJ. The effects of prone position ventilation in patients with acute respiratory distress syndrome a systematic review and metanalysis. Med Intensiva 2015;39:359-72. doi: 10.1016/j.medin 2014.11.00.   Back to cited text no. 8
    
9.
Ghelichkhani P, Esmaeili M. Prone Position in Management of COVID-19 Patients; a Commentary. Arch Acad Emerg Med 2020;8:e48.   Back to cited text no. 9
    
10.
Liu J, Zheng X, Huang Y, Shan H, Huang J. Successful use of methylprednisolone for treating severe COVID-19. J Allergy Clin Immunol 2020;146:325-7.  Back to cited text no. 10
    
11.
Darwish I, Mubareka S, Liles WC. Immunomodulatory therapy for severe influenza. Expert Rev Anti-infect Ther 2011;9:807-22.  Back to cited text no. 11
    
12.
Salton F, Confalonieri P, Santus P, Harari S, Scala R, Lanini S, et al. “Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia”. medRxiv preprint doi: https://doi.org/10.1101/2020.06.17.20134031.t.  Back to cited text no. 12
    
13.
Yu B, Li X, Chen J, Ouyang M, Zhang H, Zhao X, et al. Evaluation of variation in D-dimer levels among COVID-19 and bacterial pneumonia: A retrospective analysis. J Thromb Thrombolysis 2020:1-10. doi: 10.1007/s11239-020-02171-y.  Back to cited text no. 13
    
14.
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med 2020;382:2327-36. DOI: 10.1056/NEJMoa2007016.  Back to cited text no. 14
    
15.
Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R. Tocilizumab in patients with severe COVID-19: A retrospective cohort study. Lancet Rheumatology 2020;2:E474-484. DOI: https://doi.org/10.1016/S2665-9913(20)30173-9.  Back to cited text no. 15
    




 

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