Choosing Among Unproven Therapies for the Treatment of Life-Threatening COVID-19 Infection: A Clinician’s Opinion from the Bedside

Robert A. Raschke, MD

HonorHealth Scottsdale Osborn Medical Center

Scottsdale, AZ USA

We are clearly in unprecedented times. As clinicians watch patients die from COVID-19 infection in the ICU, many feel they cannot wait for clinical trials to prove that various proposed therapies are efficacious. Treatments for which any rationale suggest the possibility of benefit are being administered to patients and the literature abounds with reports of case series or poorly-designed observational trials in which small numbers of patients seem to have favorable outcomes when given these unproven therapies (1). In many cases, these reports are made globally available via social networking without the benefit of peer-review or are being published despite severe methodological flaws that would not have been acceptable prior to the COVID-19 outbreak. 

Standard therapy for COVID-19 has recently been published by the Surviving Sepsis Campaign, which have taken a conservative, evidence-based approach (2). But many clinicians are not able to maintain such equipoise in the face of catastrophe. Therefore, I propose an approach to consideration of bedside implementation of unproven therapies for life-threatening COVID-19 for comment and criticism. None of the therapies discussed below have even marginally-acceptable empirical evidence of clinical benefit in patients with COVID-19, so let us put critical appraisal of the literature aside for the moment, and accept that we cannot evaluate these therapies using the normal rules of evidence-based practice (3), application of which would exclude all from further consideration were this any other disease than COVID-19.

I will focus on four unproven therapies that are currently being given to patients with COVID-19 infection: hydroxychloroquine (4), tissue plasminogen activator (tPA) and heparin for presumed pulmonary microthrombosis (5), immunosuppressive treatment of “cytokine storm” (6), and transfusion of convalescent serum (7).

I based my opinions on these four unproven therapies on the following principles:

1. COVID-19 is a viral pneumonia. Although it may prove to have some distinctive features, it is likely to be similar to other viral pneumonias (such as SARS CoV-1, MERS, and H1N1 influenza) in terms of its clinical manifestations and response to therapy. We are more likely to gain helpful insights by looking at previous clinical data related to viral pneumonia than to data regarding various noninfectious entities such as high-altitude pulmonary edema or pulmonary venous occlusive disease, as some authors have suggested. COVID-19 viral pneumonia is unlikely, a priori, to respond to therapies that have never shown clinical benefit in the treatment of other viruses, particularly viral pneumonias.
2. Demonstration of in-vitro activity rarely translates into clinical efficacy (8,9). In-vitro activity should be a basis for clinical trials, not bedside implementation.
3. If unproven therapies are to be given, their safety must be an important consideration. First do no harm.
4. We should be willing to apply any treatment recommendation we make for patients to ourselves or beloved family members.

Based on these principles, I propose the following:

Hydroxychloroquine. The non-specific anti-viral properties of chloroquine and hydroxychloroquine were demonstrated in cell cultures 40 years ago. Although active in vitro against Dengue, HIV, Ebola, Influenza and other viruses, this has never convincingly translated into clinical effectiveness (9). A large cohort study focusing on prevention of influenza pneumonia included over 4000 patients receiving HCQ, and showed that they had an increased risk of hospitalization for pneumonia compared to controls (10). Given this long track record, it seems unlikely that HCQ will suddenly be found to have clinical anti-viral benefit in 2020. When it is nevertheless given, care should be exercised to monitor QTc, especially if used in conjunction with other QTc-prolonging drugs like azithromycin and/or in patients with cardiomyopathy.

tPA and heparin. A high incidence of venous thromboembolism has been observed in some cohorts of COVID-19 patients, as has previously been described in patients with H1N1 pneumonia (11).  Standard thromboprophylaxis should be employed and venous thromboembolism should be diagnosed and treated in patients with COVID-19 infection. However, some clinicians are administering tPA and therapeutic-dose heparin to patients with COVID-19 and elevated D-dimer in the absence of documented DVT or PE, based on the theory that these patients have microvascular thrombosis requiring treatment. Several large multicenter RCTs examined the use of human activated protein C (Xigris®) to prevent/treat microvascular thrombosis in patients with severe sepsis and convincingly demonstrated no clinical benefit (12). There is no other infectious disease for which the use of tPA or treatment-dose heparin has been proven to be clinically beneficial in the absence of standard indications related to documented venous thromboembolism. Lytic/antithrombotic therapy has a relatively high potential for causing life-threatening hemorrhage. In my opinion, it should not be employed without support from well-designed clinical trials. 

Cytokine Storm or HLH. The terms cytokine storm and hemophagocytic lymphohistiocytosis (HLH) have been used to describe similar (perhaps identical) maladaptive immune responses to viral infections. HLH has been well-described in H1N1 pneumonia, SARS-CoV-1 and MERS. There is a rich history of (mostly) observational clinical research supporting the use of immunosuppressive therapies including steroids, anakinra and tocilizumab to treat HLH secondary to viral infection (13). Although immunosuppression can be associated with life-threatening secondary opportunistic infections, treating secondary HLH in selected patients is an approach with a long track record and could be considered standard therapy in Covid19 patients fulfilling HLH diagnostic criteria.

Convalescent Serum. The use of convalescent serum is supported by low-quality observational data going back over 100 years. Although never proven effective in well-designed clinical trials, prior reports in patients with Spanish influenza, SARS-CoV-1 and H1N1 all suggest potentially significant reductions in mortality with acceptable safety (14-16). This therapy is more difficult to operationalize, requiring (expedited) FDA approval, collection, processing and testing of neutralizing antibody titers by a licensed blood bank (17), however based on the principles outlined above, its benefit/harm ratio seems to support its use as an investigational therapy in patients with life-threatening COVID-19.

References

1. Booth CM, Tannock IF. Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence. Br J Cancer 2014;110:551-5. [CrossRef] [PubMed]
2. Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19). Crit Care Med. 2020 Mar 27. [Epub ahead of print]. [CrossRef] [PubMed]
3. Guyatt GH, Sackett DL, Cook DJ. Users' guides to the medical literature. II. How to use an article about therapy or prevention. A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA. 1993 Dec 1;270(21):2598-601. [CrossRef] [PubMed]
4. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial [published online ahead of print, 2020 Mar 20]. Int J Antimicrob Agents. 2020;105949. [CrossRef] [PubMed]
5. Wang J., Hajizadeh N, Moore EE, et al. Tissue plasminogen activator (tpa) treatment for COVID‐19 associated acute respiratory distress syndrome (ARDS): a case series. J Thromb Haemost. 2020 (in press). [CrossRef] [PubMed]
6. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-4.[CrossRef] [PubMed]
7. Duan K, Liu B, Cesheng L, Zhang H, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020 Apr 6. pii: 202004168. [CrossRef] [PubMed]
8. Seyhan, A.A. Lost in translation: the valley of death across preclinical and clinical divide - identification of problems and overcoming obstacles. Transl Med Commun. 2019;4:18. [CrossRef]
9. Dyall J, Gross R, Kindrachuk J, et al. Middle east respiratory syndrome and severe acute respiratory syndrome: current therapeutic options and potential targets for novel therapies. Drugs. 2017;77:1935-66. [CrossRef] [PubMed]
10. Vanasse A, Courteau J, Chiu Y, Cantin A, Leduc R. Hydroxychloroquine: an observational cohort study in primary and secondary prevention of pneumonia in an at-risk population. MedRxIv .April 10, 2020. [CrossRef]
11. Bunce PE, High SM, Nadjafi M, Stanley K, Liles WC, Christian MD. Pandemic H1N1 influenza infection and vascular thrombosis.Clin Infect Dis. 2011 Jan 15;52(2):e14-7.
12. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012 May 31;366(22):2055-64. [CrossRef] [PubMed]
13. Yildiz H, Van Den Neste E, Defour JP, Danse E, Yombi JC. Adult haemophagocytic lymphohistiocytosis: a review. QJM. 2020 Jan 14. [Epub ahead of print] [CrossRef] [PubMed]
14. Luke TC, Kilbane EM, Jackson JL, et al. Meta-analysis: convalescent blood products for spanish influenza pneumonia: a future H5N1 treatment?. Ann Intern Med. 2006;145:599-609. [CrossRef] [PubMed]
15. Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011 Feb 15;52(4):447-56. [CrossRef] [PubMed]
16. Yeh KM, Chiueh TS, Siu LK, et al. Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital. J Antimicrob Chemother. 2005 Nov;56(5):919-22. [CrossRef] [PubMed]
17. US Food & Drug Administration. Recommendations for Investigational COVID-19 Convalescent Plasma. April 8, 2020. Available at:https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma (accessed 4/10/20).

Cite as: Raschke RA. Choosing among unproven therapies for the treatment of life-threatening covid-19 infection: a clinician’s opinion from the beside. Southwest J Pulm Crit Care. 2020;20(4):131-4. doi: https://doi.org/10.13175/swjpcc026-20 PDF 

April 2020 Critical Care Case of the Month: Another Emerging Cause for Infiltrative Lung Abnormalities

Henry W. Luedy, MD¹

Sandra L. Till, DO²

Robert A. Raschke, MD¹

¹HonorHealth Scottsdale Osborn Medical Center

²Banner University Medical Center-Phoenix

Phoenix, AZ USA

Editor’s Note: the following case presentation represents a compilation of several patients.

History of Present Illness

The patient is a 27-year-old man who presented to the Emergency Department in late February 2020 with fever, cough, and green sputum production. He was recently in Hawaii where he meant his Asian girlfriend and was “partying hard”. He was intoxicated and had recent nausea and vomiting.

PMH, SH and FH

No significant PMH or FH. He does admit to smoking, marijuana use, THC use, and vaping. 

Physical Examination

• Vital Signs: BP 111/54 (BP Location: Right arm)  | Pulse 74  | Temp 98.7 °F (37.1 °C) (Oral)  | Resp 18  | Ht 5' 11" (1.803 m)  | Wt 72.6 kg (160 lb)  | SpO2 99%  | BMI 22.32 kg/m²
• General:  Awake, alert, interactive, no acute distress
• HEENT:  Anicteric, moist mucosa, trachea midline
• CV:  RRR
• Lungs: bilateral lower lobe rhonchi, no wheezing, symmetric expansion
• Abdomen: Soft, non-tender, non-distended, positive bowel sounds
• Extremities: no Lower extremity edema, no clubbing, no cyanosis
• Neuro:  No focal deficits, moves all extremities.
• Psych:  Appropriate

Which of the following are appropriate at this time? (Click on the correct answer to be directed to the second of six pages.)

1. CBC
2. Chest X-ray
3. Electrolytes
4. 1 and 3
5. All of the above

Cite as: Luedy HW, Till SL, Raschke RA. April 2020 critical care case of the month: another emerging cause for infiltrative lung abnormalities. Southwest J Pulm Crit Care. 2020;20(4):119-23. doi: https://doi.org/10.13175/swjpcc018-20 PDF 

Further COVID-19 Infection Control and Management Recommendations for the ICU

Robert A. Raschke MD

HonorHealth Osborne Medical Center

Scottsdale, AZ USA

An ad hoc committee of intensivists from the Phoenix area has been meeting via Zoom. They are sharing some of their thoughts and recommendations. Like the previous ICU recommendations published in SWJPCC (1), these are not necessarily evidence-based but based on recent experience and published experience with previous coronavirus outbreaks such as SARS. They are meant to supplement CDC recommendations, not to conflict or restate them.

Infection control outside the rooms of suspected/confirmed COVID-19 patients.

1. All healthcare workers should be allowed to exercise droplet precautions at all times while at work.
2. All staff should wear a single surgical mask per day to see all non-COVID patients and for rounds. The mask mitigates droplet spread bidirectionally between patients and HCWs and also helps prevent inadvertent touching of the nose and mouth.
3. Treat all code patients with airborne / standard / contact precautions
4. Use MDIs in preference to SVNs (as long as MDIs hold out)
5. Reduce unnecessary staff and visitor traffic in all patient rooms. Avoid duplication of effort, repeated chest examinations with a stethoscope, in the same day by various doctors and nurses, are unlikely to benefit the care of most patients. Don’t enter the patient’s room without a specific purpose and try to perform multiple required tasks with each room entry.
6. Hand washing before/after: doorknobs, eating, using a computer, phones, googles.
7. Phones – use your own cellphone rather than shared landlines. Use speaker phone so you don’t have to touch your face.
8. Consolidate computer use temporally and geographically. Clean your entire workstation (keyboard, mouse, surrounding desktop) before and after each use.
9. Keep track of and clean any object on your person that might be contaminated with fomites. This includes any medical instruments that you touch will your gloved hands while seeing patients (stethoscope, pen light, googles, etc). Leave these at work.
10. When walking down hallways, don’t touch things.

Patients under investigation or with known COVID-19.

1. Avoid use of high-flow nasal cannula (HFNC) or BiPAP. This in opposition to surviving sepsis campaign recommendations, but data from SARS-CoV-1 show that non-invasive ventilation was associated with increased risk of infection of health care workers (2).
2. Use metered dose inhalers (MDIs) instead of small volume nebulizers (SVNs).
3. Use N95 or PAPR during aerosol-producing procedures such as obtaining nasopharyngeal swab for SARS-CoV-2 RT-PCR, HFNC, BiPAP, bronchoscopy, intubation, breaking ventilator circuit for any reason, extubation, tracheostomy.
4. Consider early intubation. Prepare the bag mask with a high-efficiency particulate air (HEPA) filter and attempt rapid sequence intubation with fiberoptic laryngoscope.
5. If available, powered air-purifying respirators (PAPR) using P100 HEPA filters (filter >99.97% of 0.3 um particles) should be considered over N-95 (filter 95% of 5 um particles) masks during this high risk procedure based on prior reports of SARS CoV-1 transmission to health care workers (HCW) wearing N95 masks PAPR protects the entire head and neck of the HCW, but requires additional training on donning/duffing.
6. If unable to wear PAPR, we recommend N95 masks, gowns and gloves, with googles instead of open face shielded masks. Aerosolized particles are more likely to pass around shields into eyes during these high-risk procedures. Also recommend hats and foot protection.
7. The smallest number of personnel required to safely perform the intubation should be present in the room. Fiberoptic laryngoscopy may be preferred over direct laryngoscopy to reduce exposure to aerosolized particles.
8. Once intubated:
   1. Be sure all connections in the ventilator circuit are tight and do not break the circuit casually.  
   2. Place HEPA filter on exhalational limb of ventilator.
   3. Obtain bronchial secretions using closed-circuit suction device

Code blue patients.

1. Use the same precautions as for COVID-19 patients in all patients for whom a code is called.
2. We recommend aerosol, contact and standard precautions and eye protection for all code team members for all codes - regardless of whether COVID-19 is suspected. There is no time in a code to determine the likelihood the patient has COVID-19, and bag-masking and intubation will aerosolize the patient’s respiratory secretions.
3. A HEPA filter should be placed between the patient and the bag mask to reduce aerosolization of viral particles into the atmosphere.

Diagnosis of COVID-19.

The sensitivity of RT-PCR for COVID-19 is currently uncertain, but preliminary data suggests it may only be in the range of 70% for nasopharyngeal swabs and respiratory secretions. Bronchoscopy with bronchoalveolar lavage may have sensitivity about 90%, but likely poses a risk to HCWs. This poses difficulty in ruling-out COVID-19. Bayesian logic dictates that the pre-test probability of disease influences interpretation of test results.

During active epidemic in Wuhan, the prevalence of COVID-19 among patients admitted with suspicion of having viral pneumonia was 60% (3). Assuming sensitivities by RT-PCR for NP swab of 70%, respiratory secretions 70%, and BAL 90%, and specificity >95%, the false negative rate for a single NP swab used to rule out  COVID-19 is 31.6% - that is, 31.6% of patients taken out of isolation based on the negative NP swab result would actually be infected with COVID-19. If a second test, for instance respiratory secretions or another NP swab were performed on all patients whose first test was negative, the false negative rate for the series of tests is 8.8% - likely still not good enough to rule a patient out with confidence. If the second test was a BAL, the false negative rate for the series is 3.5%.

In patients with high pre-test probability of COVID-19, a negative NP swab PCR cannot be safely relied-upon to rule out COVID-19. We recommend bronchial secretions be sent for PCR (in addition to NP swab) in all suspected patients who are intubated. A negative CT scan reduces the probability that a hospitalized patient has COVID-19, but will uncommonly be “negative” in hospitalized patients in whom the diagnosis is considered.

Infection control at home during a surge.

1. Clothes: don’t wear jewelry/watches. Wear hospital-laundered scrubs at work, or take off your work clothes when you get home and throw them in wash machine. Leave your work shoes in your car.
2. Work equipment: Leave stethoscope, pen, googles and other work-related equipment in a locker at work. Wash your hands and ID badge just before getting in your car to leave the hospital. Leave your ID badge in your car while away from work. Don’t bring your personal computer into work unless absolutely necessary.
3. Food: Put a Purell dispenser in front of the refrigerator. Stay out of the kitchen. If have your food prepared for you. Eat on paper plates and then throw them out yourself.
4. Use separate bathroom and sleeping quarters if available.

References

1. Raschke RA, Till SL, Luedy HW. COVID-19 prevention and control recommendations for the ICU. Southwest J Pulm Crit Care. 2020;20(3):95-7. [CrossRef]
2. Cheng VC, Chan JF, To KK, Yuen KY. Clinical management and infection control of SARS: lessons learned. Antiviral Res. 2013 Nov;100(2):407-19. [CrossRef] [PubMed]
3. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan W. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020 Mar 11. [Epub ahead of print] [CrossRef] [PubMed]

Cite as: Raschke RA. Further COVID-19 infection control and management recommendations for the ICU. Southwest J Pulm Crit Care. 2020;20(3):100-2. doi: https://doi.org/10.13175/swjpcc020-20 PDF 

COVID-19 Prevention and Control Recommendations for the ICU

Robert A. Raschke, MD¹

Sandra L. Till, DO²

Henry W. Luedy, MD¹

¹HonorHealth Scottsdale Osborn Medical Center

²Banner University Medical Center-Phoenix

Phoenix, AZ USA

Editor’s Note: We are planning on presenting a case of COVID-19 from Osborn as our case of the month for April. The authors felt we should publish preliminary recommendations now early in the COVID-19 pandemic. The recommendations are not necessarily evidence-based but are based on recent experience and published experience with previous coronavirus outbreaks such as SARS.

Background:

• COVID-19 is likely somewhat more infectious than influenza (R value in 2-3 range), and can be transmitted by asymptomatic/presymptomatic persons.
• COVID-19 is already in the community and likely being spread from person to person, Therefore, not all COVID-19 patients will present with a recognized exposure history. Furthermore, fever and pneumonia are not universally present.
• As of this writing, >3,300 healthcare workers have been confirmed infected globally with 6 deaths.
• Testing is currently extremely limited in the US with only a minority of potential cases having been tested at this time. This will likely improve over the next few days to weeks. True incidence likely much higher than reported rates of “confirmed COVID-19”.
• About 15% of patients with confirmed COVID-19 have severe disease and 5% require ICU level care. Mortality rates of approximately 1-2% may be confounded by undertesting, but is currently more than 10 times higher than that of influenza (approx. mortality of 0.05-0.1%) (1).

Infectious disease control issues in the ICU. We recommend droplet, contact and standard precautions when seeing any patient presenting with symptoms of acute upper or lower respiratory tract infection of unknown etiology, regardless whether they meet full CDC criteria for COVID-19 testing. 

Studies during the SARS epidemic showed that intubation, bag-mask ventilation, non-invasive ventilation and tracheostomy procedures were all associated with increased transmission of SARS to healthcare workers (2).

Code arrest. We recommend aerosol, contact and standard precautions and eye protection for all code team members for all codes - regardless of whether COVID-19 is suspected. There is no time in a code to determine the likelihood of the patient having COVID-19, and bag-masking and intubation will aerosolize the patient’s respiratory secretions. A HEPA filter should be placed between the patient and the bag mask to reduce aerosolization of viral particles into the atmosphere.

Elective or semi-elective endotracheal intubation of patients with possible or confirmed COVID-19. If available, powered air-purifying respirators (PAPR) using P100 HEPA filters (filter >99.97% of 0.3 um particles) should be considered over N-95 (filter 95% of 5 um particles) masks during this high-risk procedure based on prior reports of SARS CoV-1 transmission to healthcare workers wearing N95 masks (3). PAPR protects the entire head and neck of the HCW, but requires additional training on donning/duffing.

If unable to wear PAPR, we recommend N95 masks, gowns and gloves, with googles instead of open face shielded masks. Aerosolized particles are more likely to pass around shields into eyes during these high-risk procedures. We also recommend hats and foot protection.

The smallest number of personal required to safely perform the intubation should be present in the room. Fiberoptic laryngoscopy may be preferred over direct laryngoscopy to reduce exposure to aerosolized particles. Once intubated, a HEPA filter should be placed on the exhalational limb of the ventilator.

Non-invasive ventilation and high-flow nasal oxygen. Non-invasive ventilation and high-flow nasal oxygen likely increase the infectivity of COVID-19 by aerosolizing the patient’s respiratory secretions. Consideration should be given to early intubation in patients under investigation or confirmed for COVID-19 (4).

Visitors should not be allowed inside the rooms of such patients except under extreme circumstances and with one-on-one supervision to assure proper use of PPE and handwashing.

Furthermore, we think it is prudent to employ PPE in the rooms of all patients receiving these therapies, since patients with COVID-19 may present atypically (as in the Osborn case). The doors of their rooms should be kept closed, unnecessary traffic in the room reduced, and droplet contact and standard PPE considered, even in patients in whom COVID-19 is not suspected. (This approach has the downside of consuming PPE that might later be in short supply, but has the upside of preserving healthcare workers who also might later be in short supply).

References

1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. [Epub ahead of print]. [CrossRef] [PubMed]
2. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One. 2012;7(4):e35797. [CrossRef] [PubMed]
3. Cheng VC, Chan JF, To KK, Yuen KY. Clinical management and infection control of SARS: lessons learned. Antiviral Res. 2013 Nov;100(2):407-19. [CrossRef] [PubMed]
4. Zuo MZ, Huang YG, Ma WH, Xue ZG, Zhang JQ, Gong YH, Che L; Chinese Society of Anesthesiology Task Force on Airway Management. Expert recommendations for tracheal intubation in critically ill patients with noval [sic] coronavirus disease 2019. Chin Med Sci J. 2020 Feb 27. [CrossRef] [PubMed]

Cite as: Raschke RA, Till SL, Luedy HW. COVID-19 prevention and control recommendations for the ICU. Southwest J Pulm Crit Care. 2020;20(3):95-7. doi: https://doi.org/10.13175/swjpcc017-20 PDF