Why might hydroxychloroquine and azithromycin be effective against the novel Coronavirus SARS-CoV-2/Covid-19?

Repurposing of older drugs such as chloroquine or hydroxychloroquine (HC) and more recently, azithromycin (AZ), has received much attention recently in the treatment of Covid-19. Both HC and AZ have immune modulating and antiviral activity that may potentially be effective in our fight against Covid-19.

 
Chloroquine/HC: Chloroquine is an old drug used for its antimalarial activity as well as for its immune modulation and anti-inflammatory properties. It is active in mice against a variety of viruses, including some enteroviruses, Zika virus, and influenza A H5N1 (1). Both chloroquine and HC are active in vitro against Covid-19, though HC appears to be more active (2).

 
Azithromycin: A macrolide often used for treatment of bacterial respiratory tract infections but also with anti-inflammatory and antiviral activity. Azithromycin has been shown to augment interferon response in rhinovirus-infected bronchial epithelial cells as well as in an experimental mouse model of asthma exacerbation (3,4). It also has activity against Zika virus (5). As recently as 2016, some authors opined that macrolides may be useful in pandemic influenza characterized by excessive inflammatory cytokine production because of their anti-inflammatory and interferon-boosting potential (6).

 
March 2020 French clinical trial: A small non-randomized clinical trial involving 36 confirmed Covid-19 patients (mean age 45 y) reported that HC (200 mg 3x/day x 10 days) was associated with rapid viral clearance from nasopharynx, often within 3-6 days (7). The effect was even more pronounced when AZ (500 mg 1st day, followed by 250 mg daily x 4 days) was added in 6 patients.

It’s worth emphasizing that most subjects in this study were either asymptomatic (17%) or had mild disease with upper respiratory tract infection symptoms only (61%). Pneumonia was diagnosed in only 6 patients.  A significant number of patients in the treatment arm also dropped out of the study, some due to ICU transfer.

 
Although such preliminary reports appear promising, the proof of the efficacy and safety of HC and/or AZ in the treatment of Covid-19 awaits larger properly designed clinical studies. Stay tuned!

 

 

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References
1. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Research 2020;177. 104762. https://www.ncbi.nlm.nih.gov/pubmed/32147496
2. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respirartory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020, March 9. https://www.ncbi.nlm.nih.gov/pubmed/32150618
3. Menzel M, Akbarshai H, Bjermer L, et al. Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD patients. Scientific Reports 2016;6:28698. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923851/
4. Menzel M, Akbarshai H, Uller L. Azithromycin exhibits interferon-inducing properties in an experimental mouse model of asthma exacerbation. Eur Resp J 2015;46:PA5095. https://erj.ersjournas.com/content/46/suppl_59/PA5095
5. Retallack H, Di Lullo E, Knopp AC, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Nat Acad Sci USA 2016;113:14408-13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167169/
6. Porter JD, Watson J, Roberts LR, et al. Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III-IFN-augmenting activity in airway epithelium. J Antimicrob Chemother 2016;71:2767-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031920/
7. 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. International Journal of Antimicrobial Agents—In Press 17 March 2020-DOI: 10.1016/j.ijantimicag.2020.105949 . https://www.sciencedirect.com/science/article/pii/S0924857920300996

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why might hydroxychloroquine and azithromycin be effective against the novel Coronavirus SARS-CoV-2/Covid-19?

What findings should I look for in the chest imaging of my patients with the novel Coronavirus disease/Covid-19?

Chest imaging is often obtained to evaluate for pneumonia and progressive lung injury due to Covid-19. Given the concerns over healthcare worker exposure and environmental contamination, radiographic imaging should be minimized and obtained only when clinically indicated (1).

 
Routine chest radiograph: In a study involving over 1000 hospitalized patients with Covid-19, chest Xray abnormalities on admission were observed in about half of patients with nonsevere disease and three-quarters of those with severe disease (2). Many infiltrates are bilateral, patchy and peripheral in distribution (2,3).

 
Chest CT (without IV contrast):  CT abnormalities on admission have been observed in 84% of patients with nonsevere and 94% of patients with severe disease (2). Ground glass opacities (GGOs) and consolidation have been reported in the majority of patients. Infiltrates are often bilateral, peripheral, and posterior in distribution ( 2-5).

Compared to other causes of pneumonia, the most discriminating features of Covid-19 pneumonia on CT include peripheral distribution of infiltrates (80% vs 57%) and GGOs (91% vs 68%) (5).

CT findings are time dependent. Early during the course of infection, peripheral focal or bilateral multifocal GGOs are frequently observed, later giving rise to “crazy paving” and consolidation with occasional “reverse halo sign” as the disease progresses (see Bonus Pearl below), peaking around 9-13 days (6,7) . Pleural effusion and lymphadenopathy are uncommon (5,7).

 
Point of care ultrasound (POCUS): This relative newcomer offers a potentially useful and rapid means of evaluating for pneumonia or lung injury in Covid-19 and may be more sensitive than chest Xray. Its findings are not specific for Covid-19 lung pathology, however. In a preliminary report involving 12 patients with Covid-19 pneumonia (without ARDS) who underwent POCUS, a diffuse B-line pattern with spared areas was seen in all patients (8,9). Strict adherence to proper isolation precautions and decontamination of the ultrasound probe are essential.

 

Bonus Pearl: “Crazy paving” pattern on CT refers to GGOs with superimposed interlobular septal thickening and intralobular septal thickening, while “reversed halo sign” is a central GGO surrounded by denser consolidation of crescentic shape ring at least 2 mm in thickness (reference 7 has nice photos).

 

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References
1. ACR recommendations for the use of chest radiography and computed tomography (CT) for suspected COVID-19 infection. March 19, 2020. https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-Infection
2. Guan WJ, Zheng-yi N, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020; February 28. https://www.nejm.org/doi/full/10.1056/NEJMoa2002032
3. Ai T, Yang Z, Hou H, et al. Correlation of chest CT and RT-PCR testing in Coronavirus disease 2019 (COVID-19) in China: A report of 1014 cases. Radiology 2020. https://pubs.rsna.org/doi/10.1148/radiol.2020200642
4. Yoon SH, Lee KH, Kim JY, et al. Chest radiographic and CT findings of the 2019 Novel Coronavirus disease (COVID-19): Analysis of nine patients treated in Korea. Korean J Radiol 2020;21 :494-500. https://www.kjronline.org/Synapse/Data/PDFData/0068KJR/kjr-21-494.pdf
5. Bai HX, Hsieh B, Xiong Z, et al. Performance of radiologists in differentiating COVID-19 from viral pneumonia on chest CT. https://pubs.rsna.org/doi/10.1148/radiol.2020200823
6. Kanne JP, Little BP, Chung JH, et al. Essentials for radiologists on COVID-19: An update—Radiology scientific expert panel. Radiology 2020; February 27. https://pubs.rsna.org/doi/10.1148/radiol.2020200527

7. Bernheim A, Mei X, Huang M, et al. Chest CT findings in Coronavirus Disease-19 (COVID-19):Relations to duration of infection. Radiology 2020 Feb 20:200463.  https://pubs.rsna.org/doi/pdf/10.1148/radiol.2020200463
8. Poggiali E, Dacrema A, Bastoni D, et al. Can lung US help critical care clinicians in the early diagnosis of novel Coronavirus (COVID-19) pneumonia? Radiology 2020; https://www.ncbi.nlm.nih.gov/pubmed/32167853

9. Peng QY, Wang XT, Zhang LN, et al. Findings of lung ultrasonography of novel Coronavirus pneumonia during the 2019-2020 epidemic. Intensive Care Med 2020. https://doi.org/10.1007/s00134-020-05996.

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What findings should I look for in the chest imaging of my patients with the novel Coronavirus disease/Covid-19?

Key clinical pearls in the medical management of hospitalized patients with coronavirus (Covid-19) infection

First, a shout-out to dedicated healthcare workers everywhere who have selflessly given of themselves to care for the sick during this pandemic. Thank you! Together, I know we will get through it!

Although our understanding of Covid-19 infection is far from complete, in the spirit of clarity and brevity of my posts on Pearls4Peers, here are some key points I have gleaned from review of existing literature and the CDC that may be useful as we care for our hospitalized patients with suspected or confirmed Covid-19 infection.

  • Isolation precautions.1 Per CDC, follow a combination of airborne (particularly when aerosol generating procedures is anticipated, including nebulizer treatment) and contact precaution protocols. Routinely use masks or respirators, such as N-95s (subject to local availability and policy) and eye protection. Don gowns (subject to local availability and policy) and gloves and adhere to strict hand hygiene practices.

 

  • Diagnostic tests1-9
    • Laboratory tests. Routine admission labs include CBC, electrolytes, coagulation panels and liver and renal tests. Other frequently reported labs include LDH, C-reactive protein (CRP) and procalcitonin. Testing for high sensitivity troponin I has also been performed in some patients, presumably due to concern over ischemic cardiac injury or myocarditis.2 Check other labs as clinically indicated.
    • Chest radiograph/CT chest. One or both have been obtained in virtually all reported cases with CT having higher sensitivity for detection of lung abnormalities.
    • EKG. Frequency of checking EKGs not reported in many published reports thought 1 study reported “acute cardiac injury” in some patients, based in part on EKG findings.4 Suspect we will be checking EKGs in many patients, particularly those who are older or are at risk of heart disease.
    • Point-of-care ultrasound (POCUS). This relatively new technology appears promising in Covid-19 infections, including in rapid assessment of the severity of pneumonia or ARDS at presentation and tracking the evolution of the disease. 9 Don’t forget to disinfect the probe between uses!

 

  • Treatment 1-8
    • Specific therapies are not currently available for treatment of Covid-19 infections, but studies are underway.
    • Supportive care includes IV fluids, 02 supplementation and nutrition, as needed. Plenty of emotional support for patients and their families will likely be needed during these times.
    • Antibiotics have been used in the majority of reported cases, either on admission or during hospitalization when superimposed bacterial pneumonia or sepsis could not be excluded.
      • Prescribe antibiotics against common community-acquired pneumonia (CAP) pathogens, including those associated with post-viral/influenza pneumonia such as Streptococcus pneumoniae (eg, ceftriaxone), and Staphylococcus aureus (eg, vancomycin or linezolid if MRSA is suspected) when concurrent CAP is suspected.
      • Prescribe antibiotics against common hospital-acquired pneumonia (HAP) (eg, vancomycin plus cefepime) when HAP is suspected.
    • Corticosteroids should be avoided because of the potential for prolonging viral replication, unless indicated for other reasons such as COPD exacerbation or septic shock. 1
    • Monitor for deterioration in clinical status even when your hospitalized patient has relatively minor symptoms. This is because progression to lower respiratory tract disease due to Covid-19 often develops during the 2nd week of illness (average 9 days).
    • ICU transfer may be necessary in up to 30% of hospitalized patients due to complications such as ARDS, secondary infections, and multi-organ failure.

 

Again, thank you for caring for the sick and be safe! Feel free to leave comments or questions.

 

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References

  1. CDC. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html
  2. Ruan Q, Yang K, Wang W, Jiang L, et al. Clinical predictors of mortality due to COVID-19 based on analysis of data of 150 patients with Wuhan, China. Intensive Care Med 2020. https://link.springer.com/article/10.1007/s00134-020-05991-x
  3. Holshue ML, BeBohlt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020;382:929-36. https://www.nejm.org/doi/full/10.1056/NEJMoa2001191
  4. Huang C, Wang Y, Li Xingwang, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)30183-5.pdf
  5. Young BE, Ong SWX, Kalimuddin S, et al. Epideomiologic features and clinical course of patients infected with SARS-CoV-2 Singapore. JAMA, March 3, 2020. Doi.10.1001/jama.2020.3204 https://www.ncbi.nlm.nih.gov/pubmed/32125362
  6. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical chacteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507-13. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30211-7/fulltext
  7. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl Med 2020, Feb 28, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2002032
  8. Zhang J, Zhou L, Yang Y, et al. Therapeutic and triage strategies for 2019 novel coronavirus disease in fever clinics. Lancet 2020;8: e11-e12. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30071-0/fulltext 9.
  9. Peng QY, Wang XT, Zhang LN, et al. Findings of lung ultrasonography of novel corona virus pneumonia during the 2019-2020 epidemic. Intensive Care Med 2020. https://doi.org/10.1007/s00134-020-05996-
Key clinical pearls in the medical management of hospitalized patients with coronavirus (Covid-19) infection

What’s the evidence that respiratory viruses, including Covid-19, can be transmitted by touching contaminated surfaces?

Although no published data specific to Covid-19 is yet available, transmission by contact with contaminated surfaces has been implicated in infections due to several respiratory viruses, such as other human coronaviruses and influenza viruses. 1,2

A 2020 review article involving 22 published studies found that human coronaviruses such as SARS, MERS or common cold coronaviruses (eg, HCoV-229E) can persist on inanimate surfaces (eg, metal, glass or plastic) for hours up to 9 days depending on the level of initial viral contamination.1  

A recent NEJM study reported Covid-19 persisting  for 72 h on plastic and 48 h on stainless steel (3). Shorter survival was observed on cardboard (24 h or less) and copper surface (4 h or less). Although data on transmissibility of coronaviruses from contaminated surfaces to hands is not currently available, at least in the case of influenza A, a contact time of 5 seconds may transfer 31.6% of the viral load to the hands.4

But hand contamination doesn’t necessarily stop there.  We constantly touch our faces, including nose, eyes, and mouth, all serving as potential entry points for the virus.   One study found that, on average, subjects touched their faces 23 times per hour, with nearly one-half of that time involving either the nose, eyes or mouth. 5 Another study reported touching one’s face on average 19 times in a 2-hour period (range 0-105 times!).

For these reasons, environmental decontamination and hand hygiene have been stressed as part of the ongoing strategies to limit Covid-19 spread.

The good news is that coronaviruses are efficiently inactivated by many of the commonly available disinfectants and antiseptics, including 62%-71% ethanol, 70% isopropyl alcohol, 1:50 dilution of household bleach, and 0.5% hydrogen peroxide. 1

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References

  1. Kampf G, Todt D, Pfaender S, et al. Persistence of coronavirus on inanimate surfaces and their inactivation with biocidal agents. J Hosp Infect 2020;104:246-51. https://www.ncbi.nlm.nih.gov/pubmed/32035997
  2. Otter JA, Donskey C, Yezli S, et al. Transmission of SARS and MERS coronaviruses and influenza virus in healthcare settings: the possible role of dry surface contamination. J Hosp Infect 2016;92:235-250. https://www.ncbi.nlm.nih.gov/pubmed/26597631/
  3.  van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med 2020, March 17. https://www.nejm.org/doi/10.1056/NEJMc2004973
  4. Bean B, Moore BM, Sterner B, et al. Survival of influenza viruses on environmental surfaces. J Infect Dis 1982;146:47-51. https://www.ncbi.nlm.nih.gov/pubmed/6282993
  5. Kwok YL, Garlton J, McLaws ML. Face touching: a frequent habit that has implications for hand hygiene. Am J Infect Control 2015;43:112-4. https://www.ncbi.nlm.nih.gov/pubmed/25637115
  6. Elder NC, Sawyer W, Pallerla H, et al. Hand hygiene and face touching in family medicine offices: a Cincinnati Area Research and Improvement group (CARInG) Network Study. J Am Board Fam Med 2014;27:339-346. https://www.jabfm.org/content/27/3/339.long
What’s the evidence that respiratory viruses, including Covid-19, can be transmitted by touching contaminated surfaces?