Coronavirus;

How common are neurological symptoms in patients with Covid-19 infection?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , Leave a comment

Although we usually think of it as primarily a respiratory tract disease, neurological manifestations with Covid-19 are not at all uncommon,1-6 occurring in over one-third of hospitalized patients with Covid-19 according to one medRxiv report.1

In a Chinese study1 involving 214 hospitalized patients with Covid-19, 36.4% had 1 or more neurological symptoms, with the majority involving the central nervous system (CNS) (25.0%), of which the most common complaints were dizziness (17%) and headache (13.0%). Some patients (9.0%) had cranial nerve/peripheral nerve complaints of which the most common were difficulty with taste (hypogeusia) (6.0%) and sense of smell (hyposmia) (5.0%).  A fewer number of patients had impaired consciousness, acute cerebrovascular disease (including ischemic stroke and cerebral hemorrhage). Although not strictly-speaking a neurological manifestation, the study also reported “muscle injury” in ~20.0% of patients     (defined as myalgia plus CK >200 IU/L).

Descriptions of Covid-19 encephalopathy, including one associated with acute hemorrhagic necrotizing process, are also beginning to appear in the literature.3-5 Reports of “Neuro-Covid-19 units” in Italy further underlines the common occurrence of neurological symptoms in these patients.6

More than one mechanism for neurological complications in Covid-19 are likely,  including:1-2

  1. Direct viral invasion into the CNS which could explain the associated headache, high fever, vomiting, convulsions, and consciousness disorders. Some have reported normal CSF parameters but a report of PCR positive CSF suggests direct injury from the virus itself.2 Covid-19 virus may gain access to the CNS through direct invasion of neuronal pathways (eg. olfactory nerve given recent reports of difficulty with sense of smell) or through blood circulation.
  2. Indirect CNS injury through extreme systemic derangements such as hypoxia, or immune/inflammatory response-related injury (eg, through cytokines, hypercoagulability related to infection). Some have also posited that binding of Covid-19 virus to ACE2 may cause abnormally elevated blood pressure and increase the risk of cerebral hemorrhage.2

The fact that Covid-19 is so versatile and affects the nervous system as well shouldn’t surprise us. Neurological complications have been reported with couple of other related respiratory Coronaviruses such as those of SARS and MERS.2

 

Bonus pearl: Did you know that as early 1970-80s some coronaviruses were shown to cause “nasoencephalopathy” when injected intranasally in mice with subsequent spread to the CNS through the olfactory nerve?7 Maybe we shouldn’t be too surprised that sense of smell is impaired in some Covid-19 patients. If we could only stop the virus at the nose!

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References

  1. Mao L, Wang M, Chen S, et al. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective case series study. https://www.medrxiv.org/content/10.1101/2020.02.22.20026500v1
  2. Wu Y, Xu X, Chen Z, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, Behavior, and Immunity 2020, March 30. https://www.sciencedirect.com/science/article/pii/S0889159120303573
  3. Xiang et al. 2020. First case of 2019 novel Coronavirus disease with encephalitis. ChinaXiv, T202003 (2020), p. 00015 (obtained from reference 2).
  4. Poyiadji N, Shain G, Noujaim D, et al. COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology 2020 https://pubs.rsna.org/doi/10.1148/radiol.2020201187
  5. Filatov A, Sharma P, Hindi F, et al. Neurological complications of coronavirus (COVID-19): encephalopathy. Cureus 12(3): e7352. DOI 10.7759/cureus.7352 https://www.cureus.com/articles/29414-neurological-complications-of-coronavirus-disease-covid-19-encephalopathy
  6. Talan J. COVID-19: Neurologists in Italy to Colleagues in US: Look for poorly-defined neurologic conditions in patients with the Coronavirus. Neurology Today 2020, March 27. https://journals.lww.com/neurotodayonline/blog/breakingnews/pages/post.aspx?PostID=920
  7. Perlman S, Jacobsen G, Afifi A. Spread of a neurotropic murine Coronavirus into the CNS via the trigeminal and olfactory nerves. Virology 1989;170:556-560 https://www.sciencedirect.com/science/article/pii/0042682289904467

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!

How common are neurological symptoms in patients with Covid-19 infection?

How long are the symptoms of hospitalized patients with Covid-19 expected to last?

FA Manian MD, MPH, , , , , , , , , , , Leave a comment

Although most patients with Covid-19 may have mild or no symptoms, those who are ill enough to be hospitalized often have fever, cough, or shortness of breath that lasts for 2 weeks or longer. 

Fever: A Chinese study 1 involving 137 successfully discharged hospitalized patients reported that fever (37.3° C or 99.1° F or higher) lasted a median of 12 days (range 8-13 days). It’s important to point out that nearly one-quarter of these patients were also placed on corticosteroids during their hospitalization which might have resulted in the resolution of fever sooner and therefore altered the “natural course” of Covid-19.  In a smaller study from Singapore2 involving generally less ill hospitalized patients, fever didn’t usually last as long (median 4 days, range 0-15 days). 

Cough/shortness of breath: Cough may last nearly 3 weeks (median 19 days) while shortness of breath can go on for about 2 weeks (median 13 days).1

All symptoms: Even among those who are less ill and do not require supplemental oxygen, it may take nearly 2 weeks (median 12 days, range 5-24 days) for all the Covid-19-related symptoms (defined as fever, cough, and shortness of breath, sore throat, diarrhea, and rhinorrhea) to resolve.2 

It goes without saying that recovery from Covid-19 among hospitalized patients may be slow. In a Seattle study3 involving hospitalized patients who were admitted to the ICU, the median duration on the ventilator was 10 days (IQR 7-12 days), and the median length of hospital stay was 17 days (IQR 16-23 days).

Hopefully, as we find effective anti-Covid-19 drugs, the duration of these symptoms and length of hospitalization can be significantly reduced. Stay tuned!

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References

  1. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COCID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext
  2. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 2020; March 3, 2020 (corrected March 20). https://jamanetwork.com/journals/jama/fullarticle/2762688
  3. Bhatraju PK, Ghassemieh BJ, Nichols M, et al. Covid-19 in critically ill patients in the seattle region—Case series. N Engl J Med 2020; March 30. https://www.nejm.org/doi/full/10.1056/NEJMoa2004500

 

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!

How long are the symptoms of hospitalized patients with Covid-19 expected to last?

What is the role of prone ventilation in patients with Covid-19 and ARDS?

FA Manian MD, MPH, , , , , , , , Leave a comment

A 2017 guideline strongly recommends the use of prone ventilation for 12+ hours daily in individuals with severe ARDS (1). A JAMA article gave similar recommendations for critically ill patients with COVID-19 (2).

The recommendations are often based on a NEJM 2013 randomized-controlled study involving 466 patients with severe ARDS (3). While previous research had demonstrated improved oxygenation in the prone position (4), this study demonstrated a significant survival benefit (3).  Mortality at 28 days was 16.0% in prone patients versus 32.8% in supine patients (p<0.001; HR 0.39 with 95% CI, 0.29 – 0.67) (3). Mortality was also lower in prone patients at 90 days (3).  A meta-analysis of 4 additional randomized-controlled trials confirmed the survival benefits (1). 

In patients with Covid-19 and ARDS, a small retrospective study involving 12 patients showed a significant association between prone positioning and lung recruitability (ie, lung tissue in which aeration can be restored) (p = 0.020) (5).

Physiologically, numerous mechanisms have been proposed for these findings, including the possbility that while blood flow consistently favors the dorsal alveoli regardless of position, the prone position allows dorsal alveoli to reopen, improving ventilation/perfusion matching (6). 

Of note, some institutions find difficulties with prone positioning, including higher rates of pressure sores and endotracheal tube obstruction (1).

 

Contributed by Grant Steele, Harvard Medical Student, Boston, MA.

 

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References:

1. Fan E, Del Sorbo L, Goligher E, et al. An official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome.” Am J Respir Crit Care Med 2017;195:1253-1263. https://www.atsjournals.org/doi/abs/10.1164/rccm.201703-0548ST 
2. Murthy S, Gomersall C, & Fowler R. Care for critically ill patients with COVID-19. JAMA – Published online March 11, 2020. doi:10.1001/jama.2020.3633 https://jamanetwork.com/journals/jama/fullarticle/2762996
3. Guérin C, Reignier J, Richard J-C, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159-2168. https://www.nejm.org/doi/full/10.1056/nejmoa1214103
4. Abroug F, Ouanes-Besbes L, Elatrous S, et al. The effect of prone positioning in acute respiratory distress syndrome or acute lung injury: a meta-analysis. Areas of uncertainty and recommendations for research. Intensive Care Medicine – Published online March 19, 2008. doi: 10.1007/s00134-008-1062-3 https://link.springer.com/article/10.1007/s00134-008-1062-3
5. Pan C, Chen L, Lu C, et al. Lung Recruitability in SARS-CoV-2 Associated Acute Respiratory Distress Syndrome: A Single-center, Observational Study. Am J Respir Crit Care Med – Published online March 23, 2020. doi: 10.1164/rccm.202003-0527LE. https://www.atsjournals.org/doi/pdf/10.1164/rccm.202003-0527LE 
6. Nyrén S, Mure M, Jacobsson H, et al. Pulmonary perfusion is more uniform in the prone than in the supine position: scintigraphy in healthy humans. J Appl Physiol 1999;86:1135-1141. https://www.physiology.org/doi/abs/10.1152/jappl.1999.86.4.1135

 

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 is the role of prone ventilation in patients with Covid-19 and ARDS?

5 Covid-19 facts worth keeping in mind as we deal with our pandemic anxiety

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , 1 Comment

As an infectious disease physician who had the privilege of caring for many patients during the unsettling times of the early HIV epidemic and the more recent H1N1 pandemic influenza, I fully understand the widespread anxiety the current Covid-19 pandemic has inflicted on our society.

Here are 5 scientific facts that may be worth remembering as we try to deal with our pandemic anxiety.

 
1. On transmission in the community: For sure, Covid-19 is transmitted in the community but I am glad that it behaves more like influenza which is primarily contracted through close personal contact and droplets, and less like measles or chickenpox which are considered airborne with viral particles travelling lingering in the air for long periods of time. On average, a patient with Covid-19 may infect 2-3 susceptible contacts vs as many as 12 or more in the case of patients with measles or chickenpox (1, 2).

 
2. On transmission in healthcare settings: For sure, Covid-19 can be transmitted in the healthcare settings, just like other coronaviruses, such severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS) coronaviruses. But the good news is that, in the absence of aerosol-producing procedures (eg, intubation, nebulizer therapy) it doesn’t seem to behave like an airborne virus (see above) and adherence to droplet and contact precautions, including donning of masks, gowns, eye protection and hand hygiene has been effective (3, 4).

 
3. On surface viability after cleaning/disinfection: For sure, the novel 2019 coronavirus SARS-CoV-2, the cause of Covid-19, can be found on surfaces outside of the body. But the good news is that, in contrast to hardy viruses such as norovirus, it succumbs to common disinfection and environmental cleaning procedures. That’s because  coronaviruses have a lipid envelope that easily falls apart under usual cleaning and disinfection of surfaces. That means that simple handwashing with soap and water (minimum 20 seconds), alcohol containing hand hygiene products, detergents and diluted bleach should easily inactivate it (5-9) and that’s good!

 
4. On the course of Covid-19: For sure, Covid-19 can make people very sick and, tragically, may be fatal on occasion. But compared to diseases caused by other recent respiratory coronaviruses such as MERS or SARS, the overall mortality associated with Covid-19 is much lower (often ~ 2.0-3.0% or lower vs 36.0% for MERS and ~10.0% for SARS) (1). In fact, the majority of patients (~80%) may have no symptoms or only have mild disease (10). I am thankful that we are not dealing with a transmissible respiratory virus that has mortality rates like that of MERS.

 
5. On the timing of this pandemic: We are fortunate that this is 2020 not 1918-19 when a particularly virulent form of influenza, dubbed as “the mother of all pandemics” infected some 500 million people (a third of the world’s population at the time) and accounted for an estimated 50 million deaths (11). Imagine fighting a pandemic without the technology to identify its cause. Imagine fighting a pandemic without access to the miracles of modern science and medicine, including antibiotics for secondary bacterial pneumonia, artificial ventilation, dialysis, ICU support, and capability to screen for an infectious agent.  Imagine fighting a pandemic without scientific tools to develop effective antimicrobials or vaccines. Imagine fighting a pandemic without the luxury of the internet.

 
As unprepared as we all feel in combatting Covid-19, I take solace in the fact that our armamentarium and collective determination to mount an effective response to this pandemic has never been better. Even during these uncertain times, I reflect on what could have been and remain optimistic. Be safe!

 

 

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References:
1. Fauci AS, Lane HC, Redfield RR. Covid-19—Navigating the uncharted. N Eng J Med 2020. DOI:10.1056/NEJMe2002387. https://www.nejm.org/doi/full/10.1056/NEJMe2002387
2. Delamater PL, Street EJ, Leslie TF, et al. Complexity of the basic reproduction number (R0). Emerg infect Dis 2019;25:1-4. https://wwwnc.cdc.gov/eid/article/25/1/17-1901_article
3. Seto WH, Tsang D, Yung RWH, et al. Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS). Lancet 2003;361:1519-20. https://www.sciencedirect.com/science/article/pii/S0140673603131686
4. Ng K, Poon BH, Puar THK, et al. COVID-19 and the risk to health care workers: a case report. Ann Intern Med. 2020, March 16. https://annals.org/aim/fullarticle/2763329/covid-19-risk-health-care-workers-case-report
5. van Doremalen N, Bushmaker, Morris DH, et al. Aerosol and surface stability of HCoV-19 (SARS-CoV-2) compared to SARS-CoV-1. N Engl J Med 2020. https://doi.org/10.1101/2020.03.09.20033217
6. Kampf G. Efficacy of ethanol against viruses in hand disinfection. J Hosp Infect 2018;98:331-38. https://www.sciencedirect.com/science/article/pii/S0195670117304693
7. Grayson ML, Melvani S, Druce J, et al. Efficacy of soap and water and alcohol-based hand-rub preparations against live H1N1 influenza virus on the hands of human volunteers Clin Infect Dis 2009;48:285-91. https://www.ncbi.nlm.nih.gov/pubmed/19115974/
8. Service RF. Does disinfecting surfaces really prevent the spread of coronavirus? Science 2020, March 12. https://www.sciencemag.org/news/2020/03/does-disinfecting-surfaces-really-prevent-spread-coronavirus
9. CDC. Norovirus. https://www.cdc.gov/vitalsigns/norovirus/index.html
10. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020. First published Feb 28, 220, last updated March 6, 2020. https://www.nejm.org/doi/10.1056/NEJMoa2002032
11. Taubenberger JK, Morens DM. 1918 influenza: the mother of all pandemics. Emerg Infect Dis 2006;12:15-22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291398/

 

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!

 

 

5 Covid-19 facts worth keeping in mind as we deal with our pandemic anxiety

Do statins have a role in treating novel Coronavirus infection, COVID-19?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

There is currently no firm clinical evidence that statins improve the outcome of COVID-19. However, there are some theoretical reasons for believing that statins may have a role in the treatment of COVID-19.  That’s because beyond their cholesterol lowering action, statins may also have clinically relevant anti-inflammatory and antiviral (pleotropic) properties.  

Anti-inflammatory: Anti-inflammatory effect of statins is well known and is thought to occur through a variety of molecular pathways of the innate and adaptive immune systems as well as attenuation of several circulating proinflammatory cytokines.1 Although observational studies have suggested that statins lower hospitalization and mortality among outpatients hospitalized with infection, pneumonia or sepsis, several randomized controlled trials (RCTs) have failed to show any mortality benefit among ICU patients with sepsis and ARDS treated with statins.2

In contrast, an RCT involving patients with sepsis (majority with pneumonia, mean CRP 195 mg/dL) reported significant reduction in progression to severe sepsis among statin-naïve patients  placed on atorvastatin 40 mg/day at the time of hospitalization.3 So, perhaps timing of statin therapy before florid sepsis and ARDS is an important factor.  

Some have suggested that statins may decrease the fatality rate of a related Coronavirus, Middle East Respiratory Syndrome (MERS) virus, by blunting exuberant inflammatory response that may result in a fatal outcome. 4

Antiviral: Statins may also have antiviral properties, including activity against influenza, hepatitis C virus, Zika and dengue viruses.2,5 Whether statins have activity against coronaviruses such as the agent of COVID-19 is unclear at this time.

It’s interesting to note that cholesterol may have an important role in the membrane attachment, fusion and replication of many enveloped viruses, including influenza.5 Covid-19 is also an enveloped virus.

So what do we do? Based on the current data, it makes sense to continue statins in patients who have known clinical indications for their use and no obvious contraindications because of COVID-19 (eg. rhabdomyolysis).6 As for statin-naïve patients, particularly those in early stages of sepsis and increased risk of cardiovascular events, benefit may outweigh the risk.  Only proper clinical studies will give us more definitive answers.

Bonus Pearl: Did you know that lipids make up a major component of the envelope in enveloped viruses and that cholesterol makes up nearly one-half of total lipid and over 10% the total mass of influenza viruses?

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References

  1. Tousoulis D, Psarros C, Demosthenous M, et al. Innate and adaptive inflammation as a therapeutic target in vascular diseae: The emerging role of statins. J Am Coll Cardiol 2014;63:2491-2502. https://www.sciencedirect.com/science/article/pii/S0735109714011553?via%3Dihub
  2. Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med 2016;4:421. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124618/pdf/atm-04-21-421.pdf
  3. Patel JM, Snaith C, Thickette DR. Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial) Critical Care 2012;16:R231. https://ccforum.biomedcentral.com/track/pdf/10.1186/cc11895
  4. Espano E, Nam JH, Song EJ, et al. Lipophilic statins inhibit Zika virus production in Vero cells. Scientific Reports 2019;9:11461. https://www.nature.com/articles/s41598-019-47956-1
  5. Sun X, Whittaker GR. Role for influenza virus envelope cholesterol in virus entry and infection. J Virol 2003;77:12543-12551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC262566/
  6. Virani SS. Is there a role for statin therapy in acute viral infections. Am Coll Cardiol March 18, 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/18/15/09/is-there-a-role-for-statin-therapy-in-acute-viral-infections-covid-19

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!

Do statins have a role in treating novel Coronavirus infection, COVID-19?

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

FA Manian MD, MPH, , , , , , , , , , , , , Leave a comment

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?

FA Manian MD, MPH, , , , , , , , , , , 1 Comment

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?

How “sensitive” is the PCR in diagnosing coronavirus/Covid-19?

FA Manian MD, MPH, , , , , , , Leave a comment

A definite diagnosis of Covid-19 requires viral testing, usually through PCR performed on upper (nasopharyngeal or oropharyngeal) or lower respiratory samples (sputum, bronchoalveolar lavage [BAL] fluid). Rates of positive PCR may be affected by stage of the disease and/or its severity.
Nasopharyngeal sample: This seems to be the most practical and readily available means of confirming Covid-19 diagnosis, with positive rates of ~75% during the first 2 weeks of illness in patients considered to have severe disease. For patients with mild Covid-19, a positive PCR rate of 72% has been reported during the 1st week, dropping to 54% during the 2nd week (1).
Oropharyngeal sample: Lower positive PCR rates have been observed with throat swabs, as low as ~30% in mild Covid-19 during the 2nd week of the illness and ~60% in severe disease during the first week of illness (2).
Sputum: Sputum may have the highest positive rates ranging from ~75% in mild disease during the second week of illness to ~90% during the 1st week of severe disease. The problem with sputum sampling is that less than one-third of patients with Covid-19 can provide a sample given the usually dry nature of their cough (1,4).
BAL fluid: In a limited number of patients with severe disease who had bronchoalveolar lavage sampling during the 2nd week of illness, 3 (25%) of 12 patients with positive PCR on BAL had negative upper respiratory samples (1). So in severe disease, the virus definitely prefers to replicate in the lower respiratory tract.
Potential explanations for a negative PCR include low viral titers and specimen handling. So, in patients suspected of having Covid-19 based on clinical/laboratory/radiograph grounds, a negative upper respiratory sample, particularly oropharyngeal source, should not rule out this disease.

 

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References

1. Yang Y, Yang M, Shen C, et al. Evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections. MedRxiv. 2020. DOI: http://doi.org/10.1101/2020.02.11.20021493
2. 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
3. Bai HX, Hsieh B, Xiong Z, et al. Performance of radiologists in differentiaging COVID-19 from viral pneumonia on chest CT. Radiology 2020. https://pubs.rsna.org/doi/10.1148/radiol.2020200823 
4. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext
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!

How “sensitive” is the PCR in diagnosing coronavirus/Covid-19?

Are NSAIDS contraindicated in patients with 2019 novel Coronavirus infection (Covid-19)?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , 1 Comment

Despite recent internet reports of the association of non-steroidal anti-inflammatory drugs (NSAIDs) with worsening symptoms among patients with Covid-19 (1), firm clinical evidence to support such claims is currently lacking. However, there are some theoretical reasons why it may still be best to avoid NSAIDs in this condition due to their potential adverse impact on the innate and adaptive immune responses as well as their antipyretic properties (2-9).

 
Blunting of the innate immune response: Certain NSAIDs (eg, ibuprofen, naproxen and celecoxib) inhibit cyclooxygenase enzyme-2 (COX-2) and impair production of several pro-inflammatory cytokines important in fighting infections, such as tumor necrosis factor, interleukin 1 and 6, as well as interferon, an antiviral cytokine (2,6,8). COX-2 has been shown to be important in controlling viral replication in influenza (4). Ibuprofen has been associated with inhibitory effects on a variety of polymorphonuclear functions, including chemotaxis (2).

 
Impact on adaptive immune response: COX-2 inhibition may be associated with impaired neutralizing antibody production (3,4,8). Potential mechanisms include modulation of cytokine expression, nitric-oxide production, and antigen processing/presentation and T lymphocyte activation (3,8).

 
Antipyretic effect: NSAIDs are often given for treatment of fever which is an evolutionary host response to infection. A meta-analysis of animal studies evaluating the impact of antipyretics (including aspirin, NSAIDs, and acetaminophen) in influenza found lower survival in animals treated with antipyretics (9). Longer duration of viral shedding has also been associated with the use of aspirin or acetaminophen in rhinovirus infection (9).

 
Formal epidemiologic and experimental studies are sorely needed to evaluate the safety of NSAIDS in Covid-19.  

 

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References
1. Kolata G. Is ibuprofen really risky for Coronavirus patients? NY Times, March 17, 2020. https://www.nytimes.com/2020/03/17/health/coronavirus-ibuprofen.html
2. Graham NMH, Burrell CJ, Douglas RM, et al. Adverse effects of aspirin, acetaminophen and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis 1990;162:1277-1282. https://academic.oup.com/jid/article/162/6/1277/918184
3. Culbreth MJ, Biryunkov S, Shoe JL, et al. The use of analgesics during vaccination with a live attenuated Yersinia pestis vaccine alters the resulting immune response in mice. Vaccines 2019;7, 205; doi:10.3390/vaccines7040205 https://www.mdpi.com/2076-393X/7/4/205
4. Ramos I, Fernandez-Sesma A. Modulating the innate immune response to influenza A virus:potential therapeutic use of anti-inflammatory drugs. Frontiers in Immunology. July 2015. Volume 6. Article 361. https://www.ncbi.nlm.nih.gov/pubmed/26257731
5. Falup-Pecurariu O, Man SC, Neamtu ML, et al. Effects of prophylactic ibuprofen and paracetamol administration on the immunogenicity and reactogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugated vaccine(PHID-CV) co-administered with DTPa-combined vaccines in children:An open-label, randomized, controlled, non-inferiority trial. Human Vaccines & Immunotherapeutics 2017;13: 649-660. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360152/
6. Housby JN, Cahill CM, Chu B, et al. Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. Cytokine 1999;11:347-58. https://www.ncbi.nlm.nih.gov/pubmed/30186359
7. Agarwal D, Schmader KE, Kossenkov AV, et al. Immune response to influenza vaccination in the elderly is altered by chronic medication use. Immunity & Ageing 2018;15:19. https://www.ncbi.nlm.nih.gov/pubmed/30186359
8. Bancos S, Bernard MP, Topham DJ, et al. Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cell Immunol 2009;258:18-28. https://www.ncbi.nlm.nih.gov/pubmed/19345936
9. Eyers S, Weatherall M, Shirtcliffe P, et al. The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. J R Soc Med 2010;103:403-11. https://www.ncbi.nlm.nih.gov/pubmed/20929891

 

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!

Are NSAIDS contraindicated in patients with 2019 novel Coronavirus infection (Covid-19)?

Should I continue or discontinue angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in my patients with possible Coronavirus/Covid-19 infection?

FA Manian MD, MPH, , , , , , , , , , Leave a comment

The original reports of an association between hypertension and increased risk of mortality in hospitalized patients with Covid-19 infection raised concern over the potential deleterious role of ACEIs or ARBs in such patients.1-4 However, as stated by a joint statement of several cardiology societies, including the American Heart Association, American College of Cardiology and the European Society of Cardiology on March 13, 2020, there is no clinical or scientific evidence that ACEI or ARBS should be routinely discontinued in patients with Covid-19 infection.5

In fact, some have argued for the opposite ie, consideration for the use of ARBs, such as losartan (an angiotensin receptor 1 [AT1R] antagonist), in patients with Covid-19.6,7  Although it is true that Covid-19 appears to use ACE2 as a binding site to infect cells (just as in SARS) and that ACE2 may be upregulated in patients on chronic ACEI or ARBs,8,9 ACE2 may also potentially protect against severe lung injury associated with infections.10,11  

Two complementary mechanisms have been posited for the potential protective effect of ARBs in Covid-19 infection-related lung injury: 1. Blocking the excessive AT1R activation caused by the viral infection; and 2. Upregulation of ACE2, thereby reducing production of angiotensin II and increasing the production of the vasodilator angiotensin 1-7.7

In the absence of proper clinical studies, it is premature, however, to recommend use of losartan or other AT1R antagonists as a means of reducing the likelihood of ARDS in patients with Covid-19 at this time.

Bonus Pearl: Did you know that ARDS is a major cause of death in Covid-19 infection?12

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References

  1. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020, March 6. https://www.nejm.org/doi/pdf/10.1056/NEJMoa2002032?articleTools=true
  2. O’Mara GJ. Could ACE inhibitors, and particularly ARBs, increase susceptibility to COVID-19 infection? BMJ 2020;368:m406 ARTICLE
  3. Sommerstein R, Grani C. Preventing a Covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ2020;368:m810. https://www.bmj.com/content/368/bmj.m810/rr-2
  4. Li X, Geng M, Peng Y, et al. Molecular immune pathogenesis and diagnosis of COVID-19. Journal of Pharmaceutical Analysis 2020, doi htps://doi.org/10.106/j.jpha.2020.03.001. https://www.sciencedirect.com/science/article/pii/S2095177920302045
  5. Cardiology societies recommend patients taking ACE inhibitors, ARBs who contract COVID-19 should continue treatment. March 17, 2020. https://www.healio.com/cardiology/vascular-medicine/news/online/%7Bfe7f0842-aecb-417b-9ecf-3fe7e0ddd991%7D/cardiology-societies-recommend-patients-taking-ace-inhibitors-arbs-who-contract-covid-19-should-continue-treatment
  6. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 2020;1-4. https://www.ncbi.nlm.nih.gov/pubmed/32129518/
  7. Phadke M, Saunik S. Response to the emerging novel coronavirus outbreak. BMJ 2020;368:m406. https://www.bmj.com/content/368/bmj.m406/rr-2
  8. Zheng YY, Ma YT, Zhang JY, et al. COVID-19 and the cardiovascular system. Nature Reviews/Cardiology 2020; https://doi.org/10.1038/s41569-020-0360-5 .
  9. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;111:2605-2610. https://www.ahajournals.org/doi/full/10.1161/circulationaha.104.510461
  10. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nature Medicine 2005;11:875-79. Doi:10.1038/nm1267 https://www.nature.com/articles/nm1267?v=1
  11. Tikellis C, Thomas MC. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. International Journal of Peptides. Volume 2012, Article ID 256294, 8 pages. Doi:10.1155/2012/256294. https://research.monash.edu/en/publications/angiotensin-converting-enzyme-2-ace2-is-a-key-modulator-of-the-re

12 . Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020. https://doi.org/10.1016/S0140-6736(20)30183-5

 

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!

Should I continue or discontinue angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in my patients with possible Coronavirus/Covid-19 infection?