What’s the evidence that people without symptoms can transmit Covid-19 to those around them?

Rapid spread of Covid-19 virus has been attributed in large part to its ease of transmission from person to person even before symptoms develop, particularly since an estimated 18% to 75% of patients testing positive for Covid-19 have no symptoms. 1-4

Transmission before onset of symptoms (presymptomatic): Modeled estimates for the percentage of transmissions that occur from presymptomatic patients range from 37% to as high as 62% based on studies of patients in the cities of Tianjin and Guangzhou in China, as well as Singapore.5-7 Infectiousness appears to begin within 1-3 days prior to symptoms.8-10

Transmission when symptoms never develop (asymptomatic): Asymptomatic transmission was invoked in a familial cluster in Anyang, China where 5 patients developed Covid-19 after a 6th asymptomatic family member returned home from Wuhan, China. The asymptomatic patient never developed symptoms—such as fever or respiratory symptom— and had a normal chest CT, but briefly tested positive for Covid-19 by RT-PCR before testing negative later.11

It’s important to point out that up to ~75% of patients who are initially “asymptomatic” later develop symptoms. 12-14 So what we often call “asymptomatic” may actually be “presymptomatic.”

Transmission of Covid-19 before onset of symptoms is in distinct contrast to SARS, another coronavirus disease, which was transmitted only when a person was symptomatic and was easier to control. This unique property among coronaviruses may be explained by the high tropism of Covid-19 virus not only for the lungs (as in case of SARS virus) but also for the upper respiratory tract.15,16 As such, Covid-19 behaves more like influenza viruses whose upper respiratory tract binding is thought to promote their rapid transmission even before symptoms develop.17  No wonder, Covid-19 spread like wild fire!

 

Coauthor, Bruce Tiu, Harvard Medical Student, Boston, MA

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References

 

  1. Mizumoto K, Kagaya K, Zarebski A, et al. Estimating the asymptomatic proportion of coronavirus diseae 2019 (COID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill.2020;25(10):pii=2000180 https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.10.2000180?ftag=MSF0951a18
  2. Kimaball, A, Hatfield KM, Arons M, et al. Asymptomatic and presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled nursing facility—King County, Washington, March 2020. MMWR 2020;69:377-381. https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e1.htm
  3. Hu Z, Song C, Xu C, et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci China Life Sci 2020 Mar 4. https://www.ncbi.nlm.nih.gov/pubmed/32146694
  4. Day M. Covid-19: identifying and isolating asymptomatic people helped eliminate virus in Italian village. BMJ 2020;368 https://www.bmj.com/content/368/bmj.m1165
  5. He X, Lau E, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.15.20036707v2
  6. Ferretti L, Wymant C, Kendall M, et al. Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing [published online ahead of print, 2020 Mar 31]. Science. 2020; eabb6936. https://science.sciencemag.org/content/early/2020/03/30/science.abb6936
  7. Ganyani T, Kremer C, Chen D, et al. Estimating the generation interval for COVID-19 based on symptom onset data. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.05.20031815v1
  8. Wei WE, Li ZB, Chiew CJ, et al. Presymptomatic transmission of SARS-CoV-2 — Singapore, January 23–March 16, 2020. MMWR Morb Mortal Wkly Rep. ePub: 1 April 2020. https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e1.htm
  9. He X, Lau E, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.15.20036707v2
  10. Rothe C, Schunk M, Sothmann P, et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N Engl J Med. 2020;382(10):970–971. https://www.nejm.org/doi/full/10.1056/NEJMc2001468
  11. Bai Y, Yao L, Wei T, et al. Presumed Asymptomatic Carrier Transmission of COVID-19 [published online ahead of print, 2020 Feb 21]. JAMA. 2020;e202565. https://jamanetwork.com/journals/jama/fullarticle/2762028
  12. Kimball A, Hatfield KM, Arons M, et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility — King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep. 2020;69:377–381 https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e1.htm
  13. Chen, C. “What We Need to Understand About Asymptomatic Carriers if We’re Going to Beat Coronavirus”. ProPublica. 2020. https://www.propublica.org/article/what-we-need-to-understand-about-asymptomatic-carriers-if-were-going-to-beat-coronavirus
  14. WHO. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). 2020. https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf
  15. Woelfel R, Corman VM, Guggemos W, et al. Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.05.20030502v1
  16. Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003;361(9371):1767–1772. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)13412-5/fulltext
  17. van Riel D, den Bakker MA, Leijten LM, et al. Seasonal and pandemic human influenza viruses attach better to human upper respiratory tract epithelium than avian influenza viruses. Am J Pathol. 2010;176(4):1614–1618. https://wwwnc.cdc.gov/eid/article/26/6/20-0357_article

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’s the evidence that people without symptoms can transmit Covid-19 to those around them?

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?

The chest CT of my patient with “B” symptoms shows hilar mass and mediastinal lymphadenopathy, highly suspicious for lymphoma or malignancy per radiology report. Should I still consider tuberculosis (TB) as a possibility?

Absolutely! TB often mimics malignancy, particularly lymphoma, both clinically and radiographically, even when sophisticated imaging techniques are used.1  

There are ample reports of TB being confused with mediastinal lymphoma, 1-6 with several reports also stressing abdominal TB mimicking malignancy. 7-10 As early as  1949, a  NEJM autopsy study emphasized “the difficulty in differentiating primary progressive TB and some types of lymphoma” and metastatic neoplasms, clinically and radiographically.  Over half-century later, despite major advancement in imaging techniques, TB is often confused for lymphoma or malignancy.

One reason for confusing TB with lymphoma is that primary TB can involve any pulmonary lobe or segment and is often associated with hilar and mediastinal adenopathy. 1 TB may also be overlooked in the differential diagnosis of mediastinal mass that often highlights neoplasms such as lymphoma, thymoma and germ cell tumors. 3 Lack of concurrent pulmonary infiltrates in the presence of mediastinal adenopathy may also veer clinicians away from TB diagnosis. 2,3,6 Unfortunately, even more sophisticated PET/CT scans may not be able to differentiate TB from lymphoma.5,6,9

Besides chest and abdomen, TB can also mimic malignancy in cervical nodes, bones (particularly the spine), bowels, and brain.1,2,6,8,9  To make matters worse, splenomegaly 2,10 and elevated LDH 3 may also be seen with TB and TB may coexist with lymphoma and other malignancies. 7,9,11

One of the best advices I ever received from a radiologist was “Think of TB anytime you think of lymphoma.”

Bonus Pearl: Did you know that TB lymphadenitis is the most common form of extrapulmonary TB with the majority involving the mediastinum? 4

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References

  1. Tan CH, Kontoyiannis DP, Viswanathan C, et al. Tuberculosis: A benign impostor. AJR 2010;194:555-61. https://www.researchgate.net/publication/41509877_Tuberculosis_A_Benign_Impostor
  2. Smith DT. Progressive primary tuberculosis in the adult and its differentiation from lymphomas and mycotic infections. N Engl J Med 1949;241:198-202. https://www.ncbi.nlm.nih.gov/pubmed/18137399
  3. Maguire S, Chotirmall SH, Parihar V, et al. Isolated anterior mediastinal tuberculosis in an immunocompetent patient. BMC Pulm Med 2016;16:24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739107/
  4. Tang SS, Yang ZG, Deng W, et al. Differentiation between tuberculosis and lymphoma in mediastinal lymph nodes: evaluation with contrast-enhanced MDCT. Clin Radiol 2012;67:877-83. https://www.sciencedirect.com/science/article/abs/pii/S0009926012001079
  5. Hou S, Shen J, Tan J. Case report: Multiple systemic disseminated tuberculosis mimicking lymphoma on 18F-FDG PET/CT. Medicine 2017;96:29(e7248). https://journals.lww.com/md-journal/Pages/ArticleViewer.aspx?year=2017&issue=07210&article=00005&type=Fulltext
  6. Tian G, Xiao Y, Chen B, et al. Multi-site abdominal tuberculosis mimics malignancy on 18F-FDG PET/CT: Report of three cases. World J Gastroenterol 2010;16:4237-4242. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2932932/
  7. Dres M, Demoule A, Schmidt M, et al. Tuberculosis hiding a non-Hodgkin lymphoma “there may be more to this than meets the eye”. Resp Med Case Rep 2012;7:15-16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920344/
  8. Banerjee Ak, Coltart DJ. Abdominal tuberculosis mimicking lymphoma in a patient with sickle cell anemia. Br J Clin Pract 1990;44:660-61. https://www.ncbi.nlm.nih.gov/pubmed/2102179?dopt=Abstract
  9. Gong Y, Li S, Rong R, et al. Isolated gastric varices secondary to abdominal tuberculosis mimicking lymphoma: a case report. Gastroenterology 109;19:78. https://www.ncbi.nlm.nih.gov/pubmed/31138138
  10. Uy AB, Garcia Am Manguba A, et al. Tuberculosis: the great lymphoma pretender. Int J Cancer Res Mol Mech 2016; 2(1):doi http://dx.doi.org/10.16966/2381-3318.123
  11. Nayanagari K, Rani R, Bakka S, et al. Pulmonary tuberculosis with mediastinal lymphadenopathy and superior veno caval obstruction, mimicking lung malignancy: a case report. Int J Sci Study 2015;2:211-14. https://www.ncbi.nlm.nih.gov/pubmed/31138138
The chest CT of my patient with “B” symptoms shows hilar mass and mediastinal lymphadenopathy, highly suspicious for lymphoma or malignancy per radiology report. Should I still consider tuberculosis (TB) as a possibility?

How strong is the evidence for IV contrast-induced nephropathy (CIN) following CT scans?

Not as strong as one might expect with an increasing number of investigators questioning the causative role of IV contrast in precipitating CIN.

A 2013 meta-analysis involving observational—mostly retrospective— studies concluded that the risks of AKI, death, and dialysis were similar between IV contrast and non-contrast patients, including those with diabetes or underlying renal insufficiency1.

Two retrospective studies2,3 designed to control for a variety of factors that may affect the risk of AKI by propensity matching found divergent results with the larger and better designed study finding no significant difference in AKI between the 2 groups3. A 2017 retrospective cohort analysis of emergency department patients utilizing a similar propensity-score analysis also failed to find a difference in post-CT AKI between those receiving and not receiving IV contrast4.

Further shedding doubt on the role of IV contrast in causing AKI, a study involving patients with chronic kidney disease found no difference in the rates of excretion of 2 biomarkers of AKI (neutrophil gelatinase-associated lipocalin-NGAL, and kidney injury molecule-1-KIM-1) between patients with and without presumed CIN5. Some have even criticized experimental animal studies supporting the existence of CIN due to their poor applicability to human renal disease1.

This is not to say that IV CIN does not exist. Rather, we should keep an open mind about the pathophysiology and epidemiology of CIN. Stay tuned!

Fun pearl: Did you know that the first case of CIN was described in a patient with multiple myeloma undergoing IV pyelography (before the CT era)?

References

  1. McDonald JS, McDonald RJ, Comin J, et al. Frequency of acute kidney injury following intravenous contrast medium administration: a systematic review and meta-analysis. Radiology. 2013;267(1):119-128. https://www.ncbi.nlm.nih.gov/pubmed/23319662
  2. Davenport MS, Khalatbari S, Dillman JR, et al. Contrast material-induced nephrotoxicity and intravenous low-osmolality iodinated contrast material. Radiology. 2013;267(1):94-105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606541/pdf/121394.pdf
  3. McDonald RJ, McDonald JS, Bida JP, et al. Intravenous contrast material-induced nephropathy: causal or coincident phenomenon? Radiology 2013;267:106-18. https://www.ncbi.nlm.nih.gov/pubmed/23360742
  4. Hinson JS, Ehmann MR, Fine DM, et al. Risk of acute kidney injury after intravenous contrast media administration. Ann Emerg Med 2017; 69:577-586. https://www.ncbi.nlm.nih.gov/pubmed/28131489
  5. Kooiman J, van de Peppel WR, Sijpkens YWJ, et al. No increase in kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion following intravenous contrast enhanced-CT. Eur Radio 2015;25:1926-34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457910/pdf/330_2015_Article_3624.pdf

Contributed by Ginger Jiang, Medical Student, Harvard Medical School

How strong is the evidence for IV contrast-induced nephropathy (CIN) following CT scans?

Should I routinely consider the possibility of pulmonary embolism (PE) in my patients hospitalized for syncope?

Syncope is a well-known initial manifestation of pulmonary embolism (PE)1.  However, given the varied causes of syncope, determining the prevalence of PE among patients hospitalized for syncope is important.   

A multicenter prospective study2 enrolled 560 patients not already on anticoagulation who were hospitalized for a first episode syncope.  Of patients who had either a high pretest probability for PE, positive D-dimer assay or both, PE was diagnosed in 17%, or nearly 1 of 6 of enrolled patients, based on CT or ventilation/perfusion scan. PE was found more frequently among patients with syncope of undetermined cause than those with an alternative explanation (25.4% vs 12.7%). 

Another multicenter prospective study (2019), however, found a much lower prevalence of PE (0.6%) among patients evaluated in the ED for syncope, including those who were not hospitalized.3 A related commentary on the article reported a prevalence of 4.1% in the total study population, assuming a “worst-case scenario calculation.” 4 

Given these divergent results, perhaps the best advice is to consider PE as cause of syncope in the proper context and minimize overtesting when suspicion remains low.

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References 

  1. Thames MD, Alpert JS, Dalen JE. Syncope in patients with pulmonary embolism. JAMA 1977;238:2509-2511. https://www.ncbi.nlm.nih.gov/pubmed/578884
  2. Prandoni P, Lensing AWA, Prins MH, et al. Prevalence of pulmonary embolism among patients hospitalized for syncope. N Engl J Med 2016;375:1524-31. http://www.nejm.org/doi/full/10.1056/NEJMoa1602172
  3. Thiruganasambandamoorthy V, Sivilotti MLA, Rowe BH, et al. Prevalence of pulmonary embolism among emergency department patients with syncope: a multicenter prospective cohort study [published online January 25, 2019]. Ann Emerg Med. doi:10.106/j.annemergmed.2018. https://www.annemergmed.com/article/S0196-0644(18)31535-X/fulltext
  4. Anonymous. Pulmonary embolism uncommon in syncope hospitalizations. Pulmonology Advisor. February 6, 2019.  https://www.pulmonologyadvisor.com/pulmonary-embolism-uncommon-in-syncope-hospitalizations/printarticle/832069/

 

Contributed in part by Rebecca Berger  MD, Department of Medicine, Mass General Hospital, Boston, MA

 

Should I routinely consider the possibility of pulmonary embolism (PE) in my patients hospitalized for syncope?