COVID-19 Evidence Summary Clinical Management 10 Apr 2020

Disclaimer:Whilst every effort has been made to ensure the accuracy of this document at the time of publishing, there is still a lot of uncertainty on the management of COVID-19 and therefore the document will be updated as new information becomes available. Clinicians should ensure that they are using the most up to date version.


This is not a clinical guideline or an SOP. It is a brief summary of the evidence internationally on the presentation of COVID-19 and some suggestions as to how cases may need to be assessed within primary care.

Symptoms

We are continuing to learn about the presentation of the disease. The consistent features seem to be continuous cough and fever, but other features can be present.


COVID-19 may cause constitutional symptoms, upper respiratory symptoms, lower respiratory symptoms, and, less commonly, gastrointestinal symptoms. Most patients will present with constitutional symptoms and lower respiratory symptoms (e.g. fever and cough).


The frequency of fever is variable between studies (ranging from 43% to 98% as shown in the table above). This may relate to exact methodology used in various studies, different levels of illness severity between various cohorts, or different strains of the virus present in various locations.

Regardless of the exact numbers - absence of a fever does not exclude COVID-19.

Gastrointestinal presentations: up to 10% of patients can present initially with gastrointestinal symptoms (e.g. diarrhea, nausea), which precede the development of fever and dyspnoea(7)

"Silent hypoxemia" - some patients may develop hypoxemia and respiratory failure without dyspnoea (especially elderly).(8)

Physical examination is generally nonspecific. About 2% of patients may have pharyngitis or tonsil enlargement(1).

Clinical assessment

History taking is probably the most important part of the assessment and can be done remotely. Clinicians will need to consider pre-existing conditions or features that might suggest alternative causes for the patient's symptoms and any deterioration. Physical examination may be needed, especially in cases where the presentation is atypical. In some cases this may be possible remotely while in others a face to face consultation will be needed.


Patients with probable COVID-19 can be divided into three broad groups:


Category One Those who are acutely deteriorating and for whom urgent hospital assessment and or resuscitation is required (provided this is consistent with any previous advanced care planning)

Category Two Patients with probable COVID-19 other causes for deterioration having been discounted who after physical assessment are deemed not to need hospital admission

Category Three Patients with probable COVID-19 disease, but whose symptoms are such that they are not significantly compromised and can manage at home with adequate safety netting

There will be a group of patients whose symptoms are due to other conditions and are unlikely to be due to COVID-19.  These patients will need to be managed according to standard guidelines.

There are no nationally or internationally accepted and validated scoring systems for COVID-19 which differentiate those patients who are likely to deteriorate or require hospital care from those who may not.  Therefore, clinical judgement is important. Recording certain physiological measures may be helpful in supporting decision making, and can assist to track changes over time and guide partner agencies, such as ambulance staff.   In this regard, calculating a  NEWS2 (9, 10) score maybe helpful but as Greenhalgh et al noted:  

There is no research on the value of these tools for COVID-19 outside hospital.  NEWS2 includes blood pressure and oxygen saturation measurements  that are difficult or impossible to take remotely. It does not include age or comorbidities, which are known to be strong independent predictors of survival in COVID-19.(11)

If used at all, this score should be used alongside a wider clinical assessment of the patient and in the context of changes over time. NEWS 2 should not be used in isolation to guide hospital admission decisions and should not replace clinical judgement.

Table 1 Calculation of NEWS2 score

From what we know about sepsis, increased respiratory rate, low blood pressure and newly altered cognition/confusion are all strong indicators of being significantly unwell with infection. Pulse and temperature are less so. Oximetry is important as one of the mechanisms of acute deterioration in COVID-19 is respiratory failure which may be better picked up with good quality oximetry. Ideally, this should be done with a medical grade oximeter(12)

There is no equivalent scoring tool for children, who will need to be assessed clinically.

Table 2 Safety netting advice for patients

COVID-19 Safety Netting Advice

The following are signs to look out for, that might indicate things are getting worse. If you start to:

  • become significantly breathless,
  • or develop pains in your chest,
  • or become pale and clammy ‘like someone who is about to vomit”,
  • or seem muddled or confused

‘then you should seek urgent medical advice

Pathophysiology

  • (1) ARDS
    • The primary pathology is ARDS, characterized by diffuse alveolar damage (e.g. including hyaline membranes). Pneumocytes with viral cytopathic effect are seen, implying direct virus damage (rather than a purely hyper-inflammatory injury;
  • (2) Cytokine storm
    • Emerging evidence suggests that some patients may respond to COVID-19 with an exuberant "cytokine storm" reaction (with features of bacterial sepsis or hemophagocytic lymphohistiocytosis).
    • Clinical markers of this may include elevations of C-reactive protein and ferritin, which appear to track with disease severity and mortality(13)

Stages of illness

  • There seem to be different stages of illness that patients may move through(14).
    • (#1) Replicative stage - Viral replication occurs over a period of several days. An innate immune response occurs, but this response fails to contain the virus. Relatively mild symptoms may occur due to direct viral cytopathic effect and innate immune responses.
    • (#2) Adaptive immunity stage - An adaptive immune response eventually kicks into gear. This leads to falling titres of virus. However, it may also increase levels of inflammatory cytokines and lead to tissue damage - causing clinical deterioration.
  • This progression may explain the clinical phenomenon wherein patients are relatively OK for several days, but then suddenly deteriorate when they enter the adaptive immunity stage(2)
  • This has potentially important clinical implications:
    • Initial clinical symptoms aren't necessarily predictive of future deterioration. At present we do not have a tool to predict outcomes although we are starting to understand the groups who are prone to poor outcomes. These groups are currently being advised to shelter and socially isolate
    • Anti-viral therapies might need to be deployed early to work optimally (during the replicative stage)

Typical hospital progress

Figure 1 Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists(15)

Treatment

Supportive treatments are the mainstay of treatment currently, with the majority of patients improving without need of hospital intervention. Tamiflu and other anti-influenza drugs appear ineffective. Treatments specific for Coronavirus are actively being sought and are being assessed within research trials.

Steroids have previously been unhelpful for MERS and SARS(16) and should not be used unless there is diagnostic uncertainty e.g. Asthma or COPD. They must be used where patients are at risk of Addisonian Crisis.

Investigations

This currently includes ruling out other respiratory infections such as influenzas, or acute deterioration such as appendicitis, sepsis or other lung conditions. Currently Reverse transcriptase Polymerase Chain reaction RT-PCR and CT scans can be used to detect Corona viruses. RT-PCR and CT scans for the investigation of patients are currently only available in hospital settings.

Sensitivity

Sensitivity compared to CT scans

In a case series diagnosed on the basis of clinical criteria and CT scans, the sensitivity of RT-PCR was only ~70% (17)

Sensitivity varies depending on assumptions made about patients with conflicting data (e.g. between 66-80%;(18)

Among patients with suspected COVID-19 and a negative initial PCR, repeat PCR was positive in 15/64 patients (23%). This suggests a PCR sensitivity of <80%. Conversion from negative to positive PCR seemed to take a period of days, with CT scan often showing evidence of disease well before PCR positivity(18)

A single negative RT-PCR doesn't exclude COVID-19 (especially if obtained from a nasopharyngeal source or if taken relatively early in the disease course).

If the RT-PCR is negative but suspicion for COVID-19 remains, then ongoing isolation and re-sampling several days later should be considered.

Summary

Coronavirus probably causes direct damage to the lungs in addition to provoking a massive inflammatory response. The circulatory collapse and generalised organ failure is akin to that seen in septic shock and can be just as sudden.

Inflammatory markers seem to track the severity of the disease.

The mean onset time is 5.2 days. The presentation is variable with the primary features being temperature and dry cough. Initial symptoms do not appear to be predictive of outcome. The majority of patients make a largely uneventful recovery, but a small proportion show an acute deterioration about day five of their illness.

References

  1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. The New England journal of medicine. 2020.
  2. Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. Jama. 2020.
  3. Yang X, Yu Y, Xu J, Shu H, Xia Ja, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine. 2020.
  4. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet. 2020;395(10223):507-13.
  5. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020;395(10223):497-506.
  6. Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ (Clinical research ed). 2020;368:m606.
  7. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. Jama. 2020.
  8. Xie J, Tong Z, Guan X, Du B, Qiu H, Slutsky AS. Critical care crisis and some recommendations during the COVID-19 epidemic in China. Intensive Care Med. 2020.
  9. Royal College of General Practitioners. The use of the NEWS2 score for assessing the patient at risk of deterioration. RCGP; 2020.^https://www.rcgp.org.uk/-/media/Files/CIRC/Clinical-Policy/Position-statements/RCGP-position-statement-on-the-use-of-NEWS2-score-for-assessing-the-patient-at-risk-of-deterioration.ashx?la=en
  10. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the assessment of acute-illness severity in the NHS. In: RCP. London: RCP; 2017.^https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2
  11. Greenhalgh T, Treadwell J, Burrow R, Roberts N. NEWS (or NEWS2) score when assessing possible COVID-19 patients in primary care? 2020 [8/4/20]. Available from: https://www.cebm.net/covid-19/should-we-use-the-news-or-news2-score-when-assessing-patients-with-possible-covid-19-in-primary-care/.
  12. Hudson AJ, Benjamin J, Jardeleza T, Bergstrom C, Cronin W, Mendoza M, et al. Clinical Interpretation of Peripheral Pulse Oximeters Labeled "Not for Medical Use". Ann Fam Med. 2018;16(6):552-4.
  13. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020.
  14. Farkas J. The Internet Book of Critical Care: COVID-19 2020 [updated 16/3/2022/3/20]. Available from: https://emcrit.org/wp-content/uploads/2020/03/COVID-19-EMCrit-Project3-16.pdf.
  15. Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y, Timsit JF. Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists. Intensive Care Med. 2020.
  16. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. The Lancet. 2020;395(10223):473-5.
  17. Fang Y, Zhang H, Xie J, Lin M, Ying L, Pang P, et al. Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR. Radiology.0(0):200432.
  18. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020:200642.

Acknowledgements


We acknowledge the contribution of content from the authors of The Internet Book of Critical Care for the descriptions of Pathophysiology and other content. Also, to Kings College Hospital London who shared their Critical Care briefing.


Created 23/3/2020 Dr Simon N Stockley FRCGP, FIMC RCSEd, DUMC

Last modified: Tuesday, 14 April 2020, 2:41 PM