introduction of clinical presentation

How To Present a Patient: A Step-To-Step Guide

Last Updated on June 24, 2022 by Laura Turner

Updated and verified by Dr. Lee Burnett on March 19, 2022.

The ability to deliver oral case presentations is a core skill for any physician. Effective oral case presentations help facilitate information transfer among physicians and are essential to delivering quality patient care. Oral case presentations are also a key component of how medical students and residents are assessed during their training.

At its core, an oral case presentation functions as an argument. It is the presenter’s job to share the pertinent facts of a patient’s case with the other members of the medical care team and establish a clear diagnosis and treatment plan. Thus, the presenter should include details to support the proposed diagnosis, argue against alternative diagnoses, and exclude extraneous information. While this task may seem daunting at first, with practice, it will become easier. That said, if you are unsure if a particular detail is important to your patient’s case, it is probably best to be safe and include it.

Now, let’s go over how to present a case. While I will focus on internal medicine inpatients, the following framework can be applied to patients in any setting with slight modifications.

Oral case presentations are generally made to a medical care team, which can be composed of medical and pharmacy students, residents, pharmacists, medical attendings, and others. As the presenter, you should strive to deliver an interesting presentation that keeps your team members engaged. Here are a few things to keep in mind:

• Be confident: Speak clearly at the loudest volume appropriate to protect patient privacy, vary your tone to emphasize the most important details, and maintain eye contact with members of your team.
• Don’t fidget : Stand up straight and avoid unnecessary, distracting movements.
• Use your notes : You may glance at your notes from time to time while presenting. However, while there is no need to memorize your presentation, there is no better way to lose your team’s attention than to read your notes to them.
• Be honest: Given the importance of presentations in guiding medical care, never guess or report false information to the team. If you are unsure about a particular detail, say so.

The length of your presentation will depend on various factors, including the complexity of your patient, your audience, and your specialty. I have found that new internal medicine inpatients generally take 5-10 minutes to present. Internal medicine clerkship directors seem to agree. In a 2009 survey , they reported a range of 2-20 minutes for the ideal length of student inpatient presentations, with a median of 7 minutes.

While delivering oral case presentations is a core skill for trainees, and there have been attempts to standardize the format , expectations still vary among attending physicians. This can be a frustrating experience for trainees, and I would recommend that you clarify your attending’s expectations at the beginning of each new rotation. However, I have found that these differences are often stylistic, and content expectations are generally quite similar. Thus, developing a familiarity with the core elements of a strong oral case presentation is essential.

How to Present a Patient

You should begin every oral presentation with a brief one-liner that contains the patient’s name, age, relevant past medical history, and chief complaint. Remember that the chief complaint is why the patient sought medical care in his or her own words. An example of an effective opening is as follows: “Ms. X is a 78-year-old female with a past medical history of chronic obstructive pulmonary disease who presents to the hospital after she felt short of breath at home.”

Following the opener, elaborate on why the patient sought medical care. Describe the events that preceded the patient’s presentation in chronological order. A useful mnemonic to use when deciding what to report is OPQRST , which includes: • The Onset of the patient’s symptoms • Any Palliative or Provoking factors that make the symptoms better or worse, respectively • The Quality of his or her symptoms (how he or she describes them) • The Region of the body where the patient is experiencing his or her symptoms and (if the symptom is pain) whether the patient’s pain Radiates to another location or is well-localized • The Severity of the symptoms and any other associated Symptoms • The Time course of the symptoms (how they have changed over time and whether the patient has experienced them before) Additionally, include any other details here that may support your final diagnosis or rule out alternative diagnoses. For example, if you are concerned about a pulmonary embolism and your patient recently completed a long-distance flight, that would be worth mentioning.

The review of systems is sometimes included in the history of present illness, but it may also be separated. Given the potential breadth of the review of systems (a comprehensive list of questions that may be asked can be found here ), when presenting, only report information that is relevant to your patient’s condition.

The past medical history comes next. This should include the following information: • The patient’s medical conditions, including any that were not highlighted in the opener • Any past surgeries the patient has had and when they were performed • The timing of and reasons for past hospitalizations • Any current medications, including dosages and frequency of administration

The next section should detail the patient’s relevant family history. This should include: • Any relevant conditions that run in the patient’s family, with an emphasis on first-degree relatives

After the family history comes the social history. This section should include information about the patient’s: • Living situation • Occupation • Alcohol and tobacco use • Other substance use You may also include relevant details about the patient’s education level, recent travel history, history of animal and occupational exposures, and religious beliefs. For example, it would be worth mentioning that your anemic patient is a Jehovah’s Witness to guide medical decisions regarding blood transfusions.

Once you have finished reporting the patient’s history, you should transition to the physical exam. You should begin by reporting the patient’s vital signs, which includes the patient’s: • Temperature • Heart rate • Blood pressure • Respiratory rate • Oxygen saturation (if the patient is using supplemental oxygen, this should also be reported) Next, you should discuss the findings of your physical exam. At the minimum, this should include: • Your general impressions of the patient, including whether he or she appears “sick” or not • The results of your: • Head and neck exam • Eye exam • Respiratory exam • Cardiac exam • Abdominal exam • Extremity exam • Neurological exam Additional relevant physical examination findings may be included, as well. Quick note: resist the urge to report an exam as being “normal.” Instead, report your findings. For example, for a normal abdominal exam, you could report that “the patient’s abdomen is soft, non-tender, and non-distended, with normoactive bowel sounds.”

This section includes the results of any relevant laboratory testing, imaging, or other diagnostics that were obtained. You do not have to report the results of every test that was ordered. Before presenting, consider which results will further support your proposed diagnosis and exclude alternatives.

The emergency department (ED) course is classically reported towards the end of the presentation. However, different attendings may prefer to hear the ED course earlier, usually following the history of present illness. When unsure, report the ED course after the results of diagnostic testing. Be sure to include initial ED vital signs and any administered treatments.

You should conclude your presentation with the assessment and plan. This is the most important part of your presentation and allows you to show your team how much you really know. You should include: • A brief summary (1-2 lines) of the patient, the reason for admission, and your likely diagnosis. This should also include information regarding the patient’s clinical stability. While it can be similar to your opener, it should not be identical. An example could be: “Ms. X is a 78-year-old female with a past medical history of chronic obstructive pulmonary disease who presents with shortness of breath in the setting of an upper respiratory tract infection who is now stable on two liters of supplemental oxygen delivered via nasal cannula. Her symptoms are thought to be secondary to an acute exacerbation of chronic obstructive pulmonary disease.” • A differential diagnosis . For students, this should consist of 3-5 potential diagnoses. You should explain why you think each diagnosis is or is not the final diagnosis. Be sure to rule out potentially life-threatening conditions (unless you think your patient has one). For our fictional patient, Ms. X, for example, you could explain why you think she does not have a pulmonary embolism or acute coronary syndrome. For more advanced trainees, the differential can be more limited in scope. • Your plan . On regular inpatient floors, this should include a list of the patient’s medical problems, ordered by acuity, followed by your proposed plan for each. After going through each active medical problem, be sure to mention your choice for the patient’s diet and deep vein thrombosis prophylaxis, the patient’s stated code status, and the patient’s disposition (whether you think they need to remain in the hospital). In intensive care units, you can organize the patient’s medical problems by organ system to ensure that no stone is left unturned (if there are no active issues for an organ system, you may say so).

Presenting Patients Who Have Been in the Hospital for Multiple Days

After the initial presentation, subsequent presentations can be delivered via SOAP note format as follows:

• The  Subjective  section includes details about any significant overnight events and any new complaints the patient has.
• In the  Objective  section, report your physical exam (focus on any changes since you last examined the patient) and any significant new laboratory, imaging, or other diagnostic results.
• The  Assessment  and  Plan  are typically delivered as above. For the initial patient complaint, you do not have to restate your differential diagnosis if the diagnosis is known. For new complaints, however, you should create another differential and argue for or against each diagnosis. Be sure to update your plan every day.

Presenting Patients in Different Specialties

Before you present a patient, consider your audience. Every specialty presents patients differently. In general, surgical and OB/GYN presentations tend to be much quicker (2-3 minutes), while pediatric and family medicine presentations tend to be similar in length to internal medicine presentations. Tailor your presentations accordingly.

Presenting Patients in Outpatient Settings

Outpatients may be presented similarly to inpatients. Your presentation’s focus, however, should align with your outpatient clinic’s specialty. For example, if you are working at a cardiology clinic, your presentation should be focused on your patient’s cardiac complaints.

If your patient is returning for a follow-up visit and does not have a stated chief complaint, you should say so. You may replace the history of present illness with any relevant interval history since his or her last visit.

And that’s it! Delivering oral case presentations is challenging at first, so remember to practice. In time, you will become proficient in this essential medical skill. Good luck!

Kunal Sindhu, MD, is an assistant professor in the Department of Radiation Oncology at the Icahn School of Medicine at Mount Sinai and New York Proton Center. Dr. Sindhu specializes in treating cancers of the head, neck, and central nervous system.

2 thoughts on “How To Present a Patient: A Step-To-Step Guide”

To clarify, it should take 5-10 minutes to present (just one) new internal medicine inpatient? Or if the student had 4 patients to work up, it should take 10 minutes to present all 4 patients to the preceptor?

Good question. That’s per case, but with time you’ll become faster.

Comments are closed.

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How to present clinical cases

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• Peer review
• Ademola Olaitan , medical student 1 ,
• Oluwakemi Okunade , final year medical student 1 ,
• Jonathan Corne , consultant physician 2
• 1 University of Nottingham
• 2 Nottingham University Hospitals

Presenting a patient is an essential skill that is rarely taught

Clinical presenting is the language that doctors use to communicate with each other every day of their working lives. Effective communication between doctors is crucial, considering the collaborative nature of medicine. As a medical student and later as a doctor you will be expected to present cases to peers and senior colleagues. This may be in the setting of handovers, referring a patient to another specialty, or requesting an opinion on a patient.

A well delivered case presentation will facilitate patient care, act a stimulus for timely intervention, and help identify individual and group learning needs. 1 Case presentations are also used as a tool for assessing clinical competencies at undergraduate and postgraduate level.

Medical students are taught how to take histories, examine, and communicate effectively with patients. However, we are expected to learn how to present effectively by observation, trial, and error.

Principles of presentation

Remember that the purpose of the case presentation is to convey your diagnostic reasoning to the listener. By the end of your presentation the examiner should have a clear view of the patient’s condition. Your presentation should include all the facts required to formulate a management plan.

There are no hard and fast rules for a perfect presentation, rather the content of each presentation should be determined by the case, the context, and the audience. For example, presenting a newly admitted patient with complex social issues on a medical ward round will be very different from presenting a patient with a perforated duodenal ulcer who is in need of an emergency laparotomy.

Whether you’re presenting on a busy ward round or during an objective structured clinical …

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Tools for the Patient Presentation

The formal patient presentation.

• Posing the Clinical Question
• Searching the Medical Literature for EBM

Sources & Further Reading

First Aid for the Wards

Lingard L, Haber RJ.  Teaching and learning communications in medicine: a rhetorical approach .  Academic Medicine. 74(5):507-510 1999 May.

Lingard L, Haber RJ.  What do we mean by "relevance"? A clinical and rhetorical definition with implications for teaching and learning the case-presentation format . Academic Medicine. 74(10):S124-S127.

The Oral Presentation (A Practical Guide to Clinical Medicine, UCSD School of Medicine)  http://meded.ucsd.edu/clinicalmed/oral.htm

"Classically, the formal oral presentation is given in 7 minutes or less. Although it follows the same format as a written report, it is not simply regurgitation. A great presentation requires style as much as substance; your delivery must be succinct and smooth. No time should be wasted on superfluous information; one can read about such matters later in your admit note. Ideally, your presentation should be formulated so that your audience can anticipate your assessment and plan; that is, each piece of information should clue the listener into your thinking process and your most likely diagnosis."  [ Le, et al, p. 15 ]

Types of Patient Presentations

New Patient

New patients get the traditional H&P with assessment and plan.  Give the chief complaint and a brief and pertinent HPI.  Next give important PMH, PSH, etc.  The ROS is often left out, as anything important was in the HPI.  The PE is reviewed.  Only give pertinent positives and negatives.  The assessment and plan should include what you think is wrong and, briefly, why.  Then, state what you plan to do for the patient, including labs.  Be sure to know why things are being done: you will be asked.

The follow-up presentation differs from the presentation of a new patient.  It is an abridged presentation, perhaps referencing major patient issues that have been previously presented, but focusing on new information about these issues and/or what has changed. Give the patient’s name, age, date of admission, briefly review the present illness, physical examination and admitting diagnosis.  Then report any new finding, laboratory tests, diagnostic procedures and changes in medications.

The attending physician will ask the patient’s permission to have the medical student present their case.  After making the proper introductions the attending will let the patient know they may offer input or ask questions at any point.  When presenting at bedside the student should try to involve the patient.

Preparing for the Presentation

There are four things you must consider before you do your oral presentation

• Occasion (setting and circumstances)

Ask yourself what do you want the presentation to do

• Present a new patient to your preceptor : the amount of detail will be determined by your preceptor.  It is also likely to reflect your development and experience, with less detail being required as you progress.
• Present your patient at working or teaching rounds : the amount of detail will be determined by the customs of the group. The focus of the presentation will be influenced by the learning objectives of working responsibilities of the group.
• Request a consultant’s advice on a clinical problem : the presentation will be focused on the clinical question being posed to the consultant.
• Persuade others about a diagnosis and plan : a shorter presentation which highlights the pertinent positives and negatives that are germane to the diagnosis and/or plan being suggested.
• Enlist cooperation required for patient care : a short presentation focusing on the impact your audience can have in addressing the patient’s issues.

Preparation

• Patient evaluation : history, physical examination, review of tests, studies, procedures, and consultants’ recommendations.
• Selected reading : reference texts; to build a foundational understanding.
• Literature search : for further elucidation of any key references from selected reading, and to bring your understanding up to date, since reference text information is typically three to seven years old.
• Write-up : for oral presentation, just succinct notes to serve as a reminder or reference, since you’re not going to be reading your presentation.

Knowledge (Be prepared to answer questions about the following)

• Pathophysiology
• Complications
• Differential diagnosis
• Course of conditions
• Diagnostic tests
• Medications
• Essential Evidence Plus

Template for Oral Presentations

Chief Complaint (CC)

The opening statement should give an overview of the patient, age, sex, reason for visit and the duration of the complaint. Give marital status, race, or occupation if relevant.  If your patient has a history of a major medical problem that bears strongly on the understanding of the present illness, include it.  For ongoing care, give a one sentence recap of the history.

History of Present Illness (HPI)

This will be very similar to your written HPI. Present the most important problem first. If there is more than one problem, treat each separately. Present the information chronologically.  Cover one system before going onto the next. Characterize the chief complaint – quality, severity, location, duration, progression, and include pertinent negatives. Items from the ROS that are unrelated to the present problem may be mentioned in passing unless you are doing a very formal presentation. When you do your first patient presentation you may be expected to go into detail.  For ongoing care, present any new complaints.

Review of Systems (ROS)

Most of the ROS is incorporated at the end of the HPI. Items that are unrelated to the present problem may be briefly mentioned.  For ongoing care, present only if new complaints.  

Past Medical History (PMH)

Discuss other past medical history that bears directly on the current medical problem.  For ongoing care, have the information available to respond to questions.

Past Surgical History

Provide names of procedures, approximate dates, indications, any relevant findings or complications, and pathology reports, if applicable.  For ongoing care, have the information available to respond to questions.

Allergies/Medications

Present all current medications along with dosage, route and frequency. For the follow-up presentation just give any changes in medication.  For ongoing care, note any changes.

Smoking and Alcohol (and any other substance abuse)

Note frequency and duration. For ongoing care, have the information available to respond to questions.

Social/Work History

Home, environment, work status and sexual history.  For ongoing care, have the information available to respond to questions.

Family History Note particular family history of genetically based diseases.  For ongoing care, have the information available to respond to questions.

Physical Exam/Labs/Other Tests

Include all significant abnormal findings and any normal findings that contribute to the diagnosis. Give a brief, general description of the patient including physical appearance. Then describe vital signs touching on each major system. Try to find out in advance how thorough you need to be for your presentation. There are times when you will be expected to give more detail on each physical finding, labs and other test results.  For ongoing care, mention only further positive findings and relevant negative findings.

Assessment and Plan

Give a summary of the important aspects of the history, physical exam and formulate the differential diagnosis. Make sure to read up on the patient’s case by doing a search of the literature. 

• Include only the most essential facts; but be ready to answer ANY questions about all aspects of your patient.
• Keep your presentation lively.
• Do not read the presentation!
• Expect your listeners to ask questions.
• Follow the order of the written case report.
• Keep in mind the limitation of your listeners.
• Beware of jumping back and forth between descriptions of separate problems.
• Use the presentation to build your case.
• Your reasoning process should help the listener consider a differential diagnosis.
• Present the patient as well as the illness .
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• Published: 13 November 2020

Clinical presentations, laboratory and radiological findings, and treatments for 11,028 COVID-19 patients: a systematic review and meta-analysis

• Carlos K. H. Wong 1 , 2   na1 ,
• Janet Y. H. Wong 3   na1 ,
• Eric H. M. Tang 1 ,
• C. H. Au 1 &
• Abraham K. C. Wai 4  

Scientific Reports volume  10 , Article number:  19765 ( 2020 ) Cite this article

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This systematic review and meta-analysis investigated the comorbidities, symptoms, clinical characteristics and treatment of COVID-19 patients. Epidemiological studies published in 2020 (from January–March) on the clinical presentation, laboratory findings and treatments of COVID-19 patients were identified from PubMed/MEDLINE and Embase databases. Studies published in English by 27th March, 2020 with original data were included. Primary outcomes included comorbidities of COVID-19 patients, their symptoms presented on hospital admission, laboratory results, radiological outcomes, and pharmacological and in-patient treatments. 76 studies were included in this meta-analysis, accounting for a total of 11,028 COVID-19 patients in multiple countries. A random-effects model was used to aggregate estimates across eligible studies and produce meta-analytic estimates. The most common comorbidities were hypertension (18.1%, 95% CI 15.4–20.8%). The most frequently identified symptoms were fever (72.4%, 95% CI 67.2–77.7%) and cough (55.5%, 95% CI 50.7–60.3%). For pharmacological treatment, 63.9% (95% CI 52.5–75.3%), 62.4% (95% CI 47.9–76.8%) and 29.7% (95% CI 21.8–37.6%) of patients were given antibiotics, antiviral, and corticosteroid, respectively. Notably, 62.6% (95% CI 39.9–85.4%) and 20.2% (95% CI 14.6–25.9%) of in-patients received oxygen therapy and non-invasive mechanical ventilation, respectively. This meta-analysis informed healthcare providers about the timely status of characteristics and treatments of COVID-19 patients across different countries.

PROSPERO Registration Number: CRD42020176589

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Introduction.

Following the possible patient zero of coronavirus infection identified in early December 2019 1 , the Coronavirus Disease 2019 (COVID-19) has been recognized as a pandemic in mid-March 2020 2 , after the increasing global attention to the exponential growth of confirmed cases 3 . As on 29th March, 2020, around 690 thousand persons were confirmed infected, affecting 199 countries and territories around the world, in addition to 2 international conveyances: the Diamond Princess cruise ship harbored in Yokohama, Japan, and the Holland America's MS Zaandam cruise ship. Overall, more than 32 thousand died and about 146 thousand have recovered 4 .

A novel bat-origin virus, 2019 novel coronavirus, was identified by means of deep sequencing analysis. SARS-CoV-2 was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%) 5 , both of which were respectively responsible for two zoonotic human coronavirus epidemics in the early twenty-first century. Following a few initial human infections 6 , the disease could easily be transmitted to a substantial number of individuals with increased social gathering 7 and population mobility during holidays in December and January 8 . An early report has described its high infectivity 9 even before the infected becomes symptomatic 10 . These natural and social factors have potentially influenced the general progression and trajectory of the COVID-19 epidemiology.

By the end of March 2020, there have been approximately 3000 reports about COVID-19 11 . The number of COVID-19-related reports keeps growing everyday, yet it is still far from a clear picture on the spectrum of clinical conditions, transmissibility and mortality, alongside the limitation of medical reports associated with reporting in real time the evolution of an emerging pathogen in its early phase. Previous reports covered mostly the COVID-19 patients in China. With the spread of the virus to other continents, there is an imminent need to review the current knowledge on the clinical features and outcomes of the early patients, so that further research and measures on epidemic control could be developed in this epoch of the pandemic.

Search strategy and selection criteria

The systematic review was conducted according to the protocol registered in the PROSPERO database (CRD42020176589). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline throughout this review, data were identified by searches of MEDLINE, Embase and references from relevant articles using the search terms "COVID", “SARS-CoV-2”, and “novel coronavirus” (Supplementary material 1 ). Articles published in English up to 27th March, 2020 were included. National containment measures have been implemented at many countries, irrespective of lockdown, curfew, or stay-at-home orders, since the mid of March 2020 12 , except for China where imposed Hubei province lockdown at 23th January 2020, Studies with original data including original articles, short and brief communication, letters, correspondences were included. Editorials, viewpoints, infographics, commentaries, reviews, or studies without original data were excluded. Studies were also excluded if they were animal studies, modelling studies, or did not measure symptoms presentation, laboratory findings, treatment and therapeutics during hospitalization.

After the removal of duplicate records, two reviewers (CW and CHA) independently screened the eligibility criteria of study titles, abstracts and full-texts, and reference lists of the studies retrieved by the literature search. Disagreements regarding the procedures of database search, study selection and eligibility were resolved by discussion. The second and the last authors (JW and AW) verified the eligibility of included studies.

Outcomes definitions

Signs and symptoms were defined as the presentation of fever, cough, sore throat, headache, dyspnea, muscle pain, diarrhea, rhinorrhea, anosmia, and ageusia at the hospital admission 13 .

Laboratory findings included a complete blood count (white blood count, neutrophil, lymphocyte, platelet count), procalcitonin, prothrombin time, urea, and serum biochemical measurements (including electrolytes, renal-function and liver-function values, creatine kinase, lactate dehydrogenase, C-reactive protein, Erythrocyte sedimentation rate), and treatment measures (i.e. antiviral therapy, antibiotics, corticosteroid therapy, mechanical ventilation, intubation, respiratory support, and renal replacement therapy). Radiological outcomes included bilateral involvement identified and pneumonia identified by chest radiograph.

Comorbidities of patients evaluated in this study were hypertension, diabetes, chronic obstructive pulmonary disease (COPD), cardiovascular disease, chronic kidney disease, liver disease and cancer.

In-patient treatment included intensive care unit admission, oxygen therapy, non-invasive ventilation, mechanical ventilation, Extracorporeal membrane oxygenation (ECMO), renal replacement therapy, and pharmacological treatment. Use of antiviral and interferon drugs (Lopinavir/ritonavir, Ribavirin, Umifenovir, Interferon-alpha, or Interferon-beta), antibiotic drugs, corticosteroid, and inotropes (Nor-adrenaline, Adrenaline, Vasopressin, Phenylephrine, Dopamine, or Dobutamine) were considered.

Data analysis

Three authors (CW, EHMT and CHA) extracted data using a standardized spreadsheet to record the article type, country of origin, surname of first author, year of publications, sample size, demographics, comorbidities, symptoms, laboratory and radiology results, pharmacological and non-pharmacological treatments.

We aggregated estimates across 90 eligible studies to produce meta-analytic estimates using a random-effects model. For dichotomous outcomes, we estimated the proportion and its respective 95% confidence interval. For laboratory parameters as continuous outcomes, we estimated the mean and standard deviation from the median and interquartile range if the mean and standard deviation were not available from the study 14 , and calculated the mean and its respective 95% confidence intervals. Random-effect models on DerSimonian and Laird method were adopted due to the significant heterogeneity, checked by the I 2 statistics and the p values. I 2 statistic of < 25%, 25–75% and ≥ 75% is considered as low, moderate, high likelihood of heterogeneity. Pooled estimates were calculated and presented by using forest plots. Publication bias was estimated by Egger’s regression test. Funnel plots of outcomes were also presented to assess publication bias.

All statistical analyses were conducted using the STATA Version 13.0 (Statacorp, College Station, TX). The random effects model was generated by the Stata packages ‘Metaprop’ for proportions 15 and ‘Metan’ for continuous variables 16 .

The selection and screen process are presented in Fig.  1 . A total of 241 studies were found by our searching strategy (71 in PubMed and 170 in Embase). 46 records were excluded due to duplication. After screening the abstracts and titles, 100 English studies were with original data and included in full-text screening. By further excluding 10 studies with not reporting symptoms presentation, laboratory findings, treatment and therapeutics, 90 studies 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 and 76 studies with more than one COVID-19 case 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 34 , 35 , 36 , 37 , 38 , 39 , 42 , 43 , 44 , 45 , 49 , 50 , 51 , 53 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 67 , 69 , 70 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 98 , 100 , 101 , 102 , 103 , 104 , 105 were included in the current systematic review and meta-analysis respectively. 73.3% 66 studies were conducted in China. Newcastle–Ottawa Quality Assessment Scale has been used to assess study quality of each included cohort study 107 . 30% (27/90) of included studies had satisfactory or good quality. The summary of the included study is shown in Table 1 .

PRISMA flowchart reporting identification, searching and selection processes.

Of those 90 eligible studies, 11,028 COVID-19 patients were identified and included in the systematic review. More than half of patients (6336, 57.5%) were from mainland China. The pooled mean age was 45.8 (95% CI 38.6–52.5) years and 49.3% (pooled 95% CI 45.6–53.0%) of them were male.

For specific comorbidity status, the most prevalent comorbidity was hypertension (18.1%, 95% CI 15.4–20.8%), followed by cardiovascular disease (11.8%, 95% CI 9.4–14.2%) and diabetes (10.4%, 95% CI 8.7–12.1%). The pooled prevalence (95% CI) of COPD, chronic kidney disease, liver disease and cancer were 2.0% (1.3–2.7%), 5.2% (1.7–8.8%), 2.5% (1.7–3.4%) and 2.1% (1.3–2.8%) respectively. Moderate to substantial heterogeneity between reviewed studies were found, with I 2 statistics ranging from 39.4 to 95.9% ( p values between < 0.001–0.041), except for liver disease (I 2 statistics: 1.7%, p  = 0.433). Detailed results for comorbidity status are displayed in Fig.  2 .

Random-effects meta-analytic estimates for comorbidities. ( A ) Diabetes mellitus, ( B ) Hypertension, ( C ) Cardiovascular disease, ( D ) Chronic obstructive pulmonary disease, ( E ) Chronic kidney disease, ( F ) Cancer.

Regarding the symptoms presented at hospital admission, the most frequent symptoms were fever (pooled prevalence: 72.4%, 95% CI 67.2–77.7%) and cough (pooled prevalence: 55.5%, 95% CI 50.7–60.3%). Sore throat (pooled prevalence: 16.2%, 95% CI 12.7–19.7%), dyspnoea (pooled prevalence: 18.8%, 95% CI 14.7–22.8%) and muscle pain (pooled prevalence: 22.1%, 95% CI 18.6–25.5%) were also common symptoms found in COVID-19 patients, but headache (pooled prevalence: 10.5%, 95% CI 8.7–12.4%), diarrhoea (pooled prevalence: 7.9%, 95% CI 6.3–9.6%), rhinorrhoea (pooled prevalence: 9.2%, 95% CI 5.6–12.8%) were less common. However, none of the included papers reported prevalence of anosmia and ageusia. The I 2 statistics varied from 68.5 to 97.1% (all p values < 0.001), indicating a high heterogeneity exists across studies. Figure  3 shows the pooled proportion of symptoms of patients presented at hospital.

Random-effects meta-analytic estimates for presenting symptoms. ( A ) Fever, ( B ) Cough, ( C ) Dyspnoea, ( D ) Sore throat, ( E ) Muscle pain, ( F ) Headache.

For laboratory parameters, white blood cell (pooled mean: 5.31 × 10 9 /L, 95% CI 5.03–5.58 × 10 9 /L), neutrophil (pooled mean: 3.60 × 10 9 /L, 95% CI 3.31–3.89 × 10 9 /L), lymphocyte (pooled mean: 1.11 × 10 9 /L, 95% CI 1.04–1.17 × 10 9 /L), platelet count (pooled mean: 179.5 U/L, 95% CI 172.6–186.3 U/L), aspartate aminotransferase (pooled mean: 30.3 U/L, 95% CI 27.9–32.7 U/L), alanine aminotransferase (pooled mean: 27.0 U/L, 95% CI 24.4–29.6 U/L) and C-reactive protein (CRP) (pooled mean: 22.0 mg/L, 95% CI 18.3–25.8 mg/L) and D-dimer (0.93 mg/L, 95% CI 0.68–1.18 mg/L) were the common laboratory test taken for COVID-19 patients. Above results and other clinical factors are depicted in Fig.  4 . Same with the comorbidity status and symptoms, high likelihood of heterogeneity was detected by I 2 statistics for a majority of clinical parameters.

Random-effects meta-analytic estimates for laboratory parameters. ( A ) White blood cell, ( B ) Lymphocyte, ( C ) Neutrophil, ( D ) C-creative protein, ( E ) D-dimer, ( F ) Lactate dehydrogenase.

Figure  5 presents the distribution of the pharmacological treatments received for COVID-19 patients. 10.6% of patients admitted to intensive care units (pooled 95% CI 8.1–13.2%). For drug treatment, 63.9% (pooled 95% CI 52.5–75.3%), 62.4% (pooled 95% CI 47.9–76.8%) and 29.7% (pooled 95% CI 21.8–37.6%) patients used antibiotics, antiviral, and corticosteroid, respectively. 41.3% (pooled 95% CI 14.3–68.3%) and 50.7% (pooled 95% CI 9.2–92.3%) reported using Lopinavir/Ritonavir and interferon-alpha as antiviral drug treatment, respectively. Among 14 studies reporting proportion of corticosteroid used, 7 studies (50%) specified the formulation of corticosteroid as systemic corticosteroid. The remaining one specified the use of methylprednisolone. No reviewed studies reported the proportion of patients receiving Ribavirin, Interferon-beta, or inotropes.

Random-effects meta-analytic estimates for pharmacological treatments and intensive unit care at hospital. ( A ) Antiviral or interferon drugs, ( B ) Lopinavir/Ritonavir, ( C ) Interferon alpha (IFN-α), ( D ) Antibiotic drugs, ( E ) Corticosteroid, ( F ) Admission to Intensive care unit.

The prevalence of radiological outcomes and non-pharmacological treatments were presented in Fig.  6 . Radiology findings detected chest X-ray abnormalities, with 74.4% (95% CI 67.6–81.1%) of patients with bilateral involvement and 74.9% (95% CI 68.0–81.8%) of patients with viral pneumonia. 62.6% (pooled 95% CI 39.9–85.4%), 20.2% (pooled 95% CI 14.6–25.9%), 15.3% (pooled 95% CI 11.0–19.7%), 1.1% (pooled 95% CI 0.4–1.8%) and 4.7% (pooled 95% CI 2.1–7.4%) took oxygen therapy, non-invasive ventilation, mechanical ventilation, ECMO and dialysis respectively.

Random-effects meta-analytic estimates for radiological findings and non-pharmacological treatments at hospital. ( A ) Bilateral involvement, ( B ) Pneumonia, ( C ) Oxygen therapy, ( D ) Non-invasive ventilation, ( E ) Extracorporeal membrane oxygenation (ECMO), ( F ) Dialysis.

The funnel plots and results Egger’s test of comorbidity status, symptoms presented, laboratory test and treatment were presented in eFigure 1 – S5 in the Supplement. 63% (19/30) of the funnel plots (eFigure 1 – S5 ) showed significance in the Egger’s test for asymmetry, suggesting the possibility of publication bias or small-study effects caused by clinical heterogeneity.

This meta-analysis reveals the condition of global medical community responding to COVID-19 in the early phase. During the past 4 months, a new major epidemic focus of COVID-19, some without traceable origin, has been identified. Following its first identification in Wuhan, China, the virus has been rapidly spreading to Europe, North America, Asia, and the Middle East, in addition to African and Latin American countries. Three months since Wuhan CDC admitted that there was a cluster of unknown pneumonia cases related to Huanan Seafood Market and a new coronavirus was identified as the cause of the pneumonia 108 , as on 1 April, 2020, there have been 858,371 persons confirmed infected with COVID-19, affecting 202 countries and territories around the world. Although this rapid review is limited by the domination of reports from patients in China, and the patient population is of relative male dominance reflecting the gender imbalance of the Chinese population 109 , it provides essential information.

In this review, the pooled mean age was 45.8 years. Similar to the MERS-CoV pandemic 110 , middle-aged adults were the at-risk group for COVID-19 infections in the initial phase, which was different from the H1N1 influenza pandemic where children and adolescents were more frequently affected 111 . Biological differences may affect the clinical presentations of infections; however, in this review, studies examining the asymptomatic COVID-19 infections or reporting any previous infections were not included. It is suggested that another systematic review should be conducted to compare the age-specific incidence rates between the pre-pandemic and post-pandemic periods, so as to understand the pattern and spread of the disease, and tailor specific strategies in infection control.

Both sexes exhibited clinical presentations similar in symptomatology and frequency to those noted in other severe acute respiratory infections, namely influenza A H1N1 112 and SARS 113 , 114 . These generally included fever, new onset or exacerbation of cough, breathing difficulty, sore throat and muscle pain. Among critically ill patients usually presented with dyspnoea and chest tightness 22 , 29 , 39 , 72 , 141 (4.6%) of them with persistent or progressive hypoxia resulted in the requirement of intubation and mechanical ventilation 115 , while 194 (6.4%) of them required non-invasive ventilation, yielding a total of 11% of patients requiring ventilatory support, which was similar to SARS 116 .

The major comorbidities identified in this review included hypertension, cardiovascular diseases and diabetes mellitus. Meanwhile, the percentages of patients with chronic renal diseases and cancer were relatively low. These chronic conditions influencing the severity of COVID-19 had also been noted to have similar effects in other respiratory illnesses such as SARS, MERS-CoV and influenza 117 , 118 . Higher mortality had been observed among older patients and those with comorbidities.

Early diagnosis of COVID-19 was based on recognition of epidemiological linkages; the presence of typical clinical, laboratory, and radiographic features; and the exclusion of other respiratory pathogens. The case definition had initially been narrow, but was gradually broadened to allow for the detection of more cases, as milder cases and those without epidemiological links to Wuhan or other known cases had been identified 119 , 120 . Laboratory investigations among COVID-19 patients did not reveal specific characteristics—lymphopenia and elevated inflammatory markers such as CRP are some of the most common haematological and biochemical abnormalities, which had also been noticed in SARS 121 . None of these features were specific to COVID-19. Therefore, diagnosis should be confirmed by SARS-CoV–2 specific microbiological and serological studies, although initial management will continue to be based on a clinical and epidemiological assessment of the likelihood of a COVID-19 infection.

Radiology imaging often plays an important role in evaluating patients with acute respiratory distress; however, in this review, radiological findings of SARS-CoV-2 pneumonia were non-specific. Despite chest radiograph usually revealed bilateral involvement and Computed Tomography usually showed bilateral multiple ground-glass opacities or consolidation, there were also patients with normal chest radiograph, implying that chest radiograph might not have high specificity to rule out pneumonia in COVID-19.

Limited clinical data were available for asymptomatic COVID-19 infected persons. Nevertheless, asymptomatic infection could be unknowingly contagious 122 . From some of the official figures, 6.4% of 150 non-travel-related COVID-19 infections in Singapore 123 , 39.9% of cases from the Diamond Princess cruise ship in Japan 124 , and up to 78% of cases in China as extracted on April 1st, 2020, were found to be asymptomatic 122 . 76% (68/90) studies based on hospital setting which provided care and disease management to symptomatic patients had limited number of asymptomatic cases of COVID-19 infection. This review calls for further studies about clinical data of asymptomatic cases. Asymptomatic infection intensifies the challenges of isolation measures. More global reports are crucially needed to give a better picture of the spectrum of presentations among all COVID-19 infected persons. Also, public health policies including social and physical distancing, monitoring and surveillance, as well as contact tracing, are necessary to reduce the spread of COVID-19.

Concerning potential treatment regime, 62.4% of patients received antivirals or interferons (including oseltamivir, lopinavir-ritonavir, interferon alfa), while 63.9% received antibiotics (such as moxifloxacin, and ceftriaxone). In this review, around one-third of patients were given steroid, suggestive as an adjunct to IFN, or sepsis management. Interferon and antiviral agents such as ribavirin, and lopinavir-ritonavir were used during SARS, and the initial uncontrolled reports then noted resolution of fever and improvement in oxygenation and radiographic appearance 113 , 125 , 126 , without further evidence on its effectiveness. At the time of manuscript preparation, there has been no clear evidence guiding the use of antivirals 127 . Further research is needed to inform clinicians of the appropriate use of antivirals for specific groups of infected patients.

Limitations of this meta-analysis should be considered. First, a high statistical heterogeneity was found, which could be related to the highly varied sample sizes (9 to 4226 patients) and study designs. Second, variations of follow-up period may miss the event leading to heterogeneity. In fact, some patients were still hospitalized in the included studies. Third, since only a few studies had compared the comorbidities of severe and non-severe patients, sensitivity analysis and subgroup analysis were not conducted. Fourthly, the frequency and severity of signs and symptoms reported in included studies, primarily based on hospitalized COVID-19 patients were over-estimated. Moreover, different cutoffs for abnormal laboratory findings were applied across countries, and counties within the same countries. Lastly, this meta-analysis reviewed only a limited number of reports written in English, with a predominant patient population from China. This review is expected to inform clinicians of the epidemiology of COVID-19 at this early stage. A recent report estimated the number of confirmed cases in China could reach as high as 232,000 (95% CI 161,000, 359,000) with the case definition adopted in 5th Edition. In this connection, further evidence on the epidemiology is in imminent need.

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Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Carlos K. H. Wong, Eric H. M. Tang & C. H. Au

Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Carlos K. H. Wong

School of Nursing, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Janet Y. H. Wong

Emergency Medicine Unit, Li Ka Shing, Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Abraham K. C. Wai

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C.W., J.W. and A.W. contributed equally to all aspects of study design, conduct, data interpretation, and the writing of the manuscript. C.W., E.T. and C.H.A. contributed to eligibility screening, data extraction from eligible studies, and data analysis and interpretation.

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Wong, C.K.H., Wong, J.Y., Tang, E.H.M. et al. Clinical presentations, laboratory and radiological findings, and treatments for 11,028 COVID-19 patients: a systematic review and meta-analysis. Sci Rep 10 , 19765 (2020). https://doi.org/10.1038/s41598-020-74988-9

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REVIEW article

Coronavirus disease (covid-19): comprehensive review of clinical presentation.

• 1 Department of Medicine, King Edward Medical University/ Mayo Hospital, Lahore, Pakistan
• 2 Department of Anesthesia and Intensive Care, Post-Graduate Medical Institute/LGH, Lahore, Pakistan
• 3 Rajarshee Chhatrapati Shahu Maharaj Government Medical College, Kolhapur, India
• 4 Department of Medicine, Faculty of Medicine, University of Tlemcen, Tlemcen, Algeria
• 5 School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
• 6 Institute of Research and Development, Duy Tan University, Da Nang, Vietnam

COVID-19 is a rapidly growing pandemic with its first case identified during December 2019 in Wuhan, Hubei Province, China. Due to the rampant rise in the number of cases in China and globally, WHO declared COVID-19 as a pandemic on 11th March 2020. The disease is transmitted via respiratory droplets of infected patients during coughing or sneezing and affects primarily the lung parenchyma. The spectrum of clinical manifestations can be seen in COVID-19 patients ranging from asymptomatic infections to severe disease resulting in mortality. Although respiratory involvement is most common in COVID-19 patients, the virus can affect other organ systems as well. The systemic inflammation induced by the disease along with multisystem expression of Angiotensin Converting Enzyme 2 (ACE2), a receptor which allows viral entry into cells, explains the manifestation of extra-pulmonary symptoms affecting the gastrointestinal, cardiovascular, hematological, renal, musculoskeletal, and endocrine system. Here, we have reviewed the extensive literature available on COVID-19 about various clinical presentations based on the organ system involved as well as clinical presentation in specific population including children, pregnant women, and immunocompromised patients. We have also briefly discussed about the Multisystemic Inflammatory Syndrome occurring in children and adults with COVID-19. Understanding the various clinical presentations can help clinicians diagnose COVID-19 in an early stage and ensure appropriate measures to be undertaken in order to prevent further spread of the disease.

Introduction

COVID-19 is a growing pandemic with initial cases identified in Wuhan, Hubei province, China toward the end of December 2019. Labeled as Novel Coronavirus 2019 (2019-nCoV) initially by the Chinese Center for Disease Control and Prevention (CDC) which was subsequently renamed as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) due to its homology with SARS-CoV by the International Committee on Taxonomy of Viruses (ICTV) ( 1 , 2 ). The World Health Organization (WHO) later renamed the disease caused by SARS-CoV-2 as Coronavirus Disease-2019 (COVID-19) ( 3 ). COVID-19 is primarily a disease of the respiratory system affecting lung parenchyma with fever, cough, and shortness of breath as the predominant symptoms. Recent studies have shown that it can affect multiple organ systems and cause development of extra-pulmonary symptoms. Presence of extra-pulmonary symptoms can often lead to late diagnosis and sometimes even mis-diagnosis of COVID-19 which can be detrimental to patients. As researchers globally continue to understand COVID-19 and its implications on the human body, knowledge about the various clinical presentations of COVID-19 is paramount in early diagnosing and treatment in order to decrease the morbidity and mortality caused by the disease.

Epidemiology and Pathophysiology

While studying the early transmission dynamics of COVID-19 outbreak in Wuhan, many cases were found to be linked to the Huanan wholesale seafood market. Further investigation revealed <10% of the total cases could be linked to the market which led to the conclusion of human-to-human transmission of the virus occurring through respiratory droplets and contact transmission contributing to the rise in the number of affected individuals ( 4 ). The exponential rise in the number of cases in China and reporting of cases outside China in multiple countries led WHO to declare COVID-19 as a pandemic on 11th March 2020 ( 5 ).

SARS-CoV-2 tends to infect all age groups and is transmitted via direct contact or respiratory droplets generated during coughing or sneezing by the infected patient during both symptomatic or pre-symptomatic phase of infection. Other routes of transmission include fecal-oral route and fomites along with small risk of vertical transmission from mother to child if infection occurs during third trimester of pregnancy ( 6 , 7 ). There has also been evidence of asymptomatic transmission of COVID-19 ( 8 ). The concept of super spreaders in relation to COVID-19 is emerging where a single individual either symptomatic or asymptomatic can infect a disproportionately large number of individuals in an appropriate super spreading conditions such as mass gathering due to production of large number of infectious agent for prolonged duration of time ( 9 ). As per the literature, the incubation period of COVID-19 ranges from 2 to 14 days with a mean incubation period of 3 days ( 10 ). The basic Reproduction number (Ro) of SARS-CoV-2 is 2–2.5. Each individual infected with COVID-19 can infect 2–2.5 other individuals in a naïve population which also explains the exponential growth in the number of cases ( 10 ). The disease tends to be of mild to moderate severity in roughly 80% of patients, and severe disease is associated with infants, elderly patients above 65 years, and patients with other comorbidities such as diabetes mellitus, hypertension, coronary artery disease, and other chronic conditions ( 1 , 2 ). COVID-19 has also been found to be more severe in males than in females with a case fatality rate of 2.8% in males and 1.7% in females ( 11 ). The major organ system affected by the virus is the respiratory system, but it can affect other organ systems either directly or by the effect of host immune response. SARS-CoV-2, the causative agent of COVID-19, after entering the human host initially replicates in the epithelial mucosa of the upper respiratory tract (nose and pharynx) followed by migration to the lungs where further replication of virus occurs causing transient viraemia. The virus uses Angiotensin Converting Enzyme 2 (ACE2) receptor as a primary entry to cells. ACE2 is found abundantly in the mucosal lining of the respiratory tract, vascular endothelial cells, heart, intestine, and kidney. Thus, the virus has potential for replication in all these organs. After entry into cells, the virus undergoes further rapid replication within the target cells and induces extensive epithelial and endothelial dysfunction leading to exponential inflammatory response with the production of a large amount of proinflammatory cytokines and chemokines. Activation of proinflammatory cytokines and chemokines leads to neutrophil activation and migrations and results in the characteristic cytokine storm. The immunological downregulation of ACE2 by the virus contributes to acute lung injury in COVID-19. ACE2 also regulates the renin angiotensin system (RAS); thus, downregulation of ACE2 also causes dysfunction of RAS which contributes to enhanced inflammation ( 2 , 11 – 15 ). These entire factors contribute to symptoms of COVID-19 with sepsis, multi-organ dysfunction, acute respiratory distress syndrome (ARDS), and prothrombotic state leading to an exacerbation of organ dysfunction.

Clinical Manifestation

We review here the system based clinical features of COVID-19.

Respiratory

According to report from WHO-China-Joint Mission on COVID-19, 55,924 laboratories confirmed cases of COVID-19 had fever (87.9%), dry cough (67.7%), fatigue (38.1%), sputum production (33.4%), difficulty breathing (18.6%), sore throat (13.9%), chills (11.4%), nasal congestion (4.8%), and hemoptysis (0.9%) ( 1 ).

Some patients may rapidly progress to acute lung injury and ARDS with septic shock. The median interval between the onset of initial symptoms to development of dyspnea, hospital admission, and ARDS was 5, 7, and 8 days respectively ( 10 ). Some patients with COVID-19 may have reduced oxygen saturation in blood (≤ 93%) with oxygen saturation down to 50 or 60% but remained stable without significant distress, and as such, were termed as salient hypoxia or happy hypoxia ( 16 , 17 ). Trial of oxygen therapy, prone positioning, high flow continuous positive airway pressure, non-re-breathable mask alongside trial of anticoagulation are often used to manage these patients ( 16 , 17 ). However, further study is required to define the role of these strategies in management.

The most frequent radiological abnormality among 975 patients with COVID-19 in computed tomography (CT) scan of chest was ground glass opacity (56.4%) and bilateral patchy shadowing (51.8%) ( 18 ). A scientific review of 2,814 patients have shown that the most common chest CT finding in COVID-19 patients was ground glass opacity followed by consolidation. However, the findings can vary in different patients and at various stages of diseases. Other CT findings include interlobular septal thickening, reticular pattern, crazy paving, etc. Atypical findings like air bronchogram, bronchial wall thickening, nodule, pleural effusion, and lymphadenopathy have also been noted in some studies ( 19 ). A study showed that among 877 patients with non-severe diseases and 173 patients with severe diseases, 17.9 and 2.9% of the patients did not have any detectable radiological abnormalities, respectively ( 18 ).

ENT (Ear, Nose, and Throat)

ENT manifestations are one of the most frequent symptoms encountered by physicians in COVID-19. A peculiar clinical presentation in some COVID-19 patients includes the deterioration of sense, taste (dysgeusia), and loss of smell (anosmia). A systematic review and meta-analysis of 10 studies with 1,627 participants surveyed for olfactory deterioration and 9 studies with 1,390 participants examined for gustatory symptoms demonstrated prevalence of 52.73 and 43.93% of these symptoms among COVID-19 patients, respectively. These clinical features may often present at earlier stages of the disease ( 20 ). Additionally, sore throat, rhinorrhea, nasal congestion, tonsil edema, and enlarged cervical lymph nodes are commonly seen among otolaryngological dysfunctions in patients ( 21 ). A large observational study of 1,099 COVID-19 patients reported tonsils swelling in 23 patients (2.1%), throat congestion in 19 patients (1.7%) and enlarged lymph nodes in 2 patients (0.2%) ( 18 ). This can be explained by the fact that there is a high expression of ACE2 receptors on the epithelial cells of the oral and nasal mucosa including the tongue. It has been known that the novel coronavirus has a strong binding affinity to ACE2 receptors through which it invades host cells ( 22 ). This theory may explain the exhibition of extra-respiratory symptoms including ENT manifestations as part of COVID-19 symptoms.

Cardiovascular

Cardiac manifestation in patient with COVID-19 can occur due to cardiac strain secondary to hypoxia and respiratory failure, direct effect of SARS-CoV-2 on heart or secondary to inflammation and cytokine storm, metabolic derangements, rupture of plaque and coronary occlusion by thrombus, and consequences of drugs used for treatment ( 23 – 25 ). The need for intensive care admission, non-invasive ventilation (46.3 vs. 3.9%), and invasive mechanical ventilation (22 vs. 4.2%) were higher among patients with cardiac ailments as compared to those without cardiac involvement as well as higher hospital mortality than those without myocardial involvement (51.2 vs. 4.5%) ( 26 ). These patients tend to have electrocardiographic (ECG) changes as well as elevations in high sensitivity cardiac troponin (hsCTn) and N- terminal pro-B-type natriuretic peptide (NT proBNP) which corresponded to raised inflammatory markers. Hypertension, acute and fulminant myocarditis, ventricular arrhythmias, atrial fibrillation, stress cardiomyopathy, hypotension and heart failure, acute coronary syndrome (ACS) with ST elevation or depression MI with normal coronaries have been reported ( 23 , 27 ). In a Chinese cohort of 138 patients, 16.7% had arrhythmias with risk higher among those needing ICU care with no mention of the type of arrhythmia that was present ( 28 ). Less frequently, cardiac symptoms like chest pain or tightness and palpitation can be the initial presenting features without fever producing a diagnostic dilemma. Some of these patients eventually go on to develop respiratory symptoms as diseases progress ( 29 ). Patients who have recovered from acute illness may develop arrhythmias as a result of myocardial scar and need future monitoring ( 27 ). One important point to note is use of Renin Angiotensin Aldosterone System (RAAS) modulators in patients with COVID-19. Guidelines from ACC/AHA/HFSA recommends continuing them in high risk patient based on goal directed therapy approach supported by a recent systematic review and meta-analysis conducted by Hasan et. Al. which demonstrated use of ACEI/ARB in COVID-19 patients is associated with lower odds/ hazards of mortality and development of severe/critical diseases as compared to no use of ACEI/ARB ( 30 , 31 ).

Gastrointestinal

In the initial cohort of patients from China, nausea or vomiting and diarrhea were present in 5 and 3.7% of patients ( 1 ). Review of data from 2,023 patients showed anorexia to be the most frequently occurring gastrointestinal symptom in adults. Diarrhea was the most common presenting gastrointestinal symptom in both adults and children while vomiting was found to be more common in children ( 32 ). Other rare symptoms included nausea, abdominal pain, and gastrointestinal bleeding. There have been few instances where COVID-19 patients presented with only gastrointestinal symptoms without the development of fever or respiratory symptoms at the onset and during disease progression ( 33 ). In a smaller cohort of 204 patients, 50.5% had some form of intestinal symptoms and of those, 5.8% had only intestinal symptoms while the remaining patients developed respiratory symptoms subsequently. The most common symptoms reported among them was anorexia (78.64%), non-dehydrating diarrhea (34%), vomiting (3.9%), and abdominal pain (1.94%) ( 34 ). In addition, those with GI symptoms tend to have a longer interval between symptom onset and hospital admission (9 vs. 7.3 days) possibly due to lack of clinical suspicion and delay in diagnosis. Patients with gastrointestinal symptoms tend to have higher elevation in AST and ALT indicating coexistent liver injury ( 34 ). The mechanism behind GI illness is not clearly known but could be due to direct invasion of virus via ACE2 receptor in the intestinal mucosa. This can be supported by the fact that viral RNA can be detected in stool samples of COVID-19 patients which may also hint toward possible fecal-oral transmission ( 35 ). Liver dysfunction is likely secondary to the use of hepatotoxic drugs, hypoxia induced liver injury, systemic inflammation, and multi organ failure ( 36 ).

Renal manifestation in patients with COVID-19 can occur due to direct invasion of podocytes and proximal tubular cells by SARS-CoV-2 virus, secondary endothelial dysfunction causing effacement of foot process with vacuolation and detachment of podocytes, and acute proximal tubular dysfunction ( 37 ). Furthermore, hypoxia, cytokine storm, rhabdomyolysis, nephrotoxic drugs, and overlying infections can all exacerbate renal injury ( 38 ). Based on initial reports, prevalence of Acute Kidney Injury (AKI) among COVID-19 hospitalized patients range from 0.5 to 29%. In a cohort of 701 patients, proteinuria (43.9%), hematuria (26.7%), elevated creatinine (14.4%), elevated blood urea nitrogen (13.1%), and low glomerular filtration rate (≤ 60 ml/min/1.73 m 2 ) (13.1%) were present at the time of hospital admission with 5.1% developing AKI during the illness. AKI was more prevalent among those with baseline renal impairment ( 39 ). In another large cohort of 5,449 patients, 36.6% had AKI with prevalence higher among mechanically ventilated patients compared to non-ventilated patients (89.7 vs. 21.7%) ( 40 ). Patients developing renal impairment are prone to have higher mortality within the hospital. Another point to highlight is the presentation of COVID-19 in renal transplant recipients. Due to immunosuppression, these patients are likely to have low fever at presentation with swift clinical decline and requirement for mechanical ventilation with high mortality as compared to the general population ( 41 ).

Neurological

Most patients with COVID-19 develop neurological symptoms along with respiratory symptoms during the course of illness; however, several case reports in review of literature document patient presentation of neurological dysfunction without typical symptoms of fever, cough, and difficulty breathing ( 42 ). There is a 2.5-fold enhanced risk of severe illness and increased death in patients with a history of previous stroke with similar findings among those with Parkinson's diseases. The prevalence of neurological features ranges from 6 to 36% along with hypoxic ischemic encephalopathy up to 20% in some series of patients ( 43 ). Neurological symptoms tend to occur early in the course of illness (median 1–2 days) with most common neurological features being headache, confusion, delirium, anosmia or hyposmia, dysgeusia or ageusia, altered mental status, ataxia, and seizures ( 44 ). Among patients admitted with COVID-19, the prevalence of ischemic stroke ranges from 2.5 to 5% despite receiving prophylaxis for venous thromboembolism. Patients prone to have established cardiovascular risk factors are likely to have a more severe diseases ( 43 ). Other presentations include viral encephalitis, acute necrotizing encephalopathy (ANE), infectious toxic encephalopathy, meningitis, Guillain Barre Syndrome (GBS), Miller Fisher syndrome, and polyneuritis cranialis with GBS being the first feature of COVID-19 in few cases ( 42 , 43 , 45 ). In COVID-19 patients, CNS features are possibly due to direct invasion of neurons and glial cells by SARS-CoV-2 as well as by endothelial dysfunction of blood brain barrier (BBB). Virus can gain access to CNS via hematogenous spread or retrograde movement across the olfactory bulb. The virus can be detected in CSF by RT-PCR and on brain parenchyma during autopsy. The fact that most patients develop anosmia or hyposmia during illness support this theory ( 45 ). After entry, the virus can cause reactive gliosis with activation of the inflammatory cascade. The combination of systemic inflammation, cytokine storm, and coagulation dysfunction can impair BBB function and alter brain equilibrium causing neuronal death ( 42 ).

Ocular manifestations can vary from conjunctival injection to frank conjunctivitis. In a Chinese cohort of 38 patients, 31.6% had ocular symptoms consisting primarily of conjunctivitis while conjunctival hyperemia, foreign body sensation in eye, chemosis, tearing or epiphora were more common among severe COVID-19 patients. Among them SARS-CoV-2 can be demonstrated in conjunctival as well as nasopharyngeal swab in 5.2% of patients, indicating a potential route for viral transmission ( 46 ). Conjunctivitis or tearing can be the initial presenting symptoms of COVID-19. Despite this fact, there is no documented case of severe ocular features relating to COVID-19.

Similar to other viral infections, SARS-CoV-2 can also produce varied dermatological features. A study of 88 patients from Italy showed that about 20.4% had some form of skin manifestations with 44.4% developing features at onset and duration of the disease progression ( 47 ). Maculopapular exanthem (36.1%) was identified as most common dermatological features followed by papulovesicular rash (34.7%), painful acral red purple papules (15.3%), urticaria (9.7%), livedo reticularis (2.8%), and petechiae (1.4%) ( 48 ). A study of 375 COVID-19 cases in Spain identified five different patterns of cutaneous manifestations in patients: acral areas of erythema with vesicles or pustules (pseudo-chilblain) (19%), other vesicular eruptions (9%), urticarial lesions (19%), maculopapular eruptions (47%), and livedo or necrosis (6%) ( 49 ). Majority of patients had lesions on the trunk with some experiencing lesions on hands and feet. There are case reports of COVID-19 associated with erythema multiforme and Kawasaki Disease in children ( 50 , 51 ). Pathogenesis behind skin involvement remains unclear with some features explained by small vessel vasculitis, thrombotic events like DIC, hyaline thrombus formation, acral ischemia, or the direct effect of the virus like other viral illnesses ( 52 ).

Musculoskeletal

The initial report from China revealed 14.8% of patients had myalgia or arthralgia among 55,924 COVID-19 patients. A review article reports that of 12,046 patients, fatigue was identified in 25.6% and myalgia and/or arthralgia in 15.5% with most patients reporting symptoms from the start of illness ( 53 ). There are reports suggesting myositis and rhabdomyolysis with markedly elevated creatinine kinase can occur during COVID-19 illness especially in patients with severe diseases and multi organ failure. Additionally, in some patients, rhabdomyolysis has been documented as the initial presentation of COVID-19 illness without typical respiratory symptoms ( 54 , 55 ). A case series of four patients developing acute arthritis during hospital admission for COVID-19 has been reported with exacerbation of crystal arthropathy (gout and calcium pyrophosphate diseases) but negative for SARS-CoV-2 RT-PCR in synovial fluid ( 56 ). Treatment with steroids and colchicine was used in all four cases. An important consideration to note was that all four patients developed arthritis despite previous treatment with immunomodulatory therapy (hydroxychloroquine, tocilizumab, and pulse methylprednisolone).

Hematological

As stated, COVID-19 is a systemic disease inducing systemic inflammation and occasionally cytokine storm. This can significantly impact the process of hematopoiesis and hemostasis. During early disease, normal or decreased leukocyte and lymphocyte counts were documented with marked lymphopenia as the diseases progressed, especially in those with cytokine storms and severe disease. In a study of 1,099 patients, lymphopenia, thrombocytopenia, and leukopenia were present in 83.2, 36.2, and 33.7%, respectively, with findings more marked in those with severe diseases ( 18 ). Leukocytosis in COVID-19 patients might suggest a bacterial infection or a superinfection with leukocytosis found more commonly in severe cases (11.4%) as compared to mild and moderate cases (4.8%) ( 18 ). Similarly, thrombocytopenia has been found to be more common (57.7%) in severe cases in contrast to mild and moderate cases (31.6%) ( 18 ). Lymphopenia was also linked with an increased necessity for ICU admission and the risk of ARDS. Thrombocytosis with elevated platelet to lymphocyte ratio may indicate a more marked cytokine storm ( 57 ).

Also, coagulation abnormality can manifest in the form of thrombocytopenia, prolonged prothrombin time (PT), low serum fibrinogen level, and raised D-dimer suggesting Disseminated Intravascular Coagulation (DIC) with these changes more marked in those with severe diseases ( 58 ). Raised lactate dehydrogenase (LDH) and serum ferritin were also present and correlated with the degree of systemic inflammation. In a study of 426 COVID-19 patients, C-Reactive Protein (CRP) was noted to be increased in 75–93% of patients, more commonly in patients with severe disease. Serum procalcitonin levels might not be altered at admission, but progressive increase in its value can suggest a worsening prognosis. Severe disease is linked to increased ALT, bilirubin, serum urea, creatinine, and lowered serum albumin ( 59 ). A study of 1,426 patients showed that Interleukin-6 (IL-6) were raised more in patients with severe COVID-19 than non-severe COVID-19 with progressive rise indicating an increased risk of mortality. Thus, its levels could be regarded as an important prognostic indicator for the extensive inflammation and cytokine storm in COVID-19 patients ( 60 ). Other plasma cytokines and chemokines like IL1B, IFNγ, IP10, MCP, etc. have also been found to be elevated in patients with COVID-19 both in severe and non-severe diseases. Additionally, GCSF, IP10, IL2, IL7, IL10, MCP1, MIP1A, and TNFα were increased in patients who require ICU admission which indicates that cytokine storm is associated with a severe disease ( 61 ).

Endocrine and Reproductive

From the available literature there is no doubt that diabetes mellitus is an important risk factor for COVID-19 illness and is associated with increased risk of development of severe disease. Additionally, there are case reports of subacute thyroiditis linked to SARS-CoV-2 infection ( 62 , 63 ). Based on the statement released from European Society of Endocrinology, patients with primary adrenal failure and congenital adrenal hyperplasia may have theoretically increased susceptibility to infection with higher risk of complications and ultimately mortality but there is no current evidence to support this ( 64 ). The dose of steroids may need to be doubled if there is a clinical suspicion of infection in these patients.

Several claims have been made regarding the impact of COVID-19 on male reproductive function, hypothesizing that COVID-19 can cause potential testicular damage either by binding directly to testicular ACE2 receptors, which are highly expressed in the testicles or by damaging the testis indirectly by exciting local immune system ( 65 ). A study comparing 81 male COVID-19 patients with 100 age matched healthy adults highlighted the presence of low testosterone levels, high levels of luteinizing hormone (LH), low testosterone/LH ratios, low Follicle stimulating hormone (FSH) to LH ratio, and raised serum prolactin. This may suggest a potential COVID-19 testicular damage affecting the Leydig cells in the testis ( 66 ). COVID-19 infected male patients may have reduced sperm count and decreased motility leading to diminished male fertility for 3 months post-infection ( 67 ).

Clinical Presentation in Specific Population

In children.

A case series of 72,314 cases published by the Chinese Center for Disease Control and Prevention reported that 0.9% of the total patients were between 0 and 9 years of age, and 1.2% of the total patients were between 10 and 19 years of age ( 68 ). The most common symptoms found in children are fever, (59%), cough (46%), few cases (12%) of gastrointestinal symptoms, and some cases (26%) showed no specific symptoms initially with patchy consolidation and ground glass opacities in CT chest findings ( 69 ). Chilblain-like acral eruptions, purpuric, and erythema multiforme-like lesions have been found to be more common in children and young adult patients mainly with asymptomatic or mild disease ( 70 ). Lymphopenia in children is relatively less common which is in direct contrast in cases of SARS in children where lymphopenia was more commonly noted ( 69 ).

Multisystem inflammatory syndrome (MIS) is another feared complication of Covid-19 seen in children. Abrams et al. systematically summarized the clinical evidence of 8 studies reporting MIS in 440 children. The median age of patients ranged from 7.3 to 10 years with 59% of all patients being male. The greatest proportion of patients had gastrointestinal symptoms (87%) followed by mucocutaneous symptoms (73%) and cardiovascular symptoms (71%) while fewer patients reported respiratory (47%), neurologic (22%), and musculoskeletal (21%) symptoms. Ferritin and d-dimer were elevated in 50% of patients, and C-reactive protein, interleukin-6, and fibrinogen were elevated in at least 75% of patients. Additionally, 100% of children with cardiovascular involvement reported elevated cardiac-damage markers such as Troponin. Although respiratory manifestation is most frequently expressed in adults, children with MIS exhibited less pulmonary symptoms and more of the other manifestations ( 71 ).

In Pregnant Women

The most common symptoms reported in pregnant women are fever (61.96%), cough (38.04%), malaise (30.49%), myalgia (21.43%), sore throat (12%), and dyspnea (12.05%). Other symptoms found in pregnant women are diarrhea and nasal congestion ( 72 ). In a systematic review including 92 patients, 67.4% manifested diseases at presentation with 31.7% having negative RT-PCR though they had features of viral pneumonia. Only one patient required admission to intensive care and 0% mortality. Fetal outcomes were reported as: 63.8% preterm delivery, 61.1% fetal distress, 80% Cesarean section delivery, 76.92% neonatal intensive care admission, 42.8% low birth weight, and 66.67% had lymphopenia ( 72 ). There was no evidence of vertical transmission. A study of 41 pregnant women with COVID-19 showed that consolidation was more commonly found in CT of pregnant women in contrast to ground-glass opacities in CT of non-pregnant adults ( 73 ). WHO also recommends encouraging lactating mothers with confirmed or suspected COVID-19 to begin or continue breastfeeding including 24-h rooming in, skin to skin contact, and kangaroo mother care especially in immediate postnatal period ( 74 ). On July 14th, 2020, Vivanti et al. published the first case of transplacental transmission of COVID-19 from a 23-years-old pregnant woman to her baby ( 75 ). Thereafter, more studies reported the possibility of the vertical transmission of COVID-19. In this context, Kotlayer et al. published a systematic review of 38 studies. Out of 936 neonates from COVID-19 mothers, 27 tested positive for the virus indicating a pooled proportion of 3.2% (2.2–4.3) for vertical transmission ( 7 ).

In Immuno-Compromised Population

Due to their impaired immune response, it is not surprising that immunocompromised patients with COVID-19 infection might be at greater risk of developing severe forms of the disease and co-infections in comparison to normal populations. Nevertheless, recent studies showed the association between cytokine storm syndrome and the overreaction of the immune system with COVID-19 raising the possibility that immunodeficient states might alleviate the overexpression of the host immune system and thereby prevent deadly forms of the disease ( 76 ). After the RECOVERY trial ( 77 ) that showed the efficacy of dexamethasone in lowering the mortality in severe forms of the disease, many questions were raised regarding whether immunocompromised patients have a greater or lower risk of developing severe forms of the disease. In order to address these questions, Minotti et al. recently published a systematic review that included 16 studies with 110 patients presenting mostly with cancer along with transplantation and immunodeficiency. Out of the 110 patients, 72 (65.5%) recovered without being admitted to the intensive care unit while 23 (20.9%) died ( 76 ). The authors concluded that immunosuppression in both children and adults seem to have a better disease course in comparison to normal population. One of the limitations of this study is that the conclusion was made only based on qualitative synthesis and no meta-analysis was performed. On the other hand, Gao et al. performed a meta-analysis on 8 relevant studies with 4,007 patients. The study showed that immunosuppression and immunodeficiency were associated with non-statistically significant increased risk of severe COVID-19 disease ( 78 ). Additionally, Mirzaei et al. summarized the clinical evidence of 252 HIV positive patients co-infected with COVID-19. The clinical manifestation did not differ from that of the general population. However, out of the 252 patients, 204 (80.9%) were male. Low CD4 count (<200 cells/mm 3 ) were reported for 23 of 176 patients (13.1%). COVID-19 symptoms were present in 223 patients with the most common symptoms of fever in 165 (74.0%) patients, cough in 130 (58.3%), headache in 44 (19.7%), arthralgia and myalgia in 33 (14.8%), gastrointestinal symptoms in 29 (13.0%) followed by sore throat in 18 (8.1%) patients ( 79 ). The number of deaths accounted for 36 (14.3%). Similar to the general population, immunocompromised, and HIV patients were no different in terms of clinical manifestation or severity. However, the results from these studies should be interpreted with caution and more studies are recommended to establish the link between this particular group of patients with severity of the disease.

Multisystem Involvement in COVID-19

As evident from the discussion above, SARS-CoV-2 can affect multiple organ systems and produce a wide array of clinical presentation of COVID-19. Certain studies conducted in Europe and United States have shown that COVID-19 can also have a multi-systemic presentation in individuals in form of a multi-system inflammatory syndrome (MIS) which has been found in both children and adults and is known as MIS-C and MIS-A, respectively ( 80 – 83 ).

According to a recent CDC report about MIS-A, it was found that only half of the patients with MIS-A had preceding respiratory symptoms of COVID-19 ~2–5 weeks before ( 80 ). The most common clinical signs and symptoms included fever, chest pain, palpitations, diarrhea, abdominal pain, vomiting, skin rash, etc. Nearly all patients had electro-cardiological abnormalities like arrythmias, elevated troponin levels, and electrocardiography evidence of left or right ventricular dysfunction. Even though most patients had minimal respiratory symptoms, chest imaging had features of ground glass opacity and pleural effusion. All patients had signs of elevated laboratory markers of inflammation, coagulation markers, and lymphopenia ( 80 ).

MIS-C can clinically mimic Kawasaki Disease ( 81 ). By the end of July, about 570 cases of MIS-C with COVID-19 were found in the United States ( 81 ). In MIS-C, there is involvement of at least four organ systems, most commonly the gastrointestinal system followed by cardiovascular and dermatological systems ( 81 ). Prominent signs and symptoms found in children with MIS-C were abdominal pain, vomiting, skin rash, diarrhea, hypotension, and conjunctival injection. The majority of the children needed ICU admission due to the development of severe complications including cardiac dysfunction, shock, myocarditis, coronary artery aneurysm, and acute kidney injury ( 81 ).

Association Between Clinical Presentations, COVID-19 Severity and Prognosis

Evaluation of 55,924 laboratory confirmed COVID-19 cases in China, the presence of dyspnea, respiratory rate ≥ 30/min, blood saturation levels ≤ 93%, PaO2/FiO2 ratio ≤ 300, lung infiltrates ≥ 50% of the lung fields between 12 and 48 h were associated with severe COVID-19 infection ( 1 ). Clinical signs suggestive of respiratory failure, septic shock, or multiple organ dysfunction/failure were associated with critical disease and poor prognosis ( 1 ). Individuals at highest risk of severe disease and deaths were patients with age > 80 years and associated co-morbidities such as underlying cardiovascular disease, diabetes, hypertension, chronic respiratory disease, and cancer ( 1 ). Another study done with 418 patients in Catalonia (Spain) showed that dyspnea was an important predictor of severe disease while confusion was an important predictor of death, and the presence of cough was strongly associated with good prognosis ( 84 ). Advanced age, male sex, and obesity were independent markers of poor prognosis while eosinophilia was a marker of less severe disease ( 84 ). The mortality was lower in patients with symptoms of diarrhea, arthromyalgia, headache, and loss of smell and taste sensations while low oxygen saturation, high CRP levels, and higher number of lung quadrants affected on Xray were found to be associated with severe disease and death ( 84 ).

COVID-19 is a viral illness which can cause multi-systemic manifestations. Review of existing literature concludes that SARS-CoV-2 can affect any organ system either directly or indirectly leading to a myriad of clinical presentation. The most commonly affected system is the respiratory system with presenting symptoms of fever, cough, and shortness of breath, etc. Other systems which can be affected in COVID-19 include ENT (sore throat, loss of taste, smell, and sensations, and rhinorrhea), cardiovascular system (chest pain, chest tightness, palpitations, and arrhythmias), gastrointestinal system (anorexia, diarrhea, vomiting, nausea, and abdominal pain), renal (proteinuria, hematuria, and acute kidney injury), neurological (headache, confusion, delirium, and altered mental status), ocular (conjunctival hyperemia, foreign body sensation in the eye, chemosis, and tearing), cutaneous (rash, papules, and urticaria), musculoskeletal system (myalgia and arthralgia), hematological (lymphopenia, thrombocytopenia, leukopenia, elevated inflammatory markers, and elevated coagulation markers), endocrine (low testosterone, low FSH, and high LH) and reproductive system (decreased sperm count and decreased sperm motility). Clinical presentation in specific populations like children, pregnant women, and immunocompromised people may vary which emphasizes the importance of further investigation in order to avoid late diagnosis of COVID-19. Severe multi-systemic involvement in COVID-19 in the form of MIS-C and MIS-A can cause significant morbidity and mortality if undiagnosed. The clinical presentations of respiratory failure, acute kidney injury, septic shock, cardiovascular arrest is associated with severe COVID-19 disease and can result in poor prognosis. In the light of exponentially growing pandemic, every patient presenting to hospital must be tested for SARS-CoV-2 by RT-PCR if resources are available to detect early presentations of diseases even if the features are atypical. Understanding of the various clinical presentations of COVID-19 will help the clinicians in early detection, treatment, and isolation of patients in order to contain the virus and slow down the pandemic.

Author Contributions

All authors have contributed equally to the work, and all agreed to be accountable for the content of the work.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We would like to thank Ms. Sairah Zia (American University of Caribbean, School of Medicine, Sint Maarten), a native speaker of English, for proofreading the manuscript.

Abbreviations

ACC/AHA/HFSA, American College of Cardiology/American Heart Association/Heart Failure Society of America; IL1B, Interleukin 1B; IFNγ, Interferon Gamma; IP10, Interferon-inducible Protein 10; MCP1, Monocyte Chemoattractant Protein 1; GCSF, Granulocyte Colony Stimulating Factor; IL2, Interleukin 2; IL7, Interleukin 7; IL10, Interleukin 10; MIP1A, Macrophage Inflammatory Protein-1 alpha; TNFα, Tumor Necrosis Factor alpha.

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Keywords: SARS-CoV-2, Covid-19, symptomatology, clinical presentation, signs and symptoms, clinical features, coronavirus

Citation: Mehta OP, Bhandari P, Raut A, Kacimi SEO and Huy NT (2021) Coronavirus Disease (COVID-19): Comprehensive Review of Clinical Presentation. Front. Public Health 8:582932. doi: 10.3389/fpubh.2020.582932

Received: 13 July 2020; Accepted: 15 December 2020; Published: 15 January 2021.

Reviewed by:

Copyright © 2021 Mehta, Bhandari, Raut, Kacimi and Huy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Nguyen Tien Huy, tienhuy@nagasaki-u.ac.jp

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Coronavirus Disease 2019 (COVID-19) Clinical Presentation

• Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
• Sections Coronavirus Disease 2019 (COVID-19)
• Practice Essentials
• Route of Transmission
• Epidemiology
• Physical Examination
• Complications
• Approach Considerations
• Laboratory Studies
• CT Scanning
• Chest Radiography
• Medical Care
• Antiviral Agents
• Immunomodulators and Other Investigational Therapies
• Investigational Antibody-Directed Therapies
• Antithrombotics
• Renin Angiotensin System Blockade and COVID-19
• Diabetes and COVID-19
• Therapies Determined Ineffective
• QT Prolongation with Potential COVID-19 Pharmacotherapies
• Investigational Devices
• Guidelines Summary
• CDC Evaluating and Testing Persons Under Investigation (PUI) for COVID-19 Clinical Guidelines
• CDC Sample Collection and Testing Guidelines for COVID-19
• Guidance for Hospitals on Containing Spread of COVID-19
• American Academy of Pediatrics Guidance on Management of Infants Born to Mothers with COVID-19
• NIH Coronavirus Disease 2019 (COVID-19) Treatment Guidelines
• Infectious Diseases Society of America (IDSA) Management Guidelines
• Thromboembolism Prevention and Treatment
• Medication Summary
• Corticosteroids
• Immunomodulators
• Complement Inhibitors
• COVID-19, Monoclonal Antibodies
• Questions & Answers
• Media Gallery

Presentations of COVID-19 range from asymptomatic/mild symptoms to severe illness and mortality. Common symptoms include fever, cough, and shortness of breath. [ 100 ]  Other symptoms, such as malaise and respiratory distress, also have been described. [ 90 ]

Symptoms may develop 2 days to 2 weeks after exposure to the virus. [ 100 ]  A pooled analysis of 181 confirmed cases of COVID-19 outside Wuhan, China, found the mean incubation period was 5.1 days, and that 97.5% of individuals who developed symptoms did so within 11.5 days of infection. [ 101 ]  

Symptom rebound and viral rebound have been described in patients (with or without antiviral treatment). In untreated patients, those (n = 563) receiving placebo in the ACTIV-2/A5401 (Adaptive Platform Treatment Trial for Outpatients with COIVD-19) platform trial recorded 13 symptoms daily between days 1 and 28. Symptom rebound was identified in 26% of participants at a median of 11 days after initial symptom onset. Viral rebound was detected in 31% and high-level viral rebound in 13% of participants. [ 102 ]  

The following symptoms may indicate COVID-19 [ 100 ] :

• Fever or chills
• Shortness of breath or difficulty breathing
• Muscle or body aches
• New loss of taste or smell
• Sore throat
• Congestion or runny nose
• Nausea or vomiting

Other reported symptoms include the following:

• Sputum production
• Respiratory distress
• Neurologic (eg, headache, altered mentality) 

Wu and McGoogan reported that, among 72,314 COVID-19 cases reported to the CCDC, 81% were mild (absent or mild pneumonia), 14% were severe (hypoxia, dyspnea, >50% lung involvement within 24-48 hours), 5% were critical (shock, respiratory failure, multiorgan dysfunction), and 2.3% were fatal. [ 103 ] These general symptom distributions have been reconfirmed across multiple observations. [ 104 , 105 ]

Clinicians evaluating patients with fever and acute respiratory illness should obtain information regarding travel history or exposure to an individual who recently returned from a country or US state experiencing active local transmission. [ 106 ]

Williamson and colleagues, in an analysis of 17 million patients, reaffirmed that severe COVID-19 and mortality was more common in males, older individuals, individuals in poverty, Black persons, and patients with medical conditions such as diabetes and severe asthma, among others. [ 107 ]

A multicenter observational cohort study conducted in Europe found frailty was a greater predictor of mortality than age or comorbidities. [ 108 ]

Type A blood has been suggested as a potential factor that predisposes to severe COVID-19, specifically in terms of increasing the risk for respiratory failure. Blood type O appears to confer a protective effect. [ 109 , 110 ]

Patients with suspected COVID-19 should be reported immediately to infection-control personnel at their healthcare facility and the local or state health department. CDC guidance calls for the patient to be cared for with airborne and contact precautions (including eye shield) in place. [ 22 ] Patient candidates for such reporting include those with fever and symptoms of lower respiratory illness who have travelled from Wuhan City, China, within the preceding 14 days or who have been in contact with an individual under investigation for COVID-19 or a patient with laboratory-confirmed COVID-19 in the preceding 14 days. [ 106 ]

A complete or partial loss of the sense of smell (anosmia) has been reported as a potential history finding in patients eventually diagnosed with COVID-19. [ 20 ] A phone survey of outpatients with mildly symptomatic COVID-19 found that 64.4% (130 of 202) reported any altered sense of smell or taste. [ 111 ] In a European study of 72 patients with PCR results positive for COVID-19, 53 patients (74%) reported reduced olfaction, whereas 50 patients (69%) reported a reduced sense of taste. Forty-nine patients (68%) reported both symptoms. [ 112 ]

Patients who are under investigation for COVID-19 should be evaluated in a private room with the door closed (an airborne infection isolation room is ideal) and asked to wear a surgical mask. All other standard contact and airborne precautions should be observed, and treating healthcare personnel should wear eye protection. [ 22 ]

The most common serious manifestation of COVID-19 upon initial presentation is pneumonia. Fever, cough, dyspnea, and abnormalities on chest imaging are common in these cases. [ 113 , 114 , 115 , 116 ]

Huang and colleagues found that, among patients with pneumonia, 99% had fever, 70% reported fatigue, 59% had dry cough, 40% had anorexia, 35% experienced myalgias, 31% had dyspnea, and 27% had sputum production. [ 113 ]

Complications of COVID-19 include  pneumonia ,  acute respiratory distress syndrome , cardiac injury, arrhythmia,  septic shock , liver dysfunction,  acute kidney injury , and multi-organ failure, among others.

Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. The common complications among hospitalized patients include pneumonia (75%), ARDS (15%), AKI (9%), and acute liver injury (19%). Cardiac injury has been increasingly noted, including troponin elevation, acute heart failure, dysrhythmias, and myocarditis. Ten percent to 25 percent of hospitalized patients with COVID-19 experience prothrombotic coagulopathy resulting in venous and arterial thromboembolic events. Neurologic manifestations include impaired consciousness and stroke.

ICU case fatality is reported up to 40%. [ 104 ]  

As the COVID-19 pandemic has matured, more patients have reported long-term, post-infection sequelae. Most patients recover fully, but those who do not have reported adverse symptoms such as fatigue, dyspnea, cough, anxiety, depression, inability to focus (ie, “brain fog”), gastrointestinal problems, sleep difficulties, joint pain, and chest pain lasting weeks to months after the acute illness. Long-term studies are underway to understand the nature of these complaints. [ 117 ]  

Post-acute sequelae of SARS-CoV-2 (PASC) infection is the medical term for what is commonly called long COVID or "long haulers". The NIH includes discussion of persistent symptoms or organ dysfunction after acute COVID-19 within guidelines that discuss the clinical spectrum of the disease. [ 118 ]  

The UK National Institute for Health and Care Excellence (NICE) issued guidelines on care of long COVID that define the syndrome as: signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks, and are not explained by an alternative diagnosis. [ 119 ]  

Please see Long COVID-19 .

Future public health implications

Public health implications for long COVID need to be examined, as reviewed by Datta et al. As with other infections (eg, Lyme disease, syphilis, Ebola), late inflammatory and virologic sequelae may emerge. Accumulation of evidence beyond the acute infection and postacute hyperinflammatory illness is important to evaluate to gain a better understanding of the full spectrum of the disease. [ 120 ]  

Thrombotic manifestations of severe COVID-19 are caused by the ability of SARS-CoV-2 to invade endothelial cells via angiotensin-converting enzyme-2 (ACE-2), which is expressed on the surface of endothelial cells. Subsequent endothelial inflammation, complement activation, thrombin generation, platelet and leukocyte recruitment, and the initiation of innate and adaptive immune responses culminate in immunothrombosis, and can ultimately cause microthrombotic complications (eg, DVT, PE, stroke). [ 121 ]  

Kotecha et al describe patterns of myocardial injury in hospitalized patients with severe COVID-19 who had elevated troponin levels. During convalescence, myocarditis-like injury was observed, with limited extent and minimal functional consequence. However, in a proportion of patients, there was evidence of possible ongoing localized inflammation. Roughly 25% of patients had ischemic heart disease, of which two thirds had no previous history. [ 122 ]  

Reinfection

COVID-19 reinfection is defined as an infected person who has undergone full vaccination, whether they have had a booster or boosters. According to the CDC, reinfection is COVID-19 infection of an individual with 2 different viral strains that occurs at least 45 days apart. It also may occur when an individual has 2 positive CoV-2 RT-PCR tests with negative tests between the 2 positive tests. [ 123 ]

It is essential to determine reinfection rates to establish the effectiveness of current vaccine prophylaxis. Reinfection in vaccinated and non-vaccinated persons probably is due to a variant. [ 123 , 124 ]  

It is important to differentiate reinfection from reactivation or relapse of the virus, which occurs in a clinically recovered person within the first 4 weeks of infection, during which viral RNA testing has remained positive. During relapse, a tiny viral load of dormant virus reactivates, the reason of which often is unclear.

The only way to prove this state is to show that genetic samples taken at the beginning and at the time of reactivation differ genetically; such testing is unusual at the beginning of a person’s illness.

For more information, see COVID-19 Reinfections

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• The heart is normal in size. There are diffuse, patchy opacities throughout both lungs, which may represent multifocal viral/bacterial pneumonia versus pulmonary edema. These opacities are particularly confluent along the periphery of the right lung. There is left midlung platelike atelectasis. Obscuration of the left costophrenic angle may represent consolidation versus a pleural effusion with atelectasis. There is no pneumothorax.
• The heart is normal in size. There are bilateral hazy opacities, with lower lobe predominance. These findings are consistent with multifocal/viral pneumonia. No pleural effusion or pneumothorax are seen.
• The heart is normal in size. Patchy opacities are seen throughout the lung fields. Patchy areas of consolidation at the right lung base partially silhouettes the right diaphragm. There is no effusion or pneumothorax. Degenerative changes of the thoracic spine are noted.
• The same patient as above 10 days later.
• The trachea is in midline. The cardiomediastinal silhouette is normal in size. There are diffuse hazy reticulonodular opacities in both lungs. Differential diagnoses include viral pneumonia, multifocal bacterial pneumonia or ARDS. There is no pleural effusion or pneumothorax.
• Axial chest CT demonstrates patchy ground-glass opacities with peripheral distribution.
• Coronal reconstruction chest CT of the same patient above, showing patchy ground-glass opacities.
• Axial chest CT shows bilateral patchy consolidations (arrows), some with peripheral ground-glass opacity. Findings are in peripheral and subpleural distribution.
• Table 1. SARS-CoV-2 Monoclonal Antibodies – inactive EUAs

Contributor Information and Disclosures

David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS Associate Professor of Medicine and Pediatrics, Adult and Pediatric Infectious Diseases, Rutgers New Jersey Medical School David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS is a member of the following medical societies: American Academy of HIV Medicine , American Academy of Pediatrics , American College of Physicians , American Medical Association , HIV Medicine Association , Infectious Diseases Society of America , Medical Society of New Jersey , Pediatric Infectious Diseases Society Disclosure: Nothing to disclose.

Scott J Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP Antimicrobial Stewardship Program Coordinator, Infectious Diseases Pharmacy Residency Program Director, Department of Pharmaceutical and Nutrition Care, Division of Infectious Diseases, Nebraska Medicine; Clinical Associate Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center Scott J Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP is a member of the following medical societies: American Association of Colleges of Pharmacy , American College of Clinical Pharmacy , American Pharmacists Association , American Society for Microbiology , American Society of Health-System Pharmacists , Infectious Diseases Society of America , Society of Infectious Diseases Pharmacists Disclosure: Received research grant from: Merck & Co., Inc.

Keith M Olsen, PharmD, FCCP, FCCM Dean and Professor, College of Pharmacy, University of Nebraska Medical Center Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Nothing to disclose.

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American Medical Association , Association of Professors of Medicine , Infectious Diseases Society of America , Oklahoma State Medical Association , Southern Society for Clinical Investigation Disclosure: Nothing to disclose.

Molly Marie Miller, PharmD Clinical Infectious Diseases Pharmacist Practitioner, Nebraska Medicine Molly Marie Miller, PharmD is a member of the following medical societies: Society of Infectious Diseases Pharmacists Disclosure: Nothing to disclose.

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Presenting a Clinical Vignette: Deciding What to Present

If you are scheduled to make a presentation of a clinical vignette, reading this article will improve your performance. We describe a set of practical, proven steps that will guide your preparation of the presentation. The process of putting together a stellar presentation takes time and effort, and we assume that you will be willing to put forth the effort to make your presentation successful. This and subsequent articles will focus on planning, preparation, creating visual aids (slides), and presentation skills. The intent of this series of articles is to help you make a favorable impression and reap the rewards, personal and professional, of a job well done.

The process begins with the creation of an outline of the topics that might be presented at the meeting. Your outline should follow the typical format and sequence for this type of communication: history, physical examination, investigations, patient course, and discussion. This format is chosen because your audience understands it and uses it every day. If you have already prepared a paper for publication, it can be a rich source of content for the topic outline.

To get you started, we have prepared a generic outline to serve as an example. Look over the generic outline to get a sense of what might be addressed in your presentation. We realize that the generic outline will not precisely fit all of the types of cases; nevertheless, think about the larger principle and ask yourself, "How can I adapt this to my situation?" In order to help you visualize the type of content you might include in the outline, an example of a topic outline for a clinical vignette is presented.

Introduction

The main purpose of the introduction is to place the case in a clinical context and explain the importance or relevance of the case. Some case reports begin immediately with the description of the case, and this is perfectly acceptable.

1. Describing the clinical context and relevance

i. Ergotism is characterized by intense, generalized vasoconstriction of small and large blood vessels. ii. Ergotism is rare and therefore difficult to diagnose. iii. Failure to diagnose can lead to significant morbidity.

Case Presentation

The case report should be chronological and detail the history, physical findings, and investigations followed by the patient's course. At this point, you may wish to include more details than you might have time to present, prioritizing the content later.

i. A 34-year-old female smoker has chronic headaches, dyspnea, and burning leg pain. ii. Clinical diagnosis of mitral valve stenosis is made. iii. She returns in one week because of burning pain in the legs. iv. One month after presentation, cardiac catheterization demonstrates severe mitral valve stenosis. v. Elective mitral valve commisurotomy is scheduled, but the patient is admitted to hospital early because of increased burning pain in her feet and a painful right leg.

2. Physical Examination

i. Normal vital signs. ii. No skin findings. iii. Typical findings of mitral stenosis, no evidence of heart failure. iv. Cool, pulseless right leg. v. Normal neurological examination.

3. Investigations

i. Normal laboratory studies. ii. ECG shows left atrial enlargement. iii. Arteriogram of right femoral artery shows subtotal stenosis, collateral filling of the popliteal artery, and pseudoaneurysm formation.

4. Hospital Course

i. Mitral valve commisurotomy is performed, as well as femoral artery thombectomy, balloon dilation, and a patch graft repair. ii. On the fifth postoperative day, the patient experienced a return of burning pain in the right leg. The leg was pale, cool, mottled, and pulseless. iii. The arteriogram of femoral arteries showed smooth segmental narrowing and bilateral vasospasm suggesting large-vessel arteritis complicated by thrombosis. iv. Treatment was initiated with corticosteroids, anticoagulants, antiplatelet drugs, and oral vasodilators. v. The patient continued to deteriorate with both legs becoming cool and pulseless. vi. Additional history revealed that the patient abused ergotamine preparations for years (headaches). She used 12 tables daily for the past year and continued to receive ergotamine in hospital on days 2, 6, and 7. vii. Ergotamine preparations were stopped, intravenous nitroprusside was begun, and she showed clinical improvement within 2 hours. Nitroprusside was stopped after 24 hours, and the symptoms did not return. viii. The remainder of hospitalization was uneventful.

The main purpose of the discussion section is to articulate the lessons learned from the case. It should describe how a similar case should be approached in the future. It is sometimes appropriate to provide background information to understand the pathophysiological mechanisms associated with the patient's presentation, findings, investigations, course, or therapy.

1. Discussion

i. The most common cause of ergotism is chronic poisoning found in young females with chronic headaches. ii. Manifestations can include neurological, gastrointestinal, and vascular (list each in a table). iii. Ergotamine poisoning induces intense vasospasm, and venous thrombosis may occur from direct damage to the endothelium. iv. Vasospasm is due primarily to the direct vasoconstrictor effects on the vascular smooth muscle. v. Habitual use of ergotamine can lead to withdrawal headaches leading to a cycle of greater levels of ingestion. vi. In addition to stopping ergotamine, a direct vasodilator is usually prescribed. vii. Lesson 1: Physicians should be alert to the potential of ergotamine toxicity in young women with chronic headaches that present with neurological, gastrointestinal, or ischemic symptoms. viii. Lesson 2: The value of a complete history and checking the medication list.

Creating a topic outline will provide a list of all the topics you might possibly present at the meeting. Since you will have only ten minutes, you will prioritize the topics to determine what to keep and what to cut.

How do you decide what to cut? First, identify the basic information in the three major categories that you simply must present. This represents the "must-say" category. If you have done your job well, the content you have retained will answer the following questions:

What happened to the patient? What was the time course of these events? Why did management follow the lines that it did? What was learned?

After you have identified the "must-say" content, identify information that will help the audience better understand the case. Call this the "elaboration" category. Finally, identify the content that you think the audience would like to know, provided there is enough time, and identify this as the "nice-to-know" category.

Preparing a presentation is an iterative process. As you begin to "fit" your talk into the allotted time, certain content you originally thought of as "elaboration" may be dropped to the "nice-to-know" category due to time constraints. Use the following organizational scheme to efficiently prioritize your outline.

Prioritizing Topics in the Topic Outline

1. Use your completed topic outline.

2. Next to each entry in your outline, prioritize the importance of content.

3. Use the following code system to track your prioritization decisions:

A = Must-Say B = Elaboration C = Nice-to-Know

4. Remember, this is an iterative process; your decisions are not final.

5. Review the outline with your mentor or interested colleagues, and listen to their decisions.

Use the Preparing the Clinical Vignette Presentation Checklist to assist you in preparing the topic outline.

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Epidemiology and introduction to the clinical presentation of Wilson disease

Affiliations.

• 1 Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
• 2 Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK. Electronic address: [email protected].
• PMID: 28433111
• DOI: 10.1016/B978-0-444-63625-6.00002-1

Our understanding of the epidemiology of Wilson disease has steadily grown since Sternlieb and Scheinberg's first prevalence estimate of 5 per million individuals in 1968. Increasingly sophisticated genetic techniques have led to revised genetic prevalence estimates of 142 per million. Various population isolates exist where the prevalence of Wilson disease is higher still, the highest being 885 per million from within the mountainous region of Rucar in Romania. In Sardinia, where the prevalence of Wilson disease has been calculated at 370 per million births, six mutations account for around 85% of Wilson disease chromosomes identified. Significant variation in the patterns of presentation may however exist, even between individuals carrying the same mutations. At either extremes of presentation are an 8-month-old infant with abnormal liver function tests and individuals diagnosed in their eighth decade of life. Three main patterns of presentation have been recognized - hepatic, neurologic, and psychiatric - prompting their presentation to a diverse range of specialists. Deviations in the family history from the anticipated autosomal-recessive mode of inheritance, with apparent "pseudodominance" and mechanisms of inheritance that include uniparental isodisomy (the inheritance of both chromosomal copies from a single parent), may all further cloud the diagnosis. It can therefore take the efforts of an astute clinician with a high clinical index of suspicion to clinch the diagnosis of this eminently treatable condition.

Keywords: Epidemiology; Incidence; Neurological presentation; Population hepatic presentation; Prevalence.

© 2017 Elsevier B.V. All rights reserved.

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Clinical presentation and management of COVID ‐19

Irani thevarajan.

1 Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne VIC

2 University of Melbourne, Melbourne VIC

Kirsty L Buising

Benjamin c cowie.

3 WHO Collaborating Centre for Viral Hepatitis, Doherty Institute, Melbourne VIC

• The rapid spread of severe acute respiratory syndrome coronavirus 2 led to the declaration of a global pandemic within 3 months of its emergence.
• The majority of patients presenting with coronavirus disease 2019 ( COVID ‐19) experience a mild illness that can usually be managed in the community. Patients require careful monitoring and early referral to hospital if any signs of clinical deterioration occur.
• Increased age and the presence of comorbidities are associated with more severe disease and poorer outcomes.
• Treatment for COVID ‐19 is currently predominantly supportive care, focused on appropriate management of respiratory dysfunction.
• Clinical evidence is emerging for some specific therapies (including antiviral and immune‐modulating agents). Investigational therapies for COVID ‐19 should be used in the context of approved randomised controlled trials.
• Australian clinicians need to be able to recognise, diagnose, manage and appropriately refer patients affected by COVID ‐19, with thousands of cases likely to present over the coming years.

In December 2019, a novel coronavirus emerged in Wuhan, Hubei Province, China, leading to a global pandemic. The virus, named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), causes a clinical syndrome termed coronavirus disease 2019 (COVID‐19).

The first reports of an undiagnosed pneumonia in Wuhan on 8 December 2019 were followed by an alert from China to the World Health Organization (WHO) about a cluster of pneumonia cases on 30 December. Isolation of a novel coronavirus occurred on 3 January 2020. On 30 January, the WHO declared a public health emergency of international concern, and a pandemic was declared on 12 March 2020.

Clinical presentation

Similar to other coronaviruses, SARS‐CoV‐2 is predominantly spread by respiratory droplets, although spread by contact with contaminated fomites also occurs, as does transmission by aerosols in certain circumstances. 1

Based on the experience in China, the typical incubation period of COVID‐19 infection has been estimated to be a median of 5.1 days (95% CI, 4.5–5.8 days), with 97.5% of those who develop symptoms doing so within 11 days of exposure (95% CI, 8.2–15.6 days). This has informed the use of a 14‐day time period for quarantining potentially exposed individuals in an effort to limit onward spread. 2

The recognition of asymptomatic infection has been an area of intense interest in understanding the epidemiology of COVID‐19. The ratio of asymptomatic to symptomatic infection is currently uncertain. Cross‐sectional studies have reported asymptomatic infection in women attending a maternity service in New York (33 of 215 infected, 88% asymptomatic) 3 and in general population testing in Iceland (87 of 10 797 infected, 41% asymptomatic). 4 In such cross‐sectional studies, a proportion of those who were asymptomatic at the time of testing may in fact have been in the pre‐symptomatic phase of infection. In a study conducted in a nursing home in the United States, 48 of 76 residents tested positive, with 27 (56%) being asymptomatic at the time of testing. However, 24 (89%) of these individuals went on to develop symptoms at a median of 4 days (interquartile range [IQR], 3–5 days) after the positive test result. 5

Symptomatic COVID‐19 infection usually presents as a respiratory syndrome, most commonly with fever and cough. 6 , 7

Fever has been reported in up to 99% of people at some time during the course of their illness, but importantly in one cohort, it was reported to be present at the time of hospital presentation in only 44% of patients, and at some time during the hospital admission in 89%. 8 Other common symptoms are cough, dyspnoea, fatigue, anorexia, anosmia, myalgia and sometimes confusion. Diarrhoea may occur in up to 10% of patients. 9 Symptoms reported less frequently (< 5% of cases) include sore throat, rhinorrhoea, headache, chest pain, dizziness, abdominal pain and nausea. 6 , 7

Around 80% of COVID‐19 infections present as a mild respiratory illness in a patient who is ambulatory and can generally be managed outside the hospital. Around 15% typically need hospital care (usually for moderate to severe pneumonia), and another 5% have critical illness requiring more intensive supports. 10

Of those who require hospitalisation, the median time from first symptoms to onset of dyspnoea is 5 days (IQR, 1–10 days), the median time to hospital admission is 7 days (IQR, 4–8 days), and in those who develop more severe manifestations, the median time to acute respiratory distress syndrome is 8 days (IQR, 6–12 days). 6 About a quarter of patients who are hospitalised may need transfer to the intensive care unit (ICU) for the management of complications such as hypoxaemic respiratory failure or hypotension requiring vasopressor support. 11

At presentation to hospital, the most common laboratory feature of COVID‐19 infection is lymphopenia (reported in 70.3% of cases). 6 Radiological imaging may reveal a clear chest, unilateral or bilateral consolidation, or ground glass opacity.

Nasopharyngeal specimens, deep nasal swabs, throat swabs or lower respiratory samples (eg, sputum) sent for molecular detection of SARS‐CoV‐2 by polymerase chain reaction (PCR) are currently the best means of specific diagnosis of COVID‐19 in Australia. Faecal samples may also be PCR positive for COVID‐19 but the role of the oral–faecal route for transmission remains unclear. 12 Patients with more severe disease tend to have higher viral loads in respiratory samples. Mild cases have been shown to clear the virus earlier, with over 90% returning negative PCR test results by day 10 compared with severe cases who more often remain positive beyond day 10. 13 Viral loads appear to be highest early in the illness. Prolonged viral shedding after the onset of symptoms has been described. 14 The virus has also been detected by PCR in asymptomatic patients with comparable viral loads to those still symptomatic. 15

Patients with suspected or confirmed COVID‐19 should be assessed for features of severe disease and risk factors for progression to severe disease. This assists in determining whether a patient can safely be managed in the community or requires referral and admission to a health care facility able to provide acute inpatient care. Current data suggest that older patients and those with comorbidities have increased risk of progression to severe disease and mortality. In a large surveillance report from China including over 44 000 confirmed cases of COVID‐19, the case fatality rate was < 0.5% for patients aged < 50 years, but rose to 8.0% for those in their 70s, and 14.8% in those aged > 80 years. 16 While these surveillance‐based case fatality rates are possibly overestimates, being influenced by under‐recognition of lower severity cases, the impact of increasing age and the presence of comorbidities on risk of severe and fatal illness should be recognised, 8 and such patients should generally be offered more careful monitoring.

Clinical features that have been identified more often in COVID‐19 infected patients who have had a fatal outcome compared with those who survive are: dyspnoea at presentation (70.6% v 24.7%; P  < 0.001); lower initial oxygen saturation (median oxygen saturation, 85% [IQR, 75–91%] v 97% [IQR, 95–98%]; P  < 0.001); and higher total white blood cell count but lower lymphocyte count at presentation accompanied by a lower lymphocyte count, expressed as a lower lymphocyte percentage (median, 7.1% [IQR, 4.5–12.7%] v 23.5% [IQR, 15.3–31.3%]; P  < 0.001). 17 In developing a predictive model, Chinese researchers found four factors independently associated with disease progression during hospitalisation in 208 consecutive patients: presence of comorbidity, age > 60 years, lymphocyte count < 1.0 × 10 9 /L, and elevated lactate dehydrogenase levels. 18

A propensity for deterioration in the second week of illness has been recognised in some cohorts of patients, typically 5–10 days after the onset of symptoms. 19 All patients should be warned about symptoms of concern (such as increasing breathlessness), and early referral for hospital admission should be suggested for any patient with signs of clinical deterioration. Individual circumstances need to be considered when determining the ideal monitoring strategy and site of care for each patient ( Box ).

Assessing disease severity and consideration for setting of care for patients diagnosed with COVID‐19

Adapted from World Health Organization interim guidance, 21 Australasian Society for Infectious Diseases interim guidelines, 20 and National COVID‐19 Clinical Evidence Taskforce living guidelines. 19

General management

It is critically important to ensure optimal infection prevention from the time a patient with suspected COVID‐19 is first assessed until their infection is resolved, irrespective of the site of care. This can present particular challenges for health care staff, who must learn to use personal protective equipment safely, and for patients and their loved ones who must manage the difficulties associated with isolation.

Patients with mild disease (about 80%) 10 can often be managed in the community if they are able to self‐isolate. They must also be capable of monitoring their own condition, be aware of which symptoms should prompt medical review, and be able to escalate any concerns. 19 , 20 , 21 For some patients, a more proactive program of monitoring by phone or telehealth or in‐person monitoring (eg, hospital in the home, regular review by general practitioner, or hospital admission) may be required. Strategies for care should be individualised to suit patient circumstances. Patients whose home environment is not conducive to safe management, or which is unacceptable from an infection prevention perspective, may require admission either to hospital or to alternative safe accommodation. Discussion with public health authorities is essential to ensure that appropriate isolation and follow‐up mechanisms are in place. In the face of high health care demand during the peak of a pandemic, safe management of low risk patients in the community will likely be essential to preserve hospital capacity for the more severely ill.

Patients with moderate or severe illness will generally require admission to hospital. This includes those who are dyspnoeic on minor exertion, tachypnoeic at rest (respiratory rate > 22 breaths/min), hypoxaemic (pulse oximetry [SpO 2 ] < 94% on room air), hypotensive (systolic blood pressure < 100 mmHg), have an acutely altered mental state, or who have extensive pulmonary infiltrates evident on chest imaging. 19 , 20 , 21

Severe illness, indicated by, among other features, a respiratory rate > 30 breaths/min, SpO 2  < 92% on room air 19 , 21 or sustained hypotension, warrants urgent hospitalisation and consideration of the need for intensive care if suitable for a given patient.

Respiratory management

Supplemental oxygen should be administered for patients with SpO 2  < 92%. 19 , 20 Once stabilised, the target SpO 2 range is usually 92–96%. The target will be lower in those with chronic hypercapnoeic respiratory failure (eg, 88–92%). 19 , 20 , 21

Manoeuvres to improve gas exchange should be implemented, such as positioning patients appropriately in bed (on either side with regular turning), elevating the bed head to 30 degrees, encouraging deep breathing every hour while awake, sitting patients out of bed every day when possible, and mobilising when able. For mechanically ventilated patients with persistent hypoxaemia, prone positioning may be effective. 19 , 22

In the setting of progressive hypoxaemia despite low or moderate flow oxygen (via nasal prongs or Hudson mask), high flow oxygen can be considered. Whether high flow oxygen devices (> 10 mL/min) are potentially aerosol‐generating is being studied, but current guidelines 1 , 23 advise that airborne precautions be taken by staff (personal protective equipment including N95/P2 masks) and single rooms where possible.

There are emerging views that the respiratory dysfunction observed in COVID‐19 infections is not uniform. 22 Initial recommendations have focused on consideration of early intubation and mechanical ventilation for patients with acute respiratory distress syndrome due to COVID‐19. 1 , 19 , 20 , 21 Experience from a multicentre Italian COVID‐19 patient cohort suggests that non‐invasive ventilation such as continuous positive airways pressure and bilevel positive airways pressure may also have a role both within and outside ICUs. 24 These non‐invasive ventilation devices are clearly aerosol‐generating and as such should only be used with appropriate precautions in place. 1 , 23 Advice from experts in respiratory medicine or critical care should be sought.

Other management considerations

Empirical antibiotic therapy for bacterial pneumonia should be considered in patients whose illness is severe, where there is evidence of sepsis or septic shock, or where the patient is clinically deteriorating. 19 , 20 Empirical treatment for influenza with a neuraminidase inhibitor should be considered for patients with severe pneumonia (guided by local epidemiology) until influenza PCR results are available. 20 , 21 Empirical antibiotics are not recommended for patients with mild or moderate pneumonia unless there is additional clinical evidence to suggest bacterial infection. De‐escalation of empirical antimicrobial therapy should be undertaken as appropriate, guided by microbiology results (where available) and clinical judgement. 21

Hypovolaemia may be contributed to by reduced oral intake and increased losses, but management requires cautious administration of intravenous fluids with regular assessments given the risk of exacerbating pulmonary oedema in the setting of acute respiratory distress syndrome 19 , 22 and given the possibility of underlying cardiac injury. 25

A range of possible complications related to SARS‐CoV‐2 infection have been reported and their incidence is being monitored. These include thromboembolic events in the lungs 22 and cerebrovascular system, 26 Prophylaxis with anticoagulants for adults with moderate, severe or critical COVID‐19 infection is generally recommended, unless there are contraindications. 19 , 21 Acute cardiac injury presenting with electrocardiogram changes, arrhythmias, left ventricular dysfunction, cardiomyopathy and congestive cardiac failure have also been described, and assessment of baseline electrocardiogram is suggested for patients with moderate or severe COVID‐19 illness. 25 , 27

There is considerable interest in monitoring large patient cohorts and conducting analysis of linked datasets at a population level to establish whether there are any rare or longer term complications or associations of COVID‐19 with other medical conditions. Given the very recent emergence of SARS‐CoV‐2, data are currently limited but it is likely that information will emerge in coming months from populations that have experienced a high attack rate. An example of a rare condition with potential association is paediatric inflammatory multisystem syndrome temporally associated with SARS‐CoV‐2, presenting as hyperinflammatory shock with features similar to atypical Kawasaki disease. 28 Similarly, there is interest in monitoring long term incidence of cardiovascular complications, thromboembolic disease, chronic respiratory dysfunction, renal or neurological disorders, and post‐infectious inflammatory syndromes after COVID‐19, in addition to inspection of large datasets for complications that are as yet unsuspected.

Specific therapies

A range of pharmacotherapies have been proposed as possible treatments for COVID‐19. Early evidence of clinical benefit for some agents has emerged. The WHO interim guidance on the clinical management of COVID‐19 21 asserts that investigational therapeutics should be used only in approved randomised controlled trials. This position is endorsed by the Australasian Society for Infectious Diseases interim guidelines for the clinical management of COVID‐19 in adults, 20 and the Australian guidelines for the clinical care of people with COVID‐19, 19 which state that even where conditional recommendations for use of disease modifying agents are made, whenever possible these should be administered in the context of randomised trials with appropriate ethical approval.

The understandable interest in evaluating potential treatments has led to a large number of clinical trials being registered globally; by late April 2020, over 1100 clinical studies were registered, including over 500 randomised controlled trials. 29

Antimicrobials

Lopinavir–ritonavir.

Lopinavir–ritonavir, a combined antiretroviral agent, was proposed as a potential treatment for severe acute respiratory syndrome in 2003, based on apparent reductions in mortality in preliminary research in Hong Kong. 30 Given its hypothesised role, five of the first 18 patients diagnosed with COVID‐19 in Singapore were administered this agent. 31

On 18 March 2020, a randomised controlled open label trial of lopinavir–ritonavir in 199 hospitalised adults with COVID‐19 in China was published. 32 No benefit was observed in participants treated with the antiviral compared with controls. Nearly 14% of those receiving lopinavir–ritonavir were unable to complete 14 days of treatments owing to adverse events.

Chloroquine and hydroxychloroquine

Chloroquine and hydroxychloroquine are antimalarial agents which also have immunomodulatory properties that led to established indications for use in the treatment of rheumatological conditions. Potential adverse effects include retinal toxicity, QT interval prolongation and other cardiological and dermatological effects.

In early February 2020, chloroquine was reported to inhibit SARS‐CoV‐2 replication in vitro. 33 By mid‐February, treatment of COVID‐19 with chloroquine was being described as a “breakthrough”: a published letter stated that the results of treatment in over 100 patients in China had demonstrated that chloroquine was “superior to the control treatment”, but no data were provided. 34 A small French open label non‐randomised clinical trial examining hydroxychloroquine with or without azithromycin suggested a significant viral load reduction in those receiving therapy; 35 however, concerns have been raised about the design and analysis of the study. 36

Despite the lack of clinical evidence from randomised clinical trials, several institutional and local guidelines, and notable public figures, have supported the potential use of chloroquine or hydroxychloroquine for the treatment of COVID‐19. 37 , 38

However, given the current lack of evidence of clinical benefit and reports of significant limitations of supply of hydroxychloroquine for patients with rheumatological conditions, in March 2020, the Pharmaceutical Society of Australia and the Australasian Society for Infectious Diseases called for immediate cessation of prescribing and dispensing of hydroxychloroquine for indications relating to COVID‐19, outside use in approved clinical trials. 39 , 40

On 5 June 2020, the chief investigators on the RECOVERY trial (comprising over 11 500 patients enrolled from hospitals across the United Kingdom) issued a press release stating that no beneficial effect of hydroxychloroquine had been observed. 41 No difference in 28‐day mortality, duration of admission, or other outcomes were observed between the 1542 patients randomised to hydroxychloroquine and the 3132 patients randomised to usual care. Further details regarding this analysis are awaited.

In January 2020, the first patient diagnosed with COVID‐19 in the US received the investigational nucleotide prodrug remdesivir, supplied on a compassionate basis. 42 Developed as a potential therapy for Ebola, there is in vitro evidence that remdesivir inhibits replication of coronaviruses, including Middle East respiratory syndrome coronavirus and SARS‐CoV‐2. 33 , 43 By late March 2020, four clinical trials to assess the efficacy of remdesivir against COVID‐19 had commenced in the US and two were registered in China. 44 On 29 April, results of the first randomised clinical trial conducted in China were published; 45 while this found no clinical benefit of remdesivir, the trial was underpowered (237 participants) owing to the success of public health measures in controlling COVID‐19 in China. The authors noted a non‐significant numerical reduction in time to clinical improvement in patients commencing treatment earlier in the course of illness.

On 27 May 2020, the first positive results of a randomised double‐blind controlled trial of a treatment for COVID‐19 were published. 46 This international multicentre study reported the preliminary results of 1059 hospitalised patients who received up to 10 days of remdesivir or placebo. Those receiving remdesivir had a significantly shorter median recovery time of 11 days compared with 15 days for those receiving placebo (rate ratio for recovery, 1.32; 95% CI, 1.12–1.55; P  < 0.001); no significant difference in mortality was found. Benefit was reported for the group requiring oxygen but not yet requiring invasive or non‐invasive ventilatory support. This new evidence has led Australian national guidelines to adopt a conditional recommendation for use of remdesivir outside of a trial setting where necessary. 19

Combination therapy with interferon beta‐1b, lopinavir–ritonavir and ribavirin

In May 2020, a randomised trial in Hong Kong reported results of a comparison of lopinavir–ritonavir alone ( n  = 24) with a combination of lopinavir–ritonavir, ribavirin and subcutaneous interferon beta‐1b ( n  = 52). 47 The combination group experienced a faster median time to viral clearance (7 days v 13 days; P  < 0.0001) and shorter median length of hospital stay (8 days v 15 days; P  = 0.0030) if the combination was commenced in the first 7 days from symptom onset. Importantly, the cohort of patients studied was not particularly unwell, with very few requiring ICU support and no deaths in the group.

Immunomodulatory treatments

Corticosteroids.

Interim guidance from the WHO states that corticosteroids should not be used in routine treatment of COVID‐19. 21 This is based on systematic reviews in the context of severe acute respiratory syndrome and Middle East respiratory syndrome which showed lack of effectiveness, and possible harm. 48

In a study of 138 hospitalised patients with COVID‐19 in Wuhan, 49 72.2% of ICU patients and 35.3% of non‐ICU patients received glucocorticoid therapy. The authors commented that while the dose of methylprednisolone varied depending on disease severity, no effective outcomes were observed.

However, on 22 June 2020, a preliminary report regarding interim findings from the UK RECOVERY trial suggested that low dose dexamethasone (6 mg daily orally or intravenous for 10 days) may substantially reduce mortality in hospitalised patients with COVID‐19 who received supplemental oxygen or mechanical ventilation. 50 In comparing 2104 patients randomised to receive dexamethasone with 4321 randomised to receive usual care, dexamethasone was found to reduce mortality by 35% (rate ratio, 0.65; 95% CI, 0.51–0.82; P  < 0.001) among ventilated patients, and for those receiving oxygen without mechanical ventilation, mortality was reduced by 20% (rate ratio, 0.80; 95% CI, 0.70–0.92; P  = 0.002). No benefit of dexamethasone was observed among hospitalised patients who did not require respiratory support. While peer review and formal publication of this analysis is awaited, it is likely that these findings will be reflected in national and international guidelines.

Interleukin 6 antagonists

Tocilizumab is a humanised monoclonal antibody which binds to interleukin 6 (IL‐6) receptors, resulting in reduced immune activation and inflammation. It is licensed in Australia for use in autoimmune conditions including rheumatoid arthritis and giant cell arteritis. In addition to complications of immunosuppression including serious infections, adverse effects include hepatotoxicity and gastrointestinal complications. The theory behind use of tocilizumab or other agents that target the IL‐6 pathway (eg, sarilumab) in the context of COVID‐19 is that part of the pathogenesis in some patients may be attributable to an acute inflammatory syndrome or cytokine storm, which is associated with elevated IL‐6 levels. Clinical trials of these agents are currently underway. 44

Other agents

Numerous immunomodulatory agents have been proposed as potential adjunctive treatments for COVID‐19, with a range of different immunological targets including other inflammatory cytokines. These include anakinra (an IL‐1 receptor antagonist), bevacizumab (an antivascular endothelial growth factor agent), and eculizumab (which inhibits terminal complement and prevents formation of the membrane attack complex). 44 , 51 While clinical trials are underway overseas for several proposed agents, no data exist to support their use at this time. 44

Passive immunotherapy

A preliminary, uncontrolled case series of five critically ill Chinese patients with COVID‐19 who received convalescent plasma containing high SARS‐CoV‐2‐specific antibody titres was published on 27 March 2020. 52 While improvement in clinical status was reported following this intervention, the small sample size and uncontrolled nature of the study precludes drawing any conclusions regarding the efficacy of this intervention. Once again, further research is needed.

Holistic care

A global pandemic causes understandable fear and anxiety for many people in the community. For those at particular risk of worse outcomes of infection — older people and those with significant pre‐existing illness or multiple comorbidities — COVID‐19 represents a particular threat. In addition, the health care workforce is under substantial strain and faces a potentially overwhelming challenge in delivering care to patients. Ensuring emotional care for the most vulnerable and those experiencing high levels of stress will be a fundamental determinant of the resilience of our society during this challenge.

For vulnerable and frail patients at particular risk of poor outcomes, it is important to provide personalised care and to develop an understanding of each individual's perspectives and preferences for health management. Involving caregivers and family members in decision making and establishing goals of care is necessary. 21 Discussing goals of care early and, where appropriate, assisting patients to make advance care directives or resuscitation plans early in illness (or before infection) may provide substantial peace of mind and allow families to face the pandemic openly and with unity as they support vulnerable loved ones.

It is essential to ensure that all patients receive the best standard of care irrespective of the setting in which the care is delivered, or of the existence of any proposed limitations to life‐extending interventions. Under no circumstances should the best possible symptom control and compassionate, individualised care be denied any patient affected by COVID‐19.

SARS‐CoV‐2 has caused a global pandemic with a profound public health impact, changing the daily lives of billions of people. It has exposed weaknesses in even strong and well resourced health systems internationally, and the economic impact alone will be staggering.

However, never before has the global community had the tools currently available to address a pandemic threat. A strong commitment to social and public health strategies and communicable disease control will ensure our health system retains the capacity to address COVID‐19, including sufficient hospital and intensive care resources to care for those with severe illness.

Biomedical innovations such as new and rapid point‐of‐care diagnostics, effective specific treatments and preventive vaccines are very high priorities which are rightly attracting substantial attention and funding. In the interim, high quality, evidence‐based clinical care — scaled up to face the pandemic challenge — together with robust public health interventions will save the lives of thousands in Australia, and millions globally.

Competing interests

No relevant disclosures.

Commissioned; externally peer reviewed.

Acknowledgements

We gratefully acknowledge the contributions of Anna Deng, Louis Irving, Ashleigh Qama and Lien Tran to this article.

The unedited version of this article was published as a preprint on mja.com.au on 8 April 2020

•   UMB Digital Archive
• Interprofessional Research and Education
• Clinical and Translational Research at UMB

Introduction to Clinical Epidemiology (2018)

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Introduction to Clinical Research

Sep 26, 2014

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Introduction to Clinical Research. Clinical Research Practice 1. This Course Will Introduce You To:. The basics of clinical research, types of clinical trials and why clinical research is necessary.

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• clinical research
• informed consent
• research misconduct
• clinical research trials
• define good clinical practice

Presentation Transcript

Introduction to Clinical Research Clinical Research Practice 1

This Course Will Introduce You To: • The basics of clinical research, types of clinical trials and why clinical research is necessary. • Good Clinical Practice and Good Laboratory Practice that guide the conduct of clinical research. • The importance of protecting participants and the informed consent procedures. • The overall goals of the current trials. 2

Objectives: • Define clinical research and explain why we perform clinical research. • Define Standard Operating Procedure. • Identify the types of clinical research trials. • Define protocol. • State the protections given to human participants in clinical research. • Define Good Clinical Practice and Good Laboratory Practice. 3

Objectives: • Explain why GCP and training given by the PDP are important to you. • Identify staff that must comply to research ethics and standards. • Explain the importance of “amendments” to a protocol. • Define Case Report Forms and Source documents and their importance in a trial. • Define informed consent and list some of the rules of the process. • State the overall goals of the clinical trial you are working on. 4

What Is Clinical Research? • A scientific research study. • A clinical trial looking for answers to specific questions. • Method for finding safe, new and improved vaccines, drugs, and other treatments to improve health. • Research that relies on human volunteers. 5

So……Clinical Research Is… • Research performed on humans. • Designed to answer specific questions related to human disease, diagnosis, prevention, outcomes and treatments. 6

Why Do We PerformClinical Research? • Test new therapies and drugs. • Gather data from participants who have had a known intervention and monitor results. • Determine the safety and effectiveness of drugs, therapies, and other treatments. • Develop new drugs and treatments that are safer, more effective and faster working than any before. • Ultimately – to improve health status. 7

What Happens In a Clinical Trial? • Human participants are recruited for a particular study based on stated criteria as described in the protocol of the study. 8

Then……. • Participants are fully informed about the trial and give informed consent to participate in the clinical trial. 9

And Only Then…. • A team of doctors, nurses and other research professionals: • check the health of the participant at the beginning of the trial. • give specific instructions for participating in the trial. • monitor the participant carefully during the trial. • collect the relevant data • analyze the data and draw conclusions • report results and share conclusions 10

How Does The Team Ensure Uniformity In Research? Standard Operating Procedures Detailed, written instructions to achieveuniformity of the performance of a specific function. 11

Types of Clinical Research Trials • Treatment trials • Prevention trials • Diagnostic trials • Screening trials • Quality of life trials 12

Types of Clinical Research Trials Treatment trials:Test new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy. 13

Prevention trials:Look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. May include medicines, vitamins, vaccines, minerals, or lifestyle changes. 14

Diagnostic trials: Are conducted to find better tests or procedures for diagnosing a particular disease or condition. 15

Screening trials:Test better ways to detect a disease or particular health condition. 16

Quality of life trials: Explore ways to improve comfort and the quality of life for individuals with a chronic illness. 17

The Life Cycle Of A Clinical Research Project Write a ResearchProposal Define Research Question (What do you want to know?) Write Protocol Find Funding & Select Research Team Get RegulatoryApproval Conduct Research Analyse Results Report Results 18

Key Parts of the Process • Get Regulatory Approval:Regulatory bodies monitor and approve research. • Institutional Review Board or Ethics Committee (IRB/IEC) • Medicines Control Council (MCC) • South African National Accreditation System (SANAS) • Find Funding:A sponsor, pharmaceutical company, research institution, or other organization funds the project. • Protocol:The study plan. Written procedures detailing the steps to conduct a study, keep participants safe and ensure valid data. 19

Performing Research in South Africa Offers an Unique Environment Significant burden of disease. Hightechnologicalmedical expertise andinfrastructure. SouthAfrica Money, resources and other support for research. Racial-CulturalDiversity 20

Rapid Increase in Research • South Africa has seen a 40% growth in research since 1997. • Could lead to the potential for unscrupulous, unethical and unnecessary conduct of clinical research. RISK 21

Risk of Research MisconductGreatest When Dealing With… • Poor populations. • Low levels of literacy. • Unquestioning acceptance of authority. • Great need for health services. • No knowledge of research. 22

Research Is So “New” …Can You See Why We Need Guidelines? In the light of this growth and unique environments, the need to carefully regulate and guide the conduct of clinical trials becomes urgent and necessary. 23

HowDo We Protect Our Research Participants Against Research Misconduct? • Research principles and guidelines • Research regulations • Informed Consent 24

Principles to Protect Participants GCP GLP Good Clinical Practice Good Laboratory Practice 25

Good Clinical Practice GCP • An international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human volunteers. • Simply put …. GCP is the rules by which we conduct our research. 26

Good Laboratory Practice GLP • Represents a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived. • Simply put …. GLP is the rules of research in the lab. 27

History of GCP • Nazi Medical War Crimes Nuremberg Code- 1947 29

Declarationof Helsinki (DOH) 1964 Developed by the World Medical Association First significant effort of the medical community to regulate itself. 30

Tuskegee Syphilis Study 1932-1972 Belmont Report 1979 Cornerstone for ethical principles underlying the acceptable conduct of research using human volunteers. 31

Many regulations……needed one standard International Conference on HarmonizationApril 1990 Principles of ICH GCP 32

13 Principles of ICH GCP Two important principles are: • The rights, safety, and well-being of the trial participants are the most important considerations and should prevail over the interest of science and society. • Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). 33

History of GLP • Malpractice – 1970’s • Organization for Economic Co-operation and Development (OECD) 30 Countries-1981 OECD GLP Principles 35

OECD GLP Principles • Regulates the practices of scientists working on the safety testing of prospective drugs. • Imposed by regulatory authorities. • South African National Accreditation System (SANAS) 36

GLP: Fundamental Points • Resources • Rules • Characterization • Documentation • Quality Assurance Photo courtesy of Aeras Global TB Vaccine Foundation. 37

Why Is Following GCP and GLP Important ? Compliance with these standards assures: • participant rights are protected. • the safety of human volunteers. • participant well-being is a priority. • results are used for improvement of health and well-being of all. 38

Why Is Following GCP and GLP Important to You? As part of the research team, each and every one of us is responsible for following ethical guidelines and ensuring valid and credible results. 39

HowDo We Protect Our Research Participants Against Research Misconduct? • Research principles and guidelines • Research regulations • Informed Consent 40

How Is Research Regulated? InstitutionalReview Board or Ethics Committee Data Safety Monitoring Board Research Participant Medicines Control Council SANAS 41

……What If We Need To Change Something ? Remember the Protocol?...... Ask for a protocol amendment…… “A written description of a change(s) to or formal clarification of a protocol.” ( Definition from the ICH Guideline for Good Clinical Practice 1.45) 42

Data Collection Source Data • All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. (ICH 1.51) Source Documents • Original documents, data and records. (ICH 1.52) Case Report Form (CRF) • A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject. (ICH 1.11) 43

A Few Rules for Completing Study Documentation: • Make sure that you are designated to complete the documents. • Write legibly. • Do not leave any blank fields on documents. • Do not use correctional fluid. • Double check that information is accurate and consistent with the source document. • Make corrections and edits according to GCP guidelines. (ICH 4.9) 44

HowDo We Protect Our Research Participants Against Research Misconduct? • Research regulations • Research principles and guidelines • Informed Consent 45

Informed Consent A process by which a subject voluntarily confirms his or her willingnessto participate in a particular trial, • …after having been informed of all aspects of the trial • …that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form. (ICH 1.28) 46

Who Is Responsible For Performing The Informed Consent Procedure? According to the ICH GCP Guidelines 4.8.5.. “The investigator, or a person designated by the investigator, should fully inform the participant/legal representative, of all pertinent aspects of the trial……” 47

The Rules Of The Informed Consent Process ICH GCP GUIDELINES 4.8 (see attached handout) 48

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Under recognized yet a clinically relevant impact of aneurysm location in Distal Anterior Cerebral Artery (DACA) aneurysms: insights from a contemporary surgical experience

• Published: 31 August 2024
• Volume 47 , article number  517 , ( 2024 )

Cite this article

• Abhishek Halder 1 ,
• Kuntal Kanti Das 1 ,
• Soumen Kanjilal 1 ,
• Kamlesh Singh Bhaisora 1 ,
• Ashutosh Kumar 1 ,
• Pawan Kumar Verma 1 ,
• Ved Prakash Maurya 1 ,
• Anant Mehrotra 1 ,
• Arun Kumar Srivastava 1 &
• Awadhesh Kumar Jaiswal 1  

Aneurysms of the distal anterior cerebral artery (DACA) are rare but surgically challenging. Despite a known therapeutic implication of the aneurysm location on the DACA territory, the literature is unclear about its clinical and prognostic significance. Our surgical experience over the last 5 years was reviewed to compare the clinical, operative, and outcome characteristics between aneurysms located below the mid portion of the genu of the corpus callosum (called proximal aneurysms) to those distal to this point (called distal aneurysms). A prognostic factor analysis was done using uni and multivariable analysis. A total of 34 patients were treated (M: F = 1:2.3). The distal group had a higher frequency of poor clinical grade at presentation ( n  = 9, 47.4%) in contrast to ( n  = 2, 13.3%) proximal aneurysms ( p  = 0.039). Despite an overall tendency for a delayed functional improvement in these patients, the results were mainly due to favorable outcomes in the proximal group (favourable functional outcomes at discharge and at last follow-up being 80% and 86.7% respectively). On the multivariable analysis, only WFNS grade (> 2) at presentation (OR = 13.75; 95CI = 1.2–157.7) ( p  = 0.035) and application of temporary clips (AOR = 34.32; 95CI = 2.59–454.1) ( p  = 0.007), both of which were more in the distal group, independently predicted a poor long term functional outcome. Thus, the aneurysm location impacts the preoperative clinical grade, the intraoperative aneurysm rupture risk rate as well as the temporary clipping requirement. A combination of these factors leads to worse short and long-term functional outcomes in the distal DACA aneurysms.

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Data availability

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at the institute were the study was conducted.

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Abhishek Halder, Kuntal Kanti Das, Soumen Kanjilal, Kamlesh Singh Bhaisora, Ashutosh Kumar, Pawan Kumar Verma, Ved Prakash Maurya, Anant Mehrotra, Arun Kumar Srivastava & Awadhesh Kumar Jaiswal

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Conceptualization - AH, KKD, SK; Methodology - AH, KKD, SK, KSB; Formal analysis and investigation - AH, KKD, SK and AK; Writing – original draft - AH, KKD, SK and AM; Writing - review & editing - AH, KKD, SK, KSB, PKV and AKS; Resources - AH, KKD, SK, VPM and PKV; Supervision - KKD, AM, AKS and AKJ;

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Halder, A., Das, K.K., Kanjilal, S. et al. Under recognized yet a clinically relevant impact of aneurysm location in Distal Anterior Cerebral Artery (DACA) aneurysms: insights from a contemporary surgical experience. Neurosurg Rev 47 , 517 (2024). https://doi.org/10.1007/s10143-024-02759-5

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Received : 07 March 2024

Revised : 28 June 2024

Accepted : 23 August 2024

Published : 31 August 2024

DOI : https://doi.org/10.1007/s10143-024-02759-5

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