CME Lecture on "COVID-19 Presentation and Diagnosis" Presented at the Scientific Seminar of Philippine American Medical Association in Chicago on March 6th, 2021.

1. Tahseen J. Siddiqui, M.D, MRCP
Infectious Disease Specialist & Infection Control Chair
Holy Cross Hospital, Humboldt Park Health, St. Bernard Hospital &
Roseland Community Hospitals
Asst. Professor of Medicine, St. George's University Medical School
President, Chicago Infectious Disease Physicians
COVID-19
Presentation and
Diagnosis

2. 1. PRE-TEST
QUESTIONS
1. COVID-19 “Reinfection” is defined as clinical recurrence of symptoms compatible
with COVID-19, accompanied by positive PCR test, more than 90 days after the
onset of the primary infection, while COVID-19 “Relapse” (recurrence or
reactivation) refers to clinical recurrence of symptoms compatible with COVID-19,
accompanied by positive/persisting RT-PCR test within 90 days of primary infection.
TRUE / FALSE
1. Diagnostic testing to identify persons previously infected with SARS-CoV-2
usually involves the detection of SARS-CoV-2 nucleic acid by means of PCR
assay/Antigen Tests while Antibody tests are authorized by the FDA to detect a
current infection with SARS-CoV-2.
TRUE / FALSE

3. RISK FACTORS OF COVID-19
• It is unclear whether other conditions (e.g., uncontrolled HIV infection or use of immunosuppressive medications)
confer an increased risk of complications,

4. Relative Risks of Severe Illness in COVID-19
Blood type A: a higher risk for COVID-19 respiratory failure in people with the A blood type. Blood group A antigen is present on
respiratory epithelial cells as well as red blood cells possibly explaining the increased risk for respiratory failure in these patients.

5. CLINICAL MANIFESTATIONS OF COVID-19
• The clinical spectrum of f SARS-CoV-2 infection ranges from asymptomatic infection to critical illness.
• Incubation period — generally within 14 days following exposure, with most cases occurring approximately
4-5 days after exposure
• Among patients who are symptomatic, the median incubation period is approximately 4 to 5 days, and 97.5%
have symptoms within 11.5 days after infection
• It is estimated that 33 percent of people with SARS-CoV-2 infection never develop symptoms
• Patients with asymptomatic infection may have objective clinical abnormalities:
• In a study of 24 patients with asymptomatic infection who all underwent chest computed tomography (CT),
50 % had typical ground-glass opacities or patchy shadowing, and another 20 % had atypical imaging
abnormalities
• Presymptomatic- some individuals who are asymptomatic at the time of diagnosis go on to develop symptoms

6. DESEASE SEVERITY/MORTALITY OF COVID-19
• Mild to moderate (81%)
Hallmarks of moderate disease are the presence of clinical or radiographic evidence of lower respiratory tract disease but with a
blood oxygen saturation of 94% or higher while the patient is breathing ambient air.
• Severe (14%)
Indicators of severe disease are marked dyspnea/tachypnea (respiratory rate, ≥30 breaths per minute), hypoxemia (oxygen
saturation, ≤93%; ratio of partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (Fi02), <300), and lung
infiltrates (>50% of the lung field involved on imaging within 24 to 48 hours)
• Critical (5%) (Respiratory failure, shock, or multiorgan system dysfunction)
• Overall case fatality ratio (CFR) 2.3%.
• CFR among patients with critical disease was 49%
• CFR in people aged 85 years or older (10%–27%), aged 65–84 years (3%–11%), aged 55–64 years (1%–3%), and in people
younger than 55 years (<1%). (U.S. epidemiologic data through March 16, 2020)
• Among U.S. COVID-19 cases reported January 22–May 30, 2020:
• Overall, the proportion of people who were hospitalized was 14%, including 2% admitted to the intensive care unit (ICU).
Overall, 5% of patients died.

8. INITIAL PRESENTATION OF COVID-19
• Cough (50 %)
• Fever (43%) (subjective or >100.4°F/38°C)
(Patients hospitalized with COVID-19 in New York, only 31% had a temperature >100.4°F/38°C at presentation)
• Myalgia (36 %)
• Headache (34 %)
• Dyspnea (29 %)- (approximately one week after the onset of initial symptoms)- suggestive of worsening
disease.
• Sore throat (20 %)
• GI Sx- (18%)- (with diarrhea, nausea/vomiting, or abdominal pain reported in 13, 10, and 9 percent,
respectively)
• Loss of smell or taste (Anosmia and Dysgeusia)- (>10%) - in a meta-analysis the pooled prevalence estimates
were 52 and 44 percent respectively,- usually improves in 4 weeks - more common in women than in men.
• Rhinorrhea in fewer than 10 %
• Conjunctivitis- rare

9. INITIAL PRESENTATION OF COVID-19
• Dermatologic Manifestations :
• Maculopapular rash (22%),
• Discolored, reddish-purple lesions of the fingers and toes, like pernio (chilblains), mainly in
children and young adults (18%),
• Hives (16%) and transient livedo reticularis
• Vesicular (varicella-like) eruptions - appeared 4 to 30 days after the onset of COVID symptoms
and resolved in a median of 10 days
• Less frequently -Papulosquamous eruptions, erythema multiforme-like lesions, dengue-like
rashes, petechiae, and gangrene.
• Multisystem inflammatory syndrome in children (MIS-C)
• An erythematous, polymorphic rash, erythema and/or firm induration of hands and feet, oral
mucositis, and conjunctivitis, along with systemic, laboratory, and imaging findings of atypical,
severe Kawasaki disease

10. Covid Toes
MUCO-CUTANEOUS FEATURES OF COVID-19
MIS-C
(Multi-System
Inflammatory
Syndrome in
children

11. Clinical Spectrum of COVID-19 in Children
Key distinctions between MIS-C and KD include:
●MIS-C commonly affects older children and adolescents, whereas classic KD typically affects infants and young children.
●In MIS-C, black and Hispanic children appear to be disproportionally affected and Asian children account for only a small number of cases. By
contrast, classic KD has a higher incidence in East Asia and in children of Asian descent
●Gastrointestinal symptoms (particularly abdominal pain) are very common in MIS-C, whereas these symptoms are less prominent in classic KD.
●Myocardial dysfunction and shock occur more commonly in MIS-C compared with classic KD
●Inflammatory markers (especially CRP, ferritin, and D-dimer) tend to be more elevated in MIS-C compared with classic KD and KDSS
In addition, absolute lymphocyte and platelet counts tend to be lower in MIS-C compared with KD

12. Multisystem
Inflammatory
Syndrome in Children
(MIS-C)
• Thought to result from an abnormal
immune response to the virus, with some
clinical similarities to KD, macrophage
activation syndrome (MAS), and cytokine
release syndrome.
• Related to immune dysregulation
occurring after acute infection has passed.
(Mostly COVID-19 seropositive and PCR neg)

13. Multisystem Inflammatory Syndrome in Children (MIS-C)

14. Multisystem Inflammatory Syndrome in Children (MIS-C)

15. Multisystem Inflammatory Syndrome in Children (MIS-C)

16. CLINICAL COURSE OF COVID-19
• Some patients who have mild symptoms initially can subsequently progress with a rapid clinical
deterioration that occurs approximately 1 week after symptom onset
• Median time from their onset of illness to the time they experienced dyspnea (5–8 days)
• Median time from onset of illness to acute respiratory distress syndrome (ARDS) (8–12 days)
• Hospital admission after a median of 7 days of symptoms onset
• ICU admission after a median time from onset of illness (9.5–12 days)
• Among all hospitalized patients, 26%–32% of patients were admitted to the ICU
• The median length of hospitalization among survivors (10–13 days)
• Mortality among patients admitted to the ICU ranged from 39% to 72% depending on the study
and characteristics of patient population

17. COVID-19 ‘REINFECTION’
• Defined as clinical recurrence of symptoms compatible with COVID-19, accompanied by
positive PCR test, more than 90 days after the onset of the primary infection, supported by
close-contact exposure or outbreak settings, and no evidence of another cause of infection.
• Patients recovered from the primary infection are less likely to be re-infected for up to 90 days
• Limited data exist about reinfection with SARS-CoV-2 after recovery from COVID-19
• Serology does not play a factor in the reinfection definition and could be either positive or
negative after the first infection.
• Unclear how long people who have recovered from COVID-19 are protected against, what
concentration of antibodies is needed to confer protection, and how often reinfection may occur
• Reinfection with a SARS-CoV-2 variant virus has been reported in Brazil, U.K., and South
Africa.

18. COVID-19 ‘RELAPSE’
• COVID-19 relapse (recurrence or reactivation) defined as clinical recurrence of symptoms compatible with
COVID-19 infection and accompanied by positive/persisting RT-PCR within 90 days of primary infection
and supported by the absence of epidemiological exposure or another cause of the illness.
• Demonstration of same strain by whole-genome sequencing could definitively differentiate this entity from
reinfection
• An inflammatory syndrome, as a result of inappropriate immune response, has been suggested as an
alternative explanation
• Further research is needed to decide whether these cases should be considered for isolation?
• SARS-CoV-2 PCR ‘Re-Positivity’
• Positive RT-PCR following negative tests in an asymptomatic patient up to 90 days from the
first episode.
• Do not represent replicative virus and do not require isolation

19. Prolonged Detection of SARS-CoV-2
• The average duration of detectable virus ~ 0-4 days to 10 -14 days from symptoms onset
• Some people who have recovered may have detectable SARS-CoV-2 RNA in upper respiratory
specimens for up to 90 days after illness onset
• Detection of viral RNA during convalescence does not necessarily indicate replication-
competent virus (infectiousness) or the presence of new infectious viral strain
• Some people with severe illness might produce replication-competent virus beyond 10 days that
may warrant extending duration of isolation precautions for up to 20 days after symptom onset.
• Some severely immunocompromised patients (lymphoma, hypogammaglobulinemia,
hemopoietic stem cell transplant recipients, AIDS, those receiving immunosuppression with
chemotherapy, systemic corticosteroids and biologics) might produce replication-competent
virus beyond 20 days and require additional testing and isolation.

20. COMPLICATIONS OF COVID-19
• Acute Respiratory Failure:
• ARDS- can manifest shortly after the onset of dyspnea
• (median of 8 days in 20%, mechanical ventilation in 12% -24% )
• Cardiac/Cardiovascular complications:
• Cardiac arrhythmias, conduction system disease (prolonged QTc), acute myocardial injury, and cardiogenic
shock
• Directly and indirectly from hemodynamic derangement or hypoxemia, inflammatory myocarditis, stress
cardiomyopathy, microvascular dysfunction or thrombosis due to hypercoagulability, or systemic
inflammation (cytokine storm)
• Neurologic Complications:
• (Cerebral ischemia, acute stroke, hypoxic brain damage)
• (Histopathological examination of brain specimens obtained from patients who died 0 to 32 days after the onset of symptoms of Covid-19
showed only hypoxic changes and did not show encephalitis or other specific brain changes referable to the virus. There was no cytoplasmic
viral staining on immunohistochemical analysis)
https://www.nejm.org/doi/full/10.1056/NEJMc2019373

21. COVID-19 ASSOCIATED COAGULOPATHY
• Hypercoagulable state and increased risk for venous and arterial thrombosis of large and small vessels.
• Laboratory findings:
• Mild thrombocytopenia
• Increased D-dimer levels
• Increased fibrin degradation products
• Prolonged prothrombin time
• Clinical manifestations:
• Arterial thromboembolism: (with minimal or no symptoms of COVID-19)
• Acute ischemic stroke, acute limb ischemia, Acute myocardial injury
• Lower extremity – 71 percent /Upper extremity – 14 percent
• Cerebral ischemia – 10 percent/ Bowel ischemia – 4 percent
Multiple locations occurred – 12 percent/ Concomitant deep vein thrombosis – 16 percent
• Microvascular thrombosis of the toes (COVID toes)
• Clotting of intra-vascular catheters
• VTE – (Venous thromboembolism), including extensive deep vein thrombosis (DVT) and pulmonary embolism (PE) up to 1/3
of patients in the ICU, even when prophylactic anticoagulation.
Autopsy studies showed combination of hypercoagulability and associated inflammation in patients who died from COVID-19:
(thrombotic microangiopathy with fibrin thrombi in alveolar and glomerular capillaries)

22. Post COVID-19 Syndrome - "The Long Haulers” (PASC)
• PASC- Post-Acute Sequelae of SARS-CoV-2 infection (new name)
• Roughly 10% of coronavirus patients with COVID-19 may experience long term lingering symptoms:
• Chronic fatigue syndrome
• Body aches/Joint pain
• Shortness of breath/Cough
• Chest pain
• Loss of taste and smell — even if this didn’t occur during the height of illness
• Headaches
• Brain fog (Memory, concentration or sleep problems)
• Rash or hair loss
• Organs that may be affected by COVID-19 include:
• Heart- cardiomyopathy/CHF
• Lungs- Chronic scarring/fibrosis
• Brain- Even in young people, COVID-19 can cause strokes, seizures and Guillain-Barre syndrome and increase the risk of
developing Parkinson's disease and Alzheimer's disease.
"One common theory about patients with long-term COVID-19 symptoms is that the virus possibly remains in their bodies in some
small form. Another theory is their immune systems continue to overreact even though the infection has passed," UC Davis Health

23. DIAGNOSTIC TESTING OF COVID-19
• Diagnostic testing to identify persons currently infected with SARS-CoV-2 usually involves the detection of
SARS-CoV-2 nucleic acid by means of PCR assay/Antigen Tests.
1) SARS-CoV-2 PCR: Specificity of most assays is nearly 100%
• Just before and soon after symptom onset, the sensitivity of PCR testing of nasopharyngeal swabs is high.
• If testing is negative in a person who is suspected to have Covid-19, then repeat testing is recommended.
• RT-PCR commercial assays with multiple specimen types, including nasopharyngeal, oropharyngeal, and
mid-turbinate and anterior nares (nasal) swabs, as well as the most recently validated specimen type, saliva.
• The CDC Influenza SARS-CoV-2 (Flu SC2) Multiplex Assay is (RT-PCR) test that detects and differentiates
RNA from SARS-CoV-2, influenza A virus, and influenza B virus in upper or lower respiratory specimens
2) Rapid Antigen tests: Identify SARS-CoV-2 in a nasopharyngeal or nasal swab in 15 min
• Rapid Point-Of-Care Testing for COVID-19 in Community Settings and Schools
• Should ideally be performed within 7 days of symptoms onset.
• Antigen tests are generally less sensitive than PCR tests but less expensive ($5)
• It may be necessary to confirm a rapid POC antigen or rapid POC molecular test result with a RT-PCR test,
especially if the result of the rapid POC test is inconsistent with the clinical picture, i.e., a negative antigen
test on a symptomatic individual or on a person who is a close contact to a confirmed or probable case

24. Diagnostic testing of COVID-19
Rapid Antigen Test vs PCR (NAAT)

25. Evaluating the Results of Antigen Testing for SARS-CoV-2

26. DIAGNOSTIC TESTING OF COVID-19
Serologic tests for SARS-CoV-2
• Antibody tests: Detect a past infection with SARS-CoV-2.
• Anti–SARS-CoV-2 antibodies are detectable in the majority of patients 14 days or more after the
development of symptoms.
• The CDC does not currently recommend using antibody testing as the sole basis for diagnosing current
infection or disproving a positive result by viral testing.
• These tests measure different immunoglobulins (IgA/M/G) and detect antibodies against various viral
antigens (spike protein/nucleocapsid) with the use of different analytic methods, so direct comparison of the
tests is challenging.
• Generally reserved for people who are suspected to have Covid-19 but have negative PCR testing and in
whom symptoms began at least 14 days earlier.
• Antibody testing after 2 weeks also may be considered when there is a clinical or epidemiologic reason for
detecting past infection, such as serosurveillance.
• Because antibody levels may decrease over time and the correlates of immunity are not yet known, serologic
test results cannot currently inform whether a person is protected against reinfection

27. Laboratory Testing of COVID-19
• Laboratory testing in hospitalized patients should include a complete blood count, a comprehensive metabolic
panel, CK, troponin, coagulation studies, (D Dimer/Fibrinogen) and inflammatory markers.
(CRP/LDH/Ferritin/IL-6)
• Lymphopenia, neutrophilia, elevated ALT/AST levels, elevated lactate dehydrogenase, high C-reactive
protein (CRP), interleukin-6, high ferritin levels, may be associated with greater illness severity.
• Elevated D-dimer and lymphopenia have been associated with mortality.
• Procalcitonin is typically normal on admission but may increase among those patients admitted to an ICU.
• In addition, testing for other pathogens (e.g., influenza virus, depending on the season, and other respiratory
viruses) should be performed, if available, and chest imaging should be done.
• Baseline EKG should be obtained, especially if a medication that affects the corrected QT (QTc) interval is
considered, (Levaquin/azithromycin), and to evaluate for acute myocardial injury

28. Radiographic Testing of COVID-19
• CXR of patients with COVID-19 typically demonstrate bilateral air-space consolidation
• Chest CT images from patients with COVID-19 typically demonstrate bilateral, peripheral ground glass
opacities.
• Because this chest CT imaging pattern is non-specific and can be found in pneumonias caused by other
infections, the diagnostic value of chest CT imaging for COVID-19 may be low and dependent upon
radiographic interpretation.
• One study found that 56% of patients who presented within two days of diagnosis had a normal CT.
• Conversely, other studies have identified chest CT abnormalities in patients prior to the detection of SARS-
CoV-2 RNA in RT-PCR testing of nasopharyngeal samples.
• Given the variability in chest imaging findings, chest radiograph or CT alone is not recommended for the
diagnosis of COVID- The American College of Radiology also does not recommend CT for screening, or as a
first-line test for diagnosis of COVID-19.
• Echocardiogram- (at the baseline or when clinically indicated)
• VTE/PE – (CTA/V-Q scan/Venous/arterial dopplers)- when clinically indicated.

29. Radiographic Findings of COVID-19

30. 1. POST-TEST
QUESTIONS
1. COVID-19 “Reinfection” is defined as clinical recurrence of symptoms compatible
with COVID-19, accompanied by positive PCR test, more than 90 days after the
onset of the primary infection, while COVID-19 “Relapse” (recurrence or
reactivation) refers to clinical recurrence of symptoms compatible with COVID-19,
accompanied by positive/persisting RT-PCR test within 90 days of primary infection.
TRUE / FALSE
1. Diagnostic testing to identify persons previously infected with SARS-CoV-2
usually involves the detection of SARS-CoV-2 nucleic acid by means of PCR
assay/Antigen Tests while Antibody tests are authorized by the FDA to detect a
current infection with SARS-CoV-2.
TRUE / FALSE

31. ● https://www.yahoo.com/lifestyle/long-term-effects-of-covid-19-given-name-by-experts-
fauci-231226751.html
● https://health.ucdavis.edu/coronavirus/covid-19-information/covid-19-long-haulers.html
● https://www.kcra.com/article/covid-19-long-hauler-treated-in-sacramento-uc-davis-
health/35192445#
● https://www.nejm.org/doi/10.1056/NEJMcp2009249
● https://www.nejm.org/doi/pdf/10.1056/NEJMcp2009249
● https://www.nejm.org/doi/full/10.1056/NEJMc2019373
● https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-clinical-
features?search=covid%2019&source=search_result&selectedTitle=1~150&usage_type=de
fault&display_rank=1
● https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-cutaneous-
manifestations-and-issues-related-to-dermatologic-
care?sectionName=CUTANEOUS%20MANIFESTATIONS%20OF%20COVID-
19&search=covid%2019&topicRef=128323&anchor=H2979176773&source=see_link#H29
79176773
● https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-
patients.html
● https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30724-2/fulltext
● https://www.hematology.org/covid-19/covid-19-and-pulmonary-embolism
● https://www.mayoclinic.org/coronavirus-long-term-effects/art-20490351
REFERENCES