Covid 19 Clinical Features and Diagnosis.pptx

description of covid -19 symptomatology

1. Dr. M.G. Krishna Murthy Professor and HOD Department of Respiratory Medicine Gandhi Medical College Clinical Features and Lab diagnosis of COVID-19

2. Novel Corona Virus Novel corona virus is related to those that had caused outbreaks of Severe Acute Respiratory Syndrome (SARS) from 2002-2004 and Middle East Respiratory Syndrome (MERS) in 2012. SARS-CoV-2 particles are spherical and have proteins called spikes protruding from their surface. SARS-CoV-2 spikes bind to receptors on the human cell surface called angiotensin -converting enzyme 2 (ACE2). SARS-CoV-2 spike was 10 to 20 times more likely to bind ACE2 on human cells than the spike from the SARS virus from 2002. This may enable SARS-CoV-2 to spread more easily from person to person than the earlier. Transmission electron microscope image shows SARS-CoV-2, the virus that causes COVID-19, isolated from a patient in the U.S. Virus particles are emerging from the surface of cells cultured in the lab .

3. Proposed Routes of SARS-CoV-2 Transmission Galbadage. Front Public Health. 2020;8:163. WHO. Scientific Brief. July 9, 2020. Slide credit: clinicaloptions.com SARS-CoV-2– Infected Host Susceptible Host Aerosols < 5 µm diameter Suspended in air Contact/Droplet > 5 µm diameter Direct contact or < 1 meter distance Fomites (?) Environmental Stability Points of entry: Eyes, nose, or mouth Airborne (?) > 1 meter distance Urine/feces: RNA found in both; live virus cultivated from few specimens

4. Immune Response to SARS-CoV-2 Slide credit: clinicaloptions.com 1. Wang. 2020; J Leukoc Biol. 2020;[Epub]. 2. Sokolowska. EAACI. 2020[Epub]. Adequate immune responses [2] Timely innate/adaptive responses Quick type 1 IFN response Activation of efficient antiviral response (clearance by macrophages) Activation of Th1 cells and B-cells for production of neutralizing antibodies Inadequate immune responses [2] Delayed/limited type 1 IFN Endothelial cell death Epithelial/endothelial leakage Overactivation/exhaustion T-cells and NK cells Accumulation of activated macrophages  cytokine storm Mild Severe Normal immune response Recovery Isolation/hospitalization Supportive care Death Anti-viral and anti–cytokine storm treatment Lung injury/septic shock/organ failure/ coagulopathy Low virus titer SARS-CoV-2 Monocyte Macrophage High virus titer Activation Low High ICU Cytokines: IL-6/IL-10/TNF/ CSF/RANTES… CD4 CD8 T-cell Neutrophil Cytokine storm Immune Responses Leading to Recovery or Death [1]

5. Screening

6. Residing or working in an area with high risk of transmission* WHO: Suspect Case Definition Acute onset of fever and cough OR ≥ 3 of the following: fever, cough, general weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, anorexia/nausea/vomiting, diarrhea, altered mental status And 1 of the following within 14 days of symptom onset: Residing or travel to an area with community transmission Working in a healthcare setting WHO COVID-19 Case Definition. Updated August 7, 2020. https://www.who.int/publications/i/item/WHO-2019-nCoV-Surveillance_Case_Definition-2020.1 Slide credit: clinicaloptions.com *Closed residential settings, humanitarian settings such as camp and camp-like settings for displaced persons. OR: Patient with severe acute respiratory illness (acute respiratory infection with history of fever or measured fever ≥ 38°C and a cough; onset within last 20 days; requires hospitalization) Updated

7. Contact of probable or confirmed case or epidemiologically linked to a cluster with at least 1 confirmed case WHO: Probable Case Definition Acute onset of fever and cough OR ≥ 3 of the following: fever, cough, general weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, anorexia/nausea/vomiting, diarrhea, altered mental status AND: WHO COVID-19 Case Definition. Updated August 7, 2020. https://www.who.int/publications/i/item/WHO-2019-nCoV-Surveillance_Case_Definition-2020.1 Slide credit: clinicaloptions.com *Hazy opacities with peripheral and lower lung distribution on chest radiography; multiple bilateral ground glass opacities with peripheral and lower lung distribution on chest CT; or thickened pleural lines, B lines, or consolidative patterns on lung ultrasound. OR: Suspect case with chest imaging showing findings suggestive of COVID-19 disease* OR: Recent onset of loss of smell or taste in the absence of any other identified cause OR: Unexplained death in an adult with respiratory distress who was a contact of a probable or confirmed case or epidemiologically linked to a cluster with at least 1 confirmed case New

8. Natural History, Clinical Presentation, and Symptom Spectrum

9. COVID-19 Incubation: Infection to Illness Onset Among 10 confirmed NCIP cases in Wuhan, Hubei province, China [1] Mean incubation: 5.2 days (95% CI: 4.1-7.0) Among 181 confirmed SARS-CoV-2 infections occurring outside of Hubei province [2] Median incubation: 5.1 days (95% CI: 4.5-5.8) Symptom onset by Day 11.5 of infection in 97.5% of persons 1. Li. NEJM. 2020;382:1199. 2. Lauer. Ann Intern Med. 2020;172:577. Slide credit: clinicaloptions.com Estimated Incubation Period Distribution [1] 0.25 0.20 0.15 0.10 0.05 Relative Frequency Days From Infection to Symptom Onset 21 7 14

10. 50 40 30 20 10 COVID-NET: Lab-Confirmed COVID-19–Associated Hospitalization Rates Stratified by Age https://gis.cdc.gov/grasp/COVIDNet/COVID19_3.html Slide credit: clinicaloptions.com Covers ~ 10% of US population: 99 counties in 14 states (CA, CO, CT, GA, IA, MD, MI, MN, NM, NY, OH, OR, TN, UT) Rate per 100,000 Population 3-21-2020 4-4-2020 4-18-2020 5-2-2020 5-16-2020 5-30-2020 6-13-2020 6-27-2020 7-11-2020 3-28-2020 4-11-2020 4-25-2020 5-9-2020 5-23-2020 6-6-2020 6-20-2020 7-4-2020 3-7-2020 3-14-2020 0-4 yrs 5-17 yrs 18-49 yrs 50-64 yrs ≥ 65 yrs

11. Primary Symptoms of COVID-19 Li. J Med Virol. 2020;92:577. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html Slide credit: clinicaloptions.com Headache Congestion or runny nose, new loss of taste or smell Fatigue, muscle or body aches, fever or chills Nausea or vomiting, diarrhea Cough, sore throat Shortness of breath or difficulty breathing “Symptoms may appear 2-14 days after exposure to the virus”

12. Endocrine Hyperglycemia Diabetic ketoacidosis Extrapulmonary Manifestations Gupta. Nat Med. 2020;26:1017. Slide credit: clinicaloptions.com Neurologic Headaches Dizziness Encephalopathy Guillain-Barré New Renal Acute kidney injury Proteinuria Hematuria Hepatic Elevated ALT/AST Elevated bilirubin Cardiac Takotsubo cardiomyopathy Myocardial injury/myocarditis Cardiac arrhythmias Ageusia Myalgia Anosmia Stroke Cardiogenic shock Myocardial ischemia Acute cor pulmonale Dermatologic Petechaie Livedo reticularis Erythematous rash Urticaria Vesicles Pernio-like lesions Thromboembolism Deep vein thrombosis Pulmonary embolism Catheter-related thrombosis Gastrointestinal Diarrhea Nausea/vomiting Abdominal pain Anorexia

13. Frequency of Presenting Symptoms Among COVID-19–Positive Hospitalized Patients in the UK Docherty. BMJ. 2020;369:m1985. Slide credit: clinicaloptions.com Joint Pain Cough (Blood) Runny Nose Skin Ulcers Confusion Cough (Sputum) Diarrhea Nausea/Vomiting Muscle ache Chest Pain Headache Wheeze Abdominal Pain Sore Throat Cough Fever Shortness of Breath Fatigue Bleeding (Hemorrhage) Lymphadenopathy Ear Pain Conjunctivitis Seizures Skin Rash Lower Chest Wall Indwelling Yes No Unknown Patients With Symptoms (%) Median symptom duration preceding admission among 16,221 patients: 4 days (IQR: 1-8) 100 80 60 40 20

14. Clinical Course of Fever by Requirement for ICU Care Among COVID-19 Patients in Shanghai, China Chen. J Infect. 2020;80:e1. Slide credit: clinicaloptions.com Fever HR: 5.83 (95% CI: 3.86-8.80; P < .0001) PCR Positivity HR: 3.17 (95% CI: 2.29-4.37; P < .0001) 9 days 31 days Day After Onset of Symptoms 5 10 15 20 25 30 Non-ICU Patients (%) 100 50 Patients at Risk, n ICU Non-ICU 22 213 13 93 3 3 Day After Onset of Symptoms 5 10 15 20 25 30 ICU Patients (%) 100 50 Patients at Risk, n ICU Non-ICU 21 227 21 207 12 19 20 149 17 49 7 1

15. COVID-19 Clinical Presentation May Vary by Age, Sex Observational study of Europeans with mild-to-moderate COVID-19 (ie, no ICU admission) via standardized questionnaire during March 22-April 10, 2020 (N = 1420) [1] Mean duration of symptoms (n = 264): 11.5 ± 5.7 days Ear, nose, throat complaints more common in young patients ; fever, fatigue, loss of appetite, diarrhea in elderly patients ( P < .01) Loss of smell, headache, nasal obstruction, throat pain, fatigue more common in women ; cough, fever in men ( P < .001) Among 17 fatal COVID-19 cases detailed by the China National Health Commission, median time from first symptom to death : 14 days (range: 6-41) [2] Numerically faster in older patients : 11.5 days if ≥ 70 yrs vs 20 days if < 70 yrs ( P = .033) 1. Lechien. J Intern Med. 2020;[Epub]. 2. Wang. J Med Virol. 2020;92:441. Slide credit: clinicaloptions.com Symptom, [1] % N = 1420 Headache 70.3 Loss of smell 70.2 Nasal obstruction 67.8 Asthenia 63.3 Cough 63.2 Myalgia 62.5 Rhinorrhea 60.1 Taste dysfunction 54.2 Sore throat 52.9 Fever (> 38°C) 45.4

16. Clinical Spectrum of Covid 19

17. Variation in Clinical Course and Outcome Among Patients Hospitalized With COVID-19 in Wuhan, China Zhou. Lancet. 2020;395:1054. Slide credit: clinicaloptions.com Fever Cough Dyspnea ICU admission Systematic corticosteroid SARS-CoV-2 RNA positive Median days after onset 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Survivors (n = 137) Sepsis ARDS Discharge Fever Cough Dyspnea ICU admission Invasive ventilation Systematic corticosteroid SARS-CoV-2 RNA positive Median days after onset 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Nonsurvivors (n = 54) Sepsis ARDS Acute cardiac/ kidney injury Death Secondary infection

18. Assessing Disease Severity and Risk Factors for Severe Disease

19. Radiographic and Lab Abnormalities by Disease Severity Among COVID-19 Patients in Mainland China Guan. NEJM. 2020;382:1708. Slide credit: clinicaloptions.com Radiographic or Lab Finding All Patients (N = 1099) Nonsevere Disease (n = 926) Severe Disease (n = 173) Abnormalities on chest radiograph,* n/N (%) 162/274 (59.1) 116/214 (54.2) 46/60 (76.7) Abnormalities on chest CT,* n/N (%) 840/975 (86.2) 682/808 (84.4) 158/167 (94.6) Median white cell count per mm 3 (IQR) 4700 (3500-6000) 4900 (3800-6000) 3700 (3000-6200) Median lymphocyte count per mm 3 (IQR) 1000 (700-1300) 1000 (800-1400) 800 (600-1000) Median platelet count x 1000 per mm 3 (IQR) 168 (132-207) 172 (139-212) 137.5 (99-179.5) C-reactive protein ≥ 10 mg/L, n/N (%) 481/793 (60.7) 371/658 (56.4) 110/135 (81.5) D-dimer ≥ 0.5 mg/L, n/N (%) 260/560 (46.4) 195/451 (43.2) 65/109 (59.6) Lactate dehydrogenase ≥ 250 U/L, n/N (%) 277/675 (41.0) 205/551 (37.2) 72/124 (58.1) AST > 40 U/L, n/N (%) 168/757 (22.2) 112/615 (18.2) 56/142 (39.4) ALT > 40 U/L, n/N (%) 158/741 (21.3) 120/606 (19.8) 38/135 (28.1) *Ground-glass opacity, local patchy shadowing, bilateral patchy shadowing, or interstitial abnormalities.

20. NIH Guidelines: Defining a COVID-19 Severity Spectrum NIH COVID-19 Treatment Guidelines. Management of persons with COVID-19. Last updated June 11, 2020. Slide credit: clinicaloptions.com Stage Characteristics Asymptomatic or presymptomatic infection Positive test for SARS-CoV-2 but no symptoms Mild illness Varied symptoms (eg, fever, cough, sore throat, malaise, headache, muscle pain) but no shortness of breath, dyspnea, abnormal imaging Moderate illness SpO 2 ≥ 94% and lower respiratory disease evidenced by clinical assessment or imaging Severe illness SpO 2 < 94%, PaO 2 /FiO 2 < 300, respiratory rate > 30 breaths/min, or lung infiltrates > 50% Critical illness Respiratory failure, septic shock, and/or multiorgan dysfunction

21. Severity Grading (Ministry of Health and Family Welfare guidelines) SARI An ARI with history of fever or measured temperature ≥38 C° and cough; onset within the last ~10 days; and requiring hospitalization. However, the absence of fever does NOT exclude viral infection Severe acute respiratory infection (SARI) in a person, with history of fever and cough requiring admission to hospital, with no other aetiology that fully explains the clinical presentation1 (clinicians should also be alert to the possibility of atypical presentations in patients who are immunocompromised) A person with acute respiratory illness of any degree of severity who, within 14 days before onset of illness, had any of the following exposures: a) close physical contact2 with a confirmed case of nCoV infection, while that patient was symptomatic; or b) a healthcare facility in a country where hospital-associated nCoV infections have been reported;

22. Severity Grading (Ministry of Health and Family Welfare guidelines) Uncomplicated illness Patients with uncomplicated upper respiratory tract viral infection, may have nonspecific symptoms such as fever, cough, sore throat, nasal congestion, malaise, headache, muscle pain or malaise. The elderly and immunosuppressed may present with atypical symptoms. These patients do not have any signs of dehydration, sepsis or shortness of breath Mild pneumonia Patient with pneumonia and no signs of severe pneumonia. Child with non-severe pneumonia has cough or difficulty breathing + fast breathing: fast breathing (in breaths/min )

23. Severity Grading (Ministry of Health and Family Welfare guidelines) Severe pneumonia Adolescent or adult: fever or suspected respiratory infection, plus one of respiratory rate >30 breaths/min, severe respiratory distress, or SpO2 < 90% on room air. Child with cough or difficulty in breathing, plus at least one of the following: central cyanosis or SpO2 <90% on room air Acute Respiratory Distress Syndrome Onset: new or worsening respiratory symptoms within one week of known clinical insult. Chest imaging (radiograph, CT scan, or lung ultrasound): bilateral opacities, not fully explained by effusions, lobar or lung collapse, or nodules. Origin of oedema : respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g. echocardiography) to exclude hydrostatic cause of oedema if no risk factor present. Oxygenation (adults): • Mild ARDS : 200 mmHg < PaO2/FiO2 ≤ 300 mmHg (with PEEP or CPAP ≥5 cm H2O, or non-ventilated) • Moderate ARDS : 100 mmHg < PaO2/FiO2 ≤200 mmHg with PEEP ≥5 cm H2O, or non-ventilated) • Severe ARDS : PaO2/FiO2 ≤ 100 mmHg with PEEP ≥5 cmH2O, or nonventilated ) • When PaO2 is not available, SpO2/FiO2 ≤315 suggests ARDS (including in non-ventilated patients)

24. Severity Grading (Ministry of Health and Family Welfare guidelines) Sepsis Adults: life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection, with organ dysfunction. Signs of organ dysfunction include: altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy , thrombocytopenia, acidosis, high lactate or hyperbilirubinemia   Children: suspected or proven infection and ≥2 SIRS criteria, of which one must be abnormal temperature or white blood cell count Septic shock Adults: persisting hypotension despite volume resuscitation, requiring vasopressors to maintain MAP ≥65 mmHg and serum lactate level >2 mmol /L   Children: any hypotension (SBP 2 SD below normal for age) or 2-3 of the following: altered mental state; tachycardia or bradycardia (HR 160 bpm in infants and HR 150 bpm in children); prolonged capillary refill (>2 sec) or warm vasodilation with bounding pulses; tachypnea ; mottled skin or petechial or purpuric rash; increased lactate; oliguria ; hyperthermia or hypothermia

25. COVID-19 Severity in Mainland China Observational study of COVID-19 cases diagnosed in China’s Infectious Disease Information System as of February 11, 2020 (N = 72,314) No deaths among confirmed case patients with noncritical disease or who were ≤ 9 yrs of age Wu. JAMA. 2020;323:1239. http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51 Slide credit: clinicaloptions.com Disease Classification, % Confirmed Cases* (n = 44,672) Mild 80.9 Severe 13.8 Critical 4.7 Missing 0.6 Characteristic Case-Fatality Rate, % (n/N) All confirmed cases* 2.3 (1023/44,672) Critical 49.0 (1023/2087) ≥ 80 yrs of age 14.8 (208/1408) Cardiovascular disease 10.5 (92/873) 70-79 yrs of age 8.0 (312/3918) Diabetes 7.3 (80/1102) Chronic respiratory disease 6.3 (32/511) Hypertension 6.0 (161/2683) Cancer 5.6 (6/107) *Positive for viral nucleic acid by throat swab.

26. Comorbidity Status at Hospital Admission Among COVID-19–Positive Patients in New York City Area Case series of sequentially hospitalized patients admitted to 12 Northwell Health system hospitals in NYC, Long Island, and Westchester County, NY during March 1-April 4, 2020 (N = 5700) Median number of total comorbidities at admission: 4 (IQR: 2-8) Richardson. JAMA. 2020;323:2052. Slide credit: clinicaloptions.com Comorbidity Number, % Admissions (N = 5700) > 1 87.6 1 6.3 None 6.1 Specific Comorbidity, % Admissions (N = 5700) Hypertension 56.6 Obesity 41.7 Diabetes 33.8

27. Predictors of Mortality Among COVID-19–Positive Hospitalized Patients in the UK Prospective observational cohort study of hospital admissions in England, Wales, and Scotland during February 6 - April 19, 2020 (N = 20,133) Significantly increased risk of mortality among older patients, men, and those with chronic comorbidities Docherty. BMJ. 2020;369:m1985. Slide credit: clinicaloptions.com Multivariate Survival Analysis HR (95% CI) P Value < 50 yrs 50-59 yrs 60-69 yrs 70-79 yrs ≥ 80 yrs Female sex Chronic cardiac disease Chronic pulmonary disease Chronic kidney disease Diabetes Obesity Chronic neurological disorder Dementia Malignancy Moderate/severe liver disease 2.63 (2.06-3.35) 4.99 (3.99-6.25) 8.51 (6.85-10.57) 11.09 (8.93-13.77) 0.81 (0.75-0.86) 1.16 (1.08-1.24) 1.17 (1.09-1.27) 1.28 (1.18-1.39) 1.06 (0.99-1.14) 1.33 (1.19-1.49) 1.17 (1.06-1.29) 1.40 (1.28-1.52) 1.13 (1.02-1.24) 1.51 (1.21-1.88) Characteristic < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 .087 < .001 .001 < .001 .017 < .001 10 1 2 5

28. ≥ 24 hrs since resolution of fever, last antipyretics CDC: Discontinuation of Transmission-Based Precautions in Symptomatic COVID-19 Patients “A test-based strategy is no longer recommended [except for rare situations] because, in the majority of cases, it results in prolonged isolation of patients who continue to shed detectable SARS-CoV-2 RNA but are no longer infectious.” Symptom-Based Strategy And https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-hospitalized-patients.html Slide credit: clinicaloptions.com Improvement in symptoms (eg, cough, shortness of breath) And ≥ 10 days since symptom onset for mild to moderate illness, ≥ 20 days for severe to critical illness or those severely immunocompromised

29. LAB DIAGNOSIS

30. Strategies for COVID-19 Testing Existing strategies for COVID-19 testing : 1. Real Time RT-PCR 2. The TrueNat and CBNAAT Newer additional strategies for COVID-19 Testing : I. Rapid Point-of-Care ( PoC ) Antigen Detection Test (for diagnosis along with RT-PCR): II . IgG Antibody test for COVID-19 (Only for surveillance and not diagnosis):

31. Temporal Considerations for Diagnosis Sethuraman. JAMA. 2020;323:2249. Reproduced with permission from JAMA. 2020. doi:10.1001/jama.2020.8259. Copyright©(2020) American Medical Association. All rights reserved. Slide credit: clinicaloptions.com Wk -2 Wk -1 Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6 Symptom onset Detection unlikely PCR – Likely positive PCR – Likely negative Antibody detection Nasopharyngeal swab PCR Virus isolation from respiratory tract Bronchoalveolar lavage/sputum PCR Stool PCR IgM antibody IgG antibody After symptom onset Before symptom onset SARS-CoV-2 exposure Increasing probability of detection

32. Common COVID-19 Diagnostic Methods: RNA Udugama. ACS Nano. 2020;14:3822. Lee. Front Immunol. 2020;11:879. Slide credit: clinicaloptions.com Viral Nucleic Acid Assays Typically indicate Current infection Specimen sources Upper (eg, nasopharyngeal swabs or washes, oropharyngeal swabs, nasal aspirates) or lower (eg, sputum, bronchoalveolar lavage fluid, tracheal aspirates) respiratory tract Considerations Primary method for COVID-19 diagnosis with multiple RT-PCR kits available False negatives may result from improper sampling or handling, low viral load, or viral mutations SARS-CoV-2 RNA undetectable by ~ Day 14 following onset of illness in some cases/samples

33. WHO: Interim Guidance on Laboratory Testing for SARS-CoV-2 in Suspected Symptomatic Human Cases Routine confirmation of SARS-CoV-2 infection is based on the detection of unique sequences of RNA by nucleic acid amplification tests such as RT-PCR 1 or more negative results do not rule out the possibility of SARS-CoV-2 infection Factors Potentially Leading to Negative Result in an Infected Individual Poor specimen quality Timing of specimen collection (very early or late in infection) Specimen was not handled appropriately Technical reasons inherent in test (virus mutation or PCR inhibition) “If a negative result is obtained from a patient with a high index of suspicion for COVID-19, particularly when only upper respiratory tract specimens were collected, additional specimens, including from the lower respiratory tract if possible, should be collected” https://www.who.int/publications-detail/laboratory-testing-strategy-recommendations-for-covid-19-interim-guidance Slide credit: clinicaloptions.com

34. Common COVID-19 Diagnostic Methods: Antigen Deeks. Cochrane Database Syst Rev. 2020;6:CD013652. Lee. Front Immunol. 2020;11:879. Carter. ACS Cent Sci. 2020;6:591. Slide credit: clinicaloptions.com Updated Rapid Point-of-Care ( PoC ) Antigen Detection Test ( Standard Q COVID-19 Ag kit) Typically indicate Present infection, but may have some utility in diagnosis of current infection among larger population, specially in Containment areas or when RT-PCR unavailable. Specimen sources Most often blood serum or plasma, but may include saliva, sputum, or other biological fluids. Considerations moderate sensitivity but high specificity. Does not require a specialized machine i ) All containment zones identified by the State Governments, ii) All Central & State Government Medical Colleges and Government hospitals iii) All private hospitals approved by National Accreditation Board for Hospitals & Healthcare (NABH). iv) All private labs accredited by National Accreditation Board for Laboratories (NABL) and approved by ICMR as COVID-19 testing labs.

35. Common COVID-19 Diagnostic Methods: Antibodies Deeks. Cochrane Database Syst Rev. 2020;6:CD013652. Lee. Front Immunol. 2020;11:879. Carter. ACS Cent Sci. 2020;6:591. Slide credit: clinicaloptions.com Updated Serologic Assays Typically indicate Past infection, but may have some utility in diagnosis of current infection among those presenting late or when RT-PCR negative/unavailable Specimen sources Most often blood serum or plasma, but may include saliva, sputum, or other biological fluids Considerations Provides a delayed but wider window of time for detection May be useful for COVID-19 surveillance and identification of convalescent plasma donors False negatives : Low sensitivity in first wk after symptoms with subsequent rises during second/third wks and scant data thereafter; unclear if low-level antibody detectable in cases of mild/asymptomatic disease False positives : Due to cross-reactivity Uncertain if positive read = immune protection if re-exposed

36. Viral Antibody Response Viral infection results in the production of antibodies of different isotypes with varying targets and specificities High-affinity antibodies generated via maturation with somatic rearrangements and hypermutation of Ig genes Nonneutralizing antibodies : recognize viral epitopes that do not extinguish infective virus Neutralizing antibodies : recognize viral epitopes that eliminate or greatly diminish infective virus; critical for preventing reinfection Development of nonneutralizing antibodies typically precedes that of neutralizing antibodies Functional Activity of Ig Isotypes IgM IgD IgG1 IgG2 IgG3 IgG4 IgA IgM Neutralization + - ++ ++ ++ ++ ++ - Opsonization + - +++ - ++ + + - Sensitization for NK cell killing - - ++ - ++ - - - Sensitization of mast cells - - + - + - - +++ Complement activation +++ - ++ + +++ - + - Slide credit: clinicaloptions.com Neurath. Encyclopedia of Virology. 2008;56.

37. Advisory on Strategy for COVID-19 Testing in India (Version VI, dated 4th September 2020) A. Routine surveillance in containment zones and screening at points of entry : Choice of Test (in order of priority ): Rapid Antigen Test (RAT) ii . RT-PCR or TrueNat or CBNAAT 1. All symptomatic (ILI symptoms) cases including health care workers and frontline workers. 2 . All asymptomatic direct and high-risk contacts (in family and workplace, elderly ≥ 65 years of age, immunocompromised, those with co-morbidities etc.) of a laboratory confirmed case to be tested once between day 5 and day 10 of coming into contact. 3 . All asymptomatic high-risk individuals (elderly ≥ 65 years of age, those with co-morbidities etc.) in containment zones.

38. Advisory on Strategy for COVID-19 Testing in India (Version VI, dated 4th September 2020) B. Routine surveillance in non- containment areas : Choice of Test (in order of priority ): i . RT-PCR or TrueNat or CBNAAT ii . Rapid Antigen Test (RAT )* 4. All symptomatic (ILI symptoms) individuals with history of international travel in the last 14 days. 5 . All symptomatic (ILI symptoms) contacts of a laboratory confirmed case. 6 . All symptomatic (ILI symptoms) health care workers / frontline workers involved in containment and mitigation activities . 7.All symptomatic ILI cases among returnees and migrants within 7 days of illness. 8 . All asymptomatic high-risk contacts(contacts in family and workplace, elderly ≥ 65 years of age, those with co-morbidities etc. [RAT is recommended as the first choice of test in order of priority

39. Advisory on Strategy for COVID-19 Testing in India (Version VI, dated 4th September 2020) C. In Hospital Settings : Choice of Test ( in order of priority): i . RT-PCR or TrueNat or CBNAAT ii . Rapid Antigen Test ( RAT) 9 . All patients of Severe Acute Respiratory Infection (SARI). 10 . All symptomatic (ILI symptoms) patients presenting in a healthcare setting. 11 . Asymptomatic high-risk patients who are hospitalized or seeking immediate hospitalization such as immunocompromised individuals, patients diagnosed with malignant disease, transplant patients, patients with chronic co-morbidities, elderly ≥ 65 years. 12 . Asymptomatic patients undergoing surgical / non-surgical invasive procedures (not to be tested more than once a week during hospital stay). 13 . All pregnant women in/near labour who are hospitalized for delivery.

40. Advisory on Strategy for COVID-19 Testing in India (Version VI, dated 4th September 2020) 14. All symptomatic neonates presenting with acute respiratory / sepsis like illness. (Features suggestive of acute respiratory illness in a neonate are respiratory distress or apnea with or without cough, with or without fever. Neonates may also manifest with only non-respiratory symptoms like fever, lethargy, poor feeding, seizures or diarrhea). 15 . Patients presenting with atypical manifestations [stroke, encephalitis, hemoptysis , pulmonary embolism, acute coronary symptoms, Guillain Barre syndrome, Multiple Organ Dysfunction Syndrome, progressive gastrointestinal symptoms, Kawasaki Disease (in pediatric age group)] based on the discretion of the treating physician

41. Advisory on Strategy for COVID-19 Testing in India (Version VI, dated 4th September 2020) D. Testing on demand (State Governments to decide simplified modalities): 16 . All individuals undertaking travel to countries/Indian states mandating a negative COVID-19 test at point of entry. 17 . All individuals who wish to get themselves tested.

42. Choice of Test in order of priority (ICMR guideline- 4 th sep 2020)

43. Algorithm for Covid 19 test interpretation using rapid antigen point-of-care test. (ICMR guideline- 4 th sep 2020)

44. IDSA: SARS-CoV-2 Nucleic Acid Testing of Symptomatic Individuals IDSA. COVID-19 Guideline, Part 3: Diagnostics. Version 1.0.1. Slide credit: clinicaloptions.com Direct SARS-CoV-2 Nucleic Acid Amplification Testing Collect nasopharyngeal, nasal, or mid-turbinate rather than oropharyngeal or saliva specimens Provider-collected or self-collected specimens acceptable except nasopharyngeal Non-hospitalized Hospitalized Lower respiratory tract symptoms High Suspicion for COVID-19 Low Suspicion for COVID-19 Known exposure or high prevalence area If negative, repeat testing If negative, repeat testing (from lower tract if possible) If negative, repeat testing If negative, do not repeat testing Prioritize testing for symptomatic patients. If resources adequate, consider testing select asymptomatic individuals (eg, exposed, immunosuppressive procedure, major time-sensitive surgery, aerosol-generating procedure with limited PPE).

45. Temporal Profile of SARS-CoV-2 Viral Load Serial viral loads assessed via RT-PCR of posterior oropharyngeal saliva or endotracheal aspirate* collected from hospitalized patients in Hong Kong with laboratory confirmed COVID-19 (N = 23) [1] Viral loads highest during first wk following symptom onset [1] Pneumonia may develop late and when URT PCR is negative [2] *Intubated patients. Slide credit: clinicaloptions.com Mean Viral Load, log 10 copies/mL (SD) Days After Symptom Onset Temporal Viral Load in Patients With COVID-19 [1] 10 8 6 4 2 10 20 30 Saliva Endotracheal aspirate* Day Saliva Endotracheal 1 1 1 2 3 3 3 4 5 5 5 6 5 7 4 8 7 1 9 10 10 5 1 11 8 2 12 7 2 13 7 2 14 6 2 15 7 2 16 8 2 17 5 2 18 6 2 19 5 2 20 6 2 21 6 1 22 5 1 23 6 1 24 4 1 25 3 1 26 3 27 2 28 2 29 1 1. To. Lancet Infect Dis. 2020 ;20:565 . 2. Ai. Radiology. 2020;296:E32.

46. P = .02 P < .001 P < .001 P < .001 Figure 3. A, Viral load of different tissue samples. B, Analysis of viral load in different clinical stages of ... Viral load assessed via digital droplet PCR of samples collected from patients in Beijing with laboratory confirmed COVID-19 (N = 76) Viral Load Varies by Sample Type and Disease Stage *Early stage: multifocal bilateral or isolated round ground-glass opacity with or without patchy consolidations and prominent peripherally subpleural distribution on chest CT. Progressive stage: Increasing number, range, or density of lung lesions on chest CT. † Recovery phase: lesions gradually absorbed. ‡ Clinical cure: temperature recovery for > 3 days, improvement in respiratory symptoms, absorption of lung lesions, and 2 consecutive negative RT-PCR results from respiratory samples tested at least 1 day apart. Early and progressive stages* (n = 15) Recovery stage † (n = 49) Clinical cure ‡ (n = 5) Slide credit: clinicaloptions.com Mean Viral Load (copies/test) Mean Viral Load (copies/test) Type of Specimens 10 6 Nasal swabs Throat swabs Sputum Blood Urine 10 4 10 2 10 P < .001 Clinical Disease Stage 10 6 10 4 10 2 10 P < .001 Sputum Viral Load By Disease Stage Viral Load By Sample Type Yu. Clin Infect Dis. 2020;[Epub].

47. Estimated Sensitivity and Specificity Based on Clinical Sample Collection IDSA. COVID-19 Guideline, Part 3: Diagnostics. Version 1.0.1. Slide credit: clinicaloptions.com Test, % (95% CI) Sensitivity Specificity Sample location (3 studies) Upper respiratory tract Lower respiratory tract 76 (51-100) 89 (84-94) 100 (99-100) 100 (99-100) Upper respiratory tract samples (11 studies)* Oral Nasal Nasopharyngeal Nasal (vs nasopharyngeal) Saliva Mid-turbinate 56 (35-77) 76 (59-94) 97 (92-100) 95 (87-100) 85 (69-94) 100 (93-100) 99 (99-100) 100 (99-100) 100 (99-100) 100 (99-100) 100 (99-100) 100 (99-100) Repeat testing via nasopharyngeal swab (3 studies) Single test Repeat test 71 (65-77) 88 (80-96) 100 (99-100) 100 (99-100) *Not head-to-head comparisons. Not all specimens were collected from the same patients at the same time point, the time of collection from symptom onset was not provided in all studies, and the studies used various approaches for establishing SARS-CoV-2 positivity to define positive results.

48. SARS-CoV-2 in Stool Reports of negative pharyngeal and sputum viral tests but fecal samples testing positive for SARS-CoV-2 [1] Similar viral load but significantly longer duration of viral detection in stool vs respiratory samples [2] 1. Chen. Am J Gastroenterol. 2020;115:790. 2. Zheng. BMJ. 2020;369:m1443. Slide credit: clinicaloptions.com 10 8 6 4 2 Respiratory Stool Serum Viral Load (log 10 copies/mL) P = .04 P < .001 P < .001 40 50 30 20 10 Respiratory Stool Serum Days After Symptom Onset P = .02 P < .001 P = .07 60

49. Chest CT Abnormalities Most common hallmark features on chest CT images include bilateral peripheral ground-glass opacities and consolidations of the lungs with peak lung involvement between 6 days and 11 days post-symptom onset [1-3] In a study in Wuhan, China, chest CT imaging demonstrated a sensitivity of 97% and specificity of 25% with RT-PCR as the reference (N = 1014) [4] 60% to 93% of patients had initial positive lung CT consistent with COVID-19 before the initial positive RT-PCR result 1. Bernheim. Radiology. 2020;295:685. 2. Pan. Radiology. 2020;295:715. 3. Wang. Radiology. 2020;296:E55. 4. Ai. Radiology. 2020;296:E32. Slide credit: clinicaloptions.com 29-Yr-Old Man Presenting With Fever for 6 Days [4] Ground-glass opacities Day 6 Day 9 Day 11 Day 17 Day 23

50. CT- Appearances Ground glass Haziness Crazy-pavement appearance Sub- pleural bands Architectural distortion

51. CT- Appearances Vascular dilatation Traction Broncheictasis

52. Severity score on HRCT Another method is by scoring the percentages of each of the five lobes that is involved: < 5% involvement 5%-25% involvement 26%-49% involvement 50%-75% involvement  > 75% involvement.  The total CT score is the sum of the individual lobar scores and can range from 0 (no involvement) to 25 (maximum involvement), when all the five lobes show more than 75% involvement. Some say that the percentage of lung involvement can be calculated by multiplying the total score times 4. This however is not true. Suppose that all lobes have a 10% involvement, then this would lead to an overall score of 10, which could lead to the impression that 40% of the lungs are involved.

53. CT- Appearances Initial CT patterns in Covid - 19 Ground glass opacification 88% Bilateral involvement 88% Posterior distribution 80% Multilobar involvement 79% Peripheral Distribution 76% Consolidation 32%

54. CT- Appearances EARLY PHASE LATE PHASE

55. SARS-CoV-2 Serology for Diagnosis: Current Recommendations CDC: Given that it can take 1-3 wks to develop antibodies following infection, antibody test results should not be used to diagnose someone with an active SARS-CoV-2 infection [1,2] Royal College of Pathologists of Australasia [3] : “Molecular testing on a single throat with deep nasal swab is the current test of choice for the diagnosis of acute COVID-19 infection” “COVID-19 IgG/IgM rapid tests have no role to play in the acute diagnosis of COVID-19 virus infection . . . ” “COVID-19 IgG/IgM rapid tests will miss patients in early stages of disease when they are infectious to other people” WHO: “At present, based on current evidence, WHO recommends the use of these new point-of-care immunodiagnostic tests only in research settings” [4] Slide credit: clinicaloptions.com 1. https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antibody-tests-professional.html. 2. https://www.cdc.gov/coronavirus/2019-ncov/testing/serology-overview.html. 3. https://www.rcpa.edu.au/getattachment/bf9c7996-6467-44e6-81f2-e2e0cd71a4c7/COVID19-IgG-IgM-RAPID-POCT-TESTS.aspx. 4. https://www.who.int/news-room/commentaries/detail/advice-on-the-use-of-point-of-care-immunodiagnostic-tests-for-covid-19.

56. Burden of Thrombosis in Patients With COVID-19 Study Country Design Population N Thromboprophylaxis Screening VTE Rate, % China [1] Retrospective ICU 81 No No 25.0 France [2] Prospective ICU 150 Yes No 11.7* France [3] Retrospective ICU 26 Yes Yes 69.0 France [4] Retrospective ICU 107 Yes No 20.6 † The Netherlands [5] Retrospective ICU 184 Yes No 27.0 Italy [6] Retrospective Inpatient 388 Yes No 21.0 United Kingdom [7] Retrospective ICU 63 Yes No 27.0 *Pulmonary embolisms in COVID-19 ARDS vs 2.1% in matched non-COVID-19 ARDS. † Pulmonary embolism vs 6.1% in non–COVID-19 ICU patients. 1. Cui. J Throm Maemost. 2020;[Epub]. 2. Helms. Intesive Care Med. 2020;46:1089. 3. Llitjos. J Thromb Haemost. 2020;18:1743. 4. Poissy. Circulation. 2020;142:184. 5. Klok. Throm Res. 2020;191:145. 6. Lodigiani. Thromb Res. 2020;191:9. 7. Thomas. Thromb Res. 2020;191:76. Slide credit: clinicaloptions.com New

57. Autopsy Evidence of Lung Damage in COVID-19 Prospective study to compare clinical findings with data from autopsy (N = 12) [1] 7/12 patients had unsuspected bilateral DVT 4/7 died from PE Alveolar D amage [2] Organizing M icrothrombus [2] 1. Wichmann. Ann Int Med. 2020;[Epub]. 2. Carsana. Lancet Infect Dis. 2020. doi.org/10.1016/S1473-3099(20)30434-5. Slide credit: clinicaloptions.com New

58. Laboratory Predictors of Thrombosis in COVID-19 Slide credit: clinicaloptions.com Al-Samkari. Blood 2020;136:489. Median Value No Thrombotic or Bleeding Complication (n = 347) Thrombotic Complication (n = 38) P Value D-dimer, ng/mL Initial Minimum Peak 891 760 1377 1538 1336 4001 .0002 .0006 < .0001 Fibrinogen, mg/dL Initial Minimum Peak 579 549 662 696 669 828 .0045 .0028 .0001 CRP , mg/L Initial Minimum Peak 63.3 35.4 130.3 124.7 94.2 277.7 .0011 < .0001 < .0001 Median Value No Thrombotic or Bleeding Complication (n = 347) Thrombotic Complication (n = 38) P Value ESR, mm/hr Initial Minimum Peak 38 36 56 47 43 91 .020 .079 .0077 Ferritin, m g/L Initial Minimum Peak 504 453 707 825 750 1182 .015 .0056 .0020 New

59. Clinical Course of COVID-19 in Pregnancy Overall spectrum of COVID-19 symptoms similar in pregnant and nonpregnant women Early data from systematic review of studies to April 29, 2020, suggested pregnant women had similar COVID-19 course as nonpregnant adults [1] However, several recent studies demonstrated increased rate of hospitalizations, ICU care, and mechanical ventilation, but not death, in pregnant women vs age-matched nonpregnant controls [2-4] Slide credit: clinicaloptions.com 1. Huntley. Obstet Gynecol. 2020;136:303. 2. Ellington. MMWR. 2020;69:769. 3. Badr. Am J Obstet Gynecol . 2020;[Epub]. 4. Blitz. Am J Obstet Gynecol . 2020;[Epub]. Clinical Outcome, % (95% CI) Total (N = 538*) Severe disease 15.3 (11.1-20.8) Critical disease 1.4 (0.5-4.1) ICU admission 3.0 (1.6-5.9) *China, n = 420; US, n = 76; Europe, n = 42.

60. COVID-19 Among Pregnant vs Nonpregnant Women Ellington. MMWR. 2020;69:769. Outcome, n (%) Pregnant (n = 8207) Nonpregnant (n = 83,205) Crude Risk Ratio (95% CI) Adjusted Risk Ratio* (95% CI) Hospitalization † 2587 (31.5) 4840 (5.8) 5.4 (5.2-5.7) 5.4 (5.1-5.6) ICU admission ‡ 120 (1.5) 757 (0.9) 1.6 (1.3-1.9) 1.5 (1.2-1.8) Mechanical ventilation § 42 (0.5) 225 (0.3) 1.9 (1.4-2.6) 1.7 (1.2-2.4) Death ǁ 16 (0.2) 208 (0.2) 0.8 (0.5-1.3) 0.9 (0.5-1.5) * Adjusted for age as continuous variable, yes/no for presence of underlying conditions, categorical race/ethnicity variable; nonpregnant women are the reference group. † Missing information for 1539 (18%) pregnant women and 9744 (12%) nonpregnant women, who were assumed to have not been hospitalized. ‡ Missing information for 6079 (74%) pregnant women and 58,888 (71%) nonpregnant women, who were assumed to have not been admitted to ICU. § Missing information for 6351 (77%) pregnant women and 63,893 (77%) nonpregnant women, who were assumed to have not required mechanical ventilation. ǁ Missing information for 3819 (47%) pregnant women and 17,420 (21%) nonpregnant women, who were assumed to have survived. Increased rates of hospitalization, ICU care, and mechanical ventilation, but no increase in symptomatic disease or mortality I ndication for hospitalization not recorded (may have tested positive during hospitalization for labor and delivery) Slide credit: clinicaloptions.com New

61. ICU Admissions Among COVID-19–Positive Pregnant vs Nonpregnant Women: France, Belgium Multicenter case-control study of clinical outcomes among pregnant and nonpregnant women of reproductive age with positive SARS-CoV-2 RT-PCR test between January 1, 2020, and May 13, 2020, at 4 large university hospitals in France and Belgium (N = 200) No difference in BMI or comorbidities Clinical Outcomes, % Pregnant (n = 83) Nonpregnant (n = 107) Adjusted P Value ICU admission 11.08 2.38 .024 Hospital admission for COVID-19 58.21 17.4 < .001 Oxygen therapy 36.04 17.24 .006 Endotracheal intubation 10.16 1.67 .022 Slide credit: clinicaloptions.com Badr. Am J Obstet Gynecol . 2020;[Epub]. Ne

62. Immune Response to SARS-CoV-2 Slide credit: clinicaloptions.com 1. Wang. 2020; J Leukoc Biol. 2020;[Epub]. 2. Sokolowska. EAACI. 2020[Epub]. Adequate immune responses [2] Timely innate/adaptive responses Quick type 1 IFN response Activation of efficient antiviral response (clearance by macrophages) Activation of Th1 cells and B-cells for production of neutralizing antibodies Inadequate immune responses [2] Delayed/limited type 1 IFN Endothelial cell death Epithelial/endothelial leakage Overactivation/exhaustion T-cells and NK cells Accumulation of activated macrophages  cytokine storm Mild Severe Normal immune response Recovery Isolation/hospitalization Supportive care Death Anti-viral and anti–cytokine storm treatment Lung injury/septic shock/organ failure/ coagulopathy Low virus titer SARS-CoV-2 Monocyte Macrophage High virus titer Activation Low High ICU Cytokines: IL-6/IL-10/TNF/ CSF/RANTES… CD4 CD8 T-cell Neutrophil Cytokine storm Immune Responses Leading to Recovery or Death [1]

63. Immune-Related Risk Factors for Susceptibility to Severe COVID-19 Older persons have impaired B-cell and T-cell immune responses vs younger persons (eg, blunted antibody response to vaccination, excess risk of sepsis) [1-3] Impaired B-cell response: reduced ability to mount a neutralizing antibody response [4] Impaired T-cell response: role of T-cell response in control of ongoing SARS-CoV-2 uncertain [5-6] Likely contributing to control but not preventive/eradicative Younger persons with impaired or dysregulated B- and T-cell immune responses may also be at risk Slide credit: clinicaloptions.com 1. Mueller. Aging (Albany NY). 2020;12:9959. 2. Goodwin. Vaccine. 2006;24:1159. 3. Opal. Clin Infect Dis. 2005;41:S504. 4. Vabret. Immunity. 2020;52:910. 5. Diao. Front Immunol. 2020;[Epub]. 6. Oja. medRxiv. 2020;[Preprint]. Note: This study has not been peer reviewed.

64. CDC: COVID-19 and Immunocompromised Patients Many conditions can cause a person to be immunocompromised or have a weaker immune system Solid organ transplantation, blood/bone marrow transplantation, immune deficiencies, HIV with a low CD4 cell count or not on treatment, prolonged use of corticosteroids, or use of other immune modulatory medicines Having a weakened immune system may increase the risk of severe illness from COVID-19 Excess risk of severe COVID-19 in persons with well-treated HIV minimal Slide credit: clinicaloptions.com CDC. Updated June 25, 2020. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fneed-extra-precautions%2Fgroups-at-higher-risk.html#immunocompromised-state

65. NIH: Special Considerations for COVID-19 in Children Data on disease severity and pathogenesis of SARS-CoV-2 infection in children are limited Several large epidemiologic studies suggest that acute disease manifests as less severe in children vs adults CDC data demonstrate lower hospitalization rates in children vs adults Severe cases associated with younger age and underlying conditions Reports of children with COVID-19 requiring ICU care Multisystem inflammatory syndrome reported in children (MIS-C) NIH COVID-19 Treatment Guidelines. Last updated June 11, 2020. www.covid19treatmentguidelines.nih.gov. Slide credit: clinicaloptions.com *Severe defined as SpO 2 ≤ 94% on ambient air at sea level, requiring supplemental oxygen, mechanical ventilation, or ECMO. “Based on preliminary clinical trial data, the investigational antiviral agent remdesivir is recommended for the treatment of COVID-19 in hospitalized patients with severe* disease (see Remdesivir for detailed information). Of note, remdesivir has not been evaluated in clinical trials that include children with COVID-19. Remdesivir is available for children through an FDA Emergency Use Authorization or through a compassionate use program.” “For other agents outlined in these guidelines, there are insufficient data to recommend for or against the use of specific antivirals or immunomodulatory agents for the treatment of COVID-19 in pediatric patients.” New

66. COVID-19–Associated Hospitalization and Death Rates Increase With Age in US 1. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covid-net/purpose-methods.html. 2. https://www.cdc.gov/covid-data-tracker/index.html#demographics. Slide credit: clinicaloptions.com *Lab-confirmed COVID-19 cases; covers ~ 10% of US population: 99 counties in 14 states (CA, CO, CT, GA, IA, MD, MI, MN, NM, NY, OH, OR, TN, UT). † Data from 109,622 deaths in confirmed and probable COVID-19 cases as reported by US states and territories; age group data available for 109,602 deaths (99%). COVID-19–Associated Hospitalizations* [1] COVID-19–Associated Deaths †[2] % of Total Deaths Age Group (Yrs) Rates per 100,000 Population Wk 400 350 300 250 200 150 100 50 March 7 March 14 March 21 March 28 April 4 April 11 April 18 April 25 May 2 May 9 May 16 May 23 May 30 June 6 June 13 June 20 June 27 July 4 July 11 0-4 yrs 5-17 yrs 18-49 yrs 50-64 yrs 65+ yrs 100 10 20 30 40 50 60 70 80 90 0-4: < 0.1% 5-17: < 0.1% 18-29: 0.5% 30-39: 1.3% 40-49: 3.1% 50-64: 15.4% 65-74: 20.9% 75-84: 26.4% 85+: 32.4% New

67. No alternative plausible diagnoses CDC Case Definition: Multisystem Inflammatory Syndrome in Children Individual < 21 yrs of age presenting with fever,* laboratory evidence of inflammation, † and evidence of clinically severe illness requiring hospitalization with involvement of ≥ 2 organ systems (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic) And: Positive current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test Exposure to a suspected or confirmed COVID-19 case within 4 wks prior to symptom onset Slide credit: clinicaloptions.com And 1 of the following: *Fever ≥ 38°C for ≥ 24 hrs or report of fever lasting ≥ 24 hrs. † Including, but not limited to, elevated CRP, ESR, fibrinogen, procalcitonin, D-dimer, ferritin, LDH, or IL-6; elevated neutrophils; reduced lymphocytes; and low albumin. CDC. Multisystem Inflammatory Syndrome in Children (MIS-C). Last reviewed May 29, 2020. https://www.cdc.gov/mis-c/hcp/ New

68. CDC: Evaluation and Management of Multisystem Inflammatory Syndrome in Children Clinical presentation varies but may include persistent fever, fatigue, and a variety of signs and symptoms including multiorgan involvement and elevated inflammatory markers CDC. Multisystem Inflammatory Syndrome in Children (MIS-C). Last reviewed May 29, 2020. https://www.cdc.gov/mis-c/hcp/ Slide credit: clinicaloptions.com Laboratory Testing/Evaluations Inflammation testing: CRP, ESR, fibrinogen, procalcitonin, D-dimer, ferritin, LDH, IL-6, neutrophils, lymphocytes, albumin SARS-CoV-2 detection by RT-PCR or antigen test SARS-CoV-2 serology testing is suggested, even in the presence of a positive RT-PCR or antigen test; any serology test should be done prior to administering IVIG or exogenous antibody treatments Echocardiogram and electrocardiogram Cardiac enzyme or troponin testing B-type natriuretic peptide Management* Supportive measures: fluid resuscitation, inotropic support, respiratory support, and ECMO if needed IVIG and steroids Aspirin Antibiotics *There are no published guidelines or CDC recommendations regarding treatment and no studies comparing efficacy of treatment options. Above is a compilation from the CDC of treatments used by multiple institutions. New

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