Brigham and Women's Hospitals

Clinical Course and Epidemiology

Updated: July 11, 2020

Clinical Course

Clinical presentation

  1. Symptoms:
  1. Presentation can be extremely varied; most common is a non-specific flu-like illness. The majority of patients present with more than one sign/symptom on admission, although the combination of fever, cough and shortness of breath may be rare. (Arentz et al, JAMA, 2020; Chen et al, Lancet, 2020; Guan et al, N Engl J Med, 2020; Li et al, N Engl J Med, 2020; Wu et al, JAMA Internal Medicine 2020; Zhou et al, Lancet, 2020; WHO-China Joint Mission on COVID-19; Young et al, JAMA, 2020, Yan et al, Int Forum Allergy Rhinol 2020)
  1. Fever, 44-94% (varied temperature cutoffs in literature, no consensus)
  1. We recommend using >= 38°C, based on Washington State data (Arentz et al, JAMA, 2020).
  2. Take into account the patient’s age, immune status, medication regimen (steroids, chemotherapy, etc.), and recent use or administration of antipyretics.
  1. Cough, 68-83%
  2. Anosmia and/or ageusia ~70%
  3. Upper respiratory symptoms (sore throat, rhinorrhea, nasal or sinus congestion), 5-61%
  4. Shortness of breath, 11-40%
  5. Fatigue, 23-38%
  6. Muscle aches, 11-15%
  7. Headache 8-14%
  8. Confusion 9%
  9. GI symptoms (nausea, vomiting, diarrhea), 3-17%
  1. Children are less likely to have fever or cough (Bialek et al, MMWR 2020)
  2. ~20% of confirmed cases may be asymptomatic (Bi et al, Lancet Infect Dis, 2020; Mizumuto et al, Eurosurveillance 2020)
  1. Laboratory abnormalities:
  1. Can be present on patient admission; frequencies are not well established. Patients presenting with severe disease have been noted to have more significant laboratory aberrations. (Arentz et al, JAMA, 2020; Chen et al, Lancet, 2020; Du et al, Am J Respir Crit Care Med, 2020; Guan et al, N Engl J Med, 2020; Young et al, JAMA, 2020; Zhang et al, Lancet Gastroenterol Hepatol, 2020; Zhou et al, Lancet, 2020)
  1. Lymphopenia
  2. Mild hepatocellular injury pattern (AST / ALT ~200s)
  1. GGT often elevated, AlkPhos elevations rare (Zhang et al, Lancet Gastroenterol Hepatol, 2020).
  1. Anemia
  2. Elevated D-dimer (in absence of known culprit thrombus/embolus)
  3. Elevated CK
  4. Elevated LDH
  5. Low/normal procalcitonin, elevated in severe disease and/or superimposed bacterial infection
  6. Elevated inflammatory markers: LDH, CRP, ESR, ferritin, IL-6
  1. Many of these lab findings are associated with more severe disease or death; see “Prognosis subsection of this chapter.
  1. Imaging findings:
  1. Abnormal diagnostic imaging findings are common. See Radiology”.
  1. Coinfection:
  1. Respiratory viral co-infection is more common than previously appreciated, ~20% in Northern California (Kim et al, JAMA 2020; as well as unpublished reports from Qingdao, China).
  1. This will necessarily vary with local epidemiology and season
  1. Rates of bacterial coinfection appear to be low (Zhou et al, Lancet, 2020; Young et al, JAMA, 2020).

Disease course and progression

  1. Duration of symptoms (Zhou et al, Lancet, 2020; Young et al, JAMA, 2020):
  1. Fever, median 4-12 days in survivors
  2. Dyspnea, median 13 days
  3. Cough, median 19 days in survivors. Still present in 45% of survivors on discharge and 72% of non-survivors on death
  1. Timing of complications from illness onset (Zhou et al, Lancet, 2020, Feldstein et al, NEJM, 2020):
  1. Sepsis, median 9 days (range 7-13 days)
  2. ARDS, median 12 days (range 8-15 days)
  1. Anecdotally, respiratory status can decompensate very rapidly
  2. Duration between symptom onset and ventilation ranges from 3-12.5 days, median 10 days
  1. Acute cardiac injury, median 15 days (range 10-17 days)
  2. AKI, median 15 days (range 13-19.5 days)
  3. Secondary infection, median 17 days (range 13-19 days)
  1. Time from initiation of invasive ventilation to VAP occurrence, median 8 days (interquartile range 2-9 days)
  1. Multi-System Inflammatory Syndrome in Children (MIS-C), median 6 days from fever onset (range 4-8) - for MIS-C details, see Rheumatology
  1. Severity of disease (Wu, JAMA, 2020; Bi et al, Lancet Infect Dis, 2020):
  1. 81-91% have mild to moderate symptoms (mild symptoms to mild pneumonia)
  2. 9-14% have severe symptoms (hypoxemia or >50% lung involvement)
  3. ~5% have critical symptoms (respiratory failure, shock, multiorgan dysfunction)

ICU admission and critical illness

  1. Onset:
  1. Median time from symptom onset to ICU transfer, 12 days (Zhou et al, Lancet, 2020).
  1. Indication for ICU admission (Arentz et al, JAMA, 2020):
  1. Hypoxemic respiratory failure is the most common indication for ICU.
  1. Of all hospitalized patients, supplemental O2 initiated in ~41%, mechanical ventilation in ~6% (Guan et al, N Engl J Med, 2020).
  2. Of critically-ill patients, mechanical ventilation is initiated in 71%.
  1. 100% of ventilated patients had or developed ARDS at some point during their course.
  2. 53% of vented, critically-ill patients developed ARDS within 72 hours of initiation of mechanical ventilation.
  3. Extended use of invasive ventilation is common, with median time to extubation ranging 11-17 days (Chen et al, Lancet, 2020; Ling et al, Crit Care Resusc, 2020).
  1. Presentation with shock is rare.
  1. Vasopressors are eventually used in 67% of critically-ill patients
  1. Cardiomyopathy noted in 33% of critically-ill patients (Ruan et al, Intensive Care Med, 2020
  1. Some progress to cardiogenic shock late in course (anecdotal reports)

Death or hospital discharge

  1. Cause of death (Ruan et al, Intensive Care Med, 2020):
  1. Respiratory failure alone, 53%
  2. Circulatory failure alone (in the setting of myocardial damage), 7%
  3. Mixed respiratory and circulatory failure, 33%
  4. Unknown cause, 7%
  1. Time from illness onset to death:
  1. Median 18.5 days (interquartile range 15-22 days) (Zhou et al, Lancet, 2020), though illness severity has been noted to have two peaks at ~14 days and ~22 days (Ruan et al, Intensive Care Med, 2020).
  1. Time of illness onset to discharge:
  1. Median 21-22 days (Bi et al, Lancet Infect Dis, 2020; Zhou et al, Lancet, 2020)
  1. Duration of hospitalization:
  1. Median 12 days (Guan et al, N Engl J Med, 2020)

Prognosis

Indicators

  1. Exact hazard / odds ratios vary substantially between studies, and a wide range of demographic, clinical, laboratory, and radiographic findings have been associated with hospital outcomes and disease severity progression. See Table 1 for a more in-depth review. Some highlights / points of emphasis include:
  2. Age: increased age correlates with more severe disease and increased mortality (Wu et al, JAMA Internal Medicine 2020; Chen et al, Lancet, 2020; Yang et al, Lancet Respir Med, 2020; Qin et al, Clinical Infectious Disease 2020).
  1. Children are less likely to have severe disease, but pediatric deaths have been reported (Bialek et al, MMWR 2020)
  1. Comorbidities: Common in patients with COVID-19, more prevalent in those with severe disease and often associated with worse outcomes (Fang et al, Lancet Respir Med, 2020; Guan et al, N Engl J Med, 2020; Yang et al, Lancet Respir Med, 2020; Zhang et al, Allergy, 2020; Chen et al, Lancet, 2020; Tang et al, J Thromb Haemost, 2020; Zhou et al, Lancet, 2020; WHO-China Joint Mission on COVID-19; Yu et al, JAMA Oncology 2020).
  1. Hypertension *
  2. Diabetes *
  3. Coronary Artery Disease *
  4. Chronic Lung Disease *
  5. Malignancy *
  6. * denotes association with worse outcome in the above literature (i.e. increased odds of more severe disease or in-hospital death)
  1. Laboratory Abnormalities: Common in patients with COVID-19 (see Clinical Course) (Zhou et al, Lancet 2020; Huang et al, Lancet 2020; Chen et al, Lancet 2020; Wu et al, JAMA Internal Medicine 2020; Ruan et al, Intensive Care Med, 2020). Overall highlights of lab abnormalities associated with severe disease (ARDS / ICU admission) or death include:
  1. WBC > 10 K/uL
  2. Lymphopenia < 1.00 K/uL
  3. Platelets < 150 K/uL
  4. Creatinine > 1.5 mg/dL
  5. Albumin < 3 g/dL
  6. ALT > 40 U/L
  7. CK > 185 U/L
  8. hs-TnT > ~20 ng/L
  9. CRP > 125 mg/L
  10. LDH > 245 U/L
  11. Ferritin > 300 ug/L (severe disease); Ferritin > 1000 ug/L (death)
  12. IL-6 > 10 pg/mL
  13. D-Dimer > 1000 ng/mL
  14. Procalcitonin > 0.5 ng/mL
  1. Race: Please see Health Equity for a discussion on racial differences in COVID infection and severity

Epidemiology

Background and geographic distribution

  1. Initially recognized in December 2019 by Chinese authorities in the setting of cases of pneumonia that seemed to be clustered around a seafood market in Wuhan, Hubei Province (Wuhan Municipal Health Commission, 2019).
  2. Bronchoalveolar lavage samples collected from affected patients in late December 2019 yielded evidence of a novel betacoronavirus, genetically-distinct from previously identified SARS-CoV and MERS-CoV but genetically-similar to previously-published coronavirus strains collected from bats from southwestern China (Zhu et al, N Engl J Med, 2020), yielding hypotheses of potential zoonotic origin.
  3. The first confirmed case in the United States was documented on January 20, 2020, in Snohomish County, Washington, in a traveler who had returned from Wuhan, China, five days prior (Holshue et al, N Engl J Med, 2020).
  4. The virus has spread broadly. Worldwide case counts are published by teams at the World Health Organization, Johns Hopkins University, and others.
  5. Viral genomes have been published to GenBank from diverse geographies. Reports on real-time phylogenetic tracking of the viral genome can be found at NextStrain (Hadfield et al, Bioinformatics, 2018).
  6. The virus has differentially affected minority groups and vulnerable populations. Please see Health Equity and Ethicsfor more details

Basic epidemiology rates

  1. Population prevalence:
  1. Prevalence estimates are rapidly expanding as both viral infection and testing availability spread.
  2. Universal nasopharyngeal swab testing identified a carriage rate of 13.7% in asymptomatic pregnant patients admitted for delivery (Sutton et al, New Engl J Med, 2020).
  3. Children appear to be as likely to contract the infection as adults, although symptomatic cases of children are more rare (Bi et al, Lancet Infect Dis, 2020)
  4. Serology testing helps to determine the (sero)prevalence, with ongoing research on how long those antibodies are detectable after infection. Early reports (preprint) on Santa Clara, CA have prevalence that ranged from 2.5-4% (Bendavid et al., bioRxiv, 2020 preprint).
  1. Basic reproduction number (R0):
  1. R0 is a measure of transmissibility, denoting the theoretical expected number of secondary cases from any given case during an epidemic period of transmission. An R0 > 1 is consistent with sustained outbreak.
  2. State-by-state estimates of R0 are available at this site (not affiliated with BWH). Please keep in mind these are merely estimates and all models are fallible.
  3. Considering the period of epidemic transmission, R0 estimated at ~2-5, with min/max mean/median values ranging from 1.4-5.7; as expected, R0 has declined since outbreak in China and regions of Europe with control measures (Zhao et al, Int J Infect Dis, 2020; Riou and Althaus, Euro Surveill, 2020; Flaxman et al, Imperial College London, 2020 preprint; Read et al, medRxiv, 2020 preprint; Shen et al, medRxiv, 2020 preprint).
  4. When feasible, contact tracing identifies cases earlier and, when combined with effective isolation of those cases, can decrease the R0 (Bi et al, Lancet Infect Dis, 2020).
  5. These estimates are comparable to those estimated for epidemic transmission during the 2002-2003 SARS outbreak; secondary cases per index declined with case isolation and contact quarantining (Lipsitch et al, Science, 2003; Bauch et al, Epidemiology, 2005; Wallinga and Teunis, Am J Epidemiol, 2004).
  1. Super-spreading:
  1. Refers to events in which individuals directly spread an infection to a large number of (> 10) others, was noted in the 2002-2003 SARS outbreak (Lipsitch et al, Science, 2003).
  2. It is thought that there may be a similar role in the spread of COVID-19 given population dynamics (Li et al, N Engl J Med, 2020).
  1. A COVID-19 super-spread event is believed to have occured at a church in Daegu, South Korea, where “Patient 31” infected at least 40 others (Ryall J, The Telegraph, 2020).
  1. Case fatality rate:
  1. This is the percentage of people diagnosed with the disease who will die from it in a specified period of time
  1. CFR is subject to significant lag time bias and may be artificially low early on in disease (onset of illness to death is around 18d as described above)
  2. CFR is a function both of virulence of disease, but also demographics and the availability and quality of healthcare services
  3. CFR depends also on case definitions, infection fatality rate (IFR) may be much lower than CFR, especially given that there appears to be a significant number of asymptomatic infections
  1. Case fatality rate is variable in different countries. Johns Hopkins keeps this updated resource on mortality analysis around the globe. As of May 19, 2020 the CFR in the USA is thought to be about 6%. Range around the world seems to be between 0-16%, with most countries in the 2-6% range. CFR is approximately 2.3% in Italy (Porcheddu et al, J Infect Dev Ctries, 2020) and China (Feng et al, China CDC Weekly, 2020), though estimates range from 1-4% depending on data used (Guan et al, N Engl J Med, 2020; Wang et al, JAMA, 2020), with initial estimates as high as 15% (Huang et al, Lancet, 2020).
  1. Conservative estimates may still be an overestimate according to some (Guan et al, N Engl J Med, 2020; Klompas M, Ann Intern Med, 2020).

Transmission

  1. Transmission of SARS-CoV-2 is incompletely understood, and new data continue to emerge. Many of the studies cited below are based on limited data, and epidemiologic metrics can be highly-specific to the situation measured / may not be applicable uniformly to all populations and circumstances.
  2. Route of transmission:
  1. Transmitted human-to-human (Li et al, N Engl J Med, 2020), following a suspected zoonotic-to-human initiating event.
  2. Most often transmitted by large droplets and fomites; transmission by aerosolized particles is possible (especially in patients who are coughing, sneezing, or undergoing an aerosol generating procedures) (WHO-China Joint Mission on COVID-19).
  1. Viral particles shown to survive < 24h on cardboard, < 72h on plastic or steel; aerosolized (droplet nuclei, < 5 µm) particles appear to last at least 3h (van Dorelmalen et al, New Engl J Med, 2020).
  1. Household contacts and those travelling closely with an index case appear more likely to contract the virus than other contacts (Bi et al, Lancet Infect Dis, 2020)
  2. In addition to nasopharyngeal / oropharyngeal samples and sputum, viral RNA has been detected in stool and whole blood (Wölfel et al, Nature, 2020; Young et al, JAMA, 2020); however, significance for transmission is unclear (Chen et al, Emerg Infect Dis, 2020). Independent viral replication in the GI tract as judged by diversion of stool viral RNA load from sputum viral RNA load seems rare (Wölfel et al, Nature, 2020). Viral RNA does not seem to be found in urine (Wölfel et al, Nature, 2020).
  1. Viral shedding and symptoms:
  1. Symptomatic as well as pre-symptomatic and asymptomatic transmission Case reports support the likelihood of both presymptomatic and asymptomatic transmission (summarized in Furukawa et al, Emerg Inf Dis 2020) are possible (Bai et al, JAMA, 2020; Rothe et al, N Engl J Med, 2020; Furukawa et al, Emerg Inf Dis 2020), though symptom presence is likely associated with increased frequency of transmission.
  2. Viral replication seems to occur independently in both the throat and lower respiratory tract, with upper airway replication declining after the first 5 days post-onset of symptoms (Wölfel et al, Nature, 2020), as below.Detection rates and viral loads by nasopharyngeal and oropharyngeal swab methods for throat testing similar. Independent viral genotypes detected simultaneously in sputum and throat swab.
  3. Duration of viral shedding from illness onset is a median 20 days (interquartile range 17-24 days) (Wölfel et al, Nature, 2020; Young et al, JAMA, 2020; Zhou et al, Lancet, 2020).
  1. Nasopharyngeal viral load peaks within ~5 days of symptom onset followed by decline (Wölfel et al, Nature, 2020; Young et al, JAMA, 2020).In Wölfel’s study of patients admitted with COVID-19, last positive throat swab was found at day 28 post-symptom onset.
  2. Sputum viral RNA concentration peak noted in the first week of symptoms with more gradual decline, remaining RNA-positive in some patients for over three weeks (Wölfel et al, Nature, 2020).
  1. Virus may be detectable in sputum after symptomatic recovery (Rothe et al, N Engl J Med, 2020) or without detectable virus in serum (Holshue et al, N Engl J Med, 2020).
  1. Viral shedding duration is longer in more severe disease.
  1. Incubation period:
  1. Mean and median of ~5 days (common range 2-7 days) (Li et al, N Engl J Med, 2020; Guan et al, N Engl J Med, 2020; Velavan and Meyer, Trop Med Int Health, 2020; Chan et al, Lancet, 2020; Lauer et al, Ann Int Med 2020).
  2. Though some reports document incubation periods of up to 24 days, an analysis based on early case reports estimated that 97.5% of exposed cases will develop symptoms within 11 days and 99% within 14 days (Lauer et al, Ann Int Med 2020).
  1. Use of Masks
  1. Social distancing and universal mask / face coverings are a low-risk intervention that have shown to reduce transmission. Most data exists for the medical setting, but the CDC recommends cloth mask use in non-medical settings as well.
  1. In one study in Beijing, face masks worn by family members of pre-symptomatic COVID patients were shown to be 79% effective (OR = 0.21) at reducing transmission, though masks were not very effective after the patient became symptomatic. This suggests that presymptomatic transmission is an important mode of transmission and that masks can be effective at preventing it. (Wang et al, BMJ Glob Health, 2020)
  1. Physical distancing
  1. The CDC recommends six feet social distancing between people to reduce the transmission of coronavirus. This recommendation is based on measurements of large exhaled droplets and care worker influenza transmission, sometimes from studies in the 1930-40s (Wells, Am Jour Epidemiology, 1934).
  1. Sneezing and coughing can create turbulent gas clouds, however, that can spread droplets well past that distance. (Bourouiba, JAMA insights, 2020)
  2. The World Health Organization, in contrast, recommends social distancing of 3 feet (as of June 19th, 2020), reflective of research on bacterial meningitis and rhinovirus spread.
  1. Frequent air turnover/ ventilation and being outdoors all are thought to be protective against transmission, however specific data is not available and there remains a lack of data on the rates of transmission during specific outdoor events.
  1. In one study of transmission in China, of over 7300 cases only one was associated with outdoor transmission (Qian, Preprint, 2020)
  1. Pets, zoonotic spread:
  1. Preprint data reports evidence of viral replication in inoculated ferrets and cats, with viral transmission between cats; dogs showed low susceptibility, and pigs, chicken, and ducks were deemed not susceptible (Chen et al, bioRxiv, 2020 preprint). Virologist cited in Nature News suggests cat owners should not yet be alarmed, noting deliberate high-dose inoculation of said cats - unrepresentative of day-to-day pet/owner interactions, and that none of the infected cats developed symptoms in the aforementioned study (Mallapaty S, Nature News, 2020).
  2. The CDC now recommends that, while transmission risk from pets is low, social distancing rules should apply to pets as well as to humans. (CDC, 4/21/20)
  1. Schools:
  1. Schools are unique, multigenerational congregated settings that likely contribute to SARS-CoV-2 transmission between households and within communities. However, sustained closure of in-person schooling is expected to adversely affect the life trajectory of children and exacerbate existing inequalities.
  2. The American Academy of Pediatrics advocates that children should be physically present in school (AAP Guidance)
  3. This thorough review of the literature on school transmission and safety summarizes some of the unique challenges and recommendations (MGH COVID Resource Library)
  4. Strategies to minimize risk with in-person schools have been developed by colleagues at the TH Chan School of Public Health at Harvard University
  5. The Massachusetts Department of Elementary and Secondary Education has released guidance on strategies for return to school

Immunity

  1. Antibody Response in COVID-19:
  1. IgM, IgG, and IgA antibodies have been identified against the spike and nucleocapsid proteins of SARS-CoV-2
  1. Seroconversion interval varies, but seems to occur between 5-14 days after the onset of symptoms (To et al, Lancet Infect Dis, 2020; Guo et al, Clin Infect Dis, 2020; Xiang et al, Clin Infect Dis, 2020; Okba et al, Emerg Infect Dis, 2020) In one study of 173 patients, 100% were seropositive (total antibody) at 15 days (Zhao et al, Clin Infect Dis, 2020)
  1. Seroconversion to IgG may occur before IgM, although IgG levels reach their peak later than IgM. (Qu et al, Clin Infect Dis, 2020) Antibodies directed against the receptor-binding domain (RBD, a component of the spike protein) may show earlier seropositivity (To et al, Lancet Infect Dis, 2020; Okba et al, Emerg Infect Dis, 2020)
  2. Critically ill patients have shown delayed, but stronger antibody responses (Qu et al, Clin Infect Dis, 2020).
  1. Seropositivity rates gradually increase in the days after symptom onset, as viral RNA detectability decreases (though persistent viral shedding is seen in many cases)
  1. In one study, in the second week of illness, positivity rate was 54.0% for PCR vs 89.6% for antibody assays (Zhao et al, Clin Infect Dis, 2020) and in another study, after day 5.5 of illness, IgM detected more cases than PCR (Guo et al, Clin Infect Dis, 2020)
  2. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. (Wölfel et al, Nature, 2020)
  1. There is the potential for cross reactivity with SARS CoV-1 and other humans coronaviruses (To et al, Lancet Infect Dis, 2020; Okba et al, Emerg Infect Dis, 2020) Antibodies directed against the RBD appear to be more specific for SARS-CoV-2 infection (To et al, Lancet Infect Dis, 2020)
  1. Durability and sustainability of antibody response:
  1. We do not currently know how long antibody response to SARS-CoV-2 endures in humans. In patients with a history of SARS-CoV-1 infection, IgG and neutralizing antibody titers tended to wane with time (Cao et al, N Engl J Med, 2007)
  1. In a cohort of 23 patients with a history of SARS-CoV-1 infection, specific IgG Ab to SARS-CoV-1 was undetectable in 91.3% of former patients after 6 years (Tang et al, J Immunol 2011)
  1. Implications for immunity:
  1. Currently, it is unclear whether the presence of antibodies directed against SARS-CoV-2 confers immunity or protection from re-infection in humans, or what antibody titers might be required to develop immunity
  1. Approximately 30% of patients with PCR-confirmed SARS-CoV-2 infection failed to generate high titers of SARS-CoV-2 specific neutralizing antibodies (Wu et al, unpublished report, 2020). Elderly patients may develop higher titers than younger patients, and titers may correlate negatively with blood lymphocyte count and positively with blood CRP levels.
  2. Rhesus macaques with SARS-CoV-2 infection did not demonstrate detectable viral loads or evidence of viral replication on re-exposure to SARS-CoV-2 (Bao et al, unpublished report, 2020)
  3. Convalescent plasma from recovered COVID-19 patients has been shown in a prepreint study to specifically-inhibit SARS-CoV-2 infection of cultured cells in vitro (Wu et al, medRxiv, 2020 preprint).

Pathology

  1. This section is in development