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Social risk factors for COVID-19 pneumonia such as race, ethnicity, income inequality, and living environment correlate with infection and severity of infection.
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Biological risk factors are numerous and highly correlate with cardiovascular disease and its risk factors.
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COVID-19 pneumonia has a broad presentation, ranging from mild illness to critical illness.
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Post-Acute Sequelae of SARS-CoV-2 has protean manifestations that can persist for months to over a year and is receiving increasing attention into its physiology and potential treatments.
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Imaging findings of pneumonia can be categorized as typical, indeterminate, and atypical and may differ according to vaccine status and viral variant.
Introduction
The global disease burden from COVID-19 infection has been unprecedented in recent history, with 619 million recorded cases and 6.55 million recorded deaths worldwide as of October 5, 2022
Tanne JH. Covid-19: US cases are greatly underestimated, seroprevalence studies suggest. BMJ. Published online July 24, 2020:m2988. doi:10.1136/bmj.m2988
Our understanding of its clinical manifestations has evolved due to increasing insight into risk factors, ability to triage, evolution of viral variants
Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study.
Changes in the manifestations of COVID-19 pneumonia have also occurred, which has relevance for clinical care in ambulatory and hospital settings. Our approach to recognizing and managing COVID-19 will require ongoing study to adjust appropriately to the shifting disease burden that the global pandemic has created.
Risk Factors
Social risk factors for infection and severe disease
Since the onset of the pandemic, racial and ethnic minorities – in particular the non-Hispanic black, Hispanic, and Native American communities -- have experienced increased rates of infection, hospitalization, and mortality from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Given that SARS-CoV-2 is spread through respiratory droplets, socioeconomic conditions have contributed to the disproportionate burden of COVID-19 in these underserved communities. Contributing factors that have been posited include a self-perpetuating system of income inequality, disproportionate burden of underlying comorbidities, population dense neighborhoods, family dense households, greater likelihood to work in public-facing occupations, less ability to stop working or to accept a furlough from work, and fewer healthcare resources in the neighborhoods of these communities.
Gross CP, Essien UR, Pasha S, Gross JR, Wang S yi, Nunez-Smith M. Racial and Ethnic Disparities in Population-Level Covid-19 Mortality. J Gen Intern Med. 2020;35(10):3097-3099. doi:10.1007/s11606-020-06081-w
Wiley, Zanthia, Ross-Driscoll, Katie, et.al. Racial and Ethnic Differences and Clinical Outcomes of COVID-19 Patients Presenting to the Emergency Department. Clin Infect Dis. 2021;ciab290.
Kanter GP, Segal AG, Groeneveld PW. Income Disparities In Access To Critical Care Services: Study examines disparities in community intensive care unit beds by US communities’ median household income. Health Aff (Millwood). 2020;39(8):1362-1367. doi:10.1377/hlthaff.2020.00581
Income inequality has been strongly associated with increased case rate and mortality. One study examined COVID-19 cases and mortality and their association with the Gini index, a measure of income inequality, from January to April 2020 in a cohort of 577,414 cases and 23,424 deaths across 50 states. Multivariate regression with adjustment for multiple confounders (e.g., older age, sex, race, healthcare resources, shelter-in-place order) revealed that a one unit increase in the Gini index (i.e., greater inequality of income) was associated with approximately a 27% increase in mortality.
Race has been shown to correlate with increased risk of infection and hospitalization in multiple studies, even after adjustment for income level and other confounders. One study examined a cohort of 20,228 patients with SARS-CoV-2 in Houston in 2020, with covariate adjustment for age, sex, race, ethnicity, household income, residence population density, Charlson Comorbidity Index, hypertension, diabetes, and obesity. Higher likelihood of infection was found in non-Hispanic black individuals compared to non-Hispanic white (odds ratio (OR) 2.23, 95% confidence interval (CI) 1.90-2.60) and in Hispanic compared to non-Hispanic (OR 1.95, 95% CI 1.72-2.20).
A retrospective cohort study of 5,698 patients from University of Michigan from March to April 2020 and with an outcome update in July 2020 assessed risk of hospitalization with statistical adjustment for multiple confounders, including a customized comorbidity score from seven known risk factors for disease severity: respiratory conditions, circulatory conditions, any cancer, type 2 diabetes, kidney disease, liver disease, and autoimmune disease.
Non-Hispanic black patients were more likely to be hospitalized for SARS-CoV-2 infection than non-Hispanic white patients (OR, 1.72, 95% CI 1.15-2.58, p=0.009).
Vaccination status
Reduced access to healthcare resources includes reduced access to vaccination, an issue that has persisted even after widespread availability of vaccines for SARS-CoV-2. Large placebo-controlled trials have found lower risk of asymptomatic, symptomatic, and severe COVID-19 with vaccinations
Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.
COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study.
In one study in the United Kingdom (UK) on vaccination of healthcare workers (23,324 participants from 104 sites), rates of effectiveness – as defined by not becoming infected -- for the BNT162b2 vaccine were found to be 70% (95% CI 55-85%) at 21 days after the first dose and 85% (95% CI 74-96%) at 7 days after the second dose.
COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study.
The study included asymptomatic and symptomatic infection and was conducted during a time of high prevalence of the Alpha variant. In a subsequent large study in England investigating effectiveness of various vaccine boosters against the Delta versus Omicron variant (204,154 individuals with Delta, 886,774 individuals with Omicron, 1,572,621 individuals with negative tests), vaccination effectiveness was uniformly higher for Delta than for Omicron.
COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study.
One can see that booster vaccination with BNT162b2 or mRNA-1273 after either ChAdOx1 nCoV-19 or BNT162b2 primary vaccine courses improved effectiveness in a short time period (i.e., 2 to 4 weeks) against Omicron. That effectiveness waned rapidly, however, dropping to as low as 39.6% - 45.7% at 10 or more weeks.
Table 1Effectiveness of COVID-19 vaccine series with subsequent combination boosters.
Primary course vaccine∗
Booster vaccine
Effectiveness at 2 to 4 weeks (%, 95% CI)
Effectiveness at 5 to 9 weeks (%, 95% CI)
Effectiveness at 10 or more weeks (%, 95% CI)
ChAdOx1 nCoV-19
BNT162b2
62.4 (61.8 - 63.0)
Not measured
39.6 (38.0 - 41.1)
BNT162b2
BNT162b2
67.2 (66.5 - 67.8)
Not measured
45.7 (44.7 - 46.7)
ChAdOx1 nCoV-19
mRNA-1273
70.1 (69.5 - 70.7)
60.9 (59.7 - 62.1)
Not measured
BNT162b2
mRNA-1273
73.9 (73.1 – 74.6)
64.4 (62.6 – 66.1)
Not measured
∗ Indicates single vaccination for ChAdOx1 nCoV-19 and two vaccinations for BNT162b2.
Adapted from Andrews N, Stowe J, Kirsebom F, et al. Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant. N Engl J Med. 2022;386(16):1532-1546.
Worse clinical outcomes are much more likely to occur in persons with no vaccination versus booster vaccine and in persons with primary vaccination versus booster vaccine. In a study in Northern California including 118,078 persons that adjusted for confounders such as age, sex, comorbid burden, prior infection, and receipt of prior treatment for SARS-CoV-2, risk of hospitalization was higher in persons who were unvaccinated (adjusted hazard ratio [aHR] 8.34, 95% CI 7.25-9.60) and who had the primary vaccine course (aHR 1.72, 95% CI 1.49-1.97) compared to those who received the primary vaccine course plus a booster.
Risk of severe clinical outcomes among persons with SARS-CoV-2 infection with differing levels of vaccination during widespread Omicron (B.1.1.529) and Delta (B.1.617.2) variant circulation in Northern California: A retrospective cohort study.
Early in the pandemic, patients with advanced age and certain underlying comorbidities were noted to be at higher risk of admission and severe disease. In an analysis of 208 acute care hospitals in England, Wales, and Scotland from February to April 2020, median age of admission was 73 years (interquartile range 58-82), and men constituted 60% of admissions (n=12,068, from 18,525 total).
Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. Published online May 22, 2020:m1985. doi:10.1136/bmj.m1985
Comorbid burden was common, with only 23% of patients having no major comorbidity. Cardiovascular disease and its risk factors were common in patients: cardiac disease 31%; diabetes 21%; and chronic kidney disease 16%. Non-asthmatic chronic pulmonary disease was noted in 18% of patients. These findings were similar to data on adult hospitalization in 14 states in the U.S. in March 2020, where 89.3% of patients had at least one underlying condition: 50% hypertension; 48% obesity; 35% chronic lung disease; 28% diabetes; 28% cardiovascular disease; and 13% renal disease.
Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 — COVID-NET, 14 States, March 1–30, 2020.
Ongoing caution is important for individuals with certain risk factors even after vaccination. In a prospective, nested, case-control study from the UK using self-reported data via phone from 6,030 adults with the first vaccine dose and 2,370 adults with the second vaccine dose, infection 14 days or more after the first dose was found to be associated with frailty in individuals greater than or equal to 60 years of age (OR 1.93, 95% CI 1.50-2.48, p<0.0001).
Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study.
As before the era of widespread vaccination, residence in economically-deprived areas was associated with greater risk of infection (OR 1.11, 95% CI 1.01-1.23, p=0.03), and not being obese as defined by BMI < 30 was associated with less risk of infection (OR 0.84, 95% CI 0.75-0.94, p=0.0030). Of note, the association of increased infection risk persisted even after adjustment for compliance with preventative measures such as mask wearing. The above findings suggest than greater resources for re-vaccination, booster vaccination, and screening may be warranted in care facilities for individuals with high frailty (e.g., long term care homes) and in lower income neighborhoods.
Laboratory abnormalities associated with severe disease
There are numerous laboratory abnormalities that have been found to associate with severe disease. Leukocytosis has been associated with disease progression and severity
Lampart M, Zellweger N, Bassetti S, et al. Clinical utility of inflammatory biomarkers in COVID-19 in direct comparison to other respiratory infections—A prospective cohort study. Faverio P, ed. PLOS ONE. 2022;17(5):e0269005. doi:10.1371/journal.pone.0269005
Additionally, worse outcomes have been observed in patients with elevations in numerous, routinely available inflammatory markers: D-dimer, C-reactive protein, lactate dehydrogenase, and ferritin.
Specific cytokines have also been implicated with decreased patient survival – in particular interleukin 6, 8 and Tumor-Necrosis-Factor-alpha (TNF-alpha).
Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. Published online February 19, 2020:m606. doi:10.1136/bmj.m606
Higher plasma nucleocapsid antigen level has also been found to be strongly associated with the need for non-invasive positive pressure ventilation or supplemental oxygen by high-flow nasal cannula.
ACTIV-3/TICO Study Group∗. The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19. Ann Intern Med. Published online August 30, 2022:M22-0924. doi:10.7326/M22-0924
The spectrum of presentation for SARS-CoV-2 infection is broad. The National Institutes of Health (NIH) definitions for infection severity are detailed in Table 2.
Positive nucleic acid amplification test or antigen test but no symptoms.
Mild illness
Fever, cough, or sore throat but no dyspnea or abnormal imaging.
Moderate illness
Evidence of lower respiratory disease by auscultation of lungs or imaging and oxygen saturation >= 94% on room air at sea level.
Severe illness
Oxygen saturation <= 94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen <= 300 mm Hg, respiratory frequency > 30 per minute, or lung opacities on imaging that have increased by 50% or more in 24-48 hours.
Critical illness
Respiratory failure, shock due to sepsis, with or without non-pulmonary end-organ dysfunction.
Presymptomatic infection and mild to moderate illness are seen in the outpatient setting. A standard approach for outpatients is to note the date of symptom onset and the date of dyspnea onset, if any. This addresses the difficulty of measuring incubation period, which has median estimates of approximately 3 days for the Omicron variant
In a prospective cohort study in Baltimore of 118 outpatients infected with SARS-CoV-2 and followed from April to June 2020, the majority of patients (63.7%) had no symptoms or mild symptoms in the first week of illness.
Of those who had symptoms, fatigue or weakness were the most common (65.7%). This was followed by cough (58.8%), headache (45.6%), chills (38.2%), and anosmia (27.9%). These individuals reported returning to their baseline health at a median of 20 days (interquartile range (IQR) 13-38) after the onset of symptoms. After 28-99 days from symptom onset, 83.3% of patients reported returning to their baseline health. A total of 7.6% required hospitalization. In contrast, a large Cochrane review of 42 prospective studies with 52,608 participants found that most symptoms have low diagnostic accuracy on presentation, although anosmia and ageusia can provide unique triggers for screening and cough can warrant additional testing.
Struyf T, Deeks JJ, Dinnes J, et al. Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19. Cochrane Infectious Diseases Group, ed. Cochrane Database Syst Rev. 2022;2022(5). doi:10.1002/14651858.CD013665.pub3
In this review the summary likelihood ratio (LR) of anosmia as a presenting symptom to be associated with SARS-CoV-2 infection was 4.55 (95% CI 3.46-5.9); for ageusia 3.14 (95% CI 1.79-5.51); for cough 1.14 (95% CI 1.04-1.25); for fever 1.52 (95% CI 1.10-2.10); and for sore throat 0.814 (95% CI 0.714-0.929). The authors point out that this latter LR suggests sore throat increases the odds of an alternative infectious process, implying that isolated upper respiratory symptoms such as sore throat or rhinorrhea do not support PCR testing for SARS-CoV-2.
Patients with severe illness require admission, and common presenting symptoms in these individuals are fatigue, cough, fever, and hypoxemia. In a retrospective study from Germany of 57 patients admitted to the medicine ward from February to April 2020, the median age was 72 years (IQR 60-81), with 23% women.
Fifty-six patients had at least 1 comorbid condition, and all patients required supplemental oxygen (median 2 liters/minute, IQR 2-4) to maintain oxygen saturation levels >= 94%. Fever was the most common presenting symptom (68%), followed by cough (60%), dyspnea (44%), and fatigue (37%). A majority (77%) had bilateral opacities on initial imaging. Median fever lasted 7 days (IQR 2-11), hospitalization 12 days (IQR 7-20), and oxygen supplementation 8 days (IQR 5-13). In this study and in numerous reports since the beginning of the pandemic, hypoxemia without dyspnea has been described. Some authors posit that the observation may be due to known physiological principles such as isocapnic hypoxia having a non-linear ventilatory response in which minute ventilation increases markedly only after arterial oxygen drops below a specific threshold (e.g., PaO2 60 mm Hg).
Wilkerson RG, Adler JD, Shah NG, Brown R. Silent hypoxia: A harbinger of clinical deterioration in patients with COVID-19. Am J Emerg Med. 2020;38(10):2243.e5-2243.e6. doi:10.1016/j.ajem.2020.05.044
It is notable that a study conducted years before this pandemic by Moosavi and colleagues also found that dyspnea exhibits the same response mechanism, with a sharp increase in reported “air hunger” ratings seen primarily in isocapnic patients with PaO2 less than 60 mm Hg.
Critical illness also manifests with profound hypoxemia but has, in contrast to severe illness, the distinguishing feature of acute respiratory failure.
Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. Published online May 22, 2020:m1985. doi:10.1136/bmj.m1985
Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. Published online May 22, 2020:m1985. doi:10.1136/bmj.m1985
Argenziano MG, Bruce SL, Slater CL, et al. Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series. BMJ. Published online May 29, 2020:m1996. doi:10.1136/bmj.m1996
In patients who develop Acute Respiratory Distress Syndrome (ARDS) after infection with SARS-CoV02, the median time from confirmation of infection to the onset of dyspnea has been reported as 6.5 days.
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
The median time from onset of dyspnea to ARDS has been reported as 2.5 days. Complications such as pneumothorax and barotrauma in patients with ARDS secondary to COVID-19 pneumonia may be higher compared to other patients with ARDS.
Mechanical ventilation for ARDS in COVID-19 may be an independent risk factor for death compared to ARDS patients who experience barotrauma from non-invasive positive pressure ventilation.
on behalf of Gemelli Against COVID 2019. Barotrauma during non-invasive ventilation for acute respiratory distress syndrome caused by COVID-19: a balance between risks and benefits.
In a small study comparing ARDS secondary to COVID-19 (n=27) to non-COVID-19 ARDS (other viral n=14, bacterial n=21, culture-negative pneumonia n=30), time to ventilator liberation was longer for patients with COVID-19 after adjustment for age, sex, and nursing home residence (aHR 0.48, 95% CI 0.24-0.98, P<0.05).
No significant difference was found in 2-month mortality between the groups (aHR 0.71, 95% CI 0.33-1.56; P=0.39). Similarly, no difference in mortality at 28 days was found in a second study comparing 130 patients with COVID-19 ARDS to 382 patients with non-COVID-19 ARDS (adjusted risk ratio 1.01, 95% CI 0.72-1.42).
Recovery from acute COVID-19 ranges along a spectrum, with no clear consensus on what constitutes Post-Acute Sequelae of SARS-CoV-2 (PASC). A clinical case definition by the World Health Organization makes the distinction that acute COVID-19 lasts up to 4 weeks after the onset of illness; whereas PASC can develop during or after COVID-19 and must continue at least 3 months after the onset of illness.
Common symptoms include fatigue, cognitive impairment, and dyspnea. In a study from Germany of 96 patients with symptom onset between February 2020 and April 2020 and who had follow-up visits at 5, 9, and 12 months, the most frequent symptoms at 5 months were reduced exertional ability (53.1%), fatigue (41.7%), insomnia (32.3%), cognitive impairment (31.3%) and dyspnea (27.1%).
From 5 to 12 months, reported fatigue increased from 41.7% to 53.1% (P = 0.043); dyspnea increased from 27.1% to 37.5% (P = 0.041). All other symptoms did not change significantly. This and a second prospective study of 968 patients in France found that 80-85% of patients still reported symptoms 1 year after symptom onset.
Research into the characteristics of PASC and potential treatments is ongoing.
Associated infections
Bacterial infections in patients with COVID-19 pneumonia are uncommon and can be distinguished between co-infection and superinfection. The former is diagnosed at the time of COVID-19 pneumonia diagnosis and is presumably acquired in the community. The latter is diagnosed during the period of management for COVID-19 pneumonia. One study in Spain in 2020 reported a co-infection rate of 3.1%, primarily with Streptococcus pneumoniae and Staphylococcus aureus, and a superinfection rate of 4.7%, primarily with Pseudomonas aeruginosa and Escherichia coli.
A meta-analysis including 2,390 patients found higher rates of bacterial co-infections (8%, 95% CI 5-11%) and bacterial superinfections (20%, 95% CI 13-28%).
Musuuza JS, Watson L, Parmasad V, Putman-Buehler N, Christensen L, Safdar N. Prevalence and outcomes of co-infection and superinfection with SARS-CoV-2 and other pathogens: A systematic review and meta-analysis. Huber VC, ed. PLOS ONE. 2021;16(5):e0251170. doi:10.1371/journal.pone.0251170
Significant rates of viral and fungal secondary infections were also noted: viral co-infections, 10% (95% CI 6-14%); viral superinfections, 4% (95% CI 0-10%); fungal co-infections, 4% (95% CI 2-7%); and fungal superinfections, 8% (95% CI 4-13%). The most common bacterial pathogens for co-infection were Klebsiella pneumoniae (9.9% of all co-infections), Streptococcus pneumoniae (8.2%), and Staphylococcus aureus (7.7%). The most common bacterial pathogens for superinfection were Acinetobacter spp. (22.0%), Pseudomonas (10.8%), and Escherichia coli (6.9%).
Musuuza JS, Watson L, Parmasad V, Putman-Buehler N, Christensen L, Safdar N. Prevalence and outcomes of co-infection and superinfection with SARS-CoV-2 and other pathogens: A systematic review and meta-analysis. Huber VC, ed. PLOS ONE. 2021;16(5):e0251170. doi:10.1371/journal.pone.0251170
Aspergillus was found in 6.7% of co-infections and 13.5% of superinfections.
Radiographic Findings
Chest x-ray can be normal in early or mild disease, and when radiographic findings develop, they typically reveal bilateral opacities that are predominant in the lower lobes.
Wong, Ho Yuen Frank, Hiu Yin Sonia Lam, Ambrose Ho-Tung Fong, Siu Ting Leung, et.al. Frequency and Distribution of Chest Radiographic Findings in COVID-19 Positive Patients. Radiology. 2020;296:E72-E78.
Most patients will experience resolution, but some can progress to a more structured parenchymal injury manifesting as reticular opacities and associated fibrosis.
Figure 1 illustrates typical chest x-ray findings during initial stages of infection with COVID-19 pneumonia and the evolution to fibrotic changes over time.
Figure 1Serial chest radiographs of a 62-year old gentleman with a history of essential hypertension with COVID-19 pneumonia and requiring hospital admission and oxygen support by non-rebreather mask. He received remdesivir, dexamethasone, ceftriaxone, and azithromycin in hospital and was discharged on home oxygen. A) Day of first positive SARS-CoV-2 Polymerase Chain Reaction (PCR) test, taken 9 days after onset of symptoms. Bilateral opacities on the left greater than the right. Air bronchograms and bronchial wall thickening is noted in the right lower lobe. B) Two days after positive test. Slight worsening of bilateral opacities is seen; C) Eleven months after infection. Bilateral opacities and prominent interstitial markings are consistent with fibrotic lung disease, likely a sequelae of lung injury from acute infection.
Early in the pandemic, temporal stages of CT findings in COVID-19 pneumonia were proposed and included ultra-early, early, rapid progression, consolidation, and dissipation.
for the Zhongnan Hospital of Wuhan University Novel Coronavirus Management and Research Team, Evidence-Based Medicine Chapter of China International Exchange and Promotive Association for Medical and Health Care (CPAM), Jin YH, Cai L, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res. 2020;7(1):4. doi:10.1186/s40779-020-0233-6
The ultra-early stage can occur within 2 weeks of exposure and can present with no or scant ground glass opacities (GGOs) on imaging. Symptomatic presentation occurs during the early phase, which may include single or multiple GGOs with interlobular septal thickening. Rapid progression is expected 3-7 days after symptomatic presentation and manifests with consolidations and air bronchograms. The consolidation phase occurs 7-14 days after symptomatic presentation, when the size and density of consolidations decrease. Dissipation may occur thereafter. It can include reticulations with opacities, thickening of the bronchial wall, and interlobular septal thickening.
Typical chest CT abnormalities are consistent with viral pneumonia, with one large review finding GGOs to be the most prominent feature (83%), followed by GGOs with mixed consolidation (58%), pleural thickening (52%), and interlobular septal thickening (48%).
Criteria have been proposed by the Radiological Society of North America (RSNA) to categorize CT chest findings as typical, indeterminate, and atypical.
Radiological Society of North America. Radiological Society of North America Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA. Published online July 24, 2020. doi:10.1148/ryct.2020200152.podcast
Typical is defined as either multifocal rounded GGOs or peripheral bilateral GGOs with or without consolidation or the superimposed interlobular septal lines that constitute “crazy paving.” (Figure 2) A later stage of typical pneumonia is defined as having reverse halo sign or other signs of organizing pneumonia. Indeterminate is defined as absence of these typical features with the addition of GGOs that are non-rounded, non-peripheral and either diffuse, perihilar, unilateral, or simply lacking a specific distribution. Atypical is defined as lacking the features of typical and indeterminate and having lobar or segmental consolidation, centrilobular nodules, or lung cavitation. These acute insults can evolve into a chronic phase of inflammation, resulting in subpleural reticulation and bronchiectasis (Figure 3).
Figure 2Axial cuts of a CT angiogram of the chest of a 50-year old gentleman with a history of hyperparathyroidism with typical COVID-19 pneumonia per Radiological Society of North America criteria, taken one day after first positive PCR for SARS-CoV-2. The patient required ICU admission and oxygen support by high flow nasal cannula. He was discharged on home oxygen. A) Bilateral, peripheral ground glass opacities (GGOs) in the left upper lobe; B) bilateral GGOs with mild consolidations and mild traction bronchiectasis at the level of the carina; C) Increasing consolidative opacities intermixed with GGOs and more severe bronchiectasis; and D) Bibasilar, posterior, peripheral consolidative opacities with peripheral GGOs.
Figure 3CT chest scan 5 months after COVID-19 pneumonia in the same patient presented in Figure 1. A) Subpleural peripheral reticulations seen in the bilateral upper lobes. Traction bronchiectasis in left upper lobe takeoff; B) Peripheral GGOs with reticulation in bilateral lower lobes. These findings appear to represent fibrotic lung disease.
Vaccinations attenuate the radiographic presentations of COVID-19, consistent with the impact of vaccinations on disease severity. In a multicenter Korean study, infected patients were divided into groups of unvaccinated, partially vaccinated, and fully vaccinated and had their clinical metrics and radiographic features analyzed for comparative differences.
Vaccine status (fully vaccinated versus unvaccinated) was associated with less risk of needing supplemental oxygen (OR 0.24, 95% CI 0.09-0.64, p = 0.005) or ICU admission (OR 0.08, 95% CI 0.09-0.78, p = 0.02). Of the 761 patients, 412 received chest CT and 75% of these were diagnosed with pneumonia. The percentage of patients with negative CT chest significantly increased with vaccine status – 22% of unvaccinated compared with 59% of fully vaccinated. A majority of patients in each vaccine group had typical CT chest findings as defined by RSNA criteria, but these percentages decreased from unvaccinated (72%) to partially vaccinated (60%) to fully vaccinated (56%). This trend was largely due to a greater percentage of fully vaccinated persons having atypical CT chest findings (11%) compared to partially vaccinated (2%) and unvaccinated (3%).
A subsequent study in Korea examined CT chest findings for COVID-19 pneumonia in patients during the Delta wave (n=88) compared to the Omicron wave (n=88).
Yoon, Soon Ho, Lee, Jong Hyuk, Kim, Baek-Nam. Chest CT Findings in Hospitalized Patients with SARS-CoV-2: Delta versus Omicron Variants. Radiology. Published online June 28, 2022. doi:10.1148/radiol.220676
After adjustment for the confounders of age, comorbid burden, vaccination status, and infection duration, patients with Omicron were found to have a less typical CT appearance for COVID-19 pneumonia per RSNA criteria (OR 0.34, 95% CI 0.16-0.74, p=0.006) and more peribronchovascular involvement than patients with Delta. (OR 9.2, 95% CI 2.9-29, p<0.001). By using a neural network algorithm, the authors found that pulmonary vascular volume in vessels 5mm or less in diameter (i.e., vessels in the periphery of the lung) was greater for patients with Omicron than patients with Delta (3.8, 95% CI 0.92-6.8, p=0.01). Together, these findings reinforced prior studies that Omicron replicates more predominantly in the bronchi than in the lung parenchyma and that the differing physiological mechanisms of the variant resulted in distinct radiographic findings.
The higher volume of peripheral pulmonary vascular volume in patients with Omicron was consistent with it causing less severe pneumonia than Delta, given that lower peripheral vascular volume (i.e., blood vessel volume less than 5mm in diameter) has been found to associate with worse outcomes for COVID-19 pneumonia.
Morris MF, Pershad Y, Kang P, et al. Altered pulmonary blood volume distribution as a biomarker for predicting outcomes in COVID-19 disease. Eur Respir J. 2021;58(3):2004133. doi:10.1183/13993003.04133-2020
The study was significant in its implication that emerging variants of concern may produce radiographic findings that are increasingly atypical and therefore at risk of delayed detection.
Lessons Learned
COVID-19 has posed an unprecedented challenge to our diagnostic and prognostic approaches of viral respiratory illness. Since the beginning of the pandemic in late 2019, we have acquired knowledge in the protean manifestations of the disease and in the social and biological risk factors for infection and severe disease. This includes elucidation of critical social and biological determinants of health and codification of disease severity and imaging findings. A commitment to continuing and advancing such research will be crucial for ameliorating the impact of newer viral variants on individual and population health and for preparing for future pandemics.
As viral variants evolve and vaccines continue to be developed, we will be presented with new challenges in identifying and managing upper and lower respiratory tract infection with COVID-19. Phenomena such as Post-Acute Sequelae of COVID-19 have already become prominent, and longer-term morbidity from physiological damage caused by acute disease will continue to accumulate. The international coordination demonstrated by SARS-CoV-2 vaccine development offers a model for cooperation and scientific knowledge dissemination in these crucial domains. In a similar collaborative vein the US Centers for Disease Control and Prevention (CDC) has established a Center for Forecasting and Outbreak Analytics in April, 2022 to integrate analysts from previously siloed fields of computer science, mathematics, physics, and epidemiology and to allow for a more pre-emptive approach to future pandemics.
To ensure greater equity in vaccine distribution, the CDC has partnered with the Health Resources & Services Administration (HRSA) to deliver vaccines directly to HRSA-funded health centers. These centers serve 30 million individuals in the U.S., 93% of whom are below 200% of the federal poverty level, and 63% of whom identify as racial or ethnic minorities.
As societies have reopened and the virus has become endemic, we should continue to pay heed to the suffering and harm that could have been mitigated from this pandemic and apply these difficult lessons to such committed advancement of improved pathways for clinical care.
Clinics Care Points
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Social risk factors for COVID-19 pneumonia such as race, ethnicity, income inequality, and living environment correlate with infection and severity of infection.
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Biological risk factors are numerous and highly correlate with cardiovascular disease and its risk factors.
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COVID-19 pneumonia has a broad presentation, ranging from mild illness to critical illness.
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Post-Acute Sequelae of SARS-CoV-2 has protean manifestations that can persist for months to over a year and is receiving increasing attention into its physiology and potential treatments.
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Imaging findings of pneumonia can be categorized as typical, indeterminate, and atypical and may differ according to vaccine status and viral variant.
Acknowledgements
We would like to thank our patients in the Post-Acute COVID-19 Clinic in Stanford University.
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