In Birdy's Eyes:

 English: A Comprehensive Guide to the COVID-19 virus:

This Article (Blog Post) was written and updated: July, 22, 2022.

1. INTRODUCTION — Coronaviruses are important human and animal pathogens. At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China. It rapidly spread, resulting in an epidemic throughout China, followed by an increasing number of cases in other countries throughout the world. In February 2020, the World Health Organization designated the disease COVID-19, which stands for coronavirus disease 2019. The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); previously, it was referred to as 2019-nCoV.

2. ASYMPTOMATIC INFECTIONS

●In a COVID-19 outbreak on a cruise ship where nearly all passengers and staff were screened for SARS-CoV-2, approximately 19 % of the population on board tested positive; 58 % of the 712 confirmed COVID-19 cases were asymptomatic at the time of diagnosis []. In studies of subsets of those asymptomatic individuals, who were hospitalized and monitored, approximately 77 to 89 % remained asymptomatic over time.

●Other studies, particularly those conducted among younger populations, have reported higher proportions of infections that are asymptomatic . As an example, in an outbreak on an aircraft carrier, a quarter of the crew, among whom the mean age was 27 years, tested positive for SARS-CoV-2 .Among the 1271 cases, only 22 % were symptomatic at the time of testing and 43 % remained asymptomatic throughout the observation period. High rates of asymptomatic infection have also been reported among pregnant women presenting for delivery. Patients with asymptomatic infection may have objective clinical abnormalities.

3. SEVERITY OF SYMPTOMATIC INFECTION:

●Spectrum of infection severity – The spectrum of symptomatic infection ranges from mild to critical; most infections are not severe. Specifically, a report from the Chinese Center for Disease Control and Prevention during the first months of the pandemic included approximately 44,500 confirmed infections and found the following:

•Mild disease (no or mild pneumonia) was reported in 81% .

•Severe disease (eg, with dyspnea, hypoxia, or >50% lung involvement on imaging within 24 to 48 hours) was reported in 14% .

•Critical disease (eg, with respiratory failure, shock, or multiorgan dysfunction) was reported in 5% .

•The overall case fatality rate was 2.3% ; no deaths were reported among noncritical cases.

Similarly, in a report of 1.3 million cases reported to the United States Centers for Disease Control and Prevention (CDC) through the end of May 2020, 14% were hospitalized, 2% were admitted to the intensive care unit (ICU), and 5% died.The individual risk of severe illness varies by age, underlying comorbidities, and vaccination status.

●Infection fatality rates – The case fatality rate only indicates the mortality rate among documented cases. Since many SARS-CoV-2 infections are asymptomatic and many mild infections do not get diagnosed, the infection fatality rate (ie, the estimated mortality rate among all individuals with infection) is considerably lower and has been estimated in some analyses of unvaccinated individuals to be between 0.15 and 1% , with substantial heterogeneity by location and across risk groups. In a systematic analysis that calculated the total number of community infections through seroprevalence surveys from 53 countries (including both resource-rich and resource-limited settings) prior to vaccine availability, the infection fatality rate [IFR] was 0.005% at 1 year, decreased to 0.002% by age 7, and increased exponentially after that: 0.006% at age 15, 0.06% at age 30, 0.4% at age 50, 2.9% at age 70, and 20% at age 90. The median IFR decreased from 0.47% in April 2020 to 0.33% in March, 2021.

●Fatality rates among hospitalized patients – Among hospitalized patients, the risk of critical or fatal disease is high among unvaccinated individuals, and the in-hospital fatality rate associated with COVID-19 is higher than that for influenza.As an example, in a United States survey of over 16,000 patients hospitalized for COVID-19 between March and December 2020, the fatality rate was 11.4% overall and ranged monthly from 7.1 to 17.1 percen. Over the course of the pandemic, declining in-hospital fatality rates had been reported, even prior to widespread vaccination. The reasons for this observation are uncertain, but potential explanations include improvements in hospital care of COVID-19 and better allocation of resources when hospitals are not overburdened.

●Excess deaths during the pandemic – Neither the case fatality rate nor the infection fatality rate account for the full burden of the pandemic, which includes excess mortality from other conditions because of delayed care, overburdened health care systems, and social determinants of health’. A systematic analysis that compared all-cause mortality reports of 74 countries during 2020 and 2021 with those of the previous 11 years estimated a global all-age excess mortality rate of 120.3 deaths per 100,000 persons and 28.2 million deaths due to the COVID-19 pandemic worldwide.

●Impact of vaccination – Vaccination against COVID-19 substantially reduces the risk of severe illness and is associated with decreased mortality. Impact of COVID-19 vaccination is discussed in detail elsewhere.

Risk factors for severe illness — Severe illness can occur in otherwise healthy individuals of any age, but it predominantly occurs in adults with advanced age or certain underlying medical comorbidities. Specific demographic features and laboratory abnormalities have also been associated with severe disease. COVID-19 vaccination substantially reduces the risk of severe illness.

Increasing age — Individuals of any age can acquire SARS-CoV-2 infection, although adults of middle age and older are most commonly affected, and older adults are more likely to have severe disease. In several cohorts of hospitalized patients with confirmed COVID-19, the median age ranged from 49 to 56 years. In a report from the Chinese Center for Disease Control and Prevention that included approximately 44,500 confirmed infections, 87% of patients were between 30 and 79 years old. Similarly, in a modeling study based on data from mainland China, the hospitalization rate for COVID-19 increased with age, with a 1% rate for those 20 to 29 years old, 4% rate for those 50 to 59 years old, and 31% for those older than 80 years.

Older age is also associated with increased mortality. In a report from the Chinese Center for Disease Control and Prevention, case fatality rates were 8 and 15% among those aged 70 to 79 years and 80 years or older, respectively, in contrast to the 2.3% case fatality rate among the entire cohort.In an analysis from the United Kingdom, the risk of death among individuals 80 years and older was 20-fold that among individuals 50 to 59 years old. In the United States, 2449 patients diagnosed with COVID-19 between February 12 and March 16, 2020, had age, hospitalization, and ICU information available.; 67% of cases were diagnosed in those aged ≥45 years, and, similar to findings from China, mortality was highest among older individuals, with 80% of deaths occurring in those aged ≥65 years. In contrast, individuals aged 18 to 34 years accounted for only 5% of adults hospitalized for COVID-19 in a large health care database study and had a mortality rate of 2.7% ; morbid obesity, hypertension, and male sex were associated with mortality in that age group..

Symptomatic infection in children and adolescents is usually mild, although a small proportion experience severe and even fatal disease. Details of COVID-19 in children are discussed elsewhere. Comorbidities — Multiple comorbidities and underlying conditions have been associated with severe illness (ie, infection resulting in hospitalization, admission to the ICU, intubation or mechanical ventilation, or death). Although severe disease can occur in any individual, most with severe disease have at least one risk factor. In a report of 355 patients who died with COVID-19 in Italy, the mean number of pre-existing comorbidities was 2.7, and only 3 patients had no underlying condition.

Laboratory abnormalities — Particular laboratory features have also been associated with worse outcomes. These include:

•Lymphopenia’

•Thrombocytopenia

•Elevated liver enzymes

•Elevated lactate dehydrogenase

•Elevated inflammatory markers (eg, C-reactive protein, ferritin) and inflammatory cytokines (ie, interleukin 6 and tumor necrosis factor-alpha)

•Elevated D-dimer (>1 mcg/mL)

•Elevated prothrombin time

•Elevated troponin

•Elevated creatine phosphokinase

•Acute kidney injury

As an example, in one study, progressive decline in the lymphocyte count and rise in the D-dimer over time were observed in nonsurvivors compared with more stable levels in survivors. Deficiencies in certain micronutrients, in particular vitamin D , have been associated with more severe disease in observational studies, but multiple confounders likely impact the observed associations. There is also no high-quality evidence that reversing micronutrient deficiencies with supplementation improves COVID-19 outcomes.

Viral factors — Patients with severe disease have also been reported to have higher viral ribonucleic acid (RNA) levels in respiratory specimens than those with milder disease , although some studies have found no association between respiratory viral RNA levels and disease severity. Detection of viral RNA in the blood has been associated with severe disease, including organ damage (eg, lung, heart, kidney), coagulopathy, and mortality.

Genetic factors — Host genetic factors are also being evaluated for associations with severe disease.

As an example, one genome-wide association study identified a relationship between polymorphisms in the genes encoding the ABO blood group and respiratory failure from COVID-19 (type A associated with a higher risk). Type O has been associated with a lower risk of both infection and severe disease.

4. CLINICAL MANIFESTATIONS

Incubation period — The incubation period for COVID-19 is generally within 14 days following exposure with most cases occurring approximately four to five days after exposure. The median incubation period for the SARS-CoV-2 Omicron variant (B.1.1.159) appears to be slightly shorter, with symptoms first appearing at around three days. In a study of 1099 patients with confirmed symptomatic COVID-19, the median incubation period was four days (interquartile range two to seven days). There exists a report that suggests a longer median incubation period of 7.8 days, with 5 to 10% of individuals developing symptoms 14 days or more after exposure.

Initial presentation — Among patients with symptomatic COVID-19, cough, myalgias, and headache are the most commonly reported symptoms. Other features, including diarrhea, sore throat, and smell or taste abnormalities, are also well described. Mild upper respiratory symptoms (eg, nasal congestion, sneezing) appear to be more common with the Delta and Omicron variant. Pneumonia is the most frequent serious manifestation of infection, characterized primarily by fever, cough, dyspnea, and bilateral infiltrates on chest imaging. Although some clinical features (in particular smell or taste disorders) are more common with COVID-19 than with other viral respiratory infections, there are no specific symptoms or signs that can reliably distinguish COVID-19. However, development of dyspnea approximately one week after the onset of initial symptoms may be suggestive of COVID-19.

In a report of over 370,000 confirmed COVID-19 cases from January to May 2020 with known symptom status reported to the CDC in the United States, cough (50% ), fever (43% ), myalgias (36% ), and headache (34% ) were the most common presenting symptoms. Other cohort studies of patients with confirmed COVID-19 have reported a similar range of clinical findings. In an observational study that evaluated the reported clinical symptoms of 63,000 confirmed COVID-19 cases from two time periods (June to November 2021 when Delta variant was predominant and December 2021 to January 2022 when Omicron was predominant), nasal congestion (77 to 82% ), headache (75 to 78% ), sneezing (63 to 71% ), and sore throat (61 to 71% ) were the most common presenting symptoms .

●Fever − Fever is not a universal finding on presentation, even among hospitalized cohorts. In one study, fever was reported in almost all patients, but approximately 20% had a very low-grade fever <100.4°F (38°C) [. In another study of 1099 patients from Wuhan and other areas in China, fever (defined as an axillary temperature over 99.5°F [37.5°C]) was present in only 44% on admission but was ultimately noted in 89% during the hospitalization. In a study of over 5000 patients who were hospitalized with COVID-19 in New York, only 31% had a temperature >100.4°F (38°C) at presentation.

●Smell and taste abnormalities − In some studies, smell and taste disorders (eg, anosmia and dysgeusia) have been frequently reported, although these abnormalities appear to be less common with the Omicron variant . In a meta-analysis of observational studies, the pooled prevalence estimates for smell or taste abnormalities were 52 and 44% , respectively (although rates ranged from 5 to 98% across studies). In one survey of 202 outpatients with mild COVID-19 in Italy, 64% reported alterations in smell or taste, and 24% reported very severe alterations; smell or taste changes were reported as the only symptom in 3% overall and preceded symptoms in another 12% . However, the rate of objective smell or taste anomalies may be lower than the self-reported rates. In another study, 38% of the 86 patients who reported total lack of smell at the time of evaluation had a normal smell function on objective testing. Most subjective smell and taste disorders associated with COVID-19 do not appear to be permanent; in a follow-up survey of the 202 patients in Italy with COVID-19, 89% of those who noted smell or taste alterations reported resolution or improvement by four weeks.

●Gastrointestinal findings − Although not noted in the majority of patients, gastrointestinal symptoms (eg, nausea and diarrhea) may be the presenting complaint in some patients. In a systematic review of studies reporting on gastrointestinal symptoms in patients with confirmed COVID-19, the pooled prevalence was 18% overall, with diarrhea, nausea/vomiting, or abdominal pain reported in 13, 10, and 9% , respectively.

●Dermatologic findings − A range of dermatologic findings in patients with COVID-19 may occur. There have been reports of maculopapular/morbilliform, urticarial, and vesicular eruptions and transient livedo reticularis. Reddish-purple nodules on the distal digits similar in appearance to pernio (chilblains), or “COVID toes,” have also been described, mainly in adolescents and young adults with otherwise asymptomatic or mild infection; in some cases, these developed up to several weeks after initial COVID-19 symptoms.

●Other findings − Conjunctivitis may occur. Other clinical manifestations, such as falls, general health decline, and delirium, have been reported in older adults, particularly those over 80 years old and those with underlying neurocognitive impairment].

Several complications of COVID-19 have been described:

●Respiratory failure – Acute respiratory distress syndrome (ARDS) is the major complication in patients with severe disease and can manifest shortly after the onset of dyspnea. In the study of 138 patients described above, ARDS developed in 20% a median of eight days after the onset of symptoms; mechanical ventilation was implemented in 12.3% .n large studies from the United States, 12 to 24% of hospitalized patients have required mechanical ventilation.

●Cardiac and cardiovascular complications – Other complications have included arrhythmias, myocardial injury, heart failure, and shock, as discussed in detail elsewhere. Thromboembolic complications – Venous thromboembolism, including extensive deep vein thrombosis and pulmonary embolism, is common in severely ill patients with COVID-19, particularly among patients in the intensive care unit (ICU), among whom reported rates have ranged from 10 to 40% . Arterial thrombotic events, including acute stroke (even in patients younger than 50 years of age without risk factors) and limb ischemia, have also been reported..

●Neurologic complications – Encephalopathy is a common complication of COVID-19, particularly among critically ill patients; as an example, in one series of hospitalized patients, encephalopathy was reported in one-third. Stroke, movement disorders, motor and sensory deficits, ataxia, and seizures occur less frequently. .

●Inflammatory complications – Some patients with severe COVID-19 have laboratory evidence of an exuberant inflammatory response, with persistent fevers, elevated inflammatory markers (eg, D-dimer, ferritin), and elevated proinflammatory cytokines; these laboratory abnormalities have been associated with critical and fatal illnesses . Although these features had been likened to cytokine release syndrome (eg, in response to T cell immunotherapy), the levels of proinflammatory cytokines in COVID-19 are substantially lower than those seen with cytokine release syndrome as well as with sepsis. Other inflammatory complications and auto-antibody-mediated manifestations have been described. Guillain-Barré syndrome may occur, with onset 5 to 10 days after initial symptoms. A multisystem inflammatory syndrome with clinical features similar to those of Kawasaki disease and toxic shock syndrome has also been described in children with COVID-19. In the rare adults in whom it has been reported, this syndrome has been characterized by markedly elevated inflammatory markers and multiorgan dysfunction (in particular cardiac dysfunction).

 ●Secondary infections – Secondary infections occur in the minority of patients with COVID-19. In a systematic review of 118 studies, the rate of bacterial coinfections (identified at the time of COVID-19 diagnosis) was 8% and the rate of bacterial superinfections (identified during care for COVID-19) was 20% . Klebsiella pneumoniae, Streptococcus pneumoniae, and Staphylococcus aureus were the most common coinfecting pathogens, and Acinetobacter spp were the most common superinfecting pathogens. A meta-analysis of 22 studies examined bacterial, fungal, and viral superinfections and found a superinfection rate of 16% . Epstein-Barr virus was the most frequent organism, followed by Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Hemophilus influenza, and invasive pulmonary aspergillosis. Fungal superinfections are a risk in certain populations. Several reports have described invasive aspergillosis among critically ill immunocompetent patients with ARDS from COVID-19, although the frequency varies widely across reports, in part because of differences in diagnostic criteria] Cases of mucormycosis in patients with acute and recent COVID-19 have also been reported, particularly from India; the rhino-orbital region is the most common site of infection, and risk factors include diabetes mellitus and glucocorticoid receipt].

Autopsy studies have noted detectable SARS-CoV-2 RNA (and, in some cases, antigen) in the kidneys, liver, heart, brain, and blood in addition to respiratory tract specimens, suggesting that the virus disseminates systemically in some cases; whether direct viral cytopathic effects at these sites contribute to the complications observed is uncertain.

Recovery and long-term sequelae — The time to recovery from COVID-19 is highly variable and depends on age, vaccination status, and pre-existing comorbidities in addition to illness severity. Individuals with mild infection are expected to recover relatively quickly (eg, within two weeks) whereas many individuals with severe disease have a longer time to recovery (eg, two to three months). The most common persistent symptoms include fatigue, memory problems, dyspnea, chest pain, cough, and cognitive deficit. Data also suggest the potential for ongoing respiratory impairment and cardiac sequelae. Some patients who have recovered from COVID-19 have persistently or recurrently positive nucleic acid amplification tests for SARS-CoV-2. Although recurrent infection or reinfection cannot be definitively ruled out in these settings, evidence suggests that these are unlikely.

5. LABORATORY FINDINGS — 

Common laboratory findings among hospitalized patients with COVID-19 include lymphopenia, elevated aminotransaminase levels, elevated lactate dehydrogenase levels, elevated inflammatory markers (eg, ferritin, C-reactive protein, and erythrocyte sedimentation rate), and abnormalities in coagulation tests. .Lymphopenia is especially common, even though the total white blood cell count can var. As an example, in a series of 393 adult patients hospitalized with COVID-19 in New York City, 90% had a lymphocyte count <1500/microL; leukocytosis (>10,000/microL) and leukopenia (<4000/microL) were each reported in approximately 15%. On admission, many patients with pneumonia have normal serum procalcitonin levels; however, in those requiring ICU care, they are more likely to be elevated.

6. IMAGING FINDINGS

Chest radiographs — Chest radiographs may be normal in early or mild disease. In a retrospective study of 64 patients in Hong Kong with documented COVID-19, 20% did not have any abnormalities on chest radiograph at any point during the illness . Common abnormal radiograph findings were consolidation and ground-glass opacities, with bilateral, peripheral, and lower lung zone distributions; lung involvement increased over the course of illness, with a peak in severity at 10 to 12 days after symptom onset. Spontaneous pneumothorax has also been described, although it is relatively uncommon. In a retrospective review of over 70,000 patients with COVID-19 evaluated in emergency departments throughout Spain, spontaneous pneumothorax was identified in 40 patients (0.56% ).

Chest CT in patients with COVID-19 most commonly demonstrates ground-glass opacification with or without consolidative abnormalities, consistent with viral pneumonia. As an example, in a systematic review of studies evaluating the chest CT findings in over 2700 patients with COVID-19, the following abnormalities were noted :

●Ground-glass opacifications – 83% ●Ground-glass opacifications with mixed consolidation – 58% ●Adjacent pleural thickening – 52% ●Interlobular septal thickening – 48% ●Air bronchograms – 46%

Other less common findings were a crazy paving pattern (ground-glass opacifications with superimposed septal thickening), bronchiectasis, pleural effusion, pericardial effusion, and lymphadenopathy. Chest CT abnormalities in COVID-19 are often bilateral, have a peripheral distribution, and involve the lower lobes. Although these findings are common in COVID-19, they are not unique to it and are frequently seen with other viral pneumonias]. In a study of 1014 patients in Wuhan who underwent both RT-PCR testing and chest CT for evaluation of COVID-19, a "positive" chest CT for COVID-19 (as determined by a consensus of two radiologists) had a sensitivity of 97% , using the PCR tests as a reference; however, specificity was only 25%]. The low specificity may be related to other etiologies causing similar CT findings. In another study comparing chest CTs from 219 patients with COVID-19 in China and 205 patients with other causes of viral pneumonia in the United States, COVID-19 cases were more likely to have a peripheral distribution (80 versus 57% ), ground-glass opacities (91 versus 68% ), fine reticular opacities (56 versus 22% ), vascular thickening (59 versus 22% ), and reverse halo sign (11 versus 1% ), but less likely to have a central and peripheral distribution (14 versus 35% ), air bronchogram (14 versus 23% ), pleural thickening (15 versus 33% ), pleural effusion (4 versus 39% ), and lymphadenopathy (2.7 versus 10% ).

7. SPECIAL POPULATIONS

Pregnant and breastfeeding women — The general approach to prevention, evaluation, diagnosis, and treatment of pregnant women with suspected COVID-19 is largely similar to that in nonpregnant individuals. .

Children — Symptomatic infection in children is usually mild, although severe cases have been reported. In addition, a post-COVID syndrome entitled Multisystem Inflammatory Syndrome of Children (MIS-C) has emerged with features resembling Kawasaki Disease and occasionally exhibiting long-term sequela]. Details of COVID-19 in children are discussed elsewhere..

People with HIV — Clinical features of COVID-19 appear the same in people with human immunodeficiency virus (HIV) as in the general population. Among patients with well controlled HIV, a large proportion remain asymptomatic. However, those with HIV remain at increased risk for severe COVID-19 and complications. In several large observational studies, HIV infection has been associated with more severe COVID-19, higher rates of hospitalization, higher rates of breakthrough infections after vaccination, and in some cases, higher mortality from COVID-19. As an example, in a multicenter cohort study from Spain, the age- and sex-adjusted mortality rate of patients with HIV and COVID-19 was 3.7 compared with 2.1 per 10,000 people in the general Spanish population. In another database study of more than 1 million COVID-19 cases in the United States, COVID-19-associated hospitalization and mortality were higher in patients with HIV compared to those without HIV after adjusting for demographics, smoking, and presence of comorbidities. Among people with HIV, those who are older, have multiple comorbidities, have lower CD4 cell counts, and who identify as Black or Hispanic are at highest risk for adverse outcomes.

8. SUMMARY:

●Asymptomatic infection – The clinical spectrum of SARS-COV-2 infection ranges from asymptomatic infection to critical and fatal illness. The proportion of infections that are asymptomatic is uncertain, as the definition of "asymptomatic" varies across studies and longitudinal follow-up to identify those who ultimately develop symptoms is often not performed. Nevertheless, some estimates suggest that up to 40% of infections are asymptomatic.

●Risk of severe disease – Most symptomatic infections are mild. Severe disease (eg, with hypoxia and pneumonia) has been reported in 15 to 20% of symptomatic infections in unvaccinated individuals; it can occur in otherwise healthy individuals of any age, but predominantly occurs in adults with advanced age or certain underlying medical comorbidities. In North America and Europe, Black, Hispanic, and South Asian individuals are also more likely to have severe disease, likely related to underlying disparities in the social determinants of health.

●Incubation period – The incubation period from the time of exposure until the onset of symptoms is three to five days on average, partly depending on the variant, but it may be as long as 14 days.

●Initial presentation – Cough, myalgias, and headache are the most commonly reported symptoms. Other features, including diarrhea, sore throat, and smell or taste abnormalities, are also well described . Mild upper respiratory symptoms (eg, nasal congestion, sneezing) appear to be more common with the Delta and Omicron variants. Pneumonia, with fever, cough, dyspnea, and infiltrates on chest imaging, is the most frequent serious manifestation of infection.

 ●Complications – Acute respiratory distress syndrome (ARDS) is the major complication in patients with severe disease and can manifest shortly after the onset of dyspnea. Other complications of severe illness include thromboembolic events, acute cardiac injury, kidney injury, and inflammatory complications.

●Clinical suspicion – The possibility of COVID-19 should be considered primarily in patients with compatible symptoms, in particular fever and/or respiratory tract symptoms, who reside in or have traveled to areas with community transmission or who have had recent close contact with a confirmed or suspected individual with COVID-19.

This generalized information is a limited summary of diagnosis, treatment, and/or medication information. It is not meant to be comprehensive and should be used as a tool to help the user understand and/or assess potential diagnostic and treatment options. It does NOT include all information about conditions, treatments, medications, side effects, or risks that may apply to a specific patient. It is not intended to be medical advice or a substitute for the medical advice, diagnosis, or treatment of a health care provider based on the health care provider's examination and assessment of a patient's specific and unique circumstances. Patients must speak with a health care provider for complete information about their health, medical questions, and treatment options, including any risks or benefits regarding use of medications. This information does not endorse any treatments or medications as safe, effective, or approved for treating a specific patient.

Finally, I have done my best to put this information together for the reader, so that, you, may make those decisions necessary for your long life and happiness.

As always, stay safe!

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