The disease: COVID-19
SARS-CoV-2: a zoonotic virus
All seven human coronaviruses, e.g., SARS-CoV and MERS-CoV responsible for SARS, MERS, respectively, including SARS-CoV-2, are zoonotic viruses that are reported to have originated in other host species, specifically bats or rodents., Further to this, there is evidence of interspecies transmission of these viruses to intermediate host species (which vary depending on the coronavirus) prior to infecting the human species.,
Based on a 96.2% genetic sequence homology to a bat coronavirus, SARS-CoV-2 is believed to have originated in bats and to then have made an interspecies jump to an intermediate host (possibly pangolins, an endangered small mammal species) and eventually there was an interspecies transmission event into humans., Similar to SARS-CoV-2, SARS-CoV and MERS-CoV demonstrate strong genetic sequence homology to bat coronaviruses, supporting that these viruses also likely originated in bats; however, the intermediate species identified for SARS-CoV is palm civets, whereas the intermediate species for MERS-CoV is dromedary camels.,
SARS-CoV-2: a highly infectious and contagious virus
SARS-CoV-2 is highly infectious and contagious, and it is transmitted primarily by close personal contact with infected persons, as well as contact with contaminated surfaces and with body fluids from infected persons.
Interventions targeted at limiting and preventing the spread of the virus, such as contact tracing, self-isolation, mask wearing, and diligent hygiene, are imperative to maintain at this time.-
The transmission of SARS-CoV-2 can occur in several ways:
- Close contact with infected persons, which is defined as being within 2 meters of each other. It is believed that this type of transmission is mediated through larger respiratory droplets produced by talking, coughing, sneezing, or singing. Known factors that increase the risk of transmission include physical proximity between individuals (especially indoors in poorly ventilated areas), duration of interaction, and interaction among multiple people.-
- Contact with contaminated areas, such as when touching a contaminated (virus-laden) surface or object and then touching one’s own nose, mouth, or eyes.,,
- Contact with contaminated body fluids, including aerosols and secretions, produced by infected persons.-
- In comparing transmission of SARS-CoV-2 with SARS-CoV-1 and seasonal influenza virus, there are some important distinctions that contribute to the highly infectious and contagious nature of SARS-CoV-2.
SARS-CoV-2 compared to other important viruses
Time between infection and onset of symptoms. Serial Interval: Duration between symptom onsets of successive cases in a transmission chain.
Adapted from He, X et al. Nat Med (2020)
the average incubation period is longer, at 4 to 5 days, and viral shedding begins after symptom onset (again, in symptomatic patients).
the average incubation period is similar to that of SARS-CoV-1, at 5.2 days, but (similar to seasonal influenza virus) viral shedding begins about 2.3 days before symptom onset. As with influenza, infected patients who are not yet showing symptoms shed virus before they start to feel ill. Thus, presymptomatic shedding is a key factor in the transmissibility of the COVID-19-causing virus.-
Specific interventions to restrict SARS-CoV-2 transmission
Specific interventions to prevent or restrict SARS-CoV-2 transmission are crucial in limiting COVID-19 prevalence.
Globally, public guidelines for the prevention and control of COVID-19 issued by the World Health Organization (WHO), the European Centre for Disease Prevention and Control (ECDC), and the U.S. Centers for Disease Control and Prevention (CDC) all emphasize the following as recommended intervention measures to limit SARS-CoV-2 transmission:-
- the wearing of masks,
- good hand hygiene (i.e., thorough and frequent washing of hands or use of an alcohol-based hand sanitizer),
- avoidance of touching one’s own face,
- frequent disinfecting of surfaces,
- physical distancing of at least 1–2 meters between individuals,
- and quarantining (if one is feeling ill or has been in contact with someone who has recently been ill).
In addition to public guidelines, the WHO has also released several Country and Technical Guidance documents related to surveillance, contact history tracking and quarantining; preparedness and response (including testing guidance); and other COVID-19 technical guidance (https://www.who.int).
In line with the WHO’s COVID-19 Country and Technical Guidance, Germany’s Robert Koch Institute (RKI) has a COVID-19 surveillance system in place called CovApp (https://covapp.rki.de), which is a symptom and contact history questionnaire that analyzes a user’s responses and provides a recommendation for action.
In addition, the RKI has developed official communications for patients, including “Coronavirus Infection and Home Quarantine” (https://www.rki.de) and “Self-Isolation at Home With Confirmed COVID-19” (https://www.rki.de).
These communications include specific guidance on:
- Limiting contact by staying at least 2 m away from other people, avoiding group gatherings, avoiding close contact with people who are sick, and self-isolating-
- Wearing face coverings when around others or in public-
- Practicing good hygiene, including frequent and proper hand washing with soap and warm water for at least 20 seconds each time and coughing and sneezing into a tissue (and washing hands afterward)
- Regularly cleaning/disinfecting frequently touched surfaces and properly disposing of waste
SARS-CoV-2 infects cells by first binding to the cell surface protein ACE2 (angiotensin-converting enzyme 2), a viral entry receptor, and then binding to TMPRSS2 (transmembrane protease serine subtype 2), which helps mediate viral entry.-
The infection and replication life cycle of SARS-CoV-2 includes the following steps:
1) A viral spike protein (S) binds to ACE2 (angiotensin-converting enzyme 2) on target cells via its receptor-binding domain (RBD). ACE2 is a cell surface protein that has been identified as the viral entry receptor for SARS-CoV-2. TMPRSS2 (transmembrane serine protease 2) helps the virion enter the cell by proteolytic cleavage and activation of viral envelope proteins.,
- B cells may recognize spike protein during initial infection and begin to produce antibodies against various regions of the spike protein, including the receptor-binding domain (RBD). Of note, several immunologically important T cell epitopes for SARS-CoV-2 localized to various domains of the spike protein (not only the RBD) have been identified by computational analyses.
2) The virion uncoats its RNA and releases them into the cell’s cytoplasm.
- Upon entry into the cell, viral components may be recognized by Toll-like receptors (TLR) at various stages of the replication cycle (specifically, TLR-3, -7/8, and -9), resulting in the stimulation of anti-viral innate immunity pathways.
3) Some viral RNA is translated by cellular protein synthesis into viral non-structural proteins by the cell’s translation machinery.
4) Some of the viral proteins assemble to form a replication complex to make more viral RNA.
5) Viral proteins and RNA are assembled into new virions in the Golgi apparatus.
- Some viral proteins may also be processed by the infected cell into antigenic epitopes presented to T cells and B cells, further stimulating the anti-viral adaptive immune response.
6) The new virions are then released from the cell, where they can proceed to infect more cells and repeat the replication cycle.
- Virions released into the extracellular space may be taken up by professional antigen-presenting cells (APCs), which will further process and present viral antigenic peptides (ie, epitopes) to adaptive immune cells, stimulating cytokine production and maturation of humoral and cellular immunity against the virus.
Initial studies investigating the adaptive immune responses to SARS-CoV-2 demonstrated that B-cell immunity to the virus is primarily directed against the spike protein and the nucleocapsid protein (N), which can block further viral entry into ACE2-expressing cells and expedite viral clearance. In addition, both CD4 and CD8 T-cell immune responses, as well as a favorable TH1 cytokine profile, have been reported in humans post-SARS-CoV-2 infection, and associations between the breadth of the T-cell immune response and the severity of illness (i.e., the higher the number of T-cells circulating, the less severe the illness experienced) have been shown.
Contrary to the positive immune response needed to clear SARS-CoV-2 infection, mounting evidence suggests that mortality associated with COVID-19 may result from the manifestation of a “cytokine storm” (i.e., unregulated and excessive cytokine production) in some infected patients, resulting in severe illness and potentially death. In these patients, high concentrations of pro-inflammatory cytokines (such as IL-6, CXCL10 (IP-10), and CCL2 (MCP-1) typical for a TH2-dominant response), increases in TH17 cells, and excessive toxicity of CD8 T-cells resulting in the cytokine storm and unchecked tissue and organ damage were reported.
The symptomology and course of the disease in COVID-19 patients vary from mild (Stage 1) to severe (Stage 3), and the potential long-term sequelae for patients are beginning to be characterized.
- An estimated 18–81% of people who become infected with SARS-CoV-2 may be asymptomatic; however, most people who become infected with SARS-CoV-2 experience a mild disease (Stage 1) that manifests after an incubation period of 2 to 14 days. This stage is associated with mild and often nonspecific symptoms, such as a dry cough, shortness of breath or difficulty breathing, fever, rigor, myalgia, sore throat, and/or new anosmia or ageusia. Other, less common symptoms that have been reported include nausea, vomiting, or diarrhea. The majority of these patients recover without the need for hospitalization.,
- Patients that progress to the next stage of the disease (Stage 2) generally experience pulmonary involvement (with or without hypoxia) that manifests as a viral pneumonia in up to 75% of patients or acute respiratory distress syndrome (ARDS) in up to 15% of patients. Most Stage 2 patients need to be hospitalized for closer observation.,
- A minority of patients transition to a more severe stage of the disease (Stage 3), involving extrapulmonary systemic hyperinflammation due to an increase in inflammatory cytokines, which can result in shock, respiratory failure, and cardiopulmonary collapse. The overall prognosis for these patients is poor.
Adapted from Siddiqi, HK et al. J Heart Lung Transplant (2020)
A subset of patients who have recovered from COVID-19 may continue to experience ongoing symptoms and complications (i.e., long-term sequelae), such as neurologic complications in the brain and other parts of the body; lung injury, including scarring; cardiomyopathy and arrhythmias; and hypertension.
The extent and long-term severity of these sequelae are currently not well understood or characterized; however, at least one study, the CORAL study (COVID-19 Observational Study, funded by the U.S. National Heart, Lung, and Blood Institute), aims to better characterize, understand, and describe COVID-19 biology as well as the extent of the long-term effects of this disease.
Populations at risk for serious illness from COVID-19 include those who are immunocompromised, exposed to higher viral loads, or are genetically pre-disposed; these include:
Because ACE2 is expressed on many types of cells and tissues, several organ systems have the potential to be targeted by SARS-CoV-2, with patients experiencing different symptoms depending on which organs are involved.
- Major organ systems involved and associated symptomology:
- Pulmonary: pneumonia, acute respiratory distress syndrome (ARDS)
- Cardiovascular: myocardial infarction, critical arrhythmias, clotting events,
- Neurologic: strokes, seizures, anosmia, ageusia, encephalitis, headaches,, psychiatric disorders
- Renal: acute tubular necrosis, interstitial disease, renal failure,
- Hepatic: hepatocellular dysfunction
- Intestinal tract: diarrhea, vomiting,
- Musculoskeletal: myalgias, myositis
- Less common organ systems involved and associated symptomology:
- Dermatologic: nonspecific papular, erythematous rash; chilblains; papular, ecchymotic/petechial lesions on acral surface,,
- Ocular: conjunctivitis, epiphora,
- Multisystem Inflammatory Syndrome in children (MIS-C): a Kawasaki-like hyperinflammatory syndrome of multiorgan involvement with symptoms including (but not limited to) extended fever, left ventricular systolic dysfunction, gastrointestinal pain, liver and kidney dysfunction, and shock
Both the innate (e.g., TLR) and adaptive (e.g., B and T cells) arms of the immune response are stimulated by SARS-CoV-2 infection. Studies investigating the adaptive immune responses to SARS-CoV-2 demonstrate that neutralizing antibodies against the virus’ S and N proteins can block further viral entry into ACE2-expressing cells and expedite viral clearance. In addition, associations between the breadth of the T-cell immune response (both CD4 and CD8) and the severity of illness in patients (i.e., the more robust the T-cell response, the less severe the illness experienced) have been shown.
T-cell responses against the spike protein (S) of SARS-CoV-2 have been characterized and correlate well with immunoglobulin G (IgG) antibody titers; however, it is not yet known if protective immunity is mainly from T cells or antibodies or if both are required.
Most infected individuals mount an antibody response between 10 and 21 days postinfection. However, it is important to note that detection of antibodies does not necessarily indicate protective immunity, and correlates of protection have not yet been established.
In addition, longevity of the adaptive immune response against SARS-CoV-2 is still not known, but there is speculation that it may be similar to what has been reported with SARS-CoV-1 and MERS-CoV, in which markers of immunity were detectable when previously infected patients were tested 2–3 years after but absent when those same patients were tested 5–6 years after; however, re-infection with SARS-CoV-2 has been documented in some patients to date and it is unclear what that means for durable protective immunity against this virus.
In a recent analysis of 185 COVID-19 cases, including 41 cases at > 6 months postinfection, the authors investigated multiple components of the immune memory to SARS-CoV-2. The data demonstrated that the Spike IgG remained consistent over more than 6 months post infections and the Spike-specific memory B cells were more greater at 6 months compared to at 1 month. A decline in SARS-CoV-2-specific CD4+ T cells and CD8+ T cells was observed with a half-life of 3-5 months.
Immunopathology seen in COVID-19 patients is caused by the body’s innate and adaptive immune responses attempting to clear the SARS-CoV-2 infection, but skewing towards a TH2-dominant adaptive response, resulting in immune dysregulation that can manifest as:
- Uncontrolled proinflammatory cytokine production, along with decreased anti-inflammatory cytokine production, resulting in a “cytokine storm”
- Increased neutrophilic and monocytic inflammatory responses
- Increased interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α
- Decreased number of CD4- and CD8-T cells
- Resultant acute lung injury and multisystem organ failure
The availability and widespread implementation of SARS-CoV-2 testing are important in understanding the epidemiology of viral infection rates across populations. However, there are vast differences in testing rates from country-to-country, undermining the true prevalence of the virus in some regions as compared to others.
- For up-to-date information on SARS-CoV-2 testing rates on a country-by-country basis, please see the Our World in Data database.
- To this effect, Germany has excelled in the early establishment of SARS-CoV-2 testing (since January 2020) and continued high levels of testing throughout the COVID-19 pandemic (18.6 tests per positive case, as of May 2020).
There have been 961,320 confirmed cases of COVID-19 and 14,771 COVID-19-related deaths reported in Germany from January 3 to November 25, 2020.
- For up-to-date information on COVID-19 incidence and death rates in Germany, please see the World Health Organization’s (WHO) Coronavirus Disease (COVID-19) Dashboard for Germany.
It is interesting to note that many countries are reporting disparities between different subpopulations in terms of COVID-19-associated hospitalization rates and outcomes. For example, in the U.S. and UK, mortality rates reported for those considered to be non-White ethnic minorities (ie, Black, Asian, LatinX, Indigenous American, etc.) have been disproportionately higher than for their White counterparts;, these differences are speculated to be attributed (at least partially) to the long-standing baseline disparities in underlying comorbidities, access to healthcare, and other socioeconomic differences between Whites and non-Whites in these regions.,
In Germany, the COVID-19 disparities that have been noted in the press are particularly between immigrant and nonimmigrant Germans and have been attributed to the socioeconomic differences between those groups affecting their risks/rates of viral exposure as well as their access to healthcare.
- Increased unemployment
- Decreased overall production and demand
- GDP decline
- Steep decreases in the stock market
- Significant declines in the travel industry due to travel bans
- Decreased reservations in the food and hospitality industries due to overall financial declines as well as disruptions in the supply chains
- Effects to the healthcare system such as deferment and delay of non-COVID-19 care, disruption in supply chains and fluctuations in facilities’ capacities
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