key: cord-0948852-1gz6h6zc
authors: Lamberghini, Flavia; Testai, Fernando D.
title: COVID-19 Fundamentals
date: 2021-02-05
journal: J Am Dent Assoc
DOI: 10.1016/j.adaj.2021.01.014
sha: 11c0200c52d347384a17598a79a87cd049ddb943
doc_id: 948852
cord_uid: 1gz6h6zc

Background A novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified at the end of 2019. The disease caused by SARS-CoV-2 was named COronaVIrus Disease-19 (COVID-19). The main purpose of this review is to provide an overview of SARS-CoV-2. Methods The authors searched the MEDLINE database for clinical studies related to virus characteristics, pathogenesis, diagnosis, transmission mechanisms, and treatment options. Results As of January 27, 2021, the number of infected individuals and deaths associated with COVID-19 are approximately 100 million and 2 million worldwide, respectively. The manifestations of COVID-19 are variable, and the severity is affected by age and preexisting medical conditions. Children and adolescents are usually asymptomatic or have mild symptoms. The elderly, in comparison, may experience severe illness and have a disproportionally elevated mortality. Among those who survive, some may experience enduring deficits. The viral load is particularly elevated in saliva and oropharynx, which constitute potential sources of infection. The diagnosis of the disease may be confounded by factors related to the replicating cycle of the virus, viral load, and sensitivity of the diagnostic method utilized. At present, COVID-19 has no cure but can be prevented. Its treatment is based on supportive care along with antiviral medications and monoclonal antibodies. In severe cases with multi-organ involvement, mechanical ventilation, dialysis, and hemodynamic support may be necessary. Conclusions COVID-19 is a transmittable disease with a variable course. A substantial number of patients, particularly children, remain asymptomatic. Significant advances were done in the development of new treatments. However, the mortality in vulnerable populations remains elevated.

In December 2019, an outbreak of pneumonia of unidentified origin began in the Hubei province of China raising global health concerns due to the ease of transmission and elevated case-fatality rate reported in vulnerable populations. Researchers discovered that the etiology was a new coronavirus, which they named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The illness caused by the virus was called Coronavirus Disease-19 (COVID-19) (1).

Over next few months, the viral infection spread rapidly to the rest of the world causing a pandemic ( Fig.   1 ) (2) . On March 11, 2020 , the WHO announced a Public Health Emergency of International Concern.

The crude mortality ratio, defined as the number of reported deaths divided by the reported cases, was originally reported as 3-4%. However, with the implementation of screening programs, more mild and/or asymptomatic cases were identified and the mortality ratio is now estimated as 2% (3) . In comparison, the annual mortality of seasonal influenza is less than 0.1%. Here we present an overview of the etiology, epidemiology, pathogenesis, diagnosis and treatment of SARS-CoV-2 infection. The science of vaccines for SARS-Co-V2 is rapidly evolving, and is beyond the scope of this review.

The first human coronavirus was isolated from a boy with a common cold in 1965 (4) . Coronaviruses are single-stranded ribonucleic acid (RNA) viruses, with four structural proteins called S, M, N and E (Fig. 2) .

The S protein, a spike-like glycoprotein that radiates from the viral surface "like a solar corona", has a critical role in the attachment of virus to the host cell. The S-protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor located on human epithelial cells, followed by penetration of the cell. The J o u r n a l P r e -p r o o f expression of viral S protein at the host cell membrane may facilitate cell-to-cell fusion, resulting in the formation of a syncytia, which permits the direct spread of coronaviruses between cells (5, 6) . SARS-CoV-2 has a particular tropism for tissues with elevated expression of ACE2 such as lung, intestine, kidney, and blood vessels (7) . The M protein is the most abundant structural protein and defines the shape of the viral envelope. The E-protein is the smallest structural protein and may activate the inflammasome to drive the hyperinflammatory response observed in COVID-19. The N-protein binds to the viral genome, makes up the nucleocapsid, and has a role in the replication cycle.

It has been hypothesized that SARS-CoV-2 originated in Chinese horseshoe bats and jumped species into humans (8) . COVID-19 constitutes the third coronavirus of zoonotic origin that infects humans. The first was Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-1) that emerged in China in 2002, originating in civets. The second was the Middle Eastern Respiratory Syndrome coronavirus (MERS) that appeared in Saudi Arabia in 2012, originating from dromedary camels (9) .

People of all ages may be infected by SARS-CoV-2; however, almost 80% of cases of COVID-19 occur in adults aged 30 to 69 years old. In addition, there is emerging evidence of maternal-fetal l transmission in pregnant women infected with the virus. (10, 11) .

Although the number of cases is similar in males and females, the risk of death due to COVID-19 is higher in men. There are different hypotheses for this , including sex-specific differences in immunity, expression of ACE2, lifestyles, and the prevalence of comorbid conditions (10, 11) .

Hispanics/Latinos (H/L) and African Americans (AA) are three times more likely to become infected with COVID-19 and are nearly twice as likely to die as Whites. The high burden of the disease in these diverse J o u r n a l P r e -p r o o f groups is probably related to the higher prevalence of pre-existing medical conditions and lifestyles that prevent social distancing. As an example, the proportion of workers employed in service and manufacturing sectors is 25% for whites and 43% for non-Whites. In addition, H/L and AA are also twice as likely to live in crowded dwellings compared to Whites (12) . The epidemiology of COVID-19 may also be influenced by circumstances that compromise social distancing, including civil unrest and social gatherings during holidays. However, the effect of these and other phenomena on the incidence of the disease are only partially understood (13, 14) .

Risk factors for COVID-19 include older age, obesity, and chronic medical conditions, such as heart or lung disease, and diabetes. According to the Centers for Disease Control and Prevention (CDC), COVID-19 patients with underlying medical conditions are 6 times more likely to be hospitalized and 12 times more likely to die than those without. (15) . The need for hospitalization as well as the mortality increase exponentially with age ( Fig. 3) (16, 17) .

The routes of human-to-human transmission of SARS-CoV-2 include direct inhalation of contaminated droplets released into the environment by sneezing or coughing, and contact transmission via oral, nasal, and ocular mucous membranes (18) . Microbes in aerosols, droplets of < 5 μm in diameter, can be suspended in the air for a long period of time and transmitted to others over distances of more than 3 feet or 1 meter (19) . Transmission may also occur through direct contact with infected objects (20) .

The number of people one individual could infect is called the Reproductive Number (R0 or R-Naught).

SARS-CoV-2 has an R0 = 2 to 3. If each COVID-19 positive person infects two people, the size of the outbreak doubles quickly. Resistance to the spread of the virus can be improved by barrier measures (i.e. use of masks and face shields), social distancing, and the development of population immunity (21, J o u r n a l P r e -p r o o f 22) . Herd Immunity occurs when the infection is no longer growing exponentially; depending on multiple factors, it is estimated that this occurs when 60-80 % of the population has developed immunity (23) .

Herd immunity provides indirect protection by minimizing the probability of contact between a susceptible individual and an infected host. There are two possible approaches to build population immunity: (A) natural immunity through exposure of a significant proportion of the population to the wild-type virus, or (B) artificial immunity through mass vaccination campaigns. Establishing herd immunity through natural exposure is not a viable or safe strategy. In response to this dilemma, new vaccines against SARS-CoV-2 have been developed and are being implemented at the time of publication Long-term outcomes, including effectiveness in preventing viral transmission, preventing manifestations of COVID-19, safety, and duration of protection, are still unknown Therefore, policies that raise awareness about protective measures such as mask-wearing, strategies to prevent spread such as distancing, in combination with increased detection of asymptomatic carriers, contact tracing and isolation are likely to continue for some time despite the availability of new vaccines.

The incubation period is the time from infection to emergence of symptoms. For COVID-19, the incubation period ranges from 2 to 14 days and 50% will become ill by day 5. The infectious period, in comparison, is the time during an infected person may transmit the virus to others. In the case of COVID-19, the infectious period begins 2 days before the start of signs and symptoms, and ends when at least 10 days have passed, symptoms have disappeared, and there has been no fever for the last 72 hours. In comparison, the incubation period for the flu is 1-4 days and the infectious period 3-7 days.

The extended incubation and infectious periods of COVID-19 enhance its spreading potential (24) .

Pathogenesis Human ACE2 , the major cell-surface receptor for the viral S protein, provides the entry point for SARS-CoV-2 into the organism. (25) . In normal circumstances, ACE2 regulates blood pressure and inflammation. In pathologic conditions, ACE2 causes inflammation and tissue injury. The presentation of COVID-19 is variable and may resemble seasonal flu (Table 1) When adequate oxygen saturation cannot be spontaneously maintained, mechanical ventilation support may be necessary. If this is insufficient, Extracorporeal Membrane Oxygenation (ECMO) is employed.

With ECMO, the mortality rate of critically ill patients is 45%, in contrast to 60-70% with mechanical ventilation. (27) .

Knowledge about the long-term sequelae of COVID-19 is just emerging. Some individuals, called long-COVID or long-haulers, have a protracted recovery and experience cough, fatigue, and low-grade fever that can linger for months after the original infection. Other symptoms include headache, neurocognitive decline, muscle pain, gastrointestinal dysfunction, shortness of breath, and chest pain J o u r n a l P r e -p r o o f (28, 29) . The pathogenesis of this phenomenon is poorly defined and different mechanisms have been proposed, including chronic inflammatory or immune reaction, persistent viremia due to incomplete immune response to the infection, deconditioning, and psychogenic factors such as post-traumatic stress disorder (28) .

Approximately 2 to 5% of individuals with laboratory-confirmed COVID-19 are younger than 18 years old. Screening efforts have targeted largely adults who are considered vulnerable. (30) . Thus, the epidemiology of SARS-CoV-2 infection in children is incomplete and rapidly evolving. The reasons for the low prevalence of COVID-19 observed in children relative to adults is not fully understood ACE2 expression may be lower in pediatric populations. In addition, children may have a qualitatively different immune response to SARS-CoV-2 than adults. Furthermore, other viruses in the mucosa of the lungs and airways, common in young children, may compete with SARS-CoV-2 and limit its infectivity (31) .

Most children diagnosed with COVID-19 present mild symptoms and require only supportive care.

However, several studies have shown that, despite being asymptomatic, children may have elevated viral load and contribute to spread of the infection (32) . Similar to adults, the main signs and symptoms of the disease in children are cough and fever (Table 2) (33). Other symptoms may include shortness of breath, pharyngeal erythema, abdominal pain, conjunctivitis, poor feeding, and generalized rash (34) .

Dysgeusia with or without anosmia, is commonly reported in adults and may be an early and/or lone manifestation of COVID-19 infection, however these are uncommon in children (34) (35) (36) . (38) .

The diagnosis of COVID-19 is based on clinical signs and symptoms, laboratory testing, and imaging studies, including chest x-ray or CT. Infected individuals may develop flu-like symptoms that present at day 2 to 14 (Table 1) (39, 40) . The most common laboratory abnormalities are lymphopenia, leukopenia, hypoalbuminemia, hypertroponinemia, and elevated levels of inflammatory markers such as C-reactive protein (CRP), erythrocyte sedimentation rate, lactic dehydrogenase, interleukin-6 and ferritin. Severe cases may also present laboratory evidence of renal and liver dysfunction as well as coagulopathy. This is characterized by elevated levels of D-dimer and fibrin degradation products, thrombocytopenia, and prolonged prothrombin time and activated partial prothrombin time (41) .

Testing is crucial to diagnose SARS-CoV-2 and understand the disease prevalence, spread, and severity.

Two main types of tests are currently available: to detect the virus or to detect presence of antibodies.

Real time reverse transcriptase polymerase chain reaction (RT-PCR) is a molecular diagnostic technique J o u r n a l P r e -p r o o f that permits the identification of the viral genetic material in a specimen obtained by swab sampling of the nose, throat, mouth, or saliva. This is typically used in people with signs and symptoms of the disease, or those with confirmed exposure. Different PCR platforms are currently available. The positivity rate of this methodology depends on the viral load, the quality and type of specimen tested, and the sensitivity/specificity of the platform used (7, 9) . It is important to highlight that a negative test does not conclusively exclude the infection, particularly if the viral load is low, as may occur in individuals who are pre-symptomatic, asymptomatic, and pauci-symptomatic.

The serologic test identifies human antibodies that recognize the virus. Three isotypes of antibodies -IgG, IgM, and IgA-may be detected in blood (42) . A positive test means that the person was exposed to SARS-CoV-2 and developed antibodies against it. However, the degree of protection of these antibodies and the duration of immunity are unclear.

Another important factor that affects the sensitivity of both types of tests, is the window period. This is defined as the time from exposure to the pathogen until the laboratory test can reliably confirm the infection. The window period depends on the viral replication time (RT-PCR test) and the time required for the body to mount a measurable immune response (serologic test). Extended window periods increase the rate of false-negative results, and subsequent asymptomatic spread. (43) . Studies using serologic tests have shown highly variable immune responses, including a broad range of antibodies among people with mild symptoms of the virus, fewer antibodies among younger people, and no trace of antibodies in some individuals (44) .

The production of antibodies against the S protein and its receptor-binding domain appear to be protective against SARS-CoV-2 (45) . IgM titers increase within the first week of the SARS-CoV-2 infection, J o u r n a l P r e -p r o o f peak after two weeks and then decrease progressively. IgG levels increase after the first week, peak three weeks after, and remain elevated for at least three months (46, 47) . Antibody titers decrease over time, particularly in mild cases (46, 48) . Cases of reinfection have been reported, some of which may be explained by the emergence of new viral strains (49) . Nonetheless, the duration of immunity against SARS-CoV-2 remains to be determined. However, as the immune response matures, memory T cells and B cells are produced (50) . These cells, as opposed to circulating antibodies, ensure long-term protection.

Thus, the decrease in the titers of circulating antibodies does not imply lack of immunity as the presence of memory immune cells allows a rapid and effective response against possible reinfections (51) .

A previous study showed a higher seroprevalence of antibodies against respiratory viruses in oral surgeons than in age-matched controls (52) . The authors of this study concluded that "dentists are at occupational risk of infection with respiratory tract viruses". However, there are limited reports documenting the development of clusters of contagion among dental providers in other infectious outbreaks, due to routine infection control practices. SARS-Cov-2, in particular, is present in high concentrations in the mouth and oropharynx (53) . Dental procedures generate aerosols which could carry the virus and increase the risk for spread (54) . Thus, it is possible that dental providers could get infected if exposed to a patient with SARS-CoV-2. Despite this potential risk, a recent survey showed that the rate of COVID-19 among dentists is less than 1% (55).

More than 95% of the dental practices either closed or worked at reduced capacity during the initial peak of the pandemic (56) . Thus, the results of this study may underestimate the real risk for dental providers at this time. It is also possible that routine practices could reduce the risk of spread of the disease in the dental office. For example, it has been proposed that water or air spray could dilute the J o u r n a l P r e -p r o o f viral load. In addition, high-volume suction could reduce aerosol at source and this process could be further increased if a dental rubber dam is used to isolate the affected tooth from the oropharynx (57) .

The use of appropriate personal protective equipment including the use of respirators can prevent spread, as outlined in the CDC guidelines for dental settings, summarized in Table 3 (58) . Most dental practices have developed screening questionnaires to identify patients with signs or symptoms suggestive of COVID-19. The use of PCR testing is commonly used before medical procedures but has not been universally adopted in dentistry. In our own office, we performed PCR testing on more than 1,000 consecutive patients undergoing dental treatment who were asymptomatic and denied exposure to confirmed cases. The positivity rate in our cohort reached approximately 2-3% (submitted for publication). Our experience indicates that, though easy to implement, the use of screening questionnaires does not identify asymptomatic patients who are a source of contagion (32) .

An effective therapy against COVID-19 should target the virus and/or address complications such as the thrombotic microangiopathy, hemostatic disorders, and severe systemic inflammatory response (43) .

The most commonly used medications include A) immune-based therapy, such as corticosteroids, interferons, antimalarial drugs, and monoclonal antibodies, B) agents against viral proteins, including proteinases, helicases, and polymerases, and C) adjunctive therapy, such as zinc, vitamin D, azithromycin, ascorbic acid, and nitric oxide. In cases of procoagulability, anticoagulation with heparin, low-molecular weight heparin, or direct thrombin inhibitors may be indicated (59) . The treatment of the disease may require, in severe cases, mechanical ventilation, dialysis and/or pharmacologic hemodynamic support. The antiviral agents investigated for the treatment of SARS-CoV-2 infection include remdesivir, umifenovir, lopinavir, oseltamivir, and favipiravir (63) . Remdesivir is an inhibitor of the viral RNAdependent RNA polymerase that has in vitro activity against SARS-CoV-1 and MERS. In a randomized clinical trial including 1,062 adults with COVID-19, the use of remdesivir was associated with a J o u r n a l P r e -p r o o f significantly shorter time to recovery compared to placebo (10 days vs. 15 days; p<0.001) with no effect on mortality (64) . Based on the results of this and two other smaller studies, on October 22, 2020, the FDA approved remdesivir for use in adults and children older than 12 years with COVID-19 requiring hospitalization (65) (66) (67) .

Different strategies to mitigate the hyperinflammatory state triggered by COVID-19 have been investigated. In an open label study, the 28-day mortality was 25.7% in patients receiving usual care and 22.9% in those treated with dexamethasone (p<0.001) and this finding was more pronounced in patients requiring respiratory support (68) . Baricitinib is an oral selective inhibitor of Janus kinase (JAK) 1 and 2.

In a randomized double-blind placebo-controlled study including 1,033 adults with COVID-19, the combination of baricitinib plus remdesivir reduced the median time to recovery relative to remdesivir plus placebo (7 days vs. 8 days; p=0.03) with no significant effect on mortality. In addition, in the subgroups of patients receiving high-flow oxygen or noninvasive ventilation at enrollment, the time to recovery was 10 days in the baricitinib plus remdesivir group and 18 days in the remdesivir group (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08) (69) . On November 19, 2020, the FDA issued an EUA for the use of baricitinib in combination with remdesivir in hospitalized adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or ECMO.

Chloroquine and Hydroxychloroquine have been used as antimalarial medications for more than 70 years and also against the human immunodeficiency virus, and small clinical studies suggested potential as therapy for COVID-19. However, the administration of chloroquine and hydroxychloroquine in COVID-19 patients has been associated with an increased risk of cardiac arrhythmias and cardiac arrest so they are currently not recommended (59) . The beneficial effects of vitamin D (70) and zinc (71) have yet to be demonstrated in properly powered randomized trials (59).

Convalescent plasma (CP) refers to the acellular blood fraction from individuals who recovered from COVID-19 that contains antibodies that recognize SARS-CoV-2. On August 23, 2020, the FDA authorized the use of CP for the treatment of patients hospitalized with COVID-19. However, the panel also recognized the lack of adequately powered, controlled, randomized studies addressing the benefits and risks of this treatment. Therefore, the FDA considers that there is insufficient evidence to support or reject the use of CP or other blood products, such as SARS-CoV-2 immunoglobulins, for the treatment of COVID-19 (75) .

COVID-19 has affected our lives at multiple levels due to its rapid spread, elevated mortality rate, social impact, and economic damage worldwide. Critical thinking is necessary to interpret the results of diagnostic studies as false negative results can occur. The elderly and individuals with chronic medical conditions are vulnerable populations that are at high risk for disease and complications. In contrast, children, are frequently asymptomatic but may be a source of infection. In the last few months, different pharmacologic approaches were identified for the treatment of SARS-CoV-2 infection and several others are in the pipeline. In addition, the development of new vaccines against SARS-CoV-2 is likely to change the landscape of the pandemic. Our understanding of the disease is rapidly evolving and future findings may challenge some of the information included in this review. 

• Utilize screening tools to identify patients and staff members with signs and symptoms of COVID-19 • Develop protocols to respond to exposures to infected individuals • Implement universal source control strategies (gloves, face shield, gown, goggles, etc) • Promote social distancing • Adjust patient volume to avoid congregations in the waiting area • Adopt effective infection control strategies • Consider performing SARS-CoV-2 testing of symptomatic or asymptomatic patients Work Practice

• Consider postponing elective procedures, surgeries, and non-urgent outpatient visits • Implement teledentistry and utilize triage protocols • If aerosol generating procedures are necessary, use four-handed dentistry, high evacuation suction and dental dams • Consider using preprocedural mouth rinses with antimicrobial to minimize viral load

• Maintain ventilation systems • Consult with HVAC specialist to understand air flow patterns, filtration efficiency, enhance the percentage of outside air supply • Consider using a portable high-efficiency particulate air filtration unit for patients undergoing aerosol-generating procedures • Consider supplanting air ventilation enhancements with ultraviolet germicidal

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