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There is a current outbreak of Coronavirus (COVID-19) disease Find out more →

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Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus.

Most people infected with the virus will experience mild to moderate respiratory illness and recover without requiring special treatment. However, some will become seriously ill and require medical attention. Older people and those with underlying medical conditions like cardiovascular disease, diabetes, chronic respiratory disease, or cancer are more likely to develop serious illness. Anyone can get sick with COVID-19 and become seriously ill or die at any age.

The best way to prevent and slow down transmission is to be well informed about the disease and how the virus spreads. Protect yourself and others from infection by staying at least 1 metre apart from others, wearing a properly fitted mask, and washing your hands or using an alcohol-based rub frequently. Get vaccinated when it’s your turn and follow local guidance.

The virus can spread from an infected person’s mouth or nose in small liquid particles when they cough, sneeze, speak, sing or breathe. These particles range from larger respiratory droplets to smaller aerosols. It is important to practice respiratory etiquette, for example by coughing into a flexed elbow, and to stay home and self-isolate until you recover if you feel unwell.

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To prevent infection and to slow transmission of COVID-19, do the following:

Get vaccinated when a vaccine is available to you.
Stay at least 1 metre apart from others, even if they don’t appear to be sick.
Wear a properly fitted mask when physical distancing is not possible or when in poorly ventilated settings.
Choose open, well-ventilated spaces over closed ones. Open a window if indoors.
Wash your hands regularly with soap and water or clean them with alcohol-based hand rub.
Cover your mouth and nose when coughing or sneezing.
If you feel unwell, stay home and self-isolate until you recover.

COVID-19 affects different people in different ways. Most infected people will develop mild to moderate illness and recover without hospitalization.

Most common symptoms:

loss of taste or smell.

Less common symptoms:

sore throat
aches and pains
a rash on skin, or discolouration of fingers or toes
red or irritated eyes.

Serious symptoms:

difficulty breathing or shortness of breath
loss of speech or mobility, or confusion
chest pain.

Seek immediate medical attention if you have serious symptoms. Always call before visiting your doctor or health facility.

People with mild symptoms who are otherwise healthy should manage their symptoms at home.

On average it takes 5–6 days from when someone is infected with the virus for symptoms to show, however it can take up to 14 days.

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Wiersinga WJ , Rhodes A , Cheng AC , Peacock SJ , Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19) : A Review . JAMA. 2020;324(8):782–793. doi:10.1001/jama.2020.12839

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Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19) : A Review

1 Division of Infectious Diseases, Department of Medicine, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, the Netherlands
2 Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, the Netherlands
3 Department of Intensive Care Medicine, St George's University Hospitals Foundation Trust, London, United Kingdom
4 Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, Australia
5 School of Public Health and Preventive Medicine, Monash University, Monash University, Melbourne, Australia
6 National Infection Service, Public Health England, London, United Kingdom
7 Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
8 Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor
9 VA Center for Clinical Management Research, Ann Arbor, Michigan
Review Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19) James M. Sanders, PhD, PharmD; Marguerite L. Monogue, PharmD; Tomasz Z. Jodlowski, PharmD; James B. Cutrell, MD JAMA
Viewpoint Ensuring Scientific Integrity and Public Confidence in the Search for Effective COVID-19 Treatment Jesse L. Goodman, MD, MPH; Luciana Borio, MD JAMA
Viewpoint Monoclonal Antibodies for Prevention and Treatment of COVID-19 Mary Marovich, MD; John R. Mascola, MD; Myron S. Cohen, MD JAMA
Preliminary Communication Presence of Genetic Variants Among Young Men With Severe COVID-19 Caspar I. van der Made, MD; Annet Simons, PhD; Janneke Schuurs-Hoeijmakers, MD, PhD; Guus van den Heuvel, MD; Tuomo Mantere, PhD; Simone Kersten, MSc; Rosanne C. van Deuren, MSc; Marloes Steehouwer, BSc; Simon V. van Reijmersdal, BSc; Martin Jaeger, PhD; Tom Hofste, BSc; Galuh Astuti, PhD; Jordi Corominas Galbany, PhD; Vyne van der Schoot, MD, PhD; Hans van der Hoeven, MD, PhD; Wanda Hagmolen of ten Have, MD, PhD; Eva Klijn, MD, PhD; Catrien van den Meer, MD; Jeroen Fiddelaers, MD; Quirijn de Mast, MD, PhD; Chantal P. Bleeker-Rovers, MD, PhD; Leo A. B. Joosten, PhD; Helger G. Yntema, PhD; Christian Gilissen, PhD; Marcel Nelen, PhD; Jos W. M. van der Meer, MD, PhD; Han G. Brunner, MD, PhD; Mihai G. Netea, MD, PhD; Frank L. van de Veerdonk, MD, PhD; Alexander Hoischen, PhD JAMA
Viewpoint Strongyloides Hyperinfection Risk in COVID-19 Patients Treated With Dexamethasone William M. Stauffer, MD, MSPH; Jonathan D. Alpern, MD; Patricia F. Walker, MD, DTM&H JAMA
JAMA Patient Page Patient Information: COVID-19 W. Joost Wiersinga, MD, PhD, MBA; Hallie C. Prescott, MD, MSc JAMA
Research Letter Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions Matthijs Kox, PhD; Nicole J. B. Waalders, BSc; Emma J. Kooistra, BSc; Jelle Gerretsen, BSc; Peter Pickkers, MD, PhD JAMA
Research Letter Racial/Ethnic Variation in Nasal Transmembrane Serine Protease 2 ( TMPRSS2 ) Gene Expression Facilitating Coronavirus Entry Supinda Bunyavanich, MD, MPH, MPhil; Chantal Grant, MD; Alfin Vicencio, MD JAMA
Viewpoint Therapy for Early COVID-19—A Critical Need Peter S. Kim, MD; Sarah W. Read, MD, MHS; Anthony S. Fauci, MD JAMA

Importance The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19.

Observations SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies.

Conclusions and Relevance As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

The coronavirus disease 2019 (COVID-19) pandemic has caused a sudden significant increase in hospitalizations for pneumonia with multiorgan disease. COVID-19 is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection may be asymptomatic or it may cause a wide spectrum of symptoms, such as mild symptoms of upper respiratory tract infection and life-threatening sepsis. COVID-19 first emerged in December 2019, when a cluster of patients with pneumonia of unknown cause was recognized in Wuhan, China. As of July 1, 2020, SARS-CoV-2 has affected more than 200 countries, resulting in more than 10 million identified cases with 508 000 confirmed deaths ( Figure 1 ). This review summarizes current evidence regarding pathophysiology, transmission, diagnosis, and management of COVID-19.

We searched PubMed, LitCovid, and MedRxiv using the search terms coronavirus , severe acute respiratory syndrome coronavirus 2 , 2019-nCoV , SARS-CoV-2 , SARS-CoV , MERS-CoV , and COVID-19 for studies published from January 1, 2002, to June 15, 2020, and manually searched the references of select articles for additional relevant articles. Ongoing or completed clinical trials were identified using the disease search term coronavirus infection on ClinicalTrials.gov, the Chinese Clinical Trial Registry, and the International Clinical Trials Registry Platform. We selected articles relevant to a general medicine readership, prioritizing randomized clinical trials, systematic reviews, and clinical practice guidelines.

Coronaviruses are large, enveloped, single-stranded RNA viruses found in humans and other mammals, such as dogs, cats, chicken, cattle, pigs, and birds. Coronaviruses cause respiratory, gastrointestinal, and neurological disease. The most common coronaviruses in clinical practice are 229E, OC43, NL63, and HKU1, which typically cause common cold symptoms in immunocompetent individuals. SARS-CoV-2 is the third coronavirus that has caused severe disease in humans to spread globally in the past 2 decades. 1 The first coronavirus that caused severe disease was severe acute respiratory syndrome (SARS), which was thought to originate in Foshan, China, and resulted in the 2002-2003 SARS-CoV pandemic. 2 The second was the coronavirus-caused Middle East respiratory syndrome (MERS), which originated from the Arabian peninsula in 2012. 3

SARS-CoV-2 has a diameter of 60 nm to 140 nm and distinctive spikes, ranging from 9 nm to 12 nm, giving the virions the appearance of a solar corona ( Figure 2 ). 4 Through genetic recombination and variation, coronaviruses can adapt to and infect new hosts. Bats are thought to be a natural reservoir for SARS-CoV-2, but it has been suggested that humans became infected with SARS-CoV-2 via an intermediate host, such as the pangolin. 5 , 6

Early in infection, SARS-CoV-2 targets cells, such as nasal and bronchial epithelial cells and pneumocytes, through the viral structural spike (S) protein that binds to the angiotensin-converting enzyme 2 (ACE2) receptor 7 ( Figure 2 ). The type 2 transmembrane serine protease (TMPRSS2), present in the host cell, promotes viral uptake by cleaving ACE2 and activating the SARS-CoV-2 S protein, which mediates coronavirus entry into host cells. 7 ACE2 and TMPRSS2 are expressed in host target cells, particularly alveolar epithelial type II cells. 8 , 9 Similar to other respiratory viral diseases, such as influenza, profound lymphopenia may occur in individuals with COVID-19 when SARS-CoV-2 infects and kills T lymphocyte cells. In addition, the viral inflammatory response, consisting of both the innate and the adaptive immune response (comprising humoral and cell-mediated immunity), impairs lymphopoiesis and increases lymphocyte apoptosis. Although upregulation of ACE2 receptors from ACE inhibitor and angiotensin receptor blocker medications has been hypothesized to increase susceptibility to SARS-CoV-2 infection, large observational cohorts have not found an association between these medications and risk of infection or hospital mortality due to COVID-19. 10 , 11 For example, in a study 4480 patients with COVID-19 from Denmark, previous treatment with ACE inhibitors or angiotensin receptor blockers was not associated with mortality. 11

In later stages of infection, when viral replication accelerates, epithelial-endothelial barrier integrity is compromised. In addition to epithelial cells, SARS-CoV-2 infects pulmonary capillary endothelial cells, accentuating the inflammatory response and triggering an influx of monocytes and neutrophils. Autopsy studies have shown diffuse thickening of the alveolar wall with mononuclear cells and macrophages infiltrating airspaces in addition to endothelialitis. 12 Interstitial mononuclear inflammatory infiltrates and edema develop and appear as ground-glass opacities on computed tomographic imaging. Pulmonary edema filling the alveolar spaces with hyaline membrane formation follows, compatible with early-phase acute respiratory distress syndrome (ARDS). 12 Bradykinin-dependent lung angioedema may contribute to disease. 13 Collectively, endothelial barrier disruption, dysfunctional alveolar-capillary oxygen transmission, and impaired oxygen diffusion capacity are characteristic features of COVID-19.

In severe COVID-19, fulminant activation of coagulation and consumption of clotting factors occur. 14 , 15 A report from Wuhan, China, indicated that 71% of 183 individuals who died of COVID-19 met criteria for diffuse intravascular coagulation. 14 Inflamed lung tissues and pulmonary endothelial cells may result in microthrombi formation and contribute to the high incidence of thrombotic complications, such as deep venous thrombosis, pulmonary embolism, and thrombotic arterial complications (eg, limb ischemia, ischemic stroke, myocardial infarction) in critically ill patients. 16 The development of viral sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, may further contribute to multiorgan failure.

Epidemiologic data suggest that droplets expelled during face-to-face exposure during talking, coughing, or sneezing is the most common mode of transmission ( Box 1 ). Prolonged exposure to an infected person (being within 6 feet for at least 15 minutes) and briefer exposures to individuals who are symptomatic (eg, coughing) are associated with higher risk for transmission, while brief exposures to asymptomatic contacts are less likely to result in transmission. 25 Contact surface spread (touching a surface with virus on it) is another possible mode of transmission. Transmission may also occur via aerosols (smaller droplets that remain suspended in air), but it is unclear if this is a significant source of infection in humans outside of a laboratory setting. 26 , 27 The existence of aerosols in physiological states (eg, coughing) or the detection of nucleic acid in the air does not mean that small airborne particles are infectious. 28 Maternal COVID-19 is currently believed to be associated with low risk for vertical transmission. In most reported series, the mothers' infection with SARS-CoV-2 occurred in the third trimester of pregnancy, with no maternal deaths and a favorable clinical course in the neonates. 29 - 31

Transmission, Symptoms, and Complications of Coronavirus Disease 2019 (COVID-19)

Transmission 17 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs primarily via respiratory droplets from face-to-face contact and, to a lesser degree, via contaminated surfaces. Aerosol spread may occur, but the role of aerosol spread in humans remains unclear. An estimated 48% to 62% of transmission may occur via presymptomatic carriers.

Common symptoms 18 in hospitalized patients include fever (70%-90%), dry cough (60%-86%), shortness of breath (53%-80%), fatigue (38%), myalgias (15%-44%), nausea/vomiting or diarrhea (15%-39%), headache, weakness (25%), and rhinorrhea (7%). Anosmia or ageusia may be the sole presenting symptom in approximately 3% of individuals with COVID-19.

Common laboratory abnormalities 19 among hospitalized patients include lymphopenia (83%), elevated inflammatory markers (eg, erythrocyte sedimentation rate, C-reactive protein, ferritin, tumor necrosis factor-α, IL-1, IL-6), and abnormal coagulation parameters (eg, prolonged prothrombin time, thrombocytopenia, elevated D-dimer [46% of patients], low fibrinogen).

Common radiographic findings of individuals with COVID-19 include bilateral, lower-lobe predominate infiltrates on chest radiographic imaging and bilateral, peripheral, lower-lobe ground-glass opacities and/or consolidation on chest computed tomographic imaging.

Common complications 18 , 20 - 24 among hospitalized patients with COVID-19 include pneumonia (75%); acute respiratory distress syndrome (15%); acute liver injury, characterized by elevations in aspartate transaminase, alanine transaminase, and bilirubin (19%); cardiac injury, including troponin elevation (7%-17%), acute heart failure, dysrhythmias, and myocarditis; prothrombotic coagulopathy resulting in venous and arterial thromboembolic events (10%-25%); acute kidney injury (9%); neurologic manifestations, including impaired consciousness (8%) and acute cerebrovascular disease (3%); and shock (6%).

Rare complications among critically ill patients with COVID-19 include cytokine storm and macrophage activation syndrome (ie, secondary hemophagocytic lymphohistiocytosis).

The clinical significance of SARS-CoV-2 transmission from inanimate surfaces is difficult to interpret without knowing the minimum dose of virus particles that can initiate infection. Viral load appears to persist at higher levels on impermeable surfaces, such as stainless steel and plastic, than permeable surfaces, such as cardboard. 32 Virus has been identified on impermeable surfaces for up to 3 to 4 days after inoculation. 32 Widespread viral contamination of hospital rooms has been documented. 28 However, it is thought that the amount of virus detected on surfaces decays rapidly within 48 to 72 hours. 32 Although the detection of virus on surfaces reinforces the potential for transmission via fomites (objects such as a doorknob, cutlery, or clothing that may be contaminated with SARS-CoV-2) and the need for adequate environmental hygiene, droplet spread via face-to-face contact remains the primary mode of transmission.

Viral load in the upper respiratory tract appears to peak around the time of symptom onset and viral shedding begins approximately 2 to 3 days prior to the onset of symptoms. 33 Asymptomatic and presymptomatic carriers can transmit SARS-CoV-2. 34 , 35 In Singapore, presymptomatic transmission has been described in clusters of patients with close contact (eg, through churchgoing or singing class) approximately 1 to 3 days before the source patient developed symptoms. 34 Presymptomatic transmission is thought to be a major contributor to the spread of SARS-CoV-2. Modeling studies from China and Singapore estimated the percentage of infections transmitted from a presymptomatic individual as 48% to 62%. 17 Pharyngeal shedding is high during the first week of infection at a time in which symptoms are still mild, which might explain the efficient transmission of SARS-CoV-2, because infected individuals can be infectious before they realize they are ill. 36 Although studies have described rates of asymptomatic infection, ranging from 4% to 32%, it is unclear whether these reports represent truly asymptomatic infection by individuals who never develop symptoms, transmission by individuals with very mild symptoms, or transmission by individuals who are asymptomatic at the time of transmission but subsequently develop symptoms. 37 - 39 A systematic review on this topic suggested that true asymptomatic infection is probably uncommon. 38

Although viral nucleic acid can be detectable in throat swabs for up to 6 weeks after the onset of illness, several studies suggest that viral cultures are generally negative for SARS-CoV-2 8 days after symptom onset. 33 , 36 , 40 This is supported by epidemiological studies that have shown that transmission did not occur to contacts whose exposure to the index case started more than 5 days after the onset of symptoms in the index case. 41 This suggests that individuals can be released from isolation based on clinical improvement. The Centers for Disease Control and Prevention recommend isolating for at least 10 days after symptom onset and 3 days after improvement of symptoms. 42 However, there remains uncertainty about whether serial testing is required for specific subgroups, such as immunosuppressed patients or critically ill patients for whom symptom resolution may be delayed or older adults residing in short- or long-term care facilities.

The mean (interquartile range) incubation period (the time from exposure to symptom onset) for COVID-19 is approximately 5 (2-7) days. 43 , 44 Approximately 97.5% of individuals who develop symptoms will do so within 11.5 days of infection. 43 The median (interquartile range) interval from symptom onset to hospital admission is 7 (3-9) days. 45 The median age of hospitalized patients varies between 47 and 73 years, with most cohorts having a male preponderance of approximately 60%. 44 , 46 , 47 Among patients hospitalized with COVID-19, 74% to 86% are aged at least 50 years. 45 , 47

COVID-19 has various clinical manifestations ( Box 1 and Box 2 ). In a study of 44 672 patients with COVID-19 in China, 81% of patients had mild manifestations, 14% had severe manifestations, and 5% had critical manifestations (defined by respiratory failure, septic shock, and/or multiple organ dysfunction). 48 A study of 20 133 individuals hospitalized with COVID-19 in the UK reported that 17.1% were admitted to high-dependency or intensive care units (ICUs). 47

Commonly Asked Questions About Coronavirus Disease 2019 (COVID-19)

How is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) most commonly transmitted?

SARS-CoV-2 is most commonly spread via respiratory droplets (eg, from coughing, sneezing, shouting) during face-to-face exposure or by surface contamination.

What are the most common symptoms of COVID-19?

The 3 most common symptoms are fever, cough, and shortness of breath. Additional symptoms include weakness, fatigue, nausea, vomiting, diarrhea, changes to taste and smell.

How is the diagnosis made?

Diagnosis of COVID-19 is typically made by polymerase chain reaction testing of a nasopharyngeal swab. However, given the possibility of false-negative test results, clinical, laboratory, and imaging findings may also be used to make a presumptive diagnosis for individuals for whom there is a high index of clinical suspicion of infection.

What are current evidence-based treatments for individuals with COVID-19?

Supportive care, including supplemental oxygen, is the main treatment for most patients. Recent trials indicate that dexamethasone decreases mortality (subgroup analysis suggests benefit is limited to patients who require supplemental oxygen and who have symptoms for >7 d) and remdesivir improves time to recovery (subgroup analysis suggests benefit is limited to patients not receiving mechanical ventilation).

What percentage of people are asymptomatic carriers, and how important are they in transmitting the disease?

True asymptomatic infection is believed to be uncommon. The average time from exposure to symptoms onset is 5 days, and up to 62% of transmission may occur prior to the onset of symptoms.

Are masks effective at preventing spread?

Yes. Face masks reduce the spread of viral respiratory infection. N95 respirators and surgical masks both provide substantial protection (compared with no mask), and surgical masks provide greater protection than cloth masks. However, physical distancing is also associated with substantial reduction of viral transmission, with greater distances providing greater protection. Additional measures such as hand and environmental disinfection are also important.

Although only approximately 25% of infected patients have comorbidities, 60% to 90% of hospitalized infected patients have comorbidities. 45 - 49 The most common comorbidities in hospitalized patients include hypertension (present in 48%-57% of patients), diabetes (17%-34%), cardiovascular disease (21%-28%), chronic pulmonary disease (4%-10%), chronic kidney disease (3%-13%), malignancy (6%-8%), and chronic liver disease (<5%). 45 , 46 , 49

The most common symptoms in hospitalized patients are fever (up to 90% of patients), dry cough (60%-86%), shortness of breath (53%-80%), fatigue (38%), nausea/vomiting or diarrhea (15%-39%), and myalgia (15%-44%). 18 , 44 - 47 , 49 , 50 Patients can also present with nonclassical symptoms, such as isolated gastrointestinal symptoms. 18 Olfactory and/or gustatory dysfunctions have been reported in 64% to 80% of patients. 51 - 53 Anosmia or ageusia may be the sole presenting symptom in approximately 3% of patients. 53

Complications of COVID-19 include impaired function of the heart, brain, lung, liver, kidney, and coagulation system. COVID-19 can lead to myocarditis, cardiomyopathy, ventricular arrhythmias, and hemodynamic instability. 20 , 54 Acute cerebrovascular disease and encephalitis are observed with severe illness (in up to 8% of patients). 21 , 52 Venous and arterial thromboembolic events occur in 10% to 25% in hospitalized patients with COVID-19. 19 , 22 In the ICU, venous and arterial thromboembolic events may occur in up to 31% to 59% of patients with COVID-19. 16 , 22

Approximately 17% to 35% of hospitalized patients with COVID-19 are treated in an ICU, most commonly due to hypoxemic respiratory failure. Among patients in the ICU with COVID-19, 29% to 91% require invasive mechanical ventilation. 47 , 49 , 55 , 56 In addition to respiratory failure, hospitalized patients may develop acute kidney injury (9%), liver dysfunction (19%), bleeding and coagulation dysfunction (10%-25%), and septic shock (6%). 18 , 19 , 23 , 49 , 56

Approximately 2% to 5% of individuals with laboratory-confirmed COVID-19 are younger than 18 years, with a median age of 11 years. Children with COVID-19 have milder symptoms that are predominantly limited to the upper respiratory tract, and rarely require hospitalization. It is unclear why children are less susceptible to COVID-19. Potential explanations include that children have less robust immune responses (ie, no cytokine storm), partial immunity from other viral exposures, and lower rates of exposure to SARS-CoV-2. Although most pediatric cases are mild, a small percentage (<7%) of children admitted to the hospital for COVID-19 develop severe disease requiring mechanical ventilation. 57 A rare multisystem inflammatory syndrome similar to Kawasaki disease has recently been described in children in Europe and North America with SARS-CoV-2 infection. 58 , 59 This multisystem inflammatory syndrome in children is uncommon (2 in 100 000 persons aged <21 years). 60

Diagnosis of COVID-19 is typically made using polymerase chain reaction testing via nasal swab ( Box 2 ). However, because of false-negative test result rates of SARS-CoV-2 PCR testing of nasal swabs, clinical, laboratory, and imaging findings may also be used to make a presumptive diagnosis.

Reverse transcription polymerase chain reaction–based SARS-CoV-2 RNA detection from respiratory samples (eg, nasopharynx) is the standard for diagnosis. However, the sensitivity of testing varies with timing of testing relative to exposure. One modeling study estimated sensitivity at 33% 4 days after exposure, 62% on the day of symptom onset, and 80% 3 days after symptom onset. 61 - 63 Factors contributing to false-negative test results include the adequacy of the specimen collection technique, time from exposure, and specimen source. Lower respiratory samples, such as bronchoalveolar lavage fluid, are more sensitive than upper respiratory samples. Among 1070 specimens collected from 205 patients with COVID-19 in China, bronchoalveolar lavage fluid specimens had the highest positive rates of SARS-CoV-2 PCR testing results (93%), followed by sputum (72%), nasal swabs (63%), and pharyngeal swabs (32%). 61 SARS-CoV-2 can also be detected in feces, but not in urine. 61 Saliva may be an alternative specimen source that requires less personal protective equipment and fewer swabs, but requires further validation. 64

Several serological tests can also aid in the diagnosis and measurement of responses to novel vaccines. 62 , 65 , 66 However, the presence of antibodies may not confer immunity because not all antibodies produced in response to infection are neutralizing. Whether and how frequently second infections with SARS-CoV-2 occur remain unknown. Whether presence of antibody changes susceptibility to subsequent infection or how long antibody protection lasts are unknown. IgM antibodies are detectable within 5 days of infection, with higher IgM levels during weeks 2 to 3 of illness, while an IgG response is first seen approximately 14 days after symptom onset. 62 , 65 Higher antibody titers occur with more severe disease. 66 Available serological assays include point-of-care assays and high throughput enzyme immunoassays. However, test performance, accuracy, and validity are variable. 67

A systematic review of 19 studies of 2874 patients who were mostly from China (mean age, 52 years), of whom 88% were hospitalized, reported the typical range of laboratory abnormalities seen in COVID-19, including elevated serum C-reactive protein (increased in >60% of patients), lactate dehydrogenase (increased in approximately 50%-60%), alanine aminotransferase (elevated in approximately 25%), and aspartate aminotransferase (approximately 33%). 24 Approximately 75% of patients had low albumin. 24 The most common hematological abnormality is lymphopenia (absolute lymphocyte count <1.0 × 10 9 /L), which is present in up to 83% of hospitalized patients with COVID-19. 44 , 50 In conjunction with coagulopathy, modest prolongation of prothrombin times (prolonged in >5% of patients), mild thrombocytopenia (present in approximately 30% of patients) and elevated D-dimer values (present in 43%-60% of patients) are common. 14 , 15 , 19 , 44 , 68 However, most of these laboratory characteristics are nonspecific and are common in pneumonia. More severe laboratory abnormalities have been associated with more severe infection. 44 , 50 , 69 D-dimer and, to a lesser extent, lymphopenia seem to have the largest prognostic associations. 69

The characteristic chest computed tomographic imaging abnormalities for COVID-19 are diffuse, peripheral ground-glass opacities ( Figure 3 ). 70 Ground-glass opacities have ill-defined margins, air bronchograms, smooth or irregular interlobular or septal thickening, and thickening of the adjacent pleura. 70 Early in the disease, chest computed tomographic imaging findings in approximately 15% of individuals and chest radiograph findings in approximately 40% of individuals can be normal. 44 Rapid evolution of abnormalities can occur in the first 2 weeks after symptom onset, after which they subside gradually. 70 , 71

Chest computed tomographic imaging findings are nonspecific and overlap with other infections, so the diagnostic value of chest computed tomographic imaging for COVID-19 is limited. Some patients admitted to the hospital with polymerase chain reaction testing–confirmed SARS-CoV-2 infection have normal computed tomographic imaging findings, while abnormal chest computed tomographic imaging findings compatible with COVID-19 occur days before detection of SARS-CoV-2 RNA in other patients. 70 , 71

Currently, best practices for supportive management of acute hypoxic respiratory failure and ARDS should be followed. 72 - 74 Evidence-based guideline initiatives have been established by many countries and professional societies, 72 - 74 including guidelines that are updated regularly by the National Institutes of Health. 74

More than 75% of patients hospitalized with COVID-19 require supplemental oxygen therapy. For patients who are unresponsive to conventional oxygen therapy, heated high-flow nasal canula oxygen may be administered. 72 For patients requiring invasive mechanical ventilation, lung-protective ventilation with low tidal volumes (4-8 mL/kg, predicted body weight) and plateau pressure less than 30 mg Hg is recommended. 72 Additionally, prone positioning, a higher positive end-expiratory pressure strategy, and short-term neuromuscular blockade with cisatracurium or other muscle relaxants may facilitate oxygenation. Although some patients with COVID-19–related respiratory failure have high lung compliance, 75 they are still likely to benefit from lung-protective ventilation. 76 Cohorts of patients with ARDS have displayed similar heterogeneity in lung compliance, and even patients with greater compliance have shown benefit from lower tidal volume strategies. 76

The threshold for intubation in COVID-19–related respiratory failure is controversial, because many patients have normal work of breathing but severe hypoxemia. 77 “Earlier” intubation allows time for a more controlled intubation process, which is important given the logistical challenges of moving patients to an airborne isolation room and donning personal protective equipment prior to intubation. However, hypoxemia in the absence of respiratory distress is well tolerated, and patients may do well without mechanical ventilation. Earlier intubation thresholds may result in treating some patients with mechanical ventilation unnecessarily and exposing them to additional complications. Currently, insufficient evidence exists to make recommendations regarding earlier vs later intubation.

In observational studies, approximately 8% of hospitalized patients with COVID-19 experience a bacterial or fungal co-infection, but up to 72% are treated with broad-spectrum antibiotics. 78 Awaiting further data, it may be prudent to withhold antibacterial drugs in patients with COVID-19 and reserve them for those who present with radiological findings and/or inflammatory markers compatible with co-infection or who are immunocompromised and/or critically ill. 72

The following classes of drugs are being evaluated or developed for the management of COVID-19: antivirals (eg, remdesivir, favipiravir), antibodies (eg, convalescent plasma, hyperimmune immunoglobulins), anti-inflammatory agents (dexamethasone, statins), targeted immunomodulatory therapies (eg, tocilizumab, sarilumab, anakinra, ruxolitinib), anticoagulants (eg, heparin), and antifibrotics (eg, tyrosine kinase inhibitors). It is likely that different treatment modalities might have different efficacies at different stages of illness and in different manifestations of disease. Viral inhibition would be expected to be most effective early in infection, while, in hospitalized patients, immunomodulatory agents may be useful to prevent disease progression and anticoagulants may be useful to prevent thromboembolic complications.

More than 200 trials of chloroquine/hydroxychloroquine, compounds that inhibit viral entry and endocytosis of SARS-CoV-2 in vitro and may have beneficial immunomodulatory effects in vivo, 79 , 80 have been initiated, but early data from clinical trials in hospitalized patients with COVID-19 have not demonstrated clear benefit. 81 - 83 A clinical trial of 150 patients in China admitted to the hospital for mild to moderate COVID-19 did not find an effect on negative conversion of SARS-CoV-2 by 28 days (the main outcome measure) when compared with standard of care alone. 83 Two retrospective studies found no effect of hydroxychloroquine on risk of intubation or mortality among patients hospitalized for COVID-19. 84 , 85 One of these retrospective multicenter cohort studies compared in-hospital mortality between those treated with hydroxychloroquine plus azithromycin (735 patients), hydroxychloroquine alone (271 patients), azithromycin alone (211 patients), and neither drug (221 patients), but reported no differences across the groups. 84 Adverse effects are common, most notably QT prolongation with an increased risk of cardiac complications in an already vulnerable population. 82 , 84 These findings do not support off-label use of (hydroxy)chloroquine either with or without the coadministration of azithromycin. Randomized clinical trials are ongoing and should provide more guidance.

Most antiviral drugs undergoing clinical testing in patients with COVID-19 are repurposed antiviral agents originally developed against influenza, HIV, Ebola, or SARS/MERS. 79 , 86 Use of the protease inhibitor lopinavir-ritonavir, which disrupts viral replication in vitro, did not show benefit when compared with standard care in a randomized, controlled, open-label trial of 199 hospitalized adult patients with severe COVID-19. 87 Among the RNA-dependent RNA polymerase inhibitors, which halt SARS-CoV-2 replication, being evaluated, including ribavirin, favipiravir, and remdesivir, the latter seems to be the most promising. 79 , 88 The first preliminary results of a double-blind, randomized, placebo-controlled trial of 1063 adults hospitalized with COVID-19 and evidence of lower respiratory tract involvement who were randomly assigned to receive intravenous remdesivir or placebo for up to 10 days demonstrated that patients randomized to receive remdesivir had a shorter time to recovery than patients in the placebo group (11 vs 15 days). 88 A separate randomized, open-label trial among 397 hospitalized patients with COVID-19 who did not require mechanical ventilation reported that 5 days of treatment with remdesivir was not different than 10 days in terms of clinical status on day 14. 89 The effect of remdesivir on survival remains unknown.

Treatment with plasma obtained from patients who have recovered from viral infections was first reported during the 1918 flu pandemic. A first report of 5 critically ill patients with COVID-19 treated with convalescent plasma containing neutralizing antibody showed improvement in clinical status among all participants, defined as a combination of changes of body temperature, Sequential Organ Failure Assessment score, partial pressure of oxygen/fraction of inspired oxygen, viral load, serum antibody titer, routine blood biochemical index, ARDS, and ventilatory and extracorporeal membrane oxygenation supports before and after convalescent plasma transfusion status. 90 However, a subsequent multicenter, open-label, randomized clinical trial of 103 patients in China with severe COVID-19 found no statistical difference in time to clinical improvement within 28 days among patients randomized to receive convalescent plasma vs standard treatment alone (51.9% vs 43.1%). 91 However, the trial was stopped early because of slowing enrollment, which limited the power to detect a clinically important difference. Alternative approaches being studied include the use of convalescent plasma-derived hyperimmune globulin and monoclonal antibodies targeting SARS-CoV-2. 92 , 93

Alternative therapeutic strategies consist of modulating the inflammatory response in patients with COVID-19. Monoclonal antibodies directed against key inflammatory mediators, such as interferon gamma, interleukin 1, interleukin 6, and complement factor 5a, all target the overwhelming inflammatory response following SARS-CoV-2 infection with the goal of preventing organ damage. 79 , 86 , 94 Of these, the interleukin 6 inhibitors tocilizumab and sarilumab are best studied, with more than a dozen randomized clinical trials underway. 94 Tyrosine kinase inhibitors, such as imatinib, are studied for their potential to prevent pulmonary vascular leakage in individuals with COVID-19.

Studies of corticosteroids for viral pneumonia and ARDS have yielded mixed results. 72 , 73 However, the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, which randomized 2104 patients with COVID-19 to receive 6 mg daily of dexamethasone for up to 10 days and 4321 to receive usual care, found that dexamethasone reduced 28-day all-cause mortality (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]; P < .001). 95 The benefit was greatest in patients with symptoms for more than 7 days and patients who required mechanical ventilation. By contrast, there was no benefit (and possibility for harm) among patients with shorter symptom duration and no supplemental oxygen requirement. A retrospective cohort study of 201 patients in Wuhan, China, with confirmed COVID-19 pneumonia and ARDS reported that treatment with methylprednisolone was associated with reduced risk of death (hazard ratio, 0.38 [95% CI, 0.20-0.72]). 69

Thromboembolic prophylaxis with subcutaneous low molecular weight heparin is recommended for all hospitalized patients with COVID-19. 15 , 19 Studies are ongoing to assess whether certain patients (ie, those with elevated D-dimer) benefit from therapeutic anticoagulation.

A disproportionate percentage of COVID-19 hospitalizations and deaths occurs in lower-income and minority populations. 45 , 96 , 97 In a report by the Centers for Disease Control and Prevention of 580 hospitalized patients for whom race data were available, 33% were Black and 45% were White, while 18% of residents in the surrounding community were Black and 59% were White. 45 The disproportionate prevalence of COVID-19 among Black patients was separately reported in a retrospective cohort study of 3626 patients with COVID-19 from Louisiana, in which 77% of patients hospitalized with COVID-19 and 71% of patients who died of COVID-19 were Black, but Black individuals comprised only 31% of the area population. 97 , 98 This disproportionate burden may be a reflection of disparities in housing, transportation, employment, and health. Minority populations are more likely to live in densely populated communities or housing, depend on public transportation, or work in jobs for which telework was not possible (eg, bus driver, food service worker). Black individuals also have a higher prevalence of chronic health conditions than White individuals. 98 , 99

Overall hospital mortality from COVID-19 is approximately 15% to 20%, but up to 40% among patients requiring ICU admission. However, mortality rates vary across cohorts, reflecting differences in the completeness of testing and case identification, variable thresholds for hospitalization, and differences in outcomes. Hospital mortality ranges from less than 5% among patients younger than 40 years to 35% for patients aged 70 to 79 years and greater than 60% for patients aged 80 to 89 years. 46 Estimated overall death rates by age group per 1000 confirmed cases are provided in the Table . Because not all people who die during the pandemic are tested for COVID-19, actual numbers of deaths from COVID-19 are higher than reported numbers.

Although long-term outcomes from COVID-19 are currently unknown, patients with severe illness are likely to suffer substantial sequelae. Survival from sepsis is associated with increased risk for mortality for at least 2 years, new physical disability, new cognitive impairment, and increased vulnerability to recurrent infection and further health deterioration. Similar sequalae are likely to be seen in survivors of severe COVID-19. 100

COVID-19 is a potentially preventable disease. The relationship between the intensity of public health action and the control of transmission is clear from the epidemiology of infection around the world. 25 , 101 , 102 However, because most countries have implemented multiple infection control measures, it is difficult to determine the relative benefit of each. 103 , 104 This question is increasingly important because continued interventions will be required until effective vaccines or treatments become available. In general, these interventions can be divided into those consisting of personal actions (eg, physical distancing, personal hygiene, and use of protective equipment), case and contact identification (eg, test-trace-track-isolate, reactive school or workplace closure), regulatory actions (eg, governmental limits on sizes of gatherings or business capacity; stay-at-home orders; proactive school, workplace, and public transport closure or restriction; cordon sanitaire or internal border closures), and international border measures (eg, border closure or enforced quarantine). A key priority is to identify the combination of measures that minimizes societal and economic disruption while adequately controlling infection. Optimal measures may vary between countries based on resource limitations, geography (eg, island nations and international border measures), population, and political factors (eg, health literacy, trust in government, cultural and linguistic diversity).

The evidence underlying these public health interventions has not changed since the 1918 flu pandemic. 105 Mathematical modeling studies and empirical evidence support that public health interventions, including home quarantine after infection, restricting mass gatherings, travel restrictions, and social distancing, are associated with reduced rates of transmission. 101 , 102 , 106 Risk of resurgence follows when these interventions are lifted.

A human vaccine is currently not available for SARS-CoV-2, but approximately 120 candidates are under development. Approaches include the use of nucleic acids (DNA or RNA), inactivated or live attenuated virus, viral vectors, and recombinant proteins or virus particles. 107 , 108 Challenges to developing an effective vaccine consist of technical barriers (eg, whether S or receptor-binding domain proteins provoke more protective antibodies, prior exposure to adenovirus serotype 5 [which impairs immunogenicity in the viral vector vaccine], need for adjuvant), feasibility of large-scale production and regulation (eg, ensuring safety and effectiveness), and legal barriers (eg, technology transfer and licensure agreements). The SARS-CoV-2 S protein appears to be a promising immunogen for protection, but whether targeting the full-length protein or only the receptor-binding domain is sufficient to prevent transmission remains unclear. 108 Other considerations include the potential duration of immunity and thus the number of vaccine doses needed to confer immunity. 62 , 108 More than a dozen candidate SARS-CoV-2 vaccines are currently being tested in phase 1-3 trials.

Other approaches to prevention are likely to emerge in the coming months, including monoclonal antibodies, hyperimmune globulin, and convalscent titer. If proved effective, these approaches could be used in high-risk individuals, including health care workers, other essential workers, and older adults (particularly those in nursing homes or long-term care facilities).

This review has several limitations. First, information regarding SARS CoV-2 is limited. Second, information provided here is based on current evidence, but may be modified as more information becomes available. Third, few randomized trials have been published to guide management of COVID-19.

As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

Accepted for Publication: June 30, 2020.

Corresponding Author: W. Joost Wiersinga, MD, PhD, Division of Infectious Diseases, Department of Medicine, Amsterdam UMC, location AMC, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands ( [email protected] ).

Published Online: July 10, 2020. doi:10.1001/jama.2020.12839

Conflict of Interest Disclosures: Dr Wiersinga is supported by the Netherlands Organisation of Scientific Research outside the submitted work. Dr Prescott reported receiving grants from the US Agency for Healthcare Research and Quality (HCP by R01 HS026725), the National Institutes of Health/National Institute of General Medical Sciences, and the US Department of Veterans Affairs outside the submitted work, being the sepsis physician lead for the Hospital Medicine Safety Continuous Quality Initiative funded by BlueCross/BlueShield of Michigan, and serving on the steering committee for MI-COVID-19, a Michigan statewide registry to improve care for patients with COVID-19 in Michigan. Dr Rhodes reported being the co-chair of the Surviving Sepsis Campaign. Dr Cheng reported being a member of Australian government advisory committees, including those involved in COVID-19. No other disclosures were reported.

Disclaimer: This article does not represent the views of the US Department of Veterans Affairs or the US government. This material is the result of work supported with resources and use of facilities at the Ann Arbor VA Medical Center. The opinions in this article do not necessarily represent those of the Australian government or advisory committees.

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Overview of Viral Respiratory Infections

Diagnosis |
Treatment |

Viral infections commonly affect the upper or lower respiratory tract. Although respiratory infections can be classified by the causative virus (eg, influenza ), they are generally classified clinically according to syndrome (eg, the common cold , bronchiolitis , croup , pneumonia ). Specific pathogens commonly cause characteristic clinical manifestations (eg, rhinovirus typically causes the common cold, respiratory syncytial virus [RSV] typically causes bronchiolitis), and each pathogen can also cause many of the general symptoms of viral respiratory syndromes.

Severity of viral respiratory illness varies widely; severe disease is more likely in older adults and infants. Morbidity may result directly from viral infection or may be indirect, due to exacerbation of underlying cardiopulmonary conditions or bacterial superinfection of the lung, paranasal sinuses, or middle ear.

Causes of Common Viral Respiratory Syndromes


		Rhinoviruses Human metapneumoviruses
	Rhinoviruses	Adenoviruses Human metapneumoviruses
		Adenoviruses
-like illness		Adenoviruses Human metapneumoviruses (including )
	(including )	Rhinoviruses Human metapneumoviruses

Rhinoviruses

Human metapneumoviruses

Rhinoviruses

Adenoviruses

Human metapneumoviruses

Adenoviruses

-like illness

Adenoviruses

Human metapneumoviruses

(including )

Rhinoviruses

Human metapneumoviruses

Diagnosis of Viral Respiratory Infections

Usually history and physical examination and local epidemiology

Sometimes diagnostic testing

Viral respiratory infections are typically diagnosed clinically based on symptoms and local epidemiology. For patient care, diagnosing the syndrome is usually sufficient; identification of a specific pathogen is rarely necessary.

Diagnostic testing should be reserved for the following:

Situations in which knowing the specific pathogen affects clinical management

Epidemiologic surveillance (ie, identifying and determining the cause of an outbreak)

Pathogen identification can be important when specific antiviral therapy is indicated. Antiviral therapy is given for the following viruses and indications:

Influenza : Patients or close contacts of patients at high risk of complications; may be given to average-risk patients with symptoms for 1 )

COVID-19 : Patients at high risk of severe disease with symptoms for 2 )

RSV infection : Severely immunocompromised patients

Identifying the specific pathogen (particularly the influenza virus or RSV in hospitalized patients or patients residing in a facility) may also be important for infection prevention and control, including identifying and containing potential outbreaks.

Rapid point-of-care antigen-based and polymerase chain reaction (PCR)-based diagnostic tests are available for influenza, RSV, and SARS-CoV-2. The rapid point-of-care antigen-based tests have lower sensitivity than PCR-based laboratory tests ( 3 ). Point-of-care tests are typically reserved for cases when clinical diagnosis is uncertain and

Antiviral therapy is being considered.

Identification of the viral pathogen would prevent additional evaluation for or treatment of a bacterial infection.

Identification of the viral pathogen would aid in infection prevention and control in the inpatient setting.

PCR-based detection of viral pathogens in a multiplex panel (or individually for influenza, RSV, and SARS-CoV-2) is available in many clinical laboratories. These tests are more sensitive than antigen-based point-of-care tests and, when available, are preferred for clinical purposes.

Cell culture or serologic tests are sometimes available but are slower than PCR tests. They may be useful for epidemiologic surveillance.

Diagnosis references

1. Uyeki TM, Bernstein HH, Bradley JS, et al : Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza. Clin Infect Dis . 2019;68(6):895-902. doi:10.1093/cid/ciy874

2. Centers for Disease Control and Prevention (CDC): National Center for Immunization and Respiratory Diseases (NCIRD), Division of Viral Diseases : Interim Clinical Considerations for COVID-19 Treatment and Pre-exposure Prophylaxis in Outpatients, last updated April 12, 2024

3. Dinnes J, Sharma P, Berhane S, et al : Rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection. Cochrane Database Syst Rev. 2022;7(7):CD013705. Published 2022 Jul 22. doi:10.1002/14651858.CD013705.pub3

Treatment of Viral Respiratory Infections

Sometimes antiviral medications

Treatment of viral respiratory infections is usually supportive.

Antibacterial medications are ineffective against viral pathogens, and prophylaxis against secondary bacterial infections is not recommended. Antibiotics should be given only when secondary bacterial infections develop.

≤ 18 years with a suspected viral respiratory tract infection, because Reye syndrome is a risk.

Some patients continue to cough for 3 to 8 weeks after resolution of an upper respiratory infection ( 1 ); these symptoms may lessen with use of an inhaled bronchodilator or corticosteroids.

In some cases, antiviral medications are useful:

prevent RSV infection in infants and young children ( 5, 6, 7 ). ( Nirsevimab is preferred but may not be available to some infants; if it is not available, eligible high-risk infants and children should receive palivizumab .)

Treatment references

1. Irwin RS, French CL, Chang AB, Altman KW; CHEST Expert Cough Panel* : Classification of Cough as a Symptom in Adults and Management Algorithms: CHEST Guideline and Expert Panel Report. Chest . 2018;153(1):196-209. doi:10.1016/j.chest.2017.10.016

2. Centers for Disease Control and Prevention (CDC): National Center for Immunization and Respiratory Diseases (NCIRD) : Influenza Antiviral Medications: Summary for Clinicians, last updated December 8, 2023

3. Centers for Disease Control and Prevention (CDC): National Center for Immunization and Respiratory Diseases (NCIRD), Division of Viral Diseases : Interim Clinical Considerations for COVID-19 Treatment and Pre-exposure Prophylaxis in Outpatients, last updated April 12, 2024

4. Manothummetha K, Mongkolkaew T, Tovichayathamrong P, et al : Ribavirin treatment for respiratory syncytial virus infection in patients with haematologic malignancy and haematopoietic stem cell transplant recipients: a systematic review and meta-analysis. Clin Microbiol Infect . 2023;29(10):1272-1279. doi:10.1016/j.cmi.2023.04.021

5. Hammitt LL, Dagan R, Yuan Y, et al : Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants. N Engl J Med . 2022;386(9):837-846. doi:10.1056/NEJMoa2110275

6. Griffin MP, Yuan Y, Takas T, et al : Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants [published correction appears in N Engl J Med. 2020 Aug 13;383(7):698]. N Engl J Med. 2020;383(5):415-425. doi:10.1056/NEJMoa1913556

7. Garegnani L, Styrmisdóttir L, Roson Rodriguez P, et al : Palivizumab for preventing severe respiratory syncytial virus (RSV) infection in children. Cochrane Database Syst Rev . 2021;11(11):CD013757. Published 2021 Nov 16. doi:10.1002/14651858.CD013757.pub2

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Virology, transmission...

Virology, transmission, and pathogenesis of SARS-CoV-2

Read our latest coverage of the coronavirus outbreak.

Related content
Peer review
Muge Cevik , clinical lecturer 1 2 ,
Krutika Kuppalli , assistant professor 3 ,
Jason Kindrachuk , assistant professor of virology 4 ,
Malik Peiris , professor of virology 5
1 Division of Infection and Global Health Research, School of Medicine, University of St Andrews, St Andrews, UK
2 Specialist Virology Laboratory, Royal Infirmary of Edinburgh, Edinburgh, UK and Regional Infectious Diseases Unit, Western General Hospital, Edinburgh, UK
3 Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC, USA
4 Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada
5 School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
Correspondence to M Cevik mc349{at}st-andrews.ac.uk

What you need to know

SARS-CoV-2 is genetically similar to SARS-CoV-1, but characteristics of SARS-CoV-2—eg, structural differences in its surface proteins and viral load kinetics—may help explain its enhanced rate of transmission

In the respiratory tract, peak SARS-CoV-2 load is observed at the time of symptom onset or in the first week of illness, with subsequent decline thereafter, indicating the highest infectiousness potential just before or within the first five days of symptom onset

Reverse transcription polymerase chain reaction (RT-PCR) tests can detect viral SARS-CoV-2 RNA in the upper respiratory tract for a mean of 17 days; however, detection of viral RNA does not necessarily equate to infectiousness, and viral culture from PCR positive upper respiratory tract samples has been rarely positive beyond nine days of illness

Symptomatic and pre-symptomatic transmission (1-2 days before symptom onset), is likely to play a greater role in the spread of SARS-CoV-2 than asymptomatic transmission

A wide range of virus-neutralising antibodies have been reported, and emerging evidence suggests that these may correlate with severity of illness but wane over time

Since the emergence of SARS-CoV-2 in December 2019, there has been an unparalleled global effort to characterise the virus and the clinical course of disease. Coronavirus disease 2019 (covid-19), caused by SARS-CoV-2, follows a biphasic pattern of illness that likely results from the combination of an early viral response phase and an inflammatory second phase. Most clinical presentations are mild, and the typical pattern of covid-19 more resembles an influenza-like illness—which includes fever, cough, malaise, myalgia, headache, and taste and smell disturbance—rather than severe pneumonia (although emerging evidence about long term consequences is yet to be understood in detail). 1 In this review, we provide a broad update on the emerging understanding of SARS-CoV-2 pathophysiology, including virology, transmission dynamics, and the immune response to the virus. Any of the mechanisms and assumptions discussed in the article and in our understanding of covid-19 may be revised as further evidence emerges.

What we know about the virus

SARS-CoV-2 is an enveloped β-coronavirus, with a genetic sequence very similar to SARS-CoV-1 (80%) and bat coronavirus RaTG13 (96.2%). 2 The viral envelope is coated by spike (S) glycoprotein, envelope (E), and membrane (M) proteins ( fig 1 ). Host cell binding and entry are mediated by the S protein. The first step in infection is virus binding to a host cell through its target receptor. The S1 sub-unit of the S protein contains the receptor binding domain that binds to the peptidase domain of angiotensin-converting enzyme 2 (ACE 2). In SARS-CoV-2 the S2 sub-unit is highly preserved and is considered a potential antiviral target. The virus structure and replication cycle are described in figure 1 .

(1) The virus binds to ACE 2 as the host target cell receptor in synergy with the host’s transmembrane serine protease 2 (cell surface protein), which is principally expressed in the airway epithelial cells and vascular endothelial cells. This leads to membrane fusion and releases the viral genome into the host cytoplasm (2). Stages (3-7) show the remaining steps of viral replication, leading to viral assembly, maturation, and virus release

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Coronaviruses have the capacity for proofreading during replication, and therefore mutation rates are lower than in other RNA viruses. As SARS-CoV-2 has spread globally it has, like other viruses, accumulated some mutations in the viral genome, which contains geographic signatures. Researchers have examined these mutations to study virus characterisation and understand epidemiology and transmission patterns. In general, the mutations have not been attributed to phenotypic changes affecting viral transmissibility or pathogenicity. The G614 variant in the S protein has been postulated to increase infectivity and transmissibility of the virus. 3 Higher viral loads were reported in clinical samples with virus containing G614 than previously circulating variant D614, although no association was made with severity of illness as measured by hospitalisation outcomes. 3 These findings have yet to be confirmed with regards to natural infection.

Why is SARS-CoV-2 more infectious than SARS-CoV-1?

SARS-CoV-2 has a higher reproductive number (R 0 ) than SARS-CoV-1, indicating much more efficient spread. 1 Several characteristics of SARS-CoV-2 may help explain this enhanced transmission. While both SARS-CoV-1 and SARS-CoV-2 preferentially interact with the angiotensin-converting enzyme 2 (ACE 2) receptor, SARS-CoV-2 has structural differences in its surface proteins that enable stronger binding to the ACE 2 receptor 4 and greater efficiency at invading host cells. 1 SARS-CoV-2 also has greater affinity (or bonding) for the upper respiratory tract and conjunctiva, 5 thus can infect the upper respiratory tract and can conduct airways more easily. 6

Viral load dynamics and duration of infectiousness

Viral load kinetics could also explain some of the differences between SARS-CoV-2 and SARS-CoV-1. In the respiratory tract, peak SARS-CoV-2 load is observed at the time of symptom onset or in the first week of illness, with subsequent decline thereafter, which indicates the highest infectiousness potential just before or within the first five days of symptom onset ( fig 2 ). 7 In contrast, in SARS-CoV-1 the highest viral loads were detected in the upper respiratory tract in the second week of illness, which explains its minimal contagiousness in the first week after symptom onset, enabling early case detection in the community. 7

After the initial exposure, patients typically develop symptoms within 5-6 days (incubation period). SARS-CoV-2 generates a diverse range of clinical manifestations, ranging from mild infection to severe disease accompanied by high mortality. In patients with mild infection, initial host immune response is capable of controlling the infection. In severe disease, excessive immune response leads to organ damage, intensive care admission, or death. The viral load peaks in the first week of infection, declines thereafter gradually, while the antibody response gradually increases and is often detectable by day 14 (figure adapted with permission from https://www.sciencedirect.com/science/article/pii/S009286742030475X ; https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30230-7/fulltext )

Quantitative reverse transcription polymerase chain reaction (qRT-PCR) technology can detect viral SARS-CoV-2 RNA in the upper respiratory tract for a mean of 17 days (maximum 83 days) after symptom onset. 7 However, detection of viral RNA by qRT-PCR does not necessarily equate to infectiousness, and viral culture from PCR positive upper respiratory tract samples has been rarely positive beyond nine days of illness. 5 This corresponds to what is known about transmission based on contact tracing studies, which is that transmission capacity is maximal in the first week of illness, and that transmission after this period has not been documented. 8 Severely ill or immune-compromised patients may have relatively prolonged virus shedding, and some patients may have intermittent RNA shedding; however, low level results close to the detection limit may not constitute infectious viral particles. While asymptomatic individuals (those with no symptoms throughout the infection) can transmit the infection, their relative degree of infectiousness seems to be limited. 9 10 11 People with mild symptoms (paucisymptomatic) and those whose symptom have not yet appeared still carry large amounts of virus in the upper respiratory tract, which might contribute to the easy and rapid spread of SARS-CoV-2. 7 Symptomatic and pre-symptomatic transmission (one to two days before symptom onset) is likely to play a greater role in the spread of SARS-CoV-2. 10 12 A combination of preventive measures, such as physical distancing and testing, tracing, and self-isolation, continue to be needed.

Route of transmission and transmission dynamics

Like other coronaviruses, the primary mechanism of transmission of SARS-CoV-2 is via infected respiratory droplets, with viral infection occurring by direct or indirect contact with nasal, conjunctival, or oral mucosa, when respiratory particles are inhaled or deposited on these mucous membranes. 6 Target host receptors are found mainly in the human respiratory tract epithelium, including the oropharynx and upper airway. The conjunctiva and gastrointestinal tracts are also susceptible to infection and may serve as transmission portals. 6

Transmission risk depends on factors such as contact pattern, environment, infectiousness of the host, and socioeconomic factors, as described elsewhere. 12 Most transmission occurs through close range contact (such as 15 minutes face to face and within 2 m), 13 and spread is especially efficient within households and through gatherings of family and friends. 12 Household secondary attack rates (the proportion of susceptible individuals who become infected within a group of susceptible contacts with a primary case) ranges from 4% to 35%. 12 Sleeping in the same room as, or being a spouse of an infected individual increases the risk of infection, but isolation of the infected person away from the family is related to lower risk of infection. 12 Other activities identified as high risk include dining in close proximity with the infected person, sharing food, and taking part in group activities 12 The risk of infection substantially increases in enclosed environments compared with outdoor settings. 12 For example, a systematic review of transmission clusters found that most superspreading events occurred indoors. 11 Aerosol transmission can still factor during prolonged stay in crowded, poorly ventilated indoor settings (meaning transmission could occur at a distance >2 m). 12 14 15 16 17

The role of faecal shedding in SARS-CoV-2 transmission and the extent of fomite (through inanimate surfaces) transmission also remain to be fully understood. Both SARS-CoV-2 and SARS-CoV-1 remain viable for many days on smooth surfaces (stainless steel, plastic, glass) and at lower temperature and humidity (eg, air conditioned environments). 18 19 Thus, transferring infection from contaminated surfaces to the mucosa of eyes, nose, and mouth via unwashed hands is a possible route of transmission. This route of transmission may contribute especially in facilities with communal areas, with increased likelihood of environmental contamination. However, both SARS-CoV-1 and SARS-CoV-2 are readily inactivated by commonly used disinfectants, emphasising the potential value of surface cleaning and handwashing. SARS-CoV-2 RNA has been found in stool samples and RNA shedding often persists for longer than in respiratory samples 7 ; however, virus isolation has rarely been successful from the stool. 5 7 No published reports describe faecal-oral transmission. In SARS-CoV-1, faecal-oral transmission was not considered to occur in most circumstances; but, one explosive outbreak was attributed to aerosolisation and spread of the virus across an apartment block via a faulty sewage system. 20 It remains to be seen if similar transmission may occur with SARS-CoV-2.

Pathogenesis

Viral entry and interaction with target cells.

SARS-CoV-2 binds to ACE 2, the host target cell receptor. 1 Active replication and release of the virus in the lung cells lead to non-specific symptoms such as fever, myalgia, headache, and respiratory symptoms. 1 In an experimental hamster model, the virus causes transient damage to the cells in the olfactory epithelium, leading to olfactory dysfunction, which may explain temporary loss of taste and smell commonly seen in covid-19. 21 The distribution of ACE 2 receptors in different tissues may explain the sites of infection and patient symptoms. For example, the ACE 2 receptor is found on the epithelium of other organs such as the intestine and endothelial cells in the kidney and blood vessels, which may explain gastrointestinal symptoms and cardiovascular complications. 22 Lymphocytic endotheliitis has been observed in postmortem pathology examination of the lung, heart, kidney, and liver as well as liver cell necrosis and myocardial infarction in patients who died of covid-19. 1 23 These findings indicate that the virus directly affects many organs, as was seen in SARS-CoV-1 and influenzae.

Much remains unknown. Are the pathological changes in the respiratory tract or endothelial dysfunction the result of direct viral infection, cytokine dysregulation, coagulopathy, or are they multifactorial? And does direct viral invasion or coagulopathy directly contribute to some of the ischaemic complications such as ischaemic infarcts? These and more, will require further work to elucidate.

Immune response and disease spectrum ( figure 2 )

After viral entry, the initial inflammatory response attracts virus-specific T cells to the site of infection, where the infected cells are eliminated before the virus spreads, leading to recovery in most people. 24 In patients who develop severe disease, SARS-CoV-2 elicits an aberrant host immune response. 24 25 For example, postmortem histology of lung tissues of patients who died of covid-19 have confirmed the inflammatory nature of the injury, with features of bilateral diffuse alveolar damage, hyaline-membrane formation, interstitial mononuclear inflammatory infiltrates, and desquamation consistent with acute respiratory distress syndrome (ARDS), and is similar to the lung pathology seen in severe Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). 26 27 A distinctive feature of covid-19 is the presence of mucus plugs with fibrinous exudate in the respiratory tract, which may explain the severity of covid-19 even in young adults. 28 This is potentially caused by the overproduction of pro-inflammatory cytokines that accumulate in the lungs, eventually damaging the lung parenchyma. 24

Some patients also experience septic shock and multi-organ dysfunction. 24 For example, the cardiovascular system is often involved early in covid-19 disease and is reflected in the release of highly sensitive troponin and natriuretic peptides. 29 Consistent with the clinical context of coagulopathy, focal intra-alveolar haemorrhage and presence of platelet-fibrin thrombi in small arterial vessels is also seen. 27 Cytokines normally mediate and regulate immunity, inflammation, and haematopoiesis; however, further exacerbation of immune reaction and accumulation of cytokines in other organs in some patients may cause extensive tissue damage, or a cytokine release syndrome (cytokine storm), resulting in capillary leak, thrombus formation, and organ dysfunction. 24 30

Mechanisms underlying the diverse clinical outcomes

Clinical outcomes are influenced by host factors such as older age, male sex, and underlying medical conditions, 1 as well as factors related to the virus (such as viral load kinetics), host-immune response, and potential cross-reactive immune memory from previous exposure to seasonal coronaviruses ( box 1 ).

Risk factors associated with the development of severe disease, admission to intensive care unit, and mortality

Underlying condition.

Hypertension

Cardiovascular disease

Chronic obstructive pulmonary disease

Presentation

Higher fever (≥39°C on admission)

Dyspnoea on admission

Higher qSOFA score

Laboratory markers

Neutrophilia/lymphopenia

Raised lactate and lactate dehydrogenase

Raised C reactive protein

Raised ferritin

Raised IL-6

Raised ACE2

D-dimer >1 μg/mL

Sex-related differences in immune response have been reported, revealing that men had higher plasma innate immune cytokines and chemokines at baseline than women. 31 In contrast, women had notably more robust T cell activation than men, and among male participants T cell activation declined with age, which was sustained among female patients. These findings suggest that adaptive immune response may be important in defining the clinical outcome as older age and male sex is associated with increased risk of severe disease and mortality.

Increased levels of pro-inflammatory cytokines correlate with severe pneumonia and increased ground glass opacities within the lungs. 30 32 In people with severe illness, increased plasma concentrations of inflammatory cytokines and biomarkers were observed compared with people with non-severe illness. 30 33 34

Emerging evidence suggests a correlation between viral dynamics, the severity of illness, and disease outcome. 7 Longitudinal characteristics of immune response show a correlation between the severity of illness, viral load, and IFN- α, IFN-γ, and TNF-α response. 34 In the same study many interferons, cytokines, and chemokines were elevated early in disease for patients who had severe disease and higher viral loads. This emphasises that viral load may drive these cytokines and the possible pathological roles associated with the host defence factors. This is in keeping with the pathogenesis of influenza, SARS, and MERS whereby prolonged viral shedding was also associated with severity of illness. 7 35

Given the substantial role of the immune response in determining clinical outcomes, several immunosuppressive therapies aimed at limiting immune-mediated damage are currently in various phases of development ( table 1 ).

Therapeutics currently under investigation

View inline

Immune response to the virus and its role in protection

Covid-19 leads to an antibody response to a range of viral proteins, but the spike (S) protein and nucleocapsid are those most often used in serological diagnosis. Few antibodies are detectable in the first four days of illness, but patients progressively develop them, with most achieving a detectable response after four weeks. 36 A wide range of virus-neutralising antibodies have been reported, and emerging evidence suggests that these may correlate with severity but wane over time. 37 The duration and protectivity of antibody and T cell responses remain to be defined through studies with longer follow-up. CD-4 T cell responses to endemic human coronaviruses appear to manifest cross-reactivity with SARS-CoV-2, but their role in protection remains unclear. 38

Unanswered questions

Further understanding of the pathogenesis for SARS-CoV-2 will be vital in developing therapeutics, vaccines, and supportive care modalities in the treatment of covid-19. More data are needed to understand the determinants of healthy versus dysfunctional response and immune markers for protection and the severity of disease. Neutralising antibodies are potential correlates of protection, but other protective antibody mechanisms may exist. Similarly, the protective role of T cell immunity and duration of both antibody and T cell responses and the correlates of protection need to be defined. In addition, we need optimal testing systems and technologies to support and inform early detection and clinical management of infection. Greater understanding is needed regarding the long term consequences following acute illness and multisystem inflammatory disease, especially in children.

Education into practice

How would you describe SARS-CoV-2 transmission routes and ways to prevent infection?

How would you describe to a patient why cough, anosmia, and fever occur in covid-19?

Questions for future research

What is the role of the cytokine storm and how could it inform the development of therapeutics, vaccines, and supportive care modalities?

What is the window period when patients are most infectious?

Why do some patients develop severe disease while others, especially children, remain mildly symptomatic or do not develop symptoms?

What are the determinants of healthy versus dysfunctional response, and the biomarkers to define immune correlates of protection and disease severity for the effective triage of patients?

What is the protective role of T cell immunity and duration of both antibody and T cell responses, and how would you define the correlates of protection?

How patients were involved in the creation of this article

No patients were directly involved in the creation of this article.

How this article was created

We searched PubMed from 2000 to 18 September 2020, limited to publications in English. Our search strategy used a combination of key words including “COVID-19,” “SARS-CoV-2,” “SARS”, “MERS,” “Coronavirus,” “Novel Coronavirus,” “Pathogenesis,” “Transmission,” “Cytokine Release,” “immune response,” “antibody response.” These sources were supplemented with systematic reviews. We also reviewed technical documents produced by the Centers for Disease Control and Prevention and World Health Organization technical documents.

Author contributions: MC, KK, JK, MP drafted the first and subsequent versions of the manuscript and all authors provided critical feedback and contributed to the manuscript.

Competing interests The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none.

Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests

Provenance and peer review: commissioned; externally peer reviewed.

This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

Bamford CGG ,
Fischer WM ,
Gnanakaran S ,
Sheffield COVID-19 Genomics Group
Corbett KS ,
Corman VM ,
Guggemos W ,
Cheung MC ,
Perera RAPM ,
Cheng H-Y ,
Taiwan COVID-19 Outbreak Investigation Team
Meyerowitz E ,
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Maraolo AE ,
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↵ European Centre for Disease Prevention and Control. Surveillance definitions for COVID-19. 2020. https://www.ecdc.europa.eu/en/covid-19/surveillance/surveillance-definitions .
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↵ Centers for Disease Control and Prevention. How COVID-19 spreads. 2020. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/how-covid-spreads.html
↵ Centers for Disease Control and Prevention. Scientific brief: SARS-CoV-2 and potential airborne transmission. 2020. https://www.cdc.gov/coronavirus/2019-ncov/more/scientific-brief-sars-cov-2.html
Perera MRA ,
van Doremalen N ,
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↵ Takahashi T, Ellingson MK, Wong P, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature 2020. https://pubmed.ncbi.nlm.nih.gov/32846427/
Yale IMPACT Team
CAP-China Network
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Crit Care Explor
v.2(4); 2020 Apr

The Clinical Presentation and Immunology of Viral Pneumonia and Implications for Management of Coronavirus Disease 2019

Dijoia b. darden.

1 Department of Surgery, University of Florida College of Medicine, Gainesville, FL.

Russell B. Hawkins

Shawn d. larson, nicole m. iovine.

2 Department of Medicine, University of Florida College of Medicine, Gainesville, FL.

Donald S. Prough

3 Department of Medicine, University of Texas Medical Branch School of Medicine, Galveston, TX.

Philip A. Efron

Objectives:.

This review will briefly examine the clinical presentation and important immunology of viral pneumonia with a focus on severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019).

Data Sources, Study Selection, Data Extraction, and Data Synthesis:

The most relevant, original and review literature were assessed for inclusion in this review. Sources included the Centers for Disease Control and Prevention, World Health Organization, and PubMed.

Conclusions:

Pneumonia is a leading cause of hospitalization and death worldwide, with viral etiologies being very common. Given the rapidly emerging pandemic associated with the novel severe acute respiratory syndrome coronavirus 2 causing coronavirus disease 2019, it is important to review the clinical presentation and immunologic changes associated with viral pneumonia. Symptoms of viral pneumonia include common respiratory tract infection symptoms of cough, fever, and shortness of breath. Immunologic changes include up-regulation of airway pro-inflammatory cytokines and pathogen- and damage-associated molecular patterns contributing to cytokine and genomic changes. Coronavirus disease 2019 clinical presentation is typical of viral pneumonia with an increased prevalence of early pulmonary infiltrates and lymphopenia. Principles of early coronavirus disease 2019 management and isolation as well as potential therapeutic approaches to the emerging pandemic are discussed.

Pneumonia is the leading infectious cause of hospitalization among adults and children in the United States ( 1 ). According to the World Health Organization (WHO), lower respiratory tract infection is among the top causes of death globally ( 2 ). The Centers for Disease Control and Prevention (CDC) Etiology of Pneumonia in the Community study estimated prevalence of pneumonia-related hospitalizations among adults older than 50 to be 4–25 times higher than those 18 to 49 years old ( 3 ).

Viral infections are the leading cause of community-acquired pneumonia (CAP) and are an important source of morbidity and mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly discovered virus causing coronavirus disease 2019 (COVID-19) that is responsible for an emerging pandemic. Given the rapid spread of this virus and its association with severe pulmonary disease, the purpose of this review is to provide an overview of the presentation and immunology of viral pneumonia, principles of early management, and application to COVID-19.

CLINICAL PRESENTATION OF VIRAL PNEUMONIA

According to the CDC, the prevalence of CAP is highest among adults 65 to 79 years old ( 4 ). Hospitalization among adults is highest in elderly patients (≥ 65 yr) and those with preexisting obstructive lung disease or other cardiopulmonary disorders ( 4 , 5 ). The most common cause of community- or hospital-acquired pneumonia in adults is viral with the most frequently detected pathogen being human rhinovirus, followed by influenza (9–15% and 4–6%, respectively) ( 4 – 8 ). Other commonly detected causes of viral pneumonia include adenovirus, conventional coronaviruses, human metapneumovirus (HMPV), respiratory syncytial virus (RSV), and parainfluenza. The prevalence of viral respiratory illness is temporal in North America, with peaks of influenza, HMPV, and RSV normally seen in the winter months ( Table Table1 1 ) ( 1 ).

Characteristics of Common Respiratory Viruses

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The clinical presentation of viral pneumonia does not differentiate between the specific viral causes of respiratory infection. The common clinical presentation of acute viral respiratory infection includes cough, dyspnea, fever, and pleuritic chest pain. Viral etiologies of lower respiratory infection are less likely to cause sputum production, and if present, tends to be watery or scant. In contrast, sputum production tends to be mucopurulent when due to bacterial pneumonia ( 8 , 9 ). Clinical signs of viral respiratory illness include fever, rales (crackles) on auscultation, hypoxemia, and tachycardia. These four signs together have a positive predictive value of 57.1%, with fever as the strongest clinically predictive sign of a viral respiratory infection versus that of bacterial etiology ( 10 ). Typically, patients with viral pneumonia also will present with a normal leukocyte count and bilateral pulmonary infiltrates on chest radiograph ( 9 ). Severe viral pneumonia can manifest as sepsis and respiratory distress requiring intensive care ( 11 ). In many moderate to severe cases of pneumonia, hypoxemia occurs from impaired alveolar gas exchange ( 12 ), often necessitating mechanical ventilation.

Biopsies in pneumonia are not routinely performed due to the lack of diagnostic, prognostic, and treatment value. However, since influenza has caused the most viral respiratory epidemics to date, a number of studies have examined infected patient’s lung biopsy specimens ( 13 ). Biopsies obtained during influenza infection reveal a wide range of pathologies, including alveolar edema and exudate, interstitial inflammatory infiltration, and ulceration of bronchial mucosa to type II cell metaplasia ( 14 , 15 ). In autopsy specimens from H1N1 influenza patients, the respiratory tract exhibited tracheitis, bronchitis, diffuse hemorrhagic alveolar damage, and inflammatory infiltration of alveolar ducts and alveoli ( 16 , 17 ).

IMMUNOLOGIC CHANGES ASSOCIATED WITH VIRAL PNEUMONIA

The host response to severe viral lung infection occurs secondary to immune dysregulation leading to lung injury and the systemic inflammatory response. There have been many studies on the immunologic changes associated with influenza A virus (IAV). However, little is known about other respiratory viral illnesses in adults. Therefore, much of our discussion on the immunology of viral pneumonia will focus on IAV studies.

During a respiratory infection, airway epithelial cells, natural killer (NK), and CD8 T-cells release interferon-gamma (INF-γ) to limit viral replication ( 18 , 19 ). There is additional release of interleukin (IL)–6 and IL-8, important mediators of tissue damage and associated with disease progression, respectively ( 20 ). High levels of IL-17, tumor necrosis factor (TNF)–α, INF-γ, and IL-4 have been found in postmortem human lung tissue after severe IAV ( 21 ).

Although there seems to be a difference in cytokine response based on the cause of respiratory infection, there are mixed results in the utility of plasma cytokine levels for prediction of pneumonia etiology ( 22 , 23 ). In a recent single-center study, differences in admission plasma levels of IL-6, IL-10, IL-17A, and INF-γ were observed between different etiologies of CAP, with INF-γ most elevated in viral CAP ( 24 ). Conversely, a similar study demonstrated, admission plasma cytokine levels were not statistically different based on etiology (bacterial vs viral vs mixed bacterial-viral vs unknown etiology) ( 25 ). Other studies noted that serum transforming growth factor-beta (TGF-β) levels predicted viral pneumonia, as opposed to other etiologies of CAP, where TGF-β had negative correlations with the Sequential Organ Failure Assessment score in patients that progressed to sepsis ( 26 , 27 ). Therefore, although the specific cytokine profile elicited by particular viruses is unknown, it is clear that, as with most etiologies of sepsis, an elevation of both pro- and anti-inflammatory cytokines are responsible for the host septic and systemic inflammatory response syndrome response in all severe viral cases of pneumonia ( 23 , 28 – 30 ).

Pathogen-Associated Molecular Patterns and Damage-Associated Molecular Patterns

As with many other responses to infection, it is pertinent to recognize the role of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) in viral respiratory infection. Pattern recognition receptors on respiratory epithelial cells, such as Toll-like receptors (TLRs), detect evolutionarily conserved microbial ligands, or PAMPs ( 31 , 32 ). Viral PAMPs are typically viral envelope proteins or nucleic acids motifs within the DNA or RNA genomes of the virus, which are critical for structure and function ( 33 ). The recognition of viral PAMPs leads to transcription and release of type I interferons ( 33 ) which effect decreased expression of viral proteins and replication, enhance antigen presentation and NK cell function, and augment adaptive immune responses. Additional recognition of host cell constituents from damaged or dying cells, recognized as DAMPs, are thought to control the magnitude of the immune response ( 34 – 36 ). Together, PAMPs and DAMPs play a major role in the initiation of both the innate and adaptive immune response to viral lung infection ( 31 , 35 , 37 – 40 ).

Increased Susceptibility to Secondary Bacterial Infection/Ventilator-Associated Pneumonia

Viruses can be the primary cause of pneumonia, present in conjunction with bacterial pneumonia, and/or contribute to increased susceptibility to secondary bacterial infection. In addition to influenza, other viruses, such as rhinovirus, can cause severe pneumonia requiring mechanical ventilation, however, this usually occurs in the elderly and immunocompromised ( 8 , 41 ). Severe pneumonia associated with noninfluenza viruses is also significantly associated with bacterial coinfection ( 8 , 42 – 44 ), most commonly due to Staphylococcus aureus , Streptococcus pneumoniae , or Haemophilus influenzae ( 45 , 46 ).

A pattern of dysregulated inflammation caused by viral respiratory infection leads to this increased susceptibility to secondary bacterial pneumonia or coinfection. Most research on viral-bacterial respiratory coinfection has been focused on elucidating the pathophysiology of influenza viruses given its high propensity to cause pandemics and higher mortality when compared with the other viruses ( 13 ). Influenza A causes a reduction in murine alveolar macrophages and dysregulation of remaining macrophages and neutrophils, one of the body’s primary defense mechanisms against bacterial pathogens ( 47 – 49 ). Additionally, prior infection with influenza virus attenuates bacterial induced release of IL-17 leading to decreased innate T cell-mediated bacterial clearance ( 49 ). Replication of IAV in respiratory epithelium impairs mucociliary clearance, allowing for increased bacterial colonization ( 34 , 50 , 51 ). Additionally, there is evidence of sustained desensitization of TLR ligands following viral infection, leading to decreased chemokine release and nuclear factor kappa B activation in macrophages ( 52 , 53 ). This in turn results in attenuated neutrophil recruitment, further decreasing the ability to reduce bacterial load in secondary bacterial infection ( 52 , 53 ).

Genomic/Transcriptomic Changes Associated With Viral Pneumonia

Although CAP remains a significant source of morbidity and mortality, very little work has been done establishing genomic, epigenetic, or transcriptomic changes specifically associated with viral pneumonia ( 54 ). In particular, no clear polymorphism definitively raises the risk of viral pneumonia, limiting personalized medicine for predictive models. In one of the few studies of transcriptomics in viral pneumonia, microarray analysis and Ingenuity Pathway Analysis (Qiagen, Redwood City, CA) was performed on 19 critically ill patients with 2009 H1N1 influenza A pneumonia. The most severely ill group of 12 patients demonstrated impaired expression of numerous genes participating in adaptive immune responses (e.g., diminished antigen presentation, B-cell development, T-helper cell differentiation, and apoptosis), suggesting impaired adaptive immunity in severe viral pneumonia ( 55 ). In terms of epigenetics, many postulate that long-term epigenetic changes following severe pneumonia are responsible an increased likelihood of later infections and death, although specific epigenetic changes are yet to be identified ( 54 ).

VACCINATION AS PREVENTION AND POTENTIAL TREATMENT OF VIRAL PNEUMONIA

Natural infection with viral causes of pneumonia does not induce long-term protective immunity due to an evolutionary advantage allowing viruses to evade host immune defenses via antigenic shift and drift. Antigenic drift occurs with small point mutations in the viral genome leading to minor changes in key viral epitopes, while antigenic shift is a major change in a key gene leading to a complete exchange of a key epitope ( 56 ). Antigenic shift often leads to influenza epidemics secondary to vaccine strain-circulating strain mismatches. Antigenic shift is the molecular mechanism by which novel influenza strains emerge and is the cause of pandemics such as the 2009 H1N1 pandemic ( 57 – 61 ).

Influenza vaccines rely on conserved antigens such as ectodomain of influenza M2 protein, M2e, or hemagglutinin stalk domains. Hemagglutinin globular head specific antibodies confer immunity since it interferes with virus attachment to host cell receptors; however, they are also one of the most variable viral antigens ( 56 ). Additional adjuvants are important in vaccine formulations to induce desired immune responses that would not be triggered with the antigen alone ( 62 ). The need for adjuvants in vaccinations confers an additional important role for DAMPs and PAMPs in viral immunity. One recent study used PAMP TLR9 agonist and commonly used pharmaceutical additive to induce the release of DAMPs to improve immunogenic response to the seasonal influenza vaccine ( 63 ).

Prevention of viral pneumonia is mainly limited to influenza vaccines since the formalin-inactivated RSV vaccine in the 1960s failed secondary to adverse events ( 64 ). However, oral adenovirus vaccination has been used in military populations with 100-fold reduction of respiratory illnesses ( 65 , 66 ). Production of this vaccine was stopped in 1999 but was reintroduced in 2011, leading to a dramatic and sustained decrease of acute respiratory distress outbreaks among U.S. Army trainees ( 67 , 68 ).

Additionally, there is still ongoing work to develop a vaccine to prevent RSV infection. Recently, one study reported protective immunity against RSV with a molecularly adjuvanted adenovirus serotype 5 based RSV oral vaccine in a rat model ( 69 ). However, two recent randomized control failed to establish an effect of anti-RSV monoclonal antibodies and recurrent wheeze of early childhood or asthma ( 70 – 73 ).

IMPLICATIONS FOR COVID-19

Clinical presentation.

Since the COVID-19 caused by the novel coronavirus known as SARS-CoV-2 began its rapid spread in Wuhan, China, in November 2019, researchers have responded swiftly to help thwart the pandemic by quickly establishing studies to better understand the virus. SARS-CoV-2 is a novel beta-coronavirus that likely originated in bats. The virus uses a glycosylated spike protein to bind to and enter the human host cell predominantly via angiotensin-converting enzyme 2 receptors that are highly expressed in type 2 alveolar cells ( 74 ).

The clinical presentation of COVID-19 can be indistinguishable from other viral causes of pneumonia and include fever (83–98%), dry cough (76–82%), and fatigue or myalgia (11–44%) ( 74 , 75 ). The median age of confirmed COVID-19 cases is in the 6th decade of life with a slight male predominance. Twenty-five percent of patients have severe symptoms requiring intensive care treatment of which 10% develop respiratory failure requiring mechanical ventilation. Chest radiograph imaging of these patients reveals bilateral patchy infiltrates and CT imaging shows ground-glass infiltrates. Patients typically present with laboratory findings of prolonged prothrombin time, elevated lactate dehydrogenase, and lymphopenia (70% of patients) ( 76 ). However, it is unclear if the lymphopenia is related to direct cytotoxic effect of the virus or underlying chronic conditions ( 77 , 78 ).

There are limited publications on the autopsy results of patients who have died from COVID-19. However, pathologic samples show hyaline membrane formation, interstitial mononuclear inflammatory infiltrates, and multinucleated giant cells. There are also high levels of pro-inflammatory cytokines, such as IL-2 and TNF-α. As with other causes of severe viral pneumonia, a “cytokine storm” occurs which also contributes to the high morbidity and mortality ( 79 , 80 ).

Principles of Early Management

The most important aspect of early management of viral spread has been early isolation of those presenting with concerning symptoms, history, and high likelihood of exposure to prevent spread of the disease to those in immunocompromised states, the elderly, and/or those with comorbid conditions. A chest radiograph along with throat and mid-turbinate nasal swabs for respiratory viral panel (reverse transcriptase-polymerase chain reaction) are needed for proper diagnosis of COVID-19. Among hospitalized patients, negative pressure rooms and airborne-droplet-contact precautions are important for prevention and further spread between patients and hospital care-workers ( 81 ).

Currently, there is no approved drug or vaccination for the treatment or prevention of SARS-CoV-2 viral pneumonia. There are many trials underway attempting to attenuate the disease with remdesivir, IL-6 receptor blockers, IL-7, and antiretrovirals such as lopinavir-ritonavir ( 82 ). The New England Journal of Medicine recently published a randomized controlled trial evaluating the efficacy of lopinavir-ritonavir versus standard care alone in the treatment of adult hospitalized patients with severe COVID-19. There were no differences in hospital mortality, time to clinical improvement, or viral RNA levels. Although the median time to improvement was 1 day shorter with lopinavir-ritonavir on intention-to-treat analysis, 14% of patients had adverse events requiring treatment discontinuation. Therefore, it was concluded that there was no benefit observed with lopinavir-ritonavir treatment versus standard treatment of severe COVID-19 patients ( 83 ). Historically, hydroxychloroquine, an anti-malarial and anti-inflammatory agent, has shown some promise in reducing mortality from SARS and, therefore, is currently being studied for COVID-19 ( 84 ). In one very limited study from France ( n = 20 per group, nonrandomized), hydroxychloroquine was associated with reduced viral load and reduced duration of viral detection which was further attenuated by the addition of azithromycin ( 85 ).

Research is already underway to create a vaccine to protect against SARS-CoV-2. Taking advantage of the similarities in structure between SARS-CoV (responsible for the 2003 SARS epidemic) and SARS-CoV-2 (responsible for COVID-19), studies have mapped several epitopes to be targeted for a potential vaccine ( 86 , 87 ). WHO estimates an approximately 18-month timeframe for COVID-19 vaccine availability.

Until such time that effective therapies and vaccines become available, public health efforts should continue to focus on mitigating the spread of SARS-CoV-2 through well-established infection control strategies ( 88 ). This can be aided in the hospital with admission of SARS-CoV-2 positive patients into negative pressure rooms with contact precaution protocols requiring personal protective equipment such as gowns, gloves, fit-tested N95 respirators, and face shields. Additionally, rules limiting the people entering the isolation room and requiring logging of healthcare workers involved in COVID-19 patient care should be followed to effectively monitor patient contact and limit spread. All equipment (monitors, etc.) in the isolation room should be designated for the case patient only. Physicians should limit potential spread by recognizing any necessary aerosol-generating procedures and preparing accordingly (e.g., for intubation using controlled measures including paralytics, video laryngoscopy, N95 masks). Although fomites are suspected as the main source of transmission, there is also possible fecal-oral transmission; therefore, hand washing is a mainstay of control/prevention ( 89 ).

CONCLUSIONS

Although viral pneumonia is common, the specific inflammatory and immunosuppressive effects it has on the host is still largely unknown. COVID-19 has brought viral pneumonia and subsequent host pathology to the forefront of medical care and research. SARS-CoV-2 spread worldwide in a matter of months to cause a pandemic not seen since influenza in 1918. Our highly interconnected global society creates ample opportunity for the rapid spread of novel viruses. Since these types of viral pandemics have occurred multiple times historically (e.g., influenza in 1918, Middle East respiratory syndrome in 2014, and SARS in 2004) and will continue to occur in the future, research into immunomodulative therapies for patients afflicted with viral pneumonia will be a key aspect to improving outcomes after viral pneumonia. A personalized approach, taking into account differences in the biology of individuals and the pathophysiology of different viruses, will also be required to make significant progress in the treatment of these patients.

The authors have disclosed that they do not have any potential conflicts of interest.

Upper Respiratory Tract Infection Clinical Presentation

Author: Zab Mosenifar, MD, FACP, FCCP; Chief Editor: Zab Mosenifar, MD, FACP, FCCP more...
Sections Upper Respiratory Tract Infection
Practice Essentials
Pathophysiology
Epidemiology
Patient Education
Physical Examination
Approach Considerations
Suspected Acute Bacterial Rhinosinusitis
Suspected Mononucleosis
Suspected Herpes Simplex Virus Infection
Suspected Pertussis
Suspected Epiglottitis
Epiglottitis
Laryngotracheitis
Rhinosinusitis
Group A Streptococcal Disease
Herpetic or Gonococcal Pharyngitis
Other Conditions That May Warrant Specific Treatment
Patients With Immunocompromise
Surgical Care
Symptomatic, Nonpharmacologic Self-Care
Symptomatic, Pharmacologic Therapy
Deterrence/Prevention
Consultations
Follow-Up Care
Medication Summary
Penicillins, Natural
Penicillins, Amino
Cephalosporins, First Generation
Cephalosporins, Second Generation
Cephalosporins, Third Generation
Analgesics, Other
Anticholinergics, Respiratory
Antihistamines, First Generation
Antitussives, Non-Narcotic Combos
Antitussives, Opioid Analgesics
Alpha/Beta-Adrenergic Agonists
Corticosteroids
Decongestants, Systemic
Decongestants, Intranasal
Questions & Answers
Media Gallery

Details of the patient's history aid in differentiating a common cold from conditions that require targeted therapy, such as group A streptococcal pharyngitis, bacterial sinusitis, and lower respiratory tract infections. The table below contrasts symptoms of upper respiratory tract infection (URI) with symptoms of allergy and seasonal influenza (adapted from the National Institute of Allergy and Infectious Diseases). [ 22 , 25 ]

Table. Symptoms of Allergies, URIs, and Influenza (Open Table in a new window)


Common	Rare; conjunctivitis may occur with adenovirus	Soreness behind eyes, sometimes conjunctivitis
Common	Common	Common
Common	Common	Sometimes
Very common	Very common	Sometimes
Sometimes (postnasal drip); itchy throat	Very common	Sometimes
Sometimes	Common, mild to moderate, hacking cough	Common, dry cough, can be severe
Sometimes, facial pain	Rare	Common
Never	Rare in adults, possible in children	Very common, 100-102°F or higher (in young children), lasting 3-4 days; may have chills
Sometimes	Sometimes	Very common
Sometimes	Sometimes	Very common, can last for weeks, extreme exhaustion early in course
Never	Slight	Very common, often severe
Weeks	3-14 days	7 days, followed by additional days of cough and fatigue

Viral nasopharyngitis

Symptoms of the common cold usually begin 2-3 days after inoculation. Viral URIs typically last 6.6 days in children aged 1-2 years in home care and 8.9 days for children older than 1 year in daycare. Cold symptoms in adults can last from 3-14 days, but most people recover or have symptomatic improvement within a week. If symptoms last longer than 2 weeks, consider alternative diagnoses, such as allergy, sinusitis, mononucleosis, tuberculosis, or pneumonia.

Nasal symptoms of rhinorrhea, congestion or obstruction of nasal breathing, and sneezing are common early in the course. Clinically significant rhinorrhea is more characteristic of a viral infection rather than a bacterial infection. In viral URI, secretions often evolve from clear to opaque white to green to yellow within 2-3 days of symptom onset. [ 7 ] Thus, color and opacity do not reliably distinguish viral from bacterial illness.

On the other hand, the existence of persistent, purulent nasal discharge, especially if accompanied by crusts or sores in the nares, may indicate bacterial infection, particularly with S aureus . Other indicators of bacterial infection are skin pustules or impetigo and the presence of purulent signs in other family or household members.

Pharyngeal symptoms include sore or scratchy throat, odynophagia, or dysphagia. Sore throat is typically present at the onset of illness, although it lasts only a few days. If the uvula or posterior pharynx is inflamed, the patient may have an uncomfortable sensation of a lump when swallowing. Nasal obstruction may cause mouth breathing, which may result in a dry mouth, especially after sleep.

Cough may represent laryngeal involvement, or it may result from upper airway cough syndrome related to nasal secretions (postnasal drip). Cough typically develops on the fourth or fifth day, subsequent to nasal and pharyngeal symptoms.

Other manifestations are as follows:

Foul breath: Occurs as resident flora processes the products of the inflammatory process; foul breath may also occurs with allergic rhinitis

Hyposmia: Also termed anosmia, it is secondary to nasal inflammation

Headache: Common with many types of URI

Sinus symptoms: May include congestion or pressure and are common with viral URIs

Photophobia or conjunctivitis: May be seen with adenoviral and other viral infections; influenza may evoke pain behind the eyes, pain with eye movement, or conjunctivitis; itchy, watery eyes are common in patients with allergic conditions

Fever: Usually slight or absent in adults, but temperatures can reach 102°F in infants and young children; if present, fever typically lasts for only a few days; influenza can cause fevers as high as 40°C (104°F)

Gastrointestinal symptoms: Nausea, vomiting, and diarrhea may occur in persons with influenza, especially in children; nausea and abdominal pain may be present in individuals with strep throat and various viral syndromes

Severe myalgia: Typical of influenza infection, especially in the setting of sudden-onset sore throat, fever, chills, nonproductive cough, and headache

Fatigue or malaise: Any type of URI can produce these symptoms; extreme exhaustion is typical of influenza

Pharyngitis from group A streptococci

The history alone is rarely a reliable differentiator between viral and bacterial pharyngitis. However, persistence of symptoms beyond 10 days or progressive worsening after the first 5-7 days suggests a bacterial illness. Assessment for group A streptococci warrants special attention.

The health status of contacts and local epidemiologic trends are important factors to consider. A personal history of rheumatic fever (especially carditis or valvular disease) or a household contact with a history of rheumatic fever increases a person's risk. Other factors include occurrence from November through May and patient age of 5-15 years.

Pharyngeal symptoms of sore or scratchy throat, odynophagia, or dysphagia are common. If the uvula or posterior pharynx is inflamed, the patient may have an uncomfortable feeling of a lump when swallowing. Nasal obstruction may cause mouth breathing, which may result in dry mouth, especially in the morning. Group A streptococcal infections often produce a sudden sore throat.

Fever increases the suspicion that infection with group A streptococci is present, as does the absence of cough, rhinorrhea, and conjunctivitis, because these are common in viral syndrome; however, symptoms overlap between streptococcal and viral illness.

Secretions: May be thick or yellow; however, these features do not differentiate a bacterial infection from a viral one

Cough: May be due to laryngeal involvement or upper airway cough syndrome related to nasal secretions (postnasal drip)

Foul breath: May occur because resident flora processes the products of the inflammatory process; foul breath may also occur with allergic rhinitis and viral infections

Headache: While common with group A streptococci and mycoplasma infections, it also may reflect URI from other causes

Fatigue or malaise: These may occur with any URI; extreme exhaustion is typical of influenza

Fever: While usually slight or absent in adults, temperatures may reach 102°F in infants and young children

Rash: A rash may be seen with group A streptococcal infections, particularly in children and in adolescents younger than 18 years

Abdominal pain: This symptom may occur in streptococcal disease, most commonly in young children, but also in influenza and other viral conditions

A history of recent orogenital contact suggests possible gonococcal rather than streptococcal pharyngitis. However, most gonococcal infections of the pharynx are asymptomatic. [ 32 ]

Acute viral or bacterial rhinosinusitis

The presentation of rhinosinusitis is often similar to that of nasopharyngitis, because many viral URIs directly involve the paranasal sinuses. Symptoms may have a biphasic pattern, wherein coldlike symptoms initially improve but then worsen. Acute bacterial rhinosinusitis is not common in patients whose symptoms have lasted fewer than 7 days. Unilateral and localizing symptoms raise the suspicion for sinus involvement.

In children with bacterial sinusitis, the most common signs are cough (80%), nasal discharge (76%), and fever (63%). In adults, the classic triad of facial pain, headache, and fever is not common. [ 7 ]

The 2013 American Academy of Pediatrics (AAP) guidelines define acute bacterial sinusitis in children as a URI with any of the following [ 3 ] :

Persistent nasal discharge (any type) or cough lasting 10 days or more without improvement

Worsening course (new or worse nasal discharge, cough, fever) after initial improvement

Severe onset (fever of 102°F or greater with nasal discharge) for at least 3 consecutive days

Nasal discharge

Nasal discharge may be persistent and purulent, and sneezing may occur. Mucopurulent secretions are seen with viral and bacterial infections. Secretions may be yellow or green; however, the color does not differentiate a bacterial sinus infection from a viral one, because thick, opaque, yellow secretions may be seen with uncomplicated viral nasopharyngitis. [ 7 ]

Compared with allergy or viral infection, rhinorrhea may be less predominant, and not respond to decongestants or antihistamines. Congestion and nasal stuffiness predominate in some individuals.

Facial and dental pain

Facial or dental pressure or pain may be present. In older children and adults, symptoms tend to localize to the affected sinus. Frontal, facial, or retro-orbital pain or pressure is common. Maxillary sinus inflammation may manifest as pain in the upper teeth on the affected side. Pain radiating to the ear may represent otitis media, local adenopathy, or a peritonsillar abscess.

Sore throat and dry mouth

Sore throat may result from irritation from nasal secretions dripping down the posterior pharynx. Nasal obstruction may cause mouth breathing, which may result in dry mouth, especially in the morning. Mouth breathing may especially be noted in children. Dry mouth may be prominent, especially after sleep. Foul breath may be noted, because resident flora processes the products of the inflammatory process; this symptom may also occur with allergic rhinitis.

Frequent throat clearing or cough may develop as a result of nasal secretions (postnasal drip). Rhinosinusitis-related cough is usually present throughout the day. The cough may also be most prominent on awakening, because of secretions that have gathered in the posterior pharynx overnight.

Daytime cough that lasts more than 10-14 days suggests sinus disease, asthma, or other conditions. Nighttime-only cough is common in numerous disorders, in part because of reduced throat clearing and airway mechanics; many forms of cough are most noticeable at night.

Upper airway cough syndrome related to nasal secretions occasionally precipitates posttussive emesis; this may also occur with asthma. Clinically significant amounts of purulent sputum may suggest bronchitis or pneumonia.

Hyposmia or anosmia may result from nasal inflammation. Fatigue or malaise may be seen with any URI.

This condition is more often found in children aged 1-5 years, who present with a sudden onset of the following symptoms:

Sore throat
Drooling, odynophagia or dysphagia, difficulty or pain during swallowing, globus sensation of a lump in the throat
Muffled dysphonia or loss of voice
Dry cough or no cough, dyspnea
Fever, fatigue or malaise (may be seen with any URI)
Tripod or sniffing posture

Laryngotracheitis and laryngotracheobronchitis

Nasopharyngitis often precedes laryngitis and tracheitis by several days. Swallowing may be difficult or painful, and patients may experience a globus sensation of a lump in the throat. Hoarseness or loss of voice is a key manifestation of laryngeal involvement.

In adolescents and adults, laryngotracheal infection may manifest as severe dry cough following a typical URI prodrome. Mild hemoptysis may be present; however, hemoptysis may also be seen with tuberculosis and other conditions. Children with laryngotracheitis or laryngotracheobronchitis (croup) may have the characteristic brassy, seal-like barking cough. Symptoms may be worse at night. Diphtheria also produces a barking cough.

Myalgias are characteristic in influenza, especially in the setting of hoarseness with sudden sore throat, fever, chills, nonproductive cough, and headache. Fever may be present, but it is not typical in persons with croup. Fatigue or malaise may occur with any URI.

Whooping cough

In whooping cough, the classic whoop sound is an inspiratory gasping squeak that rises in pitch, typically interspersed between hacking coughs. The whoop is more common in children. Coughing often comes in paroxysms of a dozen coughs or more at a time and is often worst at night.

The 3 classic phases of whooping cough are as follows [ 5 ] :

Catarrhal (7-10 days) with predominantly URI symptoms
Paroxysmal (1-3 weeks) with episodic cough
Convalescent (2-3 weeks) of gradual recovery

Posttussive symptoms include gagging or emesis after paroxysms of whooping cough. Subconjunctival hemorrhage may result from severe cough. Rib pain with pinpoint tenderness worsening with respiration may reflect rib fracture associated with severe cough.

Dyspnea and increased work of breathing may be worse at night in patients with whooping cough, because of changes in airway mechanics while the patient is recumbent. Apnea may be a chief feature in infants with pertussis. Apnea may also result from upper airway obstruction due to other causes.

Patients with the common cold may have a paucity of clinical findings despite notable subjective discomfort. Findings may include the following:

Nasal mucosal erythema and edema are common

Nasal discharge: Profuse discharge is more characteristic of viral infections than bacterial infections; initially clear secretions typically become cloudy white, yellow, or green over several days, even in viral infections

Foul breath: Halitosis may be noted because resident flora process the products of the inflammatory process

Fever: Temperature is less commonly elevated in adults with the common cold, but fever may be present in children with rhinoviral infections

Viral pharyngitis

Pharyngeal erythema is typically marked in adenoviral infection. In contrast, rhinoviral and coronaviral infections are not likely to manifest as severe erythema.

Exudates may occur in half the patients with adenovirus infections. Exudative pharyngitis and tonsillitis may be seen with mononucleosis caused by Epstein-Barr virus (EBV), while exudates are uncommon in rhinoviral, coxsackievirus, and herpes simplex virus (HSV) pharyngitis. Yellow or green secretions do not differentiate a bacterial pharyngitis from a viral one. Thick, yellow secretions are commonly seen with uncomplicated viral nasopharyngeal infections.

The presence of palatal vesicles or shallow ulcers is characteristic of primary infection with herpes simplex virus. Ulcerative stomatitis may also occur in coxsackievirus or other enteroviral infections, and mucosal erosions may also be seen in primary HIV infection. Small vesicles on the soft palate, uvula, and anterior tonsillar pillars suggest herpangina, which is caused by coxsackieviral infection.

Profuse nasal discharge is more characteristic of viral infections than bacterial infections. Initially clear secretions typically become cloudy white, yellow, or green over several days, even in viral infections. Halitosis may be noted, because resident flora processes the products of the inflammatory process.

Anterior cervical lymphadenopathy is seen with viral and bacterial infections. Approximately half of EBV mononucleosis cases involve generalized adenopathy or splenomegaly. An enlarged liver may also be palpable. Primary HIV infection can be another cause of lymphadenopathy.

Conjunctivitis may be seen with adenoviral pharyngoconjunctival fever and is present in one half to one third of all adenoviral URIs. Watery, injected conjunctiva may also be seen with allergic conditions.

Other signs that may accompany viral pharyngitis include the following:

Tonsillar hypertrophy

Cough: This is more suggestive of a viral, rather than a bacterial, etiology

Diarrhea: If associated with a URI, diarrhea suggests a viral etiology

Fever: Can be caused by EBV infections and influenza

Bacterial pharyngitis

This may be difficult to distinguish from viral pharyngitis. Assessment for group A streptococcal infection warrants special attention. The following physical findings suggest a high risk for group A streptococcal disease [ 1 ] :

Erythema, swelling, or exudates of the tonsils or pharynx

Temperature of 38.3°C (100.9°F) or higher

Tender anterior cervical nodes (≥1 cm)

Absence of conjunctivitis, cough, and rhinorrhea, which are symptoms that may suggest viral illness [ 2 ]

Less common findings in streptococcal pharyngitis are petechiae of the palate and a scarlatiniform rash. These are not uniquely specific to this disorder.

Exudates manifest as white or yellow patches. A whitish coating may appear on the tongue, causing the normal bumps to appear more prominent. Yellow or green coloration does not differentiate bacterial pharyngitis from a viral disease, because thick, yellow secretions may be seen with uncomplicated viral nasopharyngitis. Foul breath may be noted because resident flora processes the products of the inflammatory process.

A whitish adherent membrane forming on the nasal septum, along with a mucopurulent blood-tinged discharge, should prompt consideration of diphtheria. Pharyngeal and tonsillar diphtheria may manifest as an adherent blue-white or gray-green membrane over the tonsils or soft palate; if bleeding has occurred, the membrane may appear blackish.

A peritonsillar abscess may manifest as unilateral palatal and tonsillar pillar swelling, with downward and medial tonsil displacement; the uvula may tilt to the opposite side. Bulging of the posterior pharyngeal wall may signal a retropharyngeal abscess .

Tender anterior cervical adenopathy may be part of the presentation in patients with streptococcal or viral infections. In persons with diphtheria, submandibular and anterior cervical edema may be present along with adenopathy.

Fever is more likely to occur in group A streptococcal infections than in other URIs, although it may be absent. Temperatures around 38.3°C (101°F) may occur in group A streptococcal infection.

Rash may be seen with group A streptococcal infections, particularly in patients younger than 18 years. The scarlet fever rash appears as tiny papules over the chest and abdomen, creating roughness similar to sandpaper and producing a sunburned appearance. The rash spreads, causing erythema in the groin and armpits. The face may be flushed, with pallor around the lips. Approximately 2-5 days later, the rash begins to resolve. Peeling is often noted on the tips of toes and fingers.

Cutaneous diphtheria may appear as a scaling rash or as well-demarcated ulcers with membranes. Neisseria gonorrhoeae infection may also cause a rash.

Uncommon findings in bacterial pharyngitis include the following:

Drooling: May be noted in cases of peritonsillar abscess, or it may denote epiglottitis

Distorted speech (“mush mouth”): As if the mouth were filled

Lower respiratory tract findings (eg, rales): In patients with concomitant URI, these suggest infection with pathogens such as Mycoplasma pneumoniae or Chlamydia pneumoniae or with viruses

Conjunctivitis, cough, and diarrhea: More common with URIs caused by virus rather than bacteria

Rhinorrhea: Not a common feature of pharyngitis caused by bacteria such as group A streptococci

In the setting of acute pharyngitis, the presence or absence of preexisting cardiac murmurs should be documented for comparative purposes in case rheumatic fever later develops.

Acute rhinosinusitis

This is most often viral; however, differentiating common viral illnesses from uncommon bacterial cases on clinical grounds alone can be challenging. Suspicion is raised for acute bacterial rhinosinusitis when symptoms last more than 7 days and when the patient has maxillary pain or tenderness in the face or teeth (especially unilateral), headache, and purulent nasal secretions. Occasionally, patients with acute bacterial sinusitis present with severe symptoms, especially unilateral facial pain, even when symptoms have not lasted at least 7 days.

However, the classic triad of fever, headache, and facial pain occurs uncommonly in adults with bacterial sinusitis; in children with bacterial sinusitis, nasal discharge is present in 76% of patients and fever is found in 63%. [ 7 ] Foul breath may be noted, because resident flora processes the products of the inflammatory process.

The paranasal sinuses develop and enlarge after birth; ethmoid and sphenoid sinuses may not be of significant size until age 3-7 years. The frontal sinuses are the last to develop and may not be of significant size until adolescence.

Mucopurulent secretions may be present in the nares with either viral or bacterial sinusitis. A lighted nasal speculum directed posteriorly allows the clinician to view secretions emanating from the area of the middle meatus. Secretions may be thick and yellow; however, color does not differentiate a bacterial sinus infection from a viral one. Thick, yellow secretions may be seen several days into the course of uncomplicated viral nasopharyngitis.

When rhinitis is present, nasal mucosa may be inflamed. Typical findings include swelling and redness of the turbinates. In many cases of sinusitis, the nares serve only as a conduit for purulent secretions, and the nasal mucosa may not be inflamed. Pallor and edema may be associated with underlying allergic rhinitis. The presence of unilateral signs suggests sinus involvement rather than uncomplicated rhinitis.

Preexisting obstructions

Nasal obstruction due to preexisting polyps or septal deviation may contribute to sinusitis. It is best appreciated upon direct inspection with nasal endoscopy.

Facial tenderness

Facial tenderness to palpation or percussion may be present and most easily appreciated over the frontal or maxillary sinuses. Percuss and apply digital pressure to the forehead above the brow to evaluate frontal sinus area tenderness. The floor of the frontal sinuses may be approached by pressing upward on the supraorbital area of the skull beneath the eyebrows.

Maxillary sinuses are posterior to the cheekbones; use digital pressure and percussion on the cheeks to elicit tenderness. Tapping on the upper teeth with a tongue depressor may evoke pain in the corresponding maxillary sinus. The floor of the maxillary sinuses may be approached by pressing upward on the palate.

Ethmoid sinuses are between the eyes and behind the nasal bridge. Palpate the area around the middle canthus to assess the ethmoids. The sphenoid sinuses are deep to the ethmoids and behind the eyes. Evaluating the ethmoid and sphenoid sinuses during routine physical examination is challenging. Periorbital swelling may be present in ethmoid sinusitis.

Sinus opacity

Sinus cavity opacity on transillumination suggests sinusitis. Opacity is best appreciated in a completely darkened room. Place the illuminator directly on the skin at the level of the infraorbital rim to evaluate the maxillary sinuses and at the medial aspect of the supraorbital rim to evaluate the frontal sinuses. The maxillary sinuses may also be transilluminated by placing a light beam inside the patient's mouth against the palate directed upward.

Bright transmission of light suggests a normal air-filled sinus; absent light transmission suggests the presence of fluid. This approach depends on the examiner's skill and experience, and results are best interpreted along with other findings. Transillumination findings may be unreliable in children. The frontal sinuses may not begin to develop until age 5-8 years.

Intracranial suppurative complications

Suspect an intracranial suppurative complication (eg, abscess) when the examination reveals signs such as the following:

Impaired extraocular movements
Decreased vision
Papilledema
Changes in mental status
Other neurologic findings

Direct visualization is the best way to confirm the diagnosis of epiglottitis. However, such examination may compromise the airway. Therefore, in suspected epiglottitis, limit the examination to observation and an assessment of the vital signs. Oropharyngeal examination performed by using a tongue depressor or speculum can provoke laryngospasm. Direct visualization of the upper airway should be performed only when emergency endotracheal intubation or cricothyroidotomy can be safely performed if necessary.

Physical findings associated with epiglottitis include the following:

Stridor: Inspiratory stridor may be notable and best appreciated with auscultation over the anterior trachea; wheezing heard only on expiration is most consistent with bronchial disease
Tenderness to gentle palpation over the larynx
Cervical adenopathy
Respiratory distress

Respiratory distress in patients with epiglottitis may manifest as tachypnea, tachycardia, and the use of accessory muscles of respiration. Observe the patient for rib retractions, use of strap muscles, and perioral cyanosis. In response to respiratory distress, patients with epiglottitis may assume the classic tripod position: sitting upright, supported by the hands, with the tongue out and head forward.

Laryngitis and laryngotracheitis

Many patients with croup or laryngotracheitis are less ill than they sound. In severe cases, however, children may have respiratory fatigue that leads to respiratory failure.

Hoarseness is a hallmark of laryngeal involvement. Lowered vocal pitch and loss of voice may occur.

Dry cough may be present with laryngeal involvement. Children with laryngotracheitis or croup may have the characteristic brassy, seal-like barking cough. A barking cough may also be present in diphtheria laryngitis. In whooping cough, the classic whoop sound is an inspiratory gasping squeak that rises in pitch, typically interspersed between hacking coughs. The whoop is more common in children than in adults.

Inspiratory stridor may be audible with croup or whooping cough. It typically can be heard without a stethoscope, but it is especially obvious with the stethoscope placed on the anterior aspect of the trachea during inspiration.

Mild hemoptysis may be present; however, hemoptysis made also be seen with tuberculosis and other conditions. Clinically significant amounts of purulent sputum may suggest bronchitis or pneumonia.

Respiratory compromise manifests as tachypnea, tachycardia, and the use of accessory muscles of respiration. Diminished breath sounds in association with pallor and cyanosis may indicate impending respiratory failure.

Paroxysms of coughing may produce conjunctival hemorrhages. Petechial hemorrhages may be noted in the upper body, resulting from severe paroxysms of coughing, such as those associated with whooping cough. Rib fracture, with pinpoint tenderness worsening with respiration, may result from severe coughing, such as that seen in whooping cough.

Lymphadenopathy may be present in the anterior cervical nodes. Fever may be present, but it is not typical in persons with croup. Fever may be seen with influenza laryngitis.

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Seasonal variation of selected upper respiratory tract infection pathogens. PIV is parainfluenza virus, RSV is respiratory syncytial virus, MPV is metapneumovirus, and Group A Strept is group A streptococcal disease.
CT scan of the sinuses demonstrates maxillary sinusitis. The left maxillary sinus is completely opacified (asterisk), and the right has mucosal thickening (arrow). Courtesy of Omar Lababede, MD, Cleveland Clinic Foundation.
Lateral neck radiograph demonstrates epiglottitis. Courtesy of Marilyn Goske, MD, Cleveland Clinic Foundation.
Gonococcal pharyngitis. Image credit: CDC Public Health Image Library (Flumara NJ, Hart G).
Strep throat with petechiae. CDC Public Health Image Library (Eichenwald HF).
Table. Symptoms of Allergies, URIs, and Influenza


Common	Rare; conjunctivitis may occur with adenovirus	Soreness behind eyes, sometimes conjunctivitis
Common	Common	Common
Common	Common	Sometimes
Very common	Very common	Sometimes
Sometimes (postnasal drip); itchy throat	Very common	Sometimes
Sometimes	Common, mild to moderate, hacking cough	Common, dry cough, can be severe
Sometimes, facial pain	Rare	Common
Never	Rare in adults, possible in children	Very common, 100-102°F or higher (in young children), lasting 3-4 days; may have chills
Sometimes	Sometimes	Very common
Sometimes	Sometimes	Very common, can last for weeks, extreme exhaustion early in course
Never	Slight	Very common, often severe
Weeks	3-14 days	7 days, followed by additional days of cough and fatigue

Contributor Information and Disclosures

Zab Mosenifar, MD, FACP, FCCP Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine Zab Mosenifar, MD, FACP, FCCP is a member of the following medical societies: American College of Chest Physicians , American College of Physicians , American Federation for Medical Research , American Thoracic Society Disclosure: Nothing to disclose.

Anne Meneghetti, MD, Assistant Professor of Medicine, Tufts University School of Medicine.

Anne Meneghetti, MD is a member of the following medical societies: National Ayurvedic Medical Association

Disclosure: Nothing to disclose.

Gregory William Rutecki, MD Professor of Medicine, Fellow of The Center for Bioethics and Human Dignity, University of South Alabama College of Medicine

Gregory William Rutecki, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American Society of Nephrology , National Kidney Foundation , and Society of General Internal Medicine

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Bacterial vs. viral infections: how do they differ, what's the difference between a bacterial infection and a viral infection.

Bacteria cause bacterial infections. Viruses cause viral infections. Antibiotic medicines kill or keep many bacteria from growing but don't treat viruses. Antiviral medicines help the body clear out some viruses.

Bacteria are single-celled microorganisms. They can live in many different types of environments.

Bacteria also live on and in the human body. Most bacteria cause no harm and some help. For example, bacteria in the intestines help digest food.

But bacteria can cause illness. For example, bacteria that travel from the anus into the urinary tract can cause a urinary tract infection.

People can come into contact with bacteria from other people, food or the environment. These bacteria can cause illnesses. Some examples are:

Strep throat.
Tuberculosis.
Salmonellosis.

Antibiotics are medicines that kill bacteria or block activities bacteria need to live or grow.

Hundreds of antibiotics exist. But bacteria have naturally occurring genetic means to help them avoid being wiped out. The bacteria that stay alive and active after being treated with antibiotics are called antibiotic-resistant bacteria.

If disease-causing bacteria become resistant to antibiotics, treating illnesses can become harder in the future. Antibiotic resistance can mean that people are sicker for longer. Some people may even die from infections that used to be treated with antibiotics. Antibiotics are unlike other types of medicine. How a person uses an antibiotic can affect how well that antibiotic works for people in the future.

People who may rely on antibiotics more than others are those who:

Are planning a surgery.
Are getting cancer treatment.
Have had an organ transplant.
Receive dialysis.
Have diabetes.

Viruses are bits of genetic information, either RNA or DNA, surrounded by protein. A virus needs a living host, such as a person, plant or animal. To spread, a virus gets into a host's body and then into the host's cells. Then it takes over the host cell's machinery, using it to make more of the virus.

Diseases caused by viruses include:

COVID-19, caused by a coronavirus called SARS-CoV-2.
Chickenpox, caused by the varicella-zoster virus.
HIV, caused by the human immunodeficiency virus.
Common colds, caused by a range of viruses, but often by rhinoviruses.

Medicine that treats viral infections is called an antiviral. These medicines usually stop a virus from making copies of itself. They also may stop a virus from going into or leaving a cell.

Many antivirals are made to target the virus and not the host cell. For this reason, antiviral medicine often needs a person's immune system to help clear out the infection. Some antiviral medicines focus on boosting parts of the host's immune system.

More than 70 antiviral medicines are used to treat human illnesses, some with major effects. For example, between 1996 and 1997 when antiviral therapy was introduced to treat HIV infection, the rate of death from HIV infection decreased 47%.

Viruses have a natural ability to escape the control of antiviral medicine. But this resistance is more likely in people with weakened immune responses. A weakened immune response allows the virus to copy itself more often, for longer. That raises the chance that it will develop a resistance.

Viruses that become resistant to antivirals have affected treatment, including for genital herpes, HIV and, in 2008, for influenza (flu).

Treating and preventing bacterial and viral infections

In some cases, it can be hard to figure out if a bacterial infection or a viral infection is causing your symptoms. Both infections can cause the same diseases, such as pneumonia, meningitis and diarrhea. A careful review of your symptoms and lab tests can help your health care provider find the right treatment.

If your provider gives you a medicine, either an antibiotic or an antiviral, take it as directed. To prevent infections, get vaccinated for viral and bacterial illnesses on schedule.

Also follow these tips to prevent illness:

Wash your hands with soap and water.
Keep your hands away from the face.
Stay away from people who are sick and avoid others if you are sick.
Cover your coughs and sneezes.
Learn how to identify an infection.
Be aware of the bacteria pets can bring into your living area or get on your hands.
Clean and disinfect items that you touch often.
Follow food safety rules.
Take steps to prevent sexually transmitted infections.

It can help to ask your provider about your risk of infection. Also ask about your risk of a more serious response to infection called sepsis.

Pritish K. Tosh, M.D.

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Ebola transmission: Can Ebola spread through the air?
Monkeypox: What is it and how can it be prevented?
Bacteria. National Human Genome Research Institute. https://www.genome.gov/genetics-glossary/Bacteria. Accessed Jan. 11, 2023.
Antibiotic use questions and answers. Centers for Disease Control and Prevention. https://www.cdc.gov/antibiotic-use/q-a.html. Accessed Jan. 11, 2023.
Strep throat: All you need to know. Centers for Disease Control and Prevention. https://www.cdc.gov/groupastrep/diseases-public/strep-throat.html. Accessed Jan. 11, 2023.
How TB spreads. Centers for Disease Control and Prevention. https://www.cdc.gov/tb/topic/basics/howtbspreads.htm. Accessed Jan. 11, 2023.
Salmonella questions and answers. Centers for Disease Control and Prevention. https://www.cdc.gov/salmonella/general/index.html. Accessed Jan. 11, 2023.
Tetanus causes and how it spreads. Centers for Disease Control and Prevention. https://www.cdc.gov/tetanus/about/causes-transmission.html. Accessed Jan. 11, 2023.
Bennett JE, et al. In: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Jan. 11, 2023.
Antimicrobial resistance questions and answers. Centers for Disease Control and Prevention. https://www.cdc.gov/antibiotic-use/q-a.html. Accessed Jan. 11, 2023.
COVID-19: U.S. impact on antimicrobial resistance, special report 2022. Centers for Disease Control and Prevention. https://www.cdc.gov/antibiotic-use/index.html. Accessed Jan. 11, 2023.
Antibiotic resistance threats in the United States, 2019. Centers for Disease Control and Prevention. https://www.cdc.gov/antibiotic-use/index.html. Accessed Jan. 11, 2023.
Virus. National Human Genome Research Institute. https://www.genome.gov/genetics-glossary/Virus. Accessed Jan. 11, 2023.
Basics of COVID-19. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/your-health/about-covid-19/basics-covid-19.html. Accessed Jan. 11, 2023.
Chickenpox (varicella) signs and symptoms. Centers for Disease Control and Prevention. https://www.cdc.gov/chickenpox/about/symptoms.html. Accessed Jan. 11, 2023.
About HIV. Centers for Disease Control and Prevention. https://www.cdc.gov/hiv/basics/whatishiv.html. Accessed Jan. 11, 2023.
Common colds: Protect yourself and others. Centers for Disease Control and Prevention. https://www.cdc.gov/features/rhinoviruses/index.html. Accessed Jan. 11, 2023.
HIV and AIDS timeline. Centers for Disease Control and Prevention. https://npin.cdc.gov/pages/hiv-and-aids-timeline#1980. Accessed Jan. 11, 2023.
Immunization schedules. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/schedules/index.html. Accessed Jan. 11, 2023.

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Bacterial vs viral infections How do they differ

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CDC is monitoring increased parvovirus B19 activity in the U.S.

Certain groups, including pregnant people, people with a weakened immune system, or people with certain blood disorders, can face serious complications from infection. Read the Health Alert Network (HAN) advisory for recommendations and prevention information.

About Parvovirus B19

At a glance.

Parvovirus B19 infection is usually mild in people who are otherwise healthy.
Common symptoms include "slapped cheek" rash in children, and joint pains in adults.
Complications can occur among people with underlying blood disorders or weakened immune system.
Infection early during pregnancy can cause a slight increase in the risk of a miscarriage.

Parvovirus B19 infection usually causes no symptoms or mild illness, such as flu-like symptoms, rashes and joint pains. In individuals with blood disorders or a weakened immune system, infection can cause a low blood count. Infection during pregnancy can sometimes lead to additional complications.

Some people who get infected with this virus will have no symptoms.

When symptoms of parvovirus B19 infection occur, they are usually mild and may include the following:

Sore throat

The clinical presentation most often associated with parvovirus B19 infection is a red rash on the face, also called a "slapped cheek" rash. This is also known as Fifth Disease (or Erythema Infectiosum). This rash typically appears a few days after the fever or flu-like symptoms. It is more common in children than adults.

Parvovirus B19 infection can also cause a general rash on the chest, back, buttocks, or arms and legs. The rash may be itchy. It usually goes away in 7 to 10 days but can come and go for several weeks. As it starts to go away, it may look lacy.

Infection with parvovirus B19 can lead to pain and swelling in the joints, called polyarthopathy syndrome. This is more common in adults and children and is most common in women.

Adults may experience joint pain without other symptoms. Joints are affected on both sides, usually in the hands, feet and knees. The joint pain usually lasts 1 to 3 weeks but can last for months or longer. It usually goes away without any long-term problems.

Complications

Parvovirus B19 infection is usually mild for children and adults who are otherwise healthy. However, for some people, it can cause serious health complications affecting the nerves, joints, or blood system.

Parvovirus B19 has been shown to cause a severe drop in blood count (anemia) in some patients with certain blood disorders or with a weakened immune system.

You may be at increased risk for complications from a parvovirus B19 infection if you have one or more of these health conditions:

Leukemia or other cancers
Organ transplant
HIV infection
Blood disorders such as sickle cell disease and thalassemia

Parvovirus B19 in pregnancy

If you get a parvovirus B19 infection during pregnancy, the virus could spread to the baby. This is not common but could cause a miscarriage. See 'Parvovirus B19 in Pregnancy' for further information.

In special circumstances, your healthcare provider may test your blood for parvovirus antibodies. The test will determine if you are susceptible or possibly immune to parvovirus B19 infection or if you were recently infected.

Talk to your healthcare provider if you have any questions about whether you should get tested.

Parvovirus B19 infections are usually mild and will go away on their own. Children and adults who are otherwise healthy usually recover completely.

Treatment usually involves relieving symptoms, such as fever, itching, and joint pain and swelling. For persons who develop a low blood count, treatment may include supportive care, blood products, and other specialized therapies.

See your healthcare provider if:

You have complications from a parvovirus B19 infection, or
You are infected while pregnant.
National Center for Immunization and Respiratory Diseases , Division of Viral Diseases , Division of Viral Diseases

Parvovirus B19 and Fifth Disease

Parvovirus B19 infection is usually mild for children and adults who are otherwise healthy, but some people may experience serious health complications.

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Medical science is moving ahead at an immense speed share the most recent scientific researches, medical advances, and treatments of viruses that have marked the history of humanity, such as the spanish flu or covid-19. gather all the necessary information in one of the presentations designed for google slides and powerpoint, and help the world know how they can prevent the spread of these viruses..

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NICE Guidance
Conditions and diseases
Respiratory conditions
Respiratory infections

Suspected acute respiratory infection in over 16s: assessment at first presentation and initial management

NICE guideline [NG237] Published: 31 October 2023 Last updated: 16 November 2023

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Quality standard - Acute respiratory infection in over 16s: initial assessment and management including virtual wards (hospital at home)

This guideline covers assessment of people aged 16 and over with symptoms and signs of acute respiratory infection (bacterial or viral) at first remote or in-person contact with NHS services. It also covers the initial management of any infections. It aims to support healthcare practitioners in making sure that people’s treatment follows the best care pathway. It forms part of a suite of work on virtual wards being undertaken by NICE.

This guideline should be read alongside NICE’s antimicrobial prescribing guidelines on:

acute cough
acute exacerbation of chronic obstructive pulmonary disease
acute sinusitis
acute sore throat .

In November 2023 , we amended our guidance to clarify that the threshold for treatment or referral for further assessment may be lower for people with an acute respiratory infection who are more likely to have a poor outcome.

This guideline includes recommendations on:

all first contact
remote contact
in-person contact

Who is it for?

Healthcare practitioners
People aged 16 and over with suspected acute respiratory infection, their families and carers

Guideline development process

How we develop NICE guidelines

This guideline replaces recommendation 1.1.1, and updates recommendations 1.2.1 and 1.2.2 from NICE guideline CG191 (published December 2014).

Your responsibility

The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or the people using their service. It is not mandatory to apply the recommendations, and the guideline does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian.

All problems (adverse events) related to a medicine or medical device used for treatment or in a procedure should be reported to the Medicines and Healthcare products Regulatory Agency using the Yellow Card Scheme .

Local commissioners and providers of healthcare have a responsibility to enable the guideline to be applied when individual professionals and people using services wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with complying with those duties.

Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible.

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Clade I mpox virus infection

Urgent public health message to all NHS service providers regarding Clade I mpox virus (MPXV) infection.

Actions for the NHS

Providers to ensure that relevant clinical services – including primary care, urgent care, sexual health services, paediatrics, obstetrics and emergency departments – are aware of the information in this public health message and that a differential diagnosis of Clade I mpox virus (MPXV) infection is considered in any patient who meets the operational case definition below.

Providers to ensure that they have adequate stocks of appropriate personal protective equipment (PPE) and relevant staff are trained in its use for the assessment and treatment of patients presenting with suspected Clade I MPXV infection.

Providers to ensure there is a clinical pathway for isolation and management of suspected Clade I MPXV cases within their setting. This should include isolation of the patient, liaison with local infection prevention and control (IPC) teams, and arrangements for discussion of the case with local infectious disease, microbiology or virology consultants if a diagnosis of Clade I MPXV is being considered so that appropriate clinical management, including testing and infection control measures, can be implemented.

All samples from all individuals testing positive for mpox must be sent to the UKHSA Rare and Imported Pathogens Laboratory (RIPL) for clade differentiating tests.

Providers to note the information below for the clinical assessment and testing of patients with potential Clade I MPXV infection.

MPXV is a virus from the same family as smallpox, that presents with a rash illness which may be mild and localised, or severe and disseminated. There are 2 distinct clades of the virus: Clade I and Clade II. Clade II MPXV is responsible for the global outbreak that began in 2022. Clade I MPXV is currently considered more severe than Clade II MPXV , leading to its classification as a high consequence infectious disease ( HCID ).

Historically, Clade I MPXV has been reported only in 5 Central African countries. However, recent cases in additional countries within Central and East Africa mark the first known expansion of its geographical range, heightening the risk of spread beyond the region. Evidence of sustained sexual transmission of Clade I MPXV has emerged in the Democratic Republic of Congo ( DRC ). Healthcare professionals should remain vigilant for Clade I MPXV , including in sexually acquired mpox cases, and should obtain comprehensive travel histories from patients.

The symptoms of mpox begin 5 to 21 days (average 6 to 16 days) after exposure with initial clinical presentation of fever, malaise, lymphadenopathy and headache. Within 1 to 5 days after the appearance of fever, a rash develops, often beginning on the face or genital area and it may then spread to other parts of the body. The rash changes and goes through different stages before finally forming a scab which later falls off. Treatment for MPXV is mainly supportive.

Clinical assessment and operational mpox HCID case definition

The following patients should be managed as HCID cases (pending confirmation of clade type where appropriate):

confirmed mpox where Clade I MPXV has been confirmed 
there is a travel history to the DRC or specified countries where there may be a risk of Clade I exposure, within 21 days of symptom onset
or a link to a suspected case from those countries (listed below), within 21 days of symptom onset
or there is an epidemiological link to a case of Clade I mpox within 21 days of symptom onset

The countries where Clade I cases have been reported, as well as countries bordering those with ongoing Clade I transmission are currently:

Republic of Congo
Central African Republic
South Sudan

Given the rapid spread of Clade I in the African region, please check the UKHSA mpox pages regularly for any updates to the countries included.

Mpox is not considered an HCID in the following circumstances:

a case has a laboratory confirmed Clade II mpox virus ( MPXV ) infection
a confirmed or clinically suspected mpox case of an unknown clade and none of the epidemiological characteristics listed above in the operational HCID case definition apply

Management of possible cases

Clinicians should be alert to the possibility of Clade I MPXV infection in patients presenting with suspected mpox where there is a link to the specified countries in the African region (as listed above). Clinicians treating patients with suspected mpox who may meet the operational case definition of an HCID (as outlined above) should discuss this with local infection specialists.

Infection Specialists should discuss all possible Clade I MPXV cases with the UKHSA Imported Fever Service ( IFS ) on 0844 778 8990 so that testing can be expedited. Patients with severe disease (who do not meet the operational case definition) should also be discussed with the IFS .

Individuals with clinically suspected mpox presenting to acute care settings who meet the case definition for possible Clade I MPXV infection should be isolated and managed as a HCID as outlined in the National Infection Prevention and Control Manual .

In outpatient settings, individuals presenting with clinically suspected mpox who meet the case definition for possible Clade I MPXV infection should be isolated appropriately (single room, closed door) and clinical staff should wear face fit tested FFP3 masks, eye protection, long-sleeved splash resistant gowns and gloves to provide care if immediately required.

Where suspected cases meeting the operational case definition present in primary care, General Practitioners should isolate the patient in a single room and contact their local infection service for advice, including appropriate arrangements for transfer into secondary care and immediate precautions in the setting.

All samples from all individuals testing positive for MPXV (regardless of whether there are potential links to Clade I or travel from the African region) must be sent to the UKHSA RIPL for clade differentiating tests. UKHSA will contact Trusts for samples for any mpox cases for which samples have not been received for clade typing.

Cases of confirmed Clade I MPXV infection will be managed through the specialist network of HCID centres.

UKHSA ’s mpox resource collection will be kept up to date with information on affected areas for the duration of the outbreak to assist NHS clinicians in diagnosis.

Additional information

HCID status of mpox
Mpox (monkeypox): diagnostic testing
Imported fever service

Updates to this page

Added clarification of the 21 days time limit.

Updates to management of possible cases section.

First published.

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Case Report
Open access
Published: 03 September 2024

Case reports of persistent SARS-CoV-2 infection outline within-host viral evolution in immunocompromised patients

Luca Ruotolo 1 ,
Silvia Silenzi 2 ,
Beatrice Mola 1 ,
Margherita Ortalli 1 , 2 ,
Tiziana Lazzarotto 1 , 2 &
Giada Rossini 2

Virology Journal volume 21 , Article number: 210 ( 2024 ) Cite this article

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SARS-CoV-2 is responsible for the ongoing global pandemic, and the continuous emergence of novel variants threatens fragile populations, such as immunocompromised patients. This subgroup of patients seems to be seriously affected by intrahost viral changes, as the pathogens, which are keen to cause replication inefficiency, affect the impaired immune system, preventing efficient clearance of the virus. Therefore, these patients may represent an optimal reservoir for the development of new circulating SARS-CoV-2 variants. The following study aimed to investigate genomic changes in SARS-CoV-2-positive immunocompromised patients over time.

SARS-CoV-2-positive nasopharyngeal swabs were collected at different time points for each patient (patient A and patient B), extracted and then analyzed through next-generation sequencing (NGS). The resulting sequences were examined to determine mutation frequencies, describing viral evolution over time.

Case presentation

Patient A was a 53-year-old patient with onco-hematological disease with prolonged infection lasting for 51 days from May 28th to July 18th, 2022. Three confirmed SARS-CoV-2-positive samples were collected on May 28th, June 15th and July 4th. Patient B was 75 years old and had onco-hematological disease with prolonged infection lasting for 146 days. Two confirmed positive SARS-CoV-2 samples were collected at the following time points: May 21st and August 18th.

Heat map construction provided evidence of gain and/or loss of mutations over time for both patients, suggesting within-host genomic evolution of the virus. In addition, mutation polymorphisms and changes in the SARS-CoV-2 lineage were observed in Patient B. Sequence analysis revealed high mutational pattern variability, reflecting the high complexity of viral replication dynamics in fragile patients.

Introduction

Since its first appearance in 2019, SARS-CoV-2 has continued to spread and evolve worldwide, showing important genetic changes which have allowed the emergence of new variants of concern (VOCs). These factors still have a significant impact on the management of the COVID-19 pandemic, as they often provide new viral adaptation skills, such as potential increases in transmissibility, escape from both natural and vaccine-induced immunity and decreased sensitivity to monoclonal antibody therapies [ 1 , 2 ]. Despite newly acquired features, the origin of SARS-CoV-2 variants has not yet been defined due to numerous factors involved in infectious mechanisms, including a high rate of RNA replication error, viral load, disease severity, disease progression, treatment outcome, drug resistance and cell tropism [ 3 , 4 ]. It has been reported that SARS-CoV-2 has a similar rate of mutation to other coronaviruses, such as SARS-CoV and MERS-CoV [ 5 ], for which within-host diversity was also reported in infected patients during these viral outbreaks [ 6 ]. Several hypotheses have been raised regarding the origin of highly divergent SARS-COV-2 variants, namely, undetected circulation in some geographical regions, a zoonotic origin, and emergence in immunocompromised patients with prolonged SARS-CoV-2 infections [ 7 , 8 ]. Notably, it is very hard to definitively prove any of these hypotheses. Understanding of the dynamics of these infections and how they correlate with global evolutionary patterns would be of great interest but mostly relies on isolated case reports [ 7 , 9 ]. One of the most efficient practices for carrying out such research is next-generation sequencing. In addition to its main role in outbreak investigations and studies on drug resistance, NGS provides deep analysis of viral genetic sequences for the determination of intrahost viral population complexity for a large plethora of pathogens [ 10 ] because of the production of high-information data outputs.

The present study investigated within-host SARS-CoV-2 variability in nasopharyngeal swabs from two different immunocompromised patients with persistent COVID-19 hospitalized at the IRCCS Azienda Ospedaliero-Universitaria di Bologna during 2022. Genomic analyses were conducted using NGS technology coupled with bioinformatic tools to establish the course of viral evolution in patients with prolonged disease and to study the occurrence of specific mutations.

This study was conducted at the Center of Regional Reference for Microbiological Emergences (CRREM) laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy. Patients were selected based on clinician requests for SARS-CoV-2 variants to establish appropriate medical treatment. Samples were collected anonymously and traced with unique internal codes from the post diagnostic phase. Sequencing was performed both for informational purposes for clinicians with patients in care and in the broader context of territorial monitoring of SARS-CoV-2 circulation. Requirements for sample analysis were based on Cycle threshold (Ct) values < 30, when possible, for at least one or more target genes, depending on the diagnostic assay (Allplex SARS-CoV-2 Assay, Seegene, Simplexa COVID-19 Direct, Diasorin, Xpert Xpress COV-2, Cepheid).

Patient A was a 53-year-old patient with onco-hematological disease with prolonged infection lasting for 51 days from May 28th to July 18th, 2022. Confirmed SARS-CoV-2-positive samples were collected at three time points: on May 28th (day 1, Ct: 21), June 15th (day 19, Ct: 22) and July 4th (day 38, Ct: 22) (Additional file 1 ).

Patient B was 75 years old and had onco-hematological disease with prolonged infection lasting for 146 days. The first positivity was reported on April 23rd, 2022, with an antigen test (not available), while the last positive molecular swab was reported on September 16th, 2022. The last nasopharyngeal swab tested negative on October 11th. Two confirmed positive SARS-CoV-2 samples were collected at the following time points: May 21st (day 1, Ct: 29) and August 18th (day 86, Ct: 22) (see Additional file 2 ).

SARS-CoV-2 viral RNA was extracted from nasopharyngeal swabs using a manual QIAamp RNA viral kit (QIAGEN, Hilden, Germany). For both Patient A and B, all selected SARS-CoV-2positive samples were extracted and subjected to whole-genome sequencing analysis via next-generation sequencing (NGS) technology (Illumina). Libraries were prepared according to the Illumina COVIDSeq assay (96 samples) library preparation kit (Illumina, USA) following an amplicon-based approach. The libraries were quantified using a Qubit dsDNA High Sensitivity (Thermo Fisher Scientific, USA) assay kit according to the manufacturer's protocol. Then, the libraries were loaded and sequenced using an Illumina MiSeq system. The sequencing results of the FASTQ files were analyzed by BaseSpace Onsite Hub software through the DRAGEN COVID Lineages Application tool (Illumina). This approach allowed sequence trimming and alignment of consensus sequences to the SARS-CoV-2 reference genome (NC_045512) to determine variant lineages and clades using the Pangolin and NextClade algorithms.

To monitor the accumulation of mutations throughout the whole genome over time, FAST-Q files were submitted to the Stanford SARS-CoV-2 analysis software to produce CodFreq files [ 11 ] using the provided pipeline with default settings [ 12 ]. CodFreq files were uploaded to the Input Sequence Reads section [ 13 ] and run with default output settings (minimum read depth ≥ 10; nucleotide mixture threshold ≤ 0.05%; mutation detection threshold ≥ 10%; see Additional files 3 and 4). Output tables were processed by a custom R-Script (RStudio, version 4.2.2; see Additional files 5 and 6) to compare the frequency percentages of a given mutation between the various time points, providing a representation of the results through heat maps. The relevant mutations resulting from the analysis were selected if the minimum allele frequency (MAF) was greater than 5% between at least two different time points [ 4 , 14 , 15 ]. A phylogenetic analysis of 201 SARS-CoV-2 sequences collected in 2022 was performed. Consensus sequences were first aligned to SARS-CoV-2 reference (NC_045512) with Unipro UGENE MUSCLE Alignment tool (v44.0) and a Maximum Likelihood tree was constructed with IQ-Tree web server [ 16 ]. The best-fitting substitution model was automatically determined (TIM + F + I chosen according to Bayesian Information Criterion, BIC) and the tree was calculated with 1000 bootstrap replicates. Branch support was approximated using the Shimodaira–Hasegawa [SH]-aLRT method (1000 replicates). The tree was rooted to the reference sequence NC_045512 and its visualization was realized with iTOL Interactive Tree of Life [ 17 ].

Patient A was a 53-year-old patient with onco-hematological disease with prolonged infection lasting for 51 days (Fig. 1 ).

Evolution of prolonged SARS-CoV-2 infection in Patient A. The blue line represents the trend of viral load based on Ct values, while black points indicate sampling days. The dotted and dashed black lines mark the thresholds for which the swab was considered negative (Ct > 42); samples with 40 < Ct < 42 were considered to have low positivity. The dashed red lines indicate the time points selected for sequencing analysis

Analyses of consensus sequences at three longitudinally collected time points (day 1, day 19 and day 38) indicated that the virus strains belonged to BA.2 Omicron lineage. Day 1 was collected on May 28th, day 19 on June 15th and day 38 on July 4th, 2022.

Heat map showing mutation frequencies in longitudinally collected Patient A samples. Genes and mutations are reported on the x-axis with “gene: mutation” wording, while time points are on the y-axis. The frequency is displayed through a color gradient ranging from light blue (for low mutations) to dark blue (for high mutations). A Heat map showing that the general representation of the detected mutations allows the discrimination of sites with low variability from those with high variability in mutation frequency. B Mutations presenting greater intrahost variability (MAF > 5% between at least two different time points) throughout three longitudinally collected samples from the same individual

Patient B was 75 years old with onco-hematological disease experiencing prolonged SARS-CoV-2 infection lasting for 146 days. The viral load, very high in the first 20 days and then gradually decreasing, showed a swinging trend (Fig. 3 ). Two nasopharyngeal samples collected on May 22nd, 2022 (day 1) and on August 18th, 2022 (day 86) were sequenced and analyzed.

Evolution of prolonged SARS-CoV-2 infection in Patient B. The blue line represents the trend of infection based on the E gene Ct values reported in the diagnostic center, while the black points indicate sampling days. The dotted and dashed black lines mark the thresholds for which the swab was considered negative (Ct > 42); samples with 40 < Ct < 42 were considered to have low positivity. The dashed red lines indicate the time points selected for genomic analyses

Heatmap showing mutation frequencies in longitudinally collected Patient B samples. Genes and mutations are reported on the x-axis with “gene: mutation” wording, while time points are on the y-axis. The frequency is displayed through a color gradient from light blue for low-frequency mutations to dark blue for high-frequency mutations. A Heat map showing that the general representation of the detected mutations allows the discrimination of sites with low variability from those with high variability in mutation frequency. B Mutations presenting greater intrahost variability (MAF > 5% between at least two different time points) throughout two longitudinally collected samples from the same individual

Compared to the first collected sample (day 1), in the sample collected on day 86, 10 de novo mutations have arisen: T35I in nsp9; Y324C in nsp13; P217H, N440K, K444N, L455F, V642G, and D1153Y in the S gene; T30I in the E gene and A182V in the N gene. For each mutation, the frequency on day 1 was 0%, while the frequency on day 86 was > 80% (Table 2 ). The mutations Q19E in E protein and R408S in S protein have been shown to increase their frequency over time, from 43.9 to 90.6% and from 24.7 to 32.9, respectively (Table 2 ).

Four de novo deletions in S protein (F374del, S375del, T376del and Y144del) emerged in the sample collected at day 86 (Table 2 ).

Most of these mutations and deletions are considered very rare and have not been subsequently seen at high prevalence in the global population [ 18 ]. The only mutations that were found at high prevalence in global population were N440K and R408S in S protein together with Q19E in M protein (Table 2 ) [ 18 ].

Furthermore, by comparing the two time points, we also observed the disappearance of four mutations present on day 1 but not on day 86: F694Y in the RdRP gene (from 18.4% to 0%) and S256L, P463R, and S1147L in the S gene. (Table 2 ).

Both Patient A and Patient B underwent phylogenetic analysis to explore the magnitude of intrahost viral diversity at the reported time points (Fig. 5 , Additional files 7, 8).

Phylogenetic tree obtained through the analysis of 201 SARS-CoV-2 sequences collected during 2022, including the considered cases at each time point. Patient A and B time points are highlighted with yellow and light green label background, respectively. Except for the analyzed cases, all samples are reported with an internal system ID, which consists of progressive numbering for each patient’s nasopharyngeal swab (NPS). Clades classification is provided by NextClade consensus sequence analysis report

Every analyzed sample was located in the corresponding Omicron BA.2 clade, as reported in previous results. Phylogenetic analysis revealed within-host viral variability in both Patient A and Patient B. Specifically, there was strong homology between the day 1 and day 19 time points for Patient A, while major diversity emerged only later on day 38. Similarly, day 1 of Patient B was similar to that of Patient A at the first time points (day 1 and day 19), as they were classified as BA.2 Omicron lineage but an important viral evolution was discovered on day 86, which is also considered a SARS-CoV-2 lineage switch from BA.2 to BA.2.1.

Since its first appearance, the viral genome of SARS-CoV-2 has undergone consistent changes because of both natural selection occurring during infection and the effect of the immune system. Consequentially, the emergence of new variants has been globally documented throughout the pandemic. A leading and widely discussed hypothesis suggested the prolonged infection in immunocompromised patients as the potential source of new variants contributing to global spread [ 19 , 20 ]. The current study provided insight into the potential within-host evolution of SARS-CoV-2 in two immunocompromised patients, Patient A and Patient B, with prolonged infection lasting for 51 and 146 days, respectively, and as in other numerous case reports, we also can provide documentation of mutations accumulation over time, mostly in spike.

The analysis of viral genomic sequences in different samples collected longitudinally, suggested the possibility of the emergence of new mutations inside the immunocompromised host that only rarely are then found at high prevalence in the general population. We observed the emergence of several de novo mutations that are non-shared between the two patients: T35I in nsp9; Y324C in nsp13; P217H, S256L, K444N, L455F, V642G, and D1153Y in S; T30I in E; A182V in N; A685S and M794I in RdRP. Most of these mutations are considered very rare, arising most probably under therapeutical pressure and that have not been subsequently seen at high prevalence in the global population. For instance, K444N and L455F in S have been associated with reduced susceptibility to several monoclonal antibodies [ 20 , 21 , 22 , 23 , 24 ], and T30I in E has been indicated as a potential marker of long-term SARS-CoV-2 infections, being one of the most frequent occurring arising mutation in persistent infection in immunocompromised patients but is absent from the global phylogeny [ 25 ]. On the other hand, N440K is a well-known region binding domain (RBD) mutation frequently observed in several Omicron lineages [ 26 ] and is associated to a better viral fitness by improving the binding to the human ACE2 receptor [ 27 ]. N440K was observed to disappear over time in Patient A and, at contrary, to increase its frequency in Patient B. The sudden loss or gain of globally recognized mutations in the SARS-CoV-2 Omicron lineages, such as N440K (loss in Patient A, gain in Patient B) and K417N (loss in Patient A) has yet to be investigated, as it is unclear whether these unusual events are random or related to unknown mechanisms of adaptation to clinically fragile hosts.

In samples from both patients, Q19E in M and R408S in S exhibited an increase in frequency over time; both these mutations have been detected in subsequent Omicron lineage sequences at high prevalence. Furthermore, de novo deletions were identified in spike: F374del, S375del, T376del and Y144del. Interestingly, Y144del is part of a group of N-terminal domain (NTD) deletions between positions 141–146 occurring in the alpha and omicron BA.1 and BA.2 variants. These deletions are associated with resistance to several NTD-binding neutralizing monoclonal antibodies, although they do not appear to reduce the neutralizing activity of plasma from convalescent or vaccinated individuals [ 28 , 29 ]. However, the presence of Y144del in BA.2 has not been broadly reported, although is common subsequently in XBB lineages.

Despite the promising and informative results, our study has some limitations. First, we included only two immunocompromised patients and only few samples for each patient could be longitudinally evaluated. Second, many clinical and therapeutic data for the two patients were not available. These limitations do not allow drawing absolute conclusions about findings and, therefore, results cannot be generalized.

Nevertheless, description of the mutational trend in these two immunocompromised patients, together to other case reports and broader cohort of patients, may provide some valid suggestions to elucidate the very complex process of virus evolution in immunocompromised patients.

Our data, even if collected from only two patients, are in line with results from Raglow Z. et al. obtained from a much larger cohort of patients, showing how some mutations, mostly in spike but also in other genomic regions, are rarely observed in global sequencing data but are strongly associated with escape from therapeutics. These observations highlight the complexity and the importance of an extensive sequencing data monitoring with different approaches to provide insights into future evolutionary patterns of SARS-CoV-2 [ 20 ].

Availability of data and materials

The datasets supporting the conclusions of this article are included within the article and its additional files. Additional file 1 : Patient A—Table of Ct.csv; Additional file 2 : Patient B—Table of Ct.csv; Additional file 3 : Patient A—Stanford Analysis.csv; Additional file 4 : Patient B—Stanford Analysis.csv; Additional file 5 : Patient A—analysis & plots.R; Additional file 6 : Patient B—analysis & plots.R; Additional file 7 : Phylogenetic tree—focus on immunocompromised patients.pdf; Additional file 8 : Phylogenetic tree—focus on immunocompromised patients.png.

Abbreviations

Next-generation sequencing

Nasopharyngeal swabs

Coronavirus disease 2019

Severe acute respiratory syndrome coronavirus 2

Cycle threshold

Bayesian Information Criterion

Region binding domain

N-terminal domain

Multiple allele frequency

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Published: 03 September 2024

Lumpy skin disease virus isolation, experimental infection, and evaluation of disease development in a calf

Kassaye Adamu 1 ,
Takele Abayneh 2 ,
Belayneh Getachew 1 ,
Hawa Mohammed 1 ,
Getaw Deresse 3 ,
Mariamawit Zekarias 4 ,
Workisa Chala 5 &
Esayas Gelaye 6

Scientific Reports volume 14 , Article number: 20460 ( 2024 ) Cite this article

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Microbiology
Molecular biology

Lumpy skin disease (LSD) is one of the most economically significant viral diseases of cattle caused by the Lumpy Skin Disease Virus (LSDV), classified as a member of the genus Capripoxvirus and belongs to the family Poxviridae . Nodular skin samples were collected from clinically sick cattle in the districts of Amuru and Wara Jarso Ethiopia to isolate LSD virus. The virus was isolated using primary lamb testis and kidney cells. The isolated LSDV was infected into a healthy calf while maintaining the necessary biosecurity measures to generate skin lesions and to assess disease progression using postmortem examinations. On the fourth day after virus inoculation, the calf developed typical LSD skin nodules with increased rectal temperature, which lasted until the 12th day, when they began to decrease. Viral shedding was detected in nasal, oral, and conjunctival swabs from 6 to 14 days after infection using real-time PCR. Post-mortem tissue specimens tested positive for LSD virus using real-time PCR and virus isolation. This study showed that LSDV were responsible for the LSD outbreaks, and the appearance of typical skin nodules accompanied by fever (> 39.5 °C) defined the virus’s virulent status. The experimental infection with the isolated infectious LSDV could serve as a platform for future vaccine evaluation study using an LSDV challenge model.

Experimental evidence of mechanical lumpy skin disease virus transmission by Stomoxys calcitrans biting flies and Haematopota spp . horseflies

Non-vector-borne transmission of lumpy skin disease virus

Genomic analysis of lumpy skin disease virus asian variants and evaluation of its cellular tropism

Introduction.

Lumpy skin disease (LSD) is a serious skin disease of cattle caused by Lumpy Skin Disease Virus (LSDV), which is a member of the family Poxviridae and the genus Capripoxvirus; and is antigenically related to Sheeppox virus and Goatpox virus 1 . LSD is characterized by nodular cutaneous eruption, lymphadenitis, and edema of one or more limbs, and it causes significant economic losses in infected cattle due to chronic debility, reduced milk production, poor growth, infertility, abortion, and in some cases, death. Furthermore, severe and permanent damage to hides can occur, lowering their commercial value. Because of its rapid spread and the potential for severe economic loss, the World Organisation for Animal Health (WOAH/OIE) considered LSD as notifiable disease 2 . LSD infection has been reported in fine-skinned breeds such as Holstein Friesian (HF) and Jersey breeds 3 , 4 .

Morbidity and mortality vary greatly depending on the breed of cattle, the population’s immunological status, insect vectors involved in mechanical transmission, and virulence nature of the virus isolates. LSD morbidity varies greatly, ranging from three to 85% in various epizootic situations. Morbidity is estimated to be 10% in endemic areas 3 , 5 . LSD related mortality ranges between 1 and 3%, but up to 40% had been reported in severe outbreak situations 6 . A recent cross-sectional study in Ethiopia across different agro-ecological zones showed an overall observed LSD animal-level prevalence of 8.1% and a mortality rate of 2.12% 7 .

Vaccination, quarantines, livestock movement controls, vector control, slaughter of infected and exposed animals, and cleaning and disinfection of the premises are all used to control and prevent LSD 1 . However, adequate financial, infrastructural, and human resources, as well as information systems, are required. Because it is not possible to implement all of these strategies in Ethiopia, vaccination has been adopted as the most important practical approach to LSD control for many years. According to the World Organisation for Animal Health (WOAH) recommendations, the Kenyan Sheep and Goat pox vaccine strain KS-1 has been used because it confers cross-protection against LSD 8 .

Within the genus, Capripoxviruses are cross-reactive. As a result, cattle can be protected against LSD by using Capripoxvirus derived strains from sheep or goats 9 . However, it is recommended that controlled trials be conducted using the most susceptible breeds before introducing a vaccine strain not commonly used in cattle. The vaccine seed strain must be of sufficient quality to be used in all breeds of cattle for which it is intended, including young and pregnant animals. It must also be non-transmissible, remain attenuated after additional tissue culture passages, and provide complete protection against virulent field strain challenge for at least one year. When administered through the recommended route, it must produce a minimum clinical reaction in all cattle breeds 1 . As a result, the current study focused on isolating and identifying lumpy skin disease virus from outbreaks, and measuring disease development and virus shading through the mucous membrane on experimental calf infection, which may pave the way for future vaccine studies using the LSDV challenge model.

Active outbreak investigation

Two active outbreaks were investigated in this study between August 2019 and December 2019. The first outbreak was reported from Amuru District Sidan Peasant association, and the second was reported from Wara Jarso District four PAs. During these outbreaks, a total of 138 cattle were affected and eight died. The disease affected all age groups of cattle with both local and cross breeds. Initial fever, skin nodules on various body parts, enlarged peripheral lymph nodes, depression, lameness, and lacrimation were the most commonly observed clinical signs of LSD (Fig. 1 ).

Cattle showing typical clinical signs of lumpy skin disease with generalized nodular skin lesions covering the entire body and perineum area.

Virus isolation

From the 12 samples collected, six (two from Amuru and four from Wara Jarso) were grown on primary lamb testis and lamb kidney cells. Starting from the third day of culture, cytopathic effects (CPE) were observed in all plates. Single cell rounding, aggregation of dead cells, and monolayer destruction were all observed as characteristic CPEs; whereas CPE was not observed in the negative control cultures (Fig. 2 ).

Monolayer of normal lamb testis cells ( A ); Lamb testis monolayer cells infected with LSDV where cytopathic effects developed at day 6 ( B ) and day 10 ( C ) (the arrows indicate infected cells aggregation and destruction).

Molecular examination

Polymerase chain reaction.

All (12) of the extracted DNA samples amplified by conventional and real time PCR were positive. On species specific conventional PCR, the tissue suspected of LSD revealed that all isolates collected from outbreaks were LSD viruses (Fig. 3 ). Supplementary Fig. 1 shows original images of the conventional PCR results on LSD outbreak samples.

Conventional PCR results on LSD outbreak samples.

Species-specific real-time PCR

To confirm the Capripoxvirus identity and genotype of the field isolates, a species-specific real-time PCR method using unlabeled snapback primer and dsDNA intercalating dye assay targeting the CaPVRPO30 gene was used. The PCR assay detects differences in SPPV, GTPV, and LSDV melting temperatures determined by fluorescence melting curve analysis. Melting curves were analyzed to determine the CaPV strain using Low Profile Hard-Shell® 8-well PCR strips (BioRad). In all PCR runs, appropriate positive controls and RNase free water were used as a negative control. All screened isolates had the same melting profile as that of the LSDV reference strain, the amplicons 73.0 °C, and the snapback 50.0 °C, as shown in the plots (Fig. 4 ). The Ct values for LSD positive skin nodule samples ranged from 19 to 30, and when compared to positive LSD controls, all of the values were lower, indicating high virus concentrations. Supplementary Fig. 2 depicts real-time PCR data displaying melting curve profiles of tested materials, normalized melt curve profiles, and melting curve analysis of LSDV field isolates and controls.

Real time PCR results. ( A ) Melting curve profiles of the tested samples and CaPV controls after PCR amplification of the RPO30 gene, ( B ) Representative normalized melt curve profiles, ( C ) Melting curve analysis of LSDV field isolates and controls.

Animal experiment

Animal inoculation, monitoring, sample collection, and postmortem examination.

This experiment used a calf that was 4½ months old. The calf was inoculated intradermally and intravenously in the neck area on the right side with 10 3.9 50% tissue culture infectious doses (TCID50). Rectal temperatures were recorded every day, and the calf was examined for clinical signs such as the development of lesions at the inoculation site and elsewhere on the body. The calf developed typical LSD skin nodules with increased rectal temperature on day 4 post inoculation, which lasted until the 15th day and was considered a positive case. A severe case was defined as cattle with the appearance of typical skin nodules and fever (> 39.5 °C) (Figs. 5 and 6 ). Supplementary Table 1 depicts the daily rectal temperature record of an experimentally infected calf with the infectious LSD virus.

The experiment’s healthy calf ( A ); and the calf after clinical disease development with typical skin nodules distributed all over the body surface ( B ).

The daily rectal temperature of an experimentally infected calf with the LSD virus.

During necropsy in addition to skin nodule, the calf showed ulcerative lesions on the mucous membranes of the oral and nasal cavities, and organs of the respiratory tract, such as lung tissue and trachea, mandibular, cervical, mesenterial lymph nodes, and nodule on the rumen clearly indicating a generalized infection (Fig. 7 ).

Gross lesions in cattle following experimental LSD virus infection. ( A ) Development of typical nodule on the rumen. ( B ) Swelling of the superficial lymph node.

To verify that these nodules were caused by LSD infection, samples were taken from skin nodule, trachea as well as mesenterial lymph node were tested using PCR and showed positive result for LSD virus genome.

Observation of infectious virus shed through mucus membrane by rt-PCR

Swab samples from the nasal, conjunctival, and oral cavity were analyzed by real time PCR for the detection of LSDV in mucosal secretions collected on days 2, 4, 6, 8, 10, 12, and 14 post infection. The virus was detected on the sixth day after inoculation from conjunctiva, the eight-day from oral cavity, and the tenth day from nasal cavity as shown in Table 1 . The results of the rt-PCR of LSD virus shedded across mucosal membranes are described in Supplementary Fig. 3 .

Clinical signs, virus isolation, and PCR analysis all confirmed that LSD virus caused the outbreaks. The presence of LSD in the current study area indicates that this insidious disease continues to affect different parts of the country. Several authors have reported the occurrence of LSD outbreaks in different parts of Ethiopia at different times to support the current study 7 , 10 , 11 . Furthermore, LSD has been an epidemic in Ethiopia since 2008 11 .

Depression, lacrimation, nasal discharge, loss of body condition, and circumscribed skin nodules over the skin were observed in the sick animals studied. These clinical manifestations were also observed in LSD affected animals 6 , 7 , 10 , 11 , 12 , 13 , 14 . Swelling limbs, lameness, and reluctant involvement of epithelial cells of the digestive organs and abortion have been reported on cross breeds 15 .

The virus isolation method was used to determine the viability of the virus in the samples. LSDV can be propagated in a variety of primary cells or cell lines of bovine, ovine, or caprine origin. In the current study, primary lamb kidney and primary lamb testis cells were used for LSDV isolation as reviewed by 16 . Lumpy skin disease virus was isolated from skin nodule samples suspected of causing LSD in Amuru and Werejarso districts. Samples were passaged three times in primary lamb kidney and testis cells. LSDV CPEs on cell lines were characterized by rounding of single cells, aggregation of dead cells, and destruction of cell monolayer.

Previously described a species-specific real-time polymerase chain reaction (PCR) was used to examine the outbreak samples 17 . A gel-based PCR method was also used for differentiation of Sheep poxvirus (SPPV) and Goat poxvirus (GTPV)/LSDV isolate 18 . This is a published CaPV species-specific molecular assay 19 , 20 , 21 . To confirm the presence of the LSD virus genome, a Capripoxvirus detection method recommended by the World Organisation for Animal Health 1 and an LSDV specific gel-based PCR was used 22 , 23 . Following testing with conventional and real-time PCR methods, the isolates were identified as LSDV.

In this study, isolated LSDV was inoculated into calf to cause generalized skin lesions, and the virus shaded through mucous membrane at the onset of clinical signs and the level of disease development was measured at postmortem examination. Shedding of the virus was detected in nasal, oral, and conjunctival swabs from 6 to 14 days post infection using real-time PCR. LSDV shedding is low in body secretions, with the highest concentration of viral particles found in skin lesions, which is consistent with previous experimental findings 5 , 16 . The postmortem findings were consistent with what has previously been reported in the literature 24 , 25 , 26 . The experimental infection of a calf with an isolated infectious LSDV could serve as a foundation for future vaccine assessment research employing an LSDV challenge model. It is recommended that the experimental infection utilizing the infectious LSDV be repeated with a small number of calves with strict biosecurity measures, as using only one calf may be considered a study limitation. Considering clinical course and molecular data, the isolated virus signifies a useful candidate for LSDV challenge model in future vaccine studies. In endemic countries such as Ethiopia, control and prevention of LSD was undertaken mainly through vaccination. Due to the nature of the disease and its rapid spread into more countries and the lack of protection observed in countries such as Ethiopia with the locally produced vaccines, there has been increased interest and concern about the effectiveness of LSD vaccines in recent years 27 . As a result, studies should be conducted to evaluate the effectiveness of the LSD vaccines for disease control.

Materials and methods

From August to December 2019, the outbreak investigations study was conducted in Horo Gudru Wollega zone of Amuru district from one peasant association (Siden) and in Central Ethiopia North Shewa Zone of Wara Jarso district (Gohatsion) from four peasant associations (01, Jemo Berbeda, Wali-Chilelo and Lencho Bursu) of Oromia Regional State (Fig. 8 ). Amuru woreda/district is located 392 km from Addis Ababa. The district has altitudes ranging from lowland of 760 to midland of 2002 m above sea level (masl). The Woreda has moist and hot climate, with average annual temperature of 11.1 to 23.6 °C and rainfall ranging from 1167 to 1737.9 mm, respectively (Shambu metrological office, 2017). The district Wara Jarso is located in the North Shewa Zone. Kuyu borders it on the south, on the west by the Muger River, which separates it from the Horo Guduru Welega Zone, on the north by the Abay River, which separates it from the Amhara Region, on the northeast by the Jamma River, which separates it from Dera, and on the east by Hidabu Abote. Filiklik, Gohatsion, and Tullu Milki are among the towns in Wara Jarso. Geographically, the district is located between 10° 10'' North latitudes and 38° 34'' East longitudes. The district’s average elevation is 1282masl. To obtain representative samples, study areas were chosen based on the presence of active LSD suspected outbreaks.

Map of Ethiopia with sample collection sites identified in yellow in the Amuru district of Horo Guduru Wellega zone and Wara Jarso district of North Shewa zone (generated using QGIS version 3.10).

Study animals

In the study areas, 39,432 cattle were at risk of LSD infection and 138 cattle were infected, with eight dead. The disease affected all age groups of both local and crossbred cattle managed by smallholder farmers with two to 20 cattle using extensive and semi-intensive management systems. This study focused on cattle with clinical signs of pox-like skin lesions.

Outbreak investigation and specimens’ collection

Two natural outbreaks suspected of LSD in different geographical locations were chosen and investigated based on reports from the Oromia Regional State Agricultural Office Animal Health Directorate. During the visit, a visual inspection was performed to detect the presence of typical clinical signs of lumpy skin disease, and sick cattle were thoroughly examined. Twelve skin nodule samples were collected from twelve sick cattle in order to identify the causative agents (four from Amuru and eight from Wara Jarso). Following the procedures outlined in the WOAH, samples for virus isolation and antigen detection were collected from clinically sick animals (2017). Cleaning the area with 70% Ethanol and removing the hairs with a sterile scalpel blade, 12 skin nodules samples were collected aseptically from representative cattle that developed severe clinical signs of the disease. Antibiotics was administered topically on skin nodules to prevent secondary bacterial infections. Tissue samples were placed in a sterilized universal bottle containing phosphate buffered saline (PBS) with antibiotics and antifungals, and transported to the NVI virology laboratory using a cold chain system and stored at − 20 °C. Furthermore, data on clinical observations, the species and age of affected animals, and vaccination history were gathered. Supplementary Table 2 contains information on clinical observations, affected animal breed and age, and vaccination history.

Laboratory techniques

Sample processing.

Skin biopsy samples were thawed at room temperature and washed three times with sterile phosphate buffer saline (PBS) containing antibiotics and antifungals in a Bio-safety cabinet class II. Tissue homogenates (10% w/v) were prepared in sterile PBS and centrifuged for 10 min at 4000xg in a refrigerated centrifuge. The supernatant was collected and stored at − 20 °C (WOAH, 2023). One ml of tissue homogenates was submitted for molecular analysis.

Virus isolation on primary lamb testis and lamb kidney

The supernatant from tissue homogenates was taken and inoculated onto a confluent monolayer of primary lamb testis and lamb kidney cells in a 25 cm 2 tissue culture flask containing 10 ml of Glasgow Minimum Essential Medium (Sigma Aldrich, Germany) supplemented with 2% fetal calf serum (Himedia). Cell cultures were incubated at 37 °C/5% CO 2 and observed daily for the development of LSDV specific cytopathic effects (CPE). When no CPE was observed after three blind passages, a sample was considered negative. Cell cultures that showed CPE were frozen at − 20 °C and thawed three times at room temperature to release the virus particle. Finally, the virus suspension was stored at − 80 °C until processed for DNA detection and animal experiment.

DNA extraction

DNA was extracted from tissue homogenate and infected cell culture suspension using DNeasy® Blood and Tissue kit (Qiagen, Germany) following the manufacturer’s instructions. In a 1.5 ml eppendorf tube, 200 μl of tissue homogenate or cell culture suspension was transferred, and 20 μl proteinase K (QIAGEN protease) was added and thoroughly mixed. 200 μl AL buffer was added to the virus suspension and gently mixed by pulse-vortexing and incubated in a water bath at 56 °C for 10 min. After adding 200 μl of 95% ethanol and thoroughly mixed, the mixture was transferred in to DNeasy mini column in a 2 ml collection tube and centrifuged at 8000xg for 1 min. The spin column was placed in to a new 2 ml collection tube and 500 μl of AW1 buffer was added and centrifuged at 6000xg for 1 min. The collection tube was discarded, and the mini spin column placed in a new 2 ml collection tube and 500 μl of AW2 buffer was added and centrifuged for 3 min at 6000xg. The mini spin column was carefully transferred into a new 1.5 ml of microcentrifuge tube, and 50 μl elution buffer added and incubated for 1 min at room temperature and centrifuged at 8000xg for 2 min. The spin column was discarded, and the microcentrifuge containing the eluted DNA was labeled and stored at − 20 °C freezer until tested by PCR.

Conventional PCR

The Capripoxvirus genome was detected using PCR with Capripox virus specific primers of SpGpRNAPol Forward: 5'-TAGGTGATTTTGGTCTAGCTACGGA-3′ and SPGpRNAPol-Reverse: 5′-AGTGATTAGGTGGTGTATTATTTTCC-3′ previously designed by 18 . PCR was performed in a 20 μl reaction volume containing 10 µl supper mix, 3 µl temple DNA, 2 μl forward primer, 2 μl reverse primer, and 3 µl RNase-free water. The PCR tube was placed in a thermal cycler, and amplification began. The program was as follows: initial denaturation at 95 °C for 4 min, followed by 40 cycles at 95 °C for 30 s, annealing at 50 °C for 30 s, extension at 72 °C for 30 s, and final extension at 72 °C for 5 min.

Agarose gel electrophoresis

To confirm the presence of DNA, amplified products were analyzed by agarose gel electrophoresis as described previously by 18 , 28 . A 3% agarose gel prepared in Tris Acetate EDTA (TAE). Aliquots of PCR products were analyzed using 3% agarose gel stained with GelRed (Biotium, inc.) for 1 h at 100 V. The DNA bands were visualized under UV transilluminator and photographed in gel documentation system (UVI TEC, UK). The PCR results were considered positive for LSD DNA when 172 bp was observed.

Real-time PCR

To confirm the Capripoxvirus identity and genotype of the field isolates, a recently developed species-specific real-time PCR method using unlabeled snapback primer and dsDNA intercalating dye assay targeting the CaPVRPO30 gene was used 21 . Real-time PCR was performed at the Molecular Biology Laboratory of the NVI using the amplification primers and PCR protocol described by 21 . Briefly, the PCR was set up in a reaction volume of 20 µL; where 4.84 µl of RNase-free water, 2µL of forward primer (CP-HRM-sb 5′-GGTGTAGTACGTATAAGATTATCGTATAGAAACAAGCCTTTA-3′, 0.16µL reverse primer CP-HRM1 5′-AATTTCTTTCTCTGTTCCATTTG-3′, 10µL of Safest EvaGreen IQ Super mix (BioRad) and 3 µL sample template. PCR was carried out with an initial denaturing step at 95 °C for 3 min, followed by 40 cycles at 95 °C for 15 s and 58 °C for 80 min using Low Profile Hard-Shell® 8-well PCR strips (BioRad). After denaturation at 95 °C for 1 min (held for 1 min), the product was cooled to 40 °C (held for 1 min), and heated continuously at 0.5 °C/10 s with fluorescence acquisition from 45 to 85 °C. Finally, for genotyping of the tested isolate, a pair of melting temperatures each for snapback tail and full amplicon were recorded as LSDV (50 °C/73 °C), GTPV (56 °C/72.5 °C), and SPPV (51 °C/72.5 °C).

The calf was obtained from NVI dairy farm and has no history of LSD infection and vaccination. Due to a calf shortage, only one calf was used for the experimental infection. The calf was inoculated intradermally and intravenously in the neck area on the right side with 10 3.9 50% tissue culture infectious dose (TCID50). Rectal temperatures were taken every day, and the calf was examined for clinical signs such as the development of lesions at the inoculation site and elsewhere on the body. On 2, 4, 6, 8, 10, 12, and 14 days post inoculation (dpi) nasal, conjunctival, and oral swabs were collected and placed in 1.25 ml of viral transport medium (phosphate buffered saline containing 1% (w/v) bovine serum albumin, 200 U/ml penicillin, 200 μg/ml streptomycin, 50 μg/ml gentamicin and 5 μg/ml amphotericin B).

Serum samples were taken at defined time points during the animal trial to examine sero-conversion. Sampling was performed on 0, 7, 14, 21, 28, and 35 dpi. During necropsy, the following organ samples were taken: lung tissue and trachea, mandibular, cervical, and mesenteric lymph nodes. In addition, samples from skin areas displaying characteristic nodular lesions were also taken. On the 15th dpi, the calf was euthanized by cutting the neck and examined for any gross pathological lesions. The necropsy samples were collected aseptically and meticulously. To access all tissues sampled, separate sterile scissors and forceps were used, and tissues were harvested onto individual sterile disposable universal bottles for further processing with separate sterile forceps and scalpels.

Data analysis

Data collected during observation from all field and laboratory investigations, such as clinical signs while investigating the outbreak, sample collection, virus isolation using cell culture, and CaPV targeted gene amplification using classical and real-time PCR, was coded, stored, and analyzed in Excel spreadsheets. The data was interpreted and presented in biological terms, such as an increased body temperature, depression, decreased in feed intake, nasal and ocular discharges, and nodular skin lesions.

Ethics approval and consent to participate

The study is reported in accordance with ARRIVE guidelines. Animal experiment was carried out in accordance with the international guidelines for care and handling of experimental animals. The Animal Research Ethic Committee of the National Veterinary Institute reviewed and approved the protocol. The calf for the experiment was obtained from NVI's dairy farm.

Data availability

All data generated or analyzed during this study are available upon request from the corresponding authors.

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Acknowledgements

The authors acknowledged Dr. Teferi Degefa and Mr. Bogale Gossaye for preparation and maintenance of cell cultures, and Mr. Amare Tesfaye for assistance with animal care and sample collection. The National Veterinary Institute of Ethiopia funded the research.

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Kassaye Adamu, Belayneh Getachew & Hawa Mohammed

Bacteriology Laboratory, Research and Development Directorate, National Veterinary Institute, P.O. Box 19, Bishoftu, Ethiopia

Takele Abayneh

Molecular Biology Laboratory, Research and Development Directorate, National Veterinary Institute, P.O. Box 19, Bishoftu, Ethiopia

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Viral Vaccine Production Laboratory, Vaccine Production Directorate, National Veterinary Institute, P.O. Box 19, Bishoftu, Ethiopia

Mariamawit Zekarias

Viral Vaccine Quality Control Laboratory, Quality Control Directorate, National Veterinary Institute, P.O. Box 19, Bishoftu, Ethiopia

Workisa Chala

Food and Agriculture Organization of the United Nations, Sub-Regional Office for Eastern Africa, P.O. Box 5536, Addis Ababa, Ethiopia

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KA, EG conceived and designed the experiments; KA, TA, BG, HM, GD, MZ, WC, EG performed the experiments and analyzed the data; TA, EG contributed reagents/materials and supervised the study; KA wrote the paper; EG edited the final manuscript. All authors read and approved the final manuscript.

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Adamu, K., Abayneh, T., Getachew, B. et al. Lumpy skin disease virus isolation, experimental infection, and evaluation of disease development in a calf. Sci Rep 14 , 20460 (2024). https://doi.org/10.1038/s41598-024-60994-8

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