1508 PART 5 Infectious Diseases

East respiratory syndrome coronavirus (MERS-CoV), first isolated in

2012, causes severe disease in humans, with ~35% mortality and >2500

cases reported to date. MERS-CoV is a zoonotic virus (transmitted

between animals and people). The virus likely emerged from bats in

the Middle East, although studies have shown that humans are infected

through direct or indirect contact with an intermediate host—infected

dromedary camels.

COVID-19 SARS-CoV-2 emerged in an outbreak in Wuhan,

China, that spread worldwide causing a severe pandemic. SARS-CoV-2

is the cause of a respiratory disease called COVID-19. The virus is

a member of lineage B of the Betacoronavirus genus that not only

includes the highly pathogenic viruses SARS-CoV-1 (which caused a

smaller epidemic in 2002−2003) and MERS-CoV (a lineage C virus

that caused small epidemics in 2012, 2015, and 2018), but also contains

the lineage A common cold viruses CoV-OC43 and CoV-HKU1 and

MERS-CoV. These are enveloped, positive-sense RNA viruses encoded

by a viral RNA genome that is quite large, a single linear RNA segment

of nearly 30,000 nucleotides that encodes four structural proteins,

designated the S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins, and a large polyprotein that is cleaved into 16 nonstructural proteins in infected cells. The trimeric S protein is primed

by the transmembrane protease serine 2 (TMPRSS2) to facilitate entry

of SARS-CoV-2. SARS-CoV-2 S protein is a type 1 fusion machine that

also mediates attachment using a receptor binding domain (RBD) that

binds to the human angiotensin-converting enzyme 2 (hACE2) protein

receptor.

EPIDEMIOLOGY OF COVID-19 The virus may have spilled over from a

bat reservoir and was first detected in humans in late 2019 in Wuhan,

China; it rapidly spread by human-to-human transmission through all

provinces of China and then worldwide. The World Health Organization (WHO) designated SARS-CoV-2 a Public Health Emergency of

International Concern on January 30, 2020, and declared the outbreak

a pandemic on March 11, 2020. By August 2021, the virus had caused

>200 million confirmed cases and >4.3 million deaths worldwide.

The basic reproduction number (R0

) (the expected number of cases

generated directly by one case in a population in which all individuals

are susceptible to infection) of SARS-CoV-2 has been estimated to be

between 5 and 6, which is substantially higher than that of seasonal

influenza (typically 1–2). Densely populated settings such as prisons,

cruise ships, nursing homes, airplanes, and large indoor gatherings

facilitate even higher transmission efficiency. Transmission in outdoor

settings is thought to be much less common. Health care workers and

those working in dentistry have high potential for exposure. Certain

individuals may have contributed to extraordinarily high transmission

events (so-called “superspreaders”). Transmission does occur in school

settings, although schools have not been considered a primary driver of

population transmission. Spread of SARS-CoV-2 is believed to be primarily via respiratory droplets transmitted between persons in proximity when the droplets make direct contact with mucous membranes.

Airborne transmission by small particle from person-to-person may

occur, but airborne transmission over long distances is unlikely. Fomite

transmission by contact with contaminated surfaces is considered a

possible but not dominant mode of transmission; therefore, handwashing in environments of exposure makes sense. Large-scale frequent

surface decontamination efforts have been deployed in public spaces,

but the effect of these cleanings on reducing transmission is uncertain.

In July 2020, a more infectious variant virus with S protein amino

acid variant G614 replaced the original D614 strain as the dominant

form in the pandemic. Thousands of virus variants have been reported

with sequences organized in an ever-evolving clade structure, including strains designated “Variants of Concern” with evidence of impact

of S protein polymorphisms on the sensitivity of diagnostic tests, the

effectiveness of antiviral drug or antibody treatments, or the preventive efficacy of vaccines. Such variants have independently arisen in

diverse geographic areas and then spread widely. Some variants may

exhibit a higher capacity to transmit from one person to another or to

cause severe disease or death in infected individuals. The probability

of dying for a person who is infected (the infection fatality rate) varies

substantially across locations, depending on local factors including the

population age and structure, number of nursing homes, and case mix

of infected and deceased individuals. The infection rate, determined

with seroprevalence studies, is difficult to ascertain reliably. Most locations appear to have an infection fatality rate of ~0.20%.

Advanced age is the principal risk factor for severe illness from

COVID-19 (marked by need for hospitalization, intensive care, and

mechanical ventilation). Over 95% of COVID-19 deaths occur in

people over age 45, and >80% of deaths occur in people over age 65.

Preexisting social and health disparities put some groups of people at

increased risk of illness or death from COVID-19, including people

with disabilities and many racial/ethnic minority groups. Male sex is

associated with higher risk of severe disease (odds ratio, ~1.8). Most

individuals who die have preexisting comorbidities. The risk of severe

COVID-19 illness increases markedly with elevated body mass index

(BMI). Overweight condition (BMI >25 kg/m2

 but <30 kg/m2

), obesity

(BMI ≥30 kg/m2

 but <40 kg/m2

), and severe obesity (BMI of ≥40 kg/

m2

) are risk factors for progressively increased severe COVID-19. Substance use, such as alcohol, opioid, or cocaine use disorder, and current

or former smoking both increase risk. Pregnant women are more likely

to suffer more severe illness. Most other medical conditions increase

the risk of severe illness, but conditions that especially increase risk are

as follows: (1) chronic lung diseases, including COPD, moderate-tosevere asthma, cystic fibrosis, and pulmonary hypertension interstitial

lung disease; (2) cancer or cancer treatments, including hematologic

malignancies, solid organ transplant, and stem cell transplant; (3)

immunodeficiency, including primary immunodeficiency caused by

inherited genetic defects or secondary or acquired immunodeficiency

caused by prolonged use of corticosteroids, other immunosuppressive

drugs, or HIV type 1 (HIV-1) infection; (4) hemoglobin blood disorders, including thalassemia or sickle cell disease; (5) cerebrovascular

disease, such as stroke; (6) cognitive impairment or other neurologic

conditions; (7) heart conditions, including arterial hypertension, heart

failure, coronary artery disease, and cardiomyopathies; (8) obstructive

sleep apnea; (9) chronic inflammatory, autoimmune diseases and rheumatic diseases; (10) type 1 or type 2 diabetes mellitus; (11) chronic liver

disease, especially cirrhosis; and (12) genetic conditions, especially

Down syndrome. A multisystem inflammatory syndrome in children

(MIS-C) has been associated with COVID-19, comprising a persistent

fever, involvement of multiple organ systems (including gastrointestinal, dermatologic, cardiac, renal, hematologic, and neurologic), and

elevated circulating inflammatory markers. The highest risk individuals for MIS-C in the United States are Black and Latino children aged

3 to 12 years. A similar syndrome in adults (MIS-A) may occur rarely.

PREVENTATIVE MEASURES FOR COVID-19 Early in the epidemic,

public health methods for prevention were mostly limited to nonpharmaceutical interventions, including social distancing (staying at least

6 feet from other people in public to avoid infection), social isolation

(staying away from other people when infected), quarantine (staying

at home for 14 days after potential exposure), limiting travel, and

working from home. When a local epidemic persists, prior to entering

health care settings, patients should be screened for clinical signs or

symptoms common in COVID-19, especially fever, respiratory symptoms (cough, dyspnea, sore throat), myalgias, and anosmia/hyposmia.

Universal masking should be required in health care settings during

epidemic conditions. A medical (surgical) mask should be universally

used by health care workers, patients, and visitors. A respirator (N95

or higher protection) without an exhalation valve is an alternative

and should be used by health care workers in place of a medical mask

during procedures that generate aerosols. When patients cannot wear

masks, goggles or a face shield may provide some additional protection

for health care workers. In general, in public settings during epidemic

conditions, well-fitting cloth masks are indicated.

CLINICAL MANIFESTATIONS OF COVID-19 The disease course varies

widely, including asymptomatic infection, mild disease, moderate

disease, or severe disease requiring hospitalization, oxygen therapy,

1509CHAPTER 199 Common Viral Respiratory Infections, Including COVID-19

intensive care, and mechanical ventilation. A substantial proportion

of patients (possibly a third of those infected) are asymptomatic, but

those individuals can transmit the virus to others. Most individuals

with symptomatic infection have mild disease (no pneumonia). Severe

disease, typically requiring hospitalization and involving pneumonia

and associated manifestations (dyspnea, radiographic involvement of

more than half of the lung, and/or hypoxia with oxygen saturation

≤94%), is common. Critical disease with manifestations of respiratory

failure requiring mechanical ventilation, multiorgan failure, or shock

occurs and requires intensive care.

DIAGNOSIS OF COVID-19 The specific diagnosis of infection typically

is made using nucleic acid amplification testing of respiratory tract

secretions. Nasopharyngeal swabs are used mostly commonly, while

saliva testing also has been implemented, especially in large-scale

population screening efforts. Other more general laboratory testing

during severe or critical illness reveals widespread abnormalities consistent with systemic disease including lymphopenia and thrombocytopenia; elevated inflammatory markers, such as interleukin 6 (IL-6),

tumor necrosis factor α, ferritin, and C-reactive protein; elevated liver

enzymes and lactate dehydrogenase; elevated markers of acute kidney

injury; elevated D-dimer and prothrombin time; and elevated troponin

and creatine phosphokinase. Research-grade tests show that beneficial

components of the adaptive immune response, including antibodies

and T cells, also arise during the first 1−2 weeks after exposure. Chest

radiographs may exhibit abnormal findings such as consolidation

and ground-glass opacities that are distributed bilaterally, especially

in the lower lung regions, but also may be normal despite respiratory

compromise. Chest computed tomography (CT) has features (groundglass opacifications with or without mixed consolidation, pleural

thickening, interlobular septal thickening, and air bronchograms) that

can be systematically interpreted as typical, indeterminate, or atypical

for COVID-19. Chest CT may be more sensitive than radiographs, but

CT should be used principally for medical management of respiratory

disease, not as a primary diagnostic tool for COVID-19. Lung ultrasound also has been used to image the lungs to detect some COVID-19

abnormalities.

CLINICAL COURSE OF COVID-19 The onset of disease is manifest

typically within 4–5 days after exposure and nearly always within

14 days. Symptoms include cough, fever, myalgia, headache, dyspnea,

sore throat, and gastrointestinal symptoms of nausea, vomiting, or

diarrhea. Sudden onset of dysgeusia and anosmia (loss of taste and

smell) occurs in a substantial number of cases, which typically resolves

in weeks to months. Diverse dermatologic findings occur in patients

with COVID-19 (see Fig. A1-57 (A-C)). General decline of health

status, including onset or worsening of dementia, can occur in older

individuals, especially those with cognitive impairment. Mental health

consequences of the acute disease, isolation measures, and medical

management regimens are common, including depression and social

anxiety.

COMPLICATIONS OF COVID-19 Severe complications of infection can

occur. The major complication in patients with severe disease is acute

respiratory distress syndrome requiring oxygen therapy and mechanical ventilation. Thromboembolic complications are common in severe

disease mostly occurring as venous thromboembolism, including

pulmonary embolism or deep vein thrombosis. Events stemming from

arterial thrombosis, including acute stroke or ischemia of the limbs,

are reported. Cardiac complications manifest as heart failure, myocardial injury, or arrhythmias and cardiovascular syndromes, especially

shock. Encephalopathy occurs commonly in critically ill patients, and

delirium in the intensive care unit setting reduces overall survival.

Other neurologic complications including seizures, ataxia, or motor

or sensory deficits have been reported. Those with COVID-19 disease

and laboratory markers of excessive inflammatory response can exhibit

a pattern of persistent fever and multiorgan disease with high risk of

fatal outcome. An excessive proinflammatory host response to SARSCoV-2 infection likely contributes directly to pulmonary pathology

and severity of COVID-19. Manifestations typically mediated by

autoantibodies have been reported. Disease is usually caused by direct

viral pathogenesis in tissues or the associated immune response, but

secondary bacterial or fungal infections do occur, usually as bacteremia

or respiratory infections.

MANAGEMENT OF COVID-19 General medical management of

COVID-19 is focused on severe respiratory illness and systemic disease

manifestations. As bacterial infection is an uncommon complication

of COVID-19, antibiotics are not generally indicated, but when the

diagnosis is uncertain, empiric antibiotic regimens for communityacquired or health care–associated pneumonia should be considered.

Nonpharmacologic social measures to reduce transmission of SARSCoV-2 have greatly reduced the incidence of influenza virus infection,

but in communities in which influenza is circulating, empiric influenza

antiviral treatment is recommended for patients hospitalized with suspected or documented COVID-19. Since there is such a substantial risk

of thromboembolic complications, many experts recommend pharmacologic prophylaxis of venous thromboembolism for all hospitalized patients with COVID-19. Nonsteroidal anti-inflammatory drugs

(NSAIDs) are often used as antipyretic agents, but questions have been

raised about a possible association between NSAID use and worse outcomes with COVID-19; when possible, the preferred antipyretic agent

is acetaminophen. Immunosuppressed individuals are at higher risk

of severe illness or death; therefore, on a case-by-case basis, providers

should decide whether to continue immunomodulatory agents such

as steroids or other immunosuppressive drugs that were indicated for

preexisting conditions prior to onset of COVID-19. Generally, experts

agree that the best course usually is to continue common preexisting

medications of aspirin, statins, and angiotensin-converting enzyme

inhibitors or angiotensin receptor blockers.

The time to recovery from COVID-19 is affected by the severity of

disease, the individual’s preexisting comorbidities, and age. Generally,

symptomatic infection is an acute syndrome that resolves in 2 weeks

in ~80% of persons, especially following mild or moderate disease.

Individuals with severe disease often require longer for recovery, on the

order of several months. However, a subset of individuals with infection progress to a recurring or persisting pattern of symptoms, most

commonly including fatigue, cognitive deficits, cough, dyspnea, or

chest pain. Those with severe acute pulmonary or cardiac injury may

have persisting respiratory or cardiac impairment. Diverse long-term

adverse mental health consequences of infection are common, and the

public health measures used to manage the pandemic also have led to

social isolation with adverse mental health consequences.

OVERVIEW OF APPROACH TO SPECIFIC TREATMENTS FOR COVID-19

The approach to specific treatment of COVID-19 of varying levels of

severity is under study in 2021 in thousands of clinical studies; summaries

of registered international clinical trials are available at the clinicaltrials.

gov and WHO websites. Availability of trial enrollment varies by locale,

and local availability of medications or other interventions may affect

what treatments are possible. Standardized medical regimens that are

optimal for individuals with varied severity of disease are not fully

established. At this time, only general principles of treatment can be

asserted with confidence. The groups of medicines most explored to

date based on mechanisms of action are antivirals and immunomodulators. Antivirals (including small-molecule inhibitors and polyclonal

or monoclonal antibodies) have the most potential to alter the clinical

course early in infection, since they may reduce the peak titer of virus,

a parameter that is likely correlated with severity of disease. Later in the

clinical course, anti-inflammatory medications may be of more benefit

since the pathogenesis of disease is driven increasingly more over time

by tissue inflammation and systemic inflammatory responses than by

direct viral cytopathic effect.

We recommend consulting up-to-date recommendations from

groups authorized to provide expert or governmental guidelines,

including the National Institutes of Health COVID-19 Treatment

Guidelines Panel in the United States (https://www.covid19treatmentguidelines.nih.gov), the National Health Service in the United Kingdom

1510 PART 5 Infectious Diseases

(https://www.england.nhs.uk/coronavirus/), and the Infectious Diseases

Society of America (https://www.idsociety.org/practice-guideline/covid-19-

guideline-treatment-and-management/). Many but not all the guidelines

from such groups are harmonized. The strongest evidence for mortality or clinical benefit from clinical trials to date supports the use

of the anti-inflammatory glucocorticoid dexamethasone, the antiviral

small-molecule drug remdesivir (with or without the Janus kinase 1 and

2 inhibitor baricitinib), tocilizumab (a monoclonal antibody against

the IL-6 receptor), and SARS-CoV-2–specific human monoclonal antibodies. In a phase 3 clinical trial, molnupiravir, an oral ribonucleoside

analog that inhibits replication of SARS-CoV-2, reduced the risk of

hospitalization or death in patients with mild-to-moderate COVID-19

by ~50%. AT-527–an oral nucleotide prodrug--reduced SARS-CoV-2

viral loads in a phase 2 clinical trial in hospitalized patients with

COVID-19. The Emergency Use Authorization (EUA) authority allows

the U.S. Food and Drug Administration (FDA) to facilitate availability

and use of medical countermeasures prior to full licensure when the secretary of the Department of Health and Human Services declares that

an EUA is appropriate for a public health emergency (https://www.fda.

gov/emergency-preparedness-and-response/mcm-legal-regulatory-andpolicy-framework/emergency-use-authorization#infoMedDev). As of

May 2021, only the following drugs and biologic therapeutic products

had obtained persisting EUA for treatment of COVID-19: (1) remdesivir for certain hospitalized COVID-19 patients; (2) a remdesivir

plus baricitinib combination; (3) two different SARS-CoV-2 spike

protein–specific monoclonal antibody cocktails bamlanivimab plus

etesevimab or REGEN-COV (casirivimab plus imdevimab); and (4)

COVID-19 convalescent plasma (containing SARS-CoV-2 polyclonal

antibodies). Three vaccines had obtained EUA for prevention of

COVID-19: (1) the two-dose Pfizer-BioNTech mRNA vaccine; (2) the

two-dose Moderna mRNA vaccine; and (3) the single-dose adenovirusbased Janssen vaccine.

Individuals who are infected but have mild disease can be treated

with supportive care only. Outpatients with certain high-risk factors

may be eligible for therapy with monoclonal antibodies or convalescent plasma following exposure (postexposure prophylaxis) or during

early mild infection (treatment). Individuals with severe respiratory

disease (marked by hypoxia [oxygen saturation ≤94% on room air]) are

administered oxygen therapy and tracheal intubation and mechanical

ventilation if respiratory failure occurs.

SMALL-MOLECULE ANTIVIRAL DRUGS Remdesivir (GS-5734, a novel

nucleotide analogue) is an enzyme inhibitor that was known prior

to the pandemic to exhibit in vitro inhibitory activity against the

coronavirus RNA–dependent, RNA polymerases of SARS-CoV-1 and

MERS-CoV. Thus, remdesivir was identified soon after the outbreak as

a promising therapeutic candidate antiviral drug because of its in vitro

activity against SARS-CoV-2. The intravenous drug is now approved

for hospitalized children ≥12 years and adults with COVID-19 with

any level of severity. The efficacy is difficult to assess because of the

many covariates in trials including differences in disease severity,

concomitant therapies, comorbidities, and other factors. Its efficacy

may be highest in those with mild to moderate disease, such as cases

requiring low-flow oxygen. A cohort study of 2344 U.S. veterans hospitalized with COVID-19, however, showed remdesivir therapy was

not associated with improved 30-day survival but was associated with

a significant increase in median time to hospital discharge. The FDA

issued an EUA for the Janus kinase inhibitor baricitinib to be used

only in combination with remdesivir in COVID-19 patients requiring oxygen or mechanical ventilation. Janus kinase inhibitors such

as baricitinib typically are used for treatment of rheumatoid arthritis

because of their known immunomodulatory effects, which probably

also improve inflammation during COVID-19, but baricitinib also

may mediate some direct antiviral effects by interfering with viral

entry into cells.

GLUCOCORTICOIDS Systemic treatment with glucocorticoids including dexamethasone, prednisone, methylprednisolone, and hydrocortisone reduces inflammation during severe COVID-19 and may be

of clinical benefit, especially in reducing mortality or the need for

mechanical ventilation; dexamethasone has the most data supporting

benefit in COVID-19. Patients treated with high-dose glucocorticoids

should be monitored for common adverse effects, especially hyperglycemia and increased risk of co-infection.

OTHER IMMUNOMODULATORS Beyond systemic glucocorticoids,

additional immunomodulators have been studied and may be of benefit in certain circumstances. Careful studies of laboratory markers of

inflammation showed that elevated blood levels of D-dimer, ferritin,

C-reactive protein, and IL-6 are associated with severe COVID-19.

The prior approval of two classes of FDA-approved IL-6 inhibitors

(monoclonal antibodies binding to either the IL-6 cytokine itself

[siltuximab] or to the IL-6 receptor [sarilumab or tocilizumab])

allowed rapid testing of the hypothesis that reducing the effects of

elevated IL-6 could benefit subjects with severe COVID-19. The most

robust data for efficacy exists for tocilizumab, and many experts suggest adding tocilizumab to dexamethasone therapy in patients with

severe or progressive COVID-19. The use of many additional types

of immunomodulators including bradykinin pathway inhibitors,

hematopoietic colony-stimulating factors, complement inhibitors, and

other cytokine or kinase inhibitors has been reported in case reports

or case series, but there is insufficient evidence to support their use

outside of clinical trial settings. Interferons are a family of cytokine

mediators that alert or activate the immune system to viral infection,

and interferon β has in vitro antiviral effects against many viruses

including SARS-CoV-2. Intravenous, subcutaneous, or inhaled interferon β is being tested, but to date, there is insufficient evidence to

support its use.

ANTIBODY-BASED THERAPIES Passive immunization with SARSCoV-2 antibodies to achieve antiviral immunity or therapeutic effect

has been tested using human monoclonal antibodies (mAbs) or convalescent plasma. Human mAbs are recombinant proteins made in the

laboratory based on the genes encoding an antibody obtained typically

from a single SARS-CoV-2–specific B cell isolated from the peripheral

blood of a convalescent individual. Three mAb products have obtained

EUA for use in outpatients with laboratory-confirmed mild-tomoderate SARS-CoV-2 infection who are at high risk for progressing

to severe disease and/or hospitalization. The cocktail bamlanivimab

plus etesevimab (EUA now revoked) and the cocktail casirivimab

plus imdevimab each contain two antibodies binding to different

epitopes on the RBD of the SARS-CoV-2 spike protein that mediates

attachment and fusion of the virus into cells. Sotrovimab is a single

mAb with a similar action. Ongoing surveillance studies of circulating

SARS-CoV-2 variants have identified variants that exhibit reduced

susceptibility to individual mAbs. Therefore, a cocktail approach is

preferred for preventing or treating COVID-19, and ongoing surveillance is needed to determine if any variants will arise that escape both

antibodies in this type of cocktail. Convalescent plasma (blood plasma

taken from people who have recovered from COVID-19) contains

polyclonal SARS-CoV-2 antibodies, and theoretically, this feature

could prevent escape of variant antibodies from the limited specificities

in the two-antibody mAb cocktails. However, the typical overall composite titer of SARS-CoV-2–neutralizing antibodies in convalescent

plasma following a single primary infection is moderately low, limiting

its effectiveness and reproducibility. In August 2020, the FDA issued an

EUA for convalescent plasma for the treatment of hospitalized patients

with COVID-19, regardless of titer of antibodies to SARS-CoV-2. In

February 2021, the FDA revised the convalescent plasma EUA to limit

the authorization to selected high-titer units of COVID-19 convalescent plasma and only for the treatment of hospitalized COVID-19

patients early in the disease course or hospitalized patients with

impaired humoral immunity.

TREATMENT OF COMPLICATIONS Bacterial superinfection of

COVID-19 probably occurs, but the incidence is uncertain. There are

insufficient data to recommend empiric broad-spectrum antimicrobial

therapy in the absence of another indication, although some experts

1511CHAPTER 199 Common Viral Respiratory Infections, Including COVID-19

routinely administer broad-spectrum antibiotics as empiric therapy for

bacterial pneumonia to all patients with COVID-19 and moderate or

severe hypoxemia. Ideally, providers initiating empiric therapy should

attempt to deescalate or stop antibiotics if there is no ongoing evidence

of bacterial infection. Many other complications of COVID-19 occur,

including acute respiratory distress syndrome, acute cardiac injury,

arrhythmias, thromboembolic events, acute kidney injury, and shock.

Management of these more generalized complications is discussed

elsewhere. Several EUAs have been issued for medical management

of complications during COVID-19, including replacement solutions

for continuous renal replacement therapy and drugs for sedation via

continuous infusion in intensive care. Anticoagulation in the face of

COVID-19–associated thromboembolic events is an especially complex situation and requires expert consultation.

Herpesviridae Several herpesviruses cause upper respiratory infections, especially infection of the oral cavity. Herpes simplex pharyngitis

is associated with characteristic clinical findings, such as acute ulcerative stomatitis and ulcerative pharyngitis. HSV types 1 and 2—also

called human herpesvirus (HHV) 1 and 2, respectively—both cause

oral lesions (Chap. 192), although >90% of oral infections are caused by

HSV-1. Primary oral disease can be severe, especially in young children,

who sometimes are admitted for rehydration therapy as a result of poor

oral intake. A significant proportion of individuals suffer recurrences

of symptomatic disease consisting of vesicles on the lips. Epstein-Barr

virus (EBV) mononucleosis syndrome (Chap. 194) is often marked

by acute or subacute exudative pharyngitis; in some cases, tonsillar

swelling in EBV pharyngitis is so severe that airway occlusion appears

imminent. Most of the viruses in the family Herpesviridae—including

CMV (Chap. 195); EBV; varicella-zoster virus (VZV; Chap. 193); and

HHV-6, -7, and -8 (Chap. 195)—can cause severe disease in immunocompromised patients, especially hematopoietic stem cell transplant

recipients.

Parvoviridae: Human Bocavirus Human bocavirus (HBoV) was

identified in 2005 in respiratory samples from children with lower

respiratory tract disease. Sequence analysis of the genome revealed that

the virus is a member of the genus Bocavirus (subfamily Parvovirinae,

family Parvoviridae). This virus has been identified as the sole agent in

a limited number of respiratory samples from individuals with respiratory tract disease, especially hospitalized young children, but the virus

is also commonly found by RT-PCR tests in respiratory samples from

healthy subjects.

Retroviridae: HIV Pharyngitis occurs with primary HIV infection

and may be associated with mucosal erosions and lymphadenopathy

(Chap. 202).

Papovaviridae: Polyomaviruses Polyomaviruses are small,

double-stranded, DNA-genome, nonenveloped icosahedral viruses

that may be oncogenic. Two major polyomaviruses, JC and BK viruses,

are known to infect humans. Of adults in the United States, ≥80%

are seropositive for these viruses. JC virus can infect the respiratory

system, kidneys, or brain. BK virus infection causes a mild respiratory

infection or pneumonia and can involve the kidneys of immunosuppressed transplant recipients.

EPIDEMIOLOGY

■ AGE

Age (along with the associated factor of prior exposure history) is a

major determinant of risk for symptomatic disease during respiratory

virus infection. Primary infection with most of the acute respiratory

viruses often is more severe than secondary infection. Indeed, reinfection with most of these viruses occurs throughout life, but primary

infection is much more likely to be associated with severe lower respiratory tract disease, while secondary infection typically is asymptomatic or associated with upper respiratory tract symptoms only. As these

infections are ubiquitous, most primary infections (and thus many of

the severe cases) occur during the first few years of life. Later, exposure

to young children (in populations such as parents of young children

and daycare workers) is a risk factor for frequent reinfection. Despite a

lifetime of previous exposures, the risk of severe disease increases with

age in the elderly, probably because of immune senescence and general

medical decline.

■ SEASON

Infections with most of the conventional respiratory viruses (e.g.,

influenza virus, RSV, and hMPV) occur in winter. Typically, there is

one dominant virus sweeping through a local community at any one

time, a pattern that suggests some population-level interference with

transmission. However, outbreaks can be closely spaced, and co-circulation of different viruses or antigenically diverse strains of one virus

does occur. In the United States, some regional differences in seasonality have been noted; for example, RSV often appears in Florida and

other southeastern states first. Seasons are, of course, reversed in the

Northern and Southern hemispheres, so that winter epidemics occur

roughly from November to March in the United States but from April

to August in Australia; therefore, “winter” epidemics are almost always

occurring somewhere in the world. Seasonal variances differ in the

tropics, where acute respiratory viral infections are more common in

the rainy season.

■ RISK FACTORS FOR DISEASE

Infection with these viruses is nearly universal, but disease expression

varies among individuals infected with identical viruses. Therefore,

investigators have sought to identify risk factors for severe disease.

Most single risk factors identified have a moderate effect on the incidence of severe disease, but an accumulation of factors is associated

with high risk. Underlying lung disease is a major factor, especially

diseases associated with the need for chronic oxygen supplementation.

COPD is one of the most profound risk factors. Other severe underlying medical conditions, especially cardiovascular disease, also enhance

risk. Smoking (or exposure to wood smoke), low socioeconomic status,

and male gender all contribute to a minor increase in the risk of lower

respiratory tract illness. Obesity causes a chronic state with features

of inflammation that are associated with impaired immunity, reduced

response to vaccination, and higher susceptibility to severe disease.

Close exposure to infected people is a major factor. For instance, living

in close quarters (e.g., housing for military trainees, college dormitories, or nursing homes) puts groups of individuals at risk for rapid

outbreaks. A breakdown in isolation and hand-washing compliance

procedures can lead to cycles of nosocomial transmission of infection

in hospital inpatient wards and intensive care units. In assessments of

severe lower respiratory tract illness, a history of travel to an area with

unusual agents should be considered carefully (e.g., exposure to avian

influenza outbreaks in Asia, exposure to MERS-CoV in the Middle

East). In 2020−2021, the dominance of the SARS-CoV-2 outbreak and

the associated health measures deployed reduced the incidence of conventional respiratory viruses.

■ TRANSMISSION

Most respiratory viruses are transmitted by two principal modes:

fomites or large-particle aerosols of respiratory droplets spread directly

from person to person by coughing or sneezing. Fomite transmission

occurs indirectly when infected respiratory droplets are deposited

on the hands or on inanimate objects and surfaces, with subsequent

transfer of secretions to a susceptible person’s nose or conjunctiva.

Most respiratory viruses do not spread by small-particle aerosols across

rooms or down halls, although measles virus and VZV do spread in

this manner. Therefore, contact and droplet precautions are sufficient

to prevent transmission in most settings; hand washing is especially

critical in health care settings during the winter. Intensive studies of the

SARS-CoV-2 pandemic are ongoing (see previous sections on COVID19), but many experts agree that exposure to large-particle droplets

likely is one of the major ways that SARS-CoV-2 spreads.

1512 PART 5 Infectious Diseases

APPROACH TO THE PATIENT

Common Viral Respiratory Infections

The principal interventions that make a difference in the care of

patients with acute respiratory virus infections are supportive, and

these factors should be managed meticulously. Hypoxia is managed

with supplemental oxygen and respiratory failure with mechanical

ventilation. Because the tachypnea and fever that often accompany

pneumonia and wheezing frequently result in dehydration, fluid

management is important. The astute clinician can narrow the

etiologic possibilities on the basis of epidemiologic knowledge;

information about viruses circulating in the community (widely

available from local reference laboratories, county and state health

departments, and the U.S. Centers for Disease Control and Prevention [CDC]); and the patient’s exposure history, age, and immunologic status, including vaccination status. Proper use of rapid

diagnostic tests is important. When diagnostic tests are applied only

to samples from individuals at high risk of exposure to an infectious

agent in the appropriate season, the positive predictive value of the

test is increased. A central medical decision is whether to use a specific antibacterial or antiviral agent to treat a respiratory infection.

Antibiotics do not improve the outcome of uncomplicated respiratory virus infections in otherwise healthy subjects. Some viral

infections, especially influenza, can be complicated by secondary

bacterial infection. There are only a limited number of licensed

antiviral drugs, which should be used when a specific viral etiology

is determined. Antiviral treatment generally is effective only when

administered early in the course of illness.

CLINICAL MANIFESTATIONS

The common cold is characterized by nasal congestion, sneezing, rhinorrhea, cough, and sore throat. Laryngitis is accompanied by hoarseness

or dysphonia. Acute bronchitis is characterized by a dry or productive

cough of <3 weeks’ duration (most prevalent in winter) in the absence

of signs and symptoms of pneumonia and of evidence of pneumonia

on chest radiography and is primarily caused by viruses. Bacteria play

a more prominent role in chronic bronchitis. Bronchiolitis is an acute

illness with wheezing and evidence of upper respiratory infection,

primarily seen in the winter in infants and young children. The typical

clinical manifestations of acute pneumonia include cough, sputum production, dyspnea, and chest pain. More systemic signs and symptoms

also occur in pneumonia, including fever, fatigue, sweats, headache,

myalgia, and occasionally nausea, abdominal pain, and diarrhea.

DIAGNOSIS

The clinical diagnosis of a respiratory syndrome and the anatomic

location of infection are based on history, physical examination, and

radiography. A specific viral etiology can be determined by specific

diagnostic tests. The gold standard for diagnosing a respiratory viral

infection is virus isolation, performed by inoculation of cell cultures

with fresh secretions and use of multiple cell types in a reference laboratory staffed by experienced technologists. Direct or indirect fluorescent antibody detection can be used to visualize virus-infected cells in

nasal secretions. Rapid antigen-based diagnostic tests are used to detect

influenza virus or RSV proteins in nasopharyngeal secretions. The

most sensitive tests typically are RT-PCR molecular diagnostic tests

that amplify and detect the presence of viral genomic RNA or DNA in

respiratory secretions. Multiplex panels assaying a sample for a dozen

or more common respiratory viruses are available. These tests must be

used and interpreted carefully because of their extreme sensitivity. If

care is not taken, it is relatively easy to contaminate a PCR test in the

laboratory with small amounts of DNA from a previous reaction. In

addition, because a viral genome can sometimes persist in nasal secretions for weeks after an infection resolves, a positive test may indicate a

recently resolved rather than a currently acute infection. Despite these

limitations, PCR tests generally are considered the most sensitive and

specific tests available. Chest radiographs should be obtained for all

patients with suspected pneumonia.

TREATMENT

Common Viral Respiratory Infections

INFLUENZA (SEE ALSO CHAP. 200)

Several drugs are licensed in the United States for the treatment

or prophylaxis of influenza. Neuraminidase inhibitors act on both

influenza A and B viruses by serving as transition-state analogs of

the viral neuraminidase that is needed to release newly budded

virion progeny from the surface of infected cells. The cell surface

normally is coated heavily with the viral receptor sialic acid. Oseltamivir is administered orally and is effective for the prevention or

treatment of uncomplicated influenza in otherwise healthy adults.

Observational studies indicate that oseltamivir also may be beneficial during serious illness. The drug is generally well tolerated,

with primarily gastrointestinal toxicity. Zanamivir, a powder that is

administered through oral inhalation, exhibits effectiveness like that

of oseltamivir. Moreover, zanamivir is active against some influenza

virus strains that are resistant to oseltamivir. Inhalation of zanamivir

powder may cause bronchospasm in patients with COPD or asthma.

Peramivir is a neuraminidase inhibitor that acts as a transition-state

analog inhibitor of the influenza neuraminidase enzyme that is

administered intravenously as a single 600-mg dose. It is efficacious

in acute, uncomplicated influenza and was approved by the FDA in

2014 for treatment of individuals who cannot take oral or inhaled

medications. Laninamivir was approved in Japan for prophylaxis

(2013) or treatment (2010) of influenza; it is under investigation in

the United States. It is a polymeric zanamivir conjugate that is delivered by oral inhalation, and it exhibits greater potency and longer

retention times than conventional zanamivir. Baloxavir marboxil is

a new class of drug for influenza. It is a prodrug whose metabolism

releases the active agent baloxavir acid that inhibits influenza virus

cap-dependent endonuclease activity in infected cells. This activity

is used by the virus for a process in which the first 10–20 residues

of a host cell RNA are removed and used as the 5′ cap and primer to

initiate the synthesis of the influenza mRNA (a process sometimes

termed “cap snatching”). Baloxavir marboxil was approved by the

FDA in 2018 for treatment of acute uncomplicated flu within 2 days

of illness onset in otherwise healthy people 12 years and older or

those at high risk of developing flu-related complications. In 2020,

the FDA approved an updated indication to include postexposure

prevention of influenza for people ≥12 years old after contact with

an infected person. The adamantanes amantadine and rimantadine

were used in the past for the treatment of influenza A infection.

These drugs interfere with the ion channel activity caused by the

M2 protein of influenza A viruses, which is needed for viral particle

uncoating after endocytosis. Widespread resistance occurs in many

currently circulating influenza A viruses; therefore, the adamantanes should not be used unless isolate sensitivity is demonstrated,

and in most influenza seasons, the CDC does not advise their

use. When they are used, they are administered orally and display

efficacy against uncomplicated influenza A caused by susceptible

strains. The effectiveness of these drugs in serious illness has not

been established. Toxicity with rimantadine generally manifests as

gastrointestinal intolerance. Toxicity with amantadine is primarily

associated with central nervous system symptoms.

RSV INFECTION

Ribavirin is a nucleoside antimetabolite prodrug whose activation

by kinases in the cell results in a 5′-triphosphate nucleotide form

that inhibits RNA replication. The drug was licensed in an aerosol

formula in the United States in 1986 for treatment of children with

severe RSV-induced lower respiratory tract infection. The efficacy

of aerosolized ribavirin therapy remains uncertain despite several

clinical trials. Most centers use it infrequently, if ever, in otherwise

healthy infants with severe RSV disease. Intravenous ribavirin has

been used for adenovirus, hantavirus, measles virus, PIV, and influenza virus infections, although a good risk/benefit profile has not

been clearly established for any of these uses.

1513CHAPTER 199 Common Viral Respiratory Infections, Including COVID-19

OTHER VIRAL TARGETS

Pleconaril, an oral drug with good bioavailability for treatment of

infections caused by picornaviruses, has been tested for treatment

of rhinovirus infection. This drug acts by binding to a hydrophobic

pocket in the VP1 protein and stabilizing the protein capsid, preventing release of viral RNA into the cell. Pleconaril reduces mucus

secretions and other symptoms and is being further examined

for this indication. Acyclovir and related compounds are guanineanalogue antiviral drugs used in the treatment of herpesvirus infections. HSV stomatitis in immunocompromised patients is treated

with famciclovir or valacyclovir, and immunocompetent patients

with severe oral disease compromising oral intake are sometimes

treated with these agents. These compounds have also been used

prophylactically to prevent the recurrence of outbreaks, with mixed

results. Intravenous acyclovir is effective against HSV or VZV pneumonia in immunocompromised patients. Ganciclovir, given together

with human immunoglobulin, may reduce the mortality rates associated with CMV pneumonia in hematopoietic stem cell transplant

recipients and has been used as monotherapy in other patient groups.

Cidofovir is a nucleotide analog with activity against many viruses,

including adenoviruses. Intravenous cidofovir has been effective in

the management of severe adenoviral infection in immunocompromised patients but may cause serious nephrotoxicity.

COMPLICATIONS: CO-INFECTIONS

Co-infections with two or more viruses can occur because of the overlap in the winter season of these viruses in temperate areas. In general,

in careful studies using cell culture techniques for virus isolation, two

or more viruses were isolated from respiratory secretions of otherwise

healthy adults with acute respiratory illness in ~5–10% of cases. There

is little evidence that more severe disease occurs during co-infections.

The incidence of positive results in two molecular diagnostic tests

(generally RT-PCR for these RNA viruses) is expected to be higher

than that of culture because, as discussed above, molecular tests can

remain positive for an extended period after shedding of infectious

virus has ended.

PREVENTION

■ VACCINES

Numerous vaccines against influenza viruses have been licensed. In

the United States, trivalent and quadrivalent inactivated intramuscular

vaccines (covering H3N2, H1N1, and one or two B antigens) and a live

attenuated trivalent vaccine for intranasal administration are available

(although components of the live attenuated vaccine were only ~3%

effective during the 2013−2016 seasons and that vaccine was not

available during the 2016–2018 seasons). Vaccines are effective when

the vaccine strains chosen for inclusion are highly related antigenically

to the epidemic strain, but occasional antigenic mismatches cause

negligible efficacy of a vaccine component. Antigenic drift caused by

point mutations in the hemagglutinin (HA) and neuraminidase (NA)

molecules leads to antigenic divergence, requiring the production of

new vaccines each year. The segmented influenza genome allows reassortment of two viruses during co-infection of one individual or animal; sometimes the consequence is a major antigenic shift resulting in

a pandemic. On average, pandemics occur every 20–30 years. There is

current concern about the potential for an H5N1 or H7N9 pandemic,

and experimental vaccines are being tested for these viruses.

Vaccines were developed for adenovirus serotypes 4 and 7 and were

approved for prevention of epidemic respiratory illness among military

recruits. Essentially, these vaccines consisted of unmodified viruses

given by the enteric route in capsules instead of by the respiratory

route—the natural route of infection leading to disease. Inoculation by

the altered route resulted in an immunizing asymptomatic infection.

Most U.S. military recruits are vaccinated against adenovirus, and epidemic disease recurs in the absence of vaccination.

Live attenuated and subunit vaccine candidates against RSV are

under development and are being tested in clinical trials. Subunit

RSV vaccines are being tested for maternal immunization and in the

elderly. There are no licensed vaccines against rhinoviruses; as there is

little or no cross-protection between serotypes, it will be challenging to

develop a vaccine covering >100 serotypes. Efforts to develop seasonal

coronavirus vaccines are in the preclinical stage.

■ PASSIVE PROTECTION WITH IMMUNOTHERAPY

Palivizumab, a humanized mouse monoclonal antibody to the F protein

of RSV, is licensed for prevention of RSV hospitalization in high-risk

infants, in half or more of whom it is effective. Experimental treatment

of both immunocompetent and immunocompromised RSV-infected

individuals has been reported, but the efficacy of this approach has

not been established. Next-generation antibodies with higher potency

and an extended half-life of ~90 days are being tested. In 2019, the

FDA granted Breakthrough Therapy designation for a potential nextgeneration RSV monoclonal antibody—MEDI8897. This designation

was based on a favorable primary analysis of the phase 2B trial that

demonstrated the safety and efficacy of this RSV-neutralizing human

monoclonal antibody.

■ ISOLATION PROCEDURES, PERSONAL

PROTECTIVE EQUIPMENT, AND HAND WASHING

Most respiratory viruses are spread by direct contact—i.e., bodysurface to body-surface contact and physical transfer of microorganisms between a susceptible person and an infected person. Poor hand

hygiene is probably the most common cause of contact transmission of

viruses, which occurs often in family, school, and workplace settings.

Transmission between health care workers and patients also takes place

when hand-washing compliance is low. Fomites (objects or substances

capable of carrying infectious organisms), including instruments,

stethoscopes, and other objects in medical environments, can contribute to transmission. Small-particle-mediated airborne transmission

can occur but is probably not the dominant mode of transmission

for most respiratory viruses. Particle size affects the epidemiology

of airborne pathogens. The composition and size distribution of the

generated particles affect the duration of suspension of the infectious

agents in the air, the distance across which they can be transported,

the interval during which the virus remains infectious, and the site

of deposition in the airway of a susceptible host. Direct exposure to

large-particle aerosols (e.g., exposure at close range—up to 3 ft—to a

cough or sneeze) causes some transmission. Particles of small size can

remain suspended in the air for long periods; for instance, particles of

~1 μm can remain suspended for hours. However, in general, only a

few respiratory viruses are thought to be transmitted by small-particle

aerosols. Protection from transmission in health care environments

can be achieved by proper implementation of and adherence to established procedures for the appropriate level of precaution.

Standard and Contact Precautions Standard precautions, the

basic level of infection control that is always used in the care of all

patients, reduces the risk of transmission of viruses from respiratory

tract secretions and mucous membranes. Contact precautions, the

second level, require a single room for the patient when possible and

the use of additional personal protective equipment, including the

wearing of clean, nonsterile gloves when touching a patient or coming into contact with secretions. Fluid-resistant nonsterile gowns are

used to protect skin and clothing during activities where contact with

secretions is anticipated, and providers should wear each gown for the

care of only one patient. A face mask is used when there is potential

for direct contact with respiratory secretions. Eye protection (goggles

or face shields) is worn in anticipation of potential splashing of respiratory secretions. Good hand hygiene should always follow any patient

contact, including washing for 20 s with soap and warm water or cleaning with an alcohol-based hand rub. Providers should attempt to avoid

the contamination of clothing and the transfer of microorganisms to

other patients, surfaces, or environments.

Droplet Precautions Large-particle droplets are generated during

sneezing and coughing and during the performance of some medical procedures, such as airway suctioning in critical care units or