32-06: Common Viral Respiratory Infections

General Considerations

In late 2019, a novel coronavirus emerged, spreading quickly from its origin in China across the globe. The virus was initially named “novel coronavirus 2019” (2019-nCoV), accounting for the year of discovery, its status as a “novel” virus, and its family name (coronavirus, CoV). The CDC-recommended terminology for the virus is SARS-CoV-2, and the illness caused by this virus is called “Coronavirus Disease 2019” or COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/summary.html).

Coronaviruses are a large family of viruses commonly found in humans as well as many other species of animals, including bats, camels, cattle, and feral cats. Like SARS-CoV and MERS-CoV as well as human common cold coronaviruses HC43 and HKU1, the SARS-CoV-2 virus is a betacoronavirus, which is one of the four genera of coronaviruses (only the alphacoronaviruses [coronavirus NL63 and 229E] and betacoronaviruses affect humans). All these coronaviruses have their origins in bats. SARS-CoV-1 and MERS- CoV were identified 7 and 17 years before SARS-CoV-2 was identified. The spread of SARS-CoV-2 from bats was perhaps amplified by pangolins, an Asian anteater whose scales are traded on black markets for circulatory problems, although this latter theory remains under investigation.

SARS-CoV-2 appears to have made its transition from bats to humans in late 2019 at a wet market in Wuhan, the capital of the Chinese province of Hubei. Early in the outbreak, most fatalities were from Wuhan and other parts of the Hubei province. As cases were reported from other countries, COVID-19 was declared a pandemic by the WHO on March 11, 2020. By early March 2020, case numbers outside of China were growing faster than inside China (see the Johns Hopkins Coronavirus Resource Center website for specifics at a given time https://coronavirus.jhu.edu/).

The earliest known case in the United States was documented on January 21, 2020, in a man who had recently returned to the state of Washington from China. The first US case that was not associated with travel or contact with infected travelers was identified on February 26, 2020 in Solano, California, although community transmission likely began in late January or early February (three cases that occurred in February and early March 2020 from Santa Clara County, California, were identified as COVID-19 by postmortem examination).

As of September 11, 2020, global cases surpassed 28.2 million, including over 911,000 deaths. The ten most impacted countries are the United States, India, Brazil, Russia, Peru, Colombia, Mexico, the Republic of South Africa, Spain, and Argentina. The United States reports the largest number of recognized cases in a single country at over 6.43 million and over 192,000 deaths. China, the original epicenter of the emerging pandemic now ranks 37th in number of total cases among the 188 world nations reporting infections. In the United States, the five states with the highest total cases are California, Texas, Florida, Georgia, and Illinois; the five states with the highest per capita cases are Louisiana, Florida, Mississippi, Alabama, and Georgia, and the five states with the highest total deaths are New York, New Jersey, California, Texas, and Florida.

Since April 2020, the CDC has recommended that travelers avoid nonessential international travel, restrict domestic travel, and stay at home as much as possible, especially if sick. The CDC website continues to provide a complex set of guidelines and suggestions regarding travel (www.cdc.gov). All travelers should be aware of the likelihood of evolving quarantine regulations both abroad and on return based on origin and destination of travel. Most nations are currently restricting American travel in the wake of the recent surge of cases in the United States. A case tally and other current information are available through the WHO website (https://www.who.int/emergencies/diseases/novel-coronavirus-2019) and, with an interactive map, through The Johns Hopkins University Coronavirus Resource Center website (https://coronavirus.jhu.edu/map.html). Highly informative weekly University of California, San Francisco (UCSF) Medical Grand Rounds focused entirely on COVID-19 since March 19, 2020 can be found on YouTube.

A. Clinical Epidemiology and Transmission

SARS-CoV-2 shows a higher rate of person-to-person spread than the 2003 SARS-CoV-1 virus. Some COVID-19 strains from Western Europe have enhanced transmissibility as a function of a modified Spike protein. Specifically, a SARS-CoV-2 variant carrying the Spike protein amino acid change D614G, initially the most prevalent form in the global pandemic, has been superseded by a new SARS-CoV-2 variant, G614, suggesting that the G614 variant may have a fitness advantage. A pattern of mutations is being described as phylodynamic and three main groups comprise current global strains, with ongoing efforts underway to identify new variants as they emerge.

A number of angiotensin-converting enzyme–2 (ACE-2) mutations appear to confer altered host sensitivity to COVID-19. A specific gene cluster (3p21.31) has also been identified as a genetic susceptibility locus for respiratory failure in patients with COVID-19. A deletion in the toll-like receptor 7 (TLR7, involved in interferon production) is recognized to be associated with progressive COVID-19 disease in a small cohort of young individuals.

R₀ is the basic reproductive number signifying the number of contacts infected by an infected individual. Calculations of R₀ for SARS-CoV-2 have varied but the true R₀ likely lies somewhere between 2 and 3. Transmission has been shown to be extremely efficient within higher-density living facilities (such as nursing homes, homeless encampments, jails and prisons, some Native American reservations, and certain employment settings [such as meat packing plants]). Simply talking (or singing) in close quarters may efficiently spread the virus, as shown by a study of a choir in the state of Washington where 52 of 61 choir members became ill in March 2020.

Superspreading events (ie, when a person infected with SARS-CoV-2 is at the most infectious stage [usually around day 4 of infection] and infects a disproportionate number of susceptible person[s]) are increasingly recognized as playing an important role in SARS-CoV-2 transmission. One example of a superspreading event was a biopharmaceutical executive meeting that was held in Boston in February 2020 where the disease developed in 28 of the 175 participants; through genomic analysis, it was determined that subsequent superspreading was responsible for over 20,000 cases (2.7% of all American cases) throughout the United States, including cases among homeless shelter clients in Boston. Conversely, certain variants of SARS-CoV-2 did not appear to be as likely to induce widespread dissemination. Nonetheless, the importance of venues outside the home for spreading infection is evident from a Japanese review in which 61% of all national cases were traceable to clusters outside the home, including restaurants, bars, event venues, and workplaces.

While the case-fatality rate was higher with the 2003 SARS-CoV-1, the number of infected cases is much higher with SARS-CoV-2 than with either the SARS or MERS viruses. The incubation period for SARS-CoV-2 ranges from 2 to 24 days with an average of about 5 days. Presymptomatic spread accounts for a large number of cases, and the viral load for SARS-CoV-2 is highest in the presymptomatic phase. A CDC telephone survey of infected individuals showed that only 46% reported contact with a known case, and among the known contacts, the most common were family members (46%) or work colleagues (34%).

The principal mode of transmission is respiratory droplets, which can be propelled 6 feet or more by sneezing or coughing (and have been documented to be propelled as far as 27 feet). Studies of SARS-CoV-2 aerosolization during loud talking have brought into question the adequacy of the “6 feet/1.8 meter” rule currently recommended for physical distancing. The degree that SARS-CoV-2 is aerosolized during coughing and respiratory procedures, the transmission potential of aerosolized particles containing live virus, and the inactivation potential of UV-C light all remain under study. The CDC currently recommends that airborne precautions be used in healthcare settings principally for healthcare providers performing respiratory procedures (such as collecting induced sputum or intubating the patient). Nonetheless, aerosols are considered a much less likely mode of transmission than respiratory droplets. The current reported rates of transmission are 5% for close contacts and 10–40% for household contacts.

Hospital-related transmission to staff or other patients was reported in 41% of 138 hospitalized patients from Wuhan, China. A study of more than 3000 symptomatic healthcare workers in Seattle, WA, however, showed that the prevalence of positive SARS-CoV-2 tests among symptomatic “frontline” workers was comparable to that of symptomatic non-frontline staff (about 5%).

As of September 11, 2020, the CDC reported that 158,519 healthcare personnel had become infected in the United States. Survival data are available for 112,361 of these healthcare personnel; 697 had died. Non-CDC sources show even higher death tolls for healthcare worker; the Manchester Guardian and the Kaiser Family Foundation maintain a database of healthcare-associated mortality, and as of August 27, 2020, the healthcare deaths had increased to 1087 in the United States with nurses being the group at highest risk. The reported prevalence of SARS-CoV-2–infected clinical personnel at a large Houston hospital was 5.4%. Recent seroprevalence studies suggest that a large number of SARS-CoV-2 cases likely went undetected in healthcare workers.

Reviews of death data imply that reported deaths from COVID-19 only capture about two-thirds of all excess deaths that are reported late or misattributed to other respiratory and nonrespiratory illnesses. In the New York outbreak, cardiac causes were responsible for most of these excess deaths.

Severe disease seems to develop in adults much more often than in children, and symptomatic disease appears to develop in men more often than in women. The coding of the ACE receptor protein occurs on the X chromosome and the presence of variants in this protein may explain some of the clinical variation based on sex.

SARS-CoV-2 certainly can infect children and may be able to spread efficiently in children in close contact settings, such as schools. As the 2020–21 school year begins, some schools and universities that opened for in-person classes in August 2020 have since closed or restricted student movement due to increasing case numbers. Children have lower concentrations of ACE-2 receptors in lung tissue, which may explain their lower propensity toward severe infection. With the advent of COVID-19, the CDC reports a fall in immunization rates for the vaccine preventable diseases of childhood. The unique complications of SARS-CoV-2 among children are discussed below.

SARS-CoV-2 infection is particularly serious in the elderly and in those with comorbid conditions of immunocompromise (including post-organ transplant) or chronic diseases (diabetes; obesity; hypertension; chronic heart, lung, or kidney disease; and prior stroke). In one large multiethnic cohort study of adults hospitalized with COVID-19, obesity was associated with an increased risk of death or intubation independent of age, sex, race/ethnicity, and comorbid conditions. While the infection shows a predilection for pulmonary tissues, data regarding susceptibility of persons who smoke cigarettes and those with asthma are unclear.

Preliminary evidence is mixed regarding the risk of SARS-CoV-2 infection in immunosuppressed patients (including those immunosuppressed due to rheumatologic conditions). In one recent review, the subgroups of cancer patients who had disproportionately high mortality from COVID-19 included individuals with lung cancer (case fatality rate [CFR] 18–55%) and those with hematologic malignancy (CFR 33–41%). Recent active therapy for cancer (including immunotherapy and tyrosine kinase inhibitors) has been associated with worse outcomes. Studies of people living with HIV suggest that their risk of developing COVID-19 is just as high if not higher than that of the general population (see Chapter 31). In one recent study of 286 people living with HIV, 57.3% of patients were hospitalized, 16.5% required ICU care, and the overall mortality rate was 9.4%. As in the general population, older age, chronic lung disease, and hypertension were associated with worse outcomes.

The full spectrum of complications associated with pregnancy is unknown. Reports of in utero transmission from Italy (2 of 31 pregnancies) require confirmation. The duration of IgM to coronavirus in potentially infected neonates is much shorter than that seen with other neonatal viral infections. The virus does not appear to be transmitted in breast milk. A team based at UCSF (the Priority study) is assessing prospectively the complications associated with pregnancy, delivery, and breastfeeding. (See https://www.nejm.org/coronavirus for review of cases and https://obgyn.ucsf.edu/block/theme-priority-study for enrollment of women in the above categories). Among pregnant women with SARS-CoV-2 infection, CDC studies document an increased risk of hospitalization, ICU admission, and mechanical ventilation but not death.

B. Public Health Concerns

Among many COVID-19–related US public health concerns, the most urgent needs include the following: (1) widespread implementation of (and adherence to) containment measures (physical distancing and self-quarantining) to prevent spread of the disease in vulnerable populations; (2) increased availability of masks, personal protection equipment, and ventilators; (3) standardization of nucleic acid (and making available easy-to-use home kits for early infection) and serologic assays and broadened surveillance to help control infection and determine duration of natural immunity; (4) continued surveillance to determine the relative importance of asymptomatic transmission; (5) increased attention to minority populations, particularly black and Latinx populations, since they are at high risk for infection and complications (importantly, the most recent analysis shows that these minority populations are at higher risk for COVID-19–associated mortality because of concomitant socioeconomic risk factors rather than genetic factors); (6) guidelines for nursing home safety and support; (7) standardization of state-by-state data reporting; (8) improving data-based guidelines for children and staff to safely return to schools and policies for universities to provide a safe learning environment for students and faculty; (9) emergence of antibiotic resistance exacerbated by the inappropriate use of antibiotics for COVID-19; and (10) vaccine research, including the identification of markers of protection and the role of mucosal immunity.

At this time, lockdown and physical distancing restrictions have been relaxed or modified in many parts of the United States. Four benchmarks developed by a panel of US governmental and academic advisors to recommend the readiness of jurisdictions to ease restrictions include (1) the ability of hospitals to safely care for patients without requiring a crisis standard of care, (2) the ability of a state to test all who have symptoms, (3) a robust system of contact tracing, and (4) a documented decline in incidence of COVID-19 for 14 days. Unfortunately, the reopening of businesses without strict requirements to maintain physical distancing standards has led to increasing case numbers in many US cities, particularly in the American South and Southwest, and subsequently the American Midwest. Consequently, many communities are evaluating ways to estimate the incidence and prevalence of SARS-CoV-2 infection to inform decision-making (ie, integrated community and seroepidemiologic surveys combined with modeling approaches). In an attempt to address the increasing need for rapid diagnostic community testing in the United States, the FDA issued the first emergency use authorization (EUA) for sample pooling in COVID-19 diagnostic testing on July 18, 2020.

The CDC has published guidelines for workplaces, schools, childcare centers, and other entities (https://www.cdc.gov/coronavirus/2019-ncov/community/index.html) in July 2020. These guidelines include wearing face coverings in public, maintaining physical distancing measures, and cleaning “high touch” surfaces. Further suggestions based on data to suppress the spread of aerosolized SARS-CoV-2 inside public buildings include engineering controls such as implementation of effective ventilation with air filtration and disinfection and avoidance of air recirculation and overcrowding. On June 26, 2020, the American Academy of Pediatrics released a statement strongly advocating for in-person learning. Despite these measures, significant concern exists regarding whether grade schools should go forward with virtual versus in-person classes. The many issues attendant with testing for return to work include the day-to-day variability in exposure and positivity, the needs for informed consent for those tested and for employers to learn results, the nonreplicative nature of late positive tests, and the unreliability of many assays.

Clinical Findings

A. Symptoms and Signs

Most infected individuals are asymptomatic, although the ratio of asymptomatic to symptomatic infection remains unclear and changes as more individuals are tested. Adults can manifest a wide range of symptoms from mild to severe illness that begin 2–14 days (the mean is 5 days) after exposure to SARS-CoV-2. The CDC reports that symptomatic patients may have any of the following: cough, fever, chills/rigors, or myalgias. The presence of dyspnea is variable, but it is the most common symptom among patients with life-threatening infection and is highly prevalent in advanced, severe infection. No one symptom should be used as a discriminant for disease. Less common symptoms include rhinitis; pharyngitis; abdominal symptoms, including nausea and diarrhea; headaches; anosmia; and ageusia. It appears that 15–20% of adults with COVID-19 require hospitalization and 3–5% require critical care. “Classic” respiratory manifestations of COVID-19 develop in few children; unless immunocompromised or younger than 1 year old, children typically have asymptomatic or only mild disease after SARS-CoV-2 exposure. Symptomatic disease in children is more likely to present with gastrointestinal symptoms and less likely to present with respiratory symptoms.

B. Laboratory Findings

Hematologic findings include neutrophilia, absolute lymphopenia, and an increased neutrophil to lymphocyte ratio. As disease advances, blood chemistry findings often include elevated liver biochemical tests and total bilirubin. Serum markers of systemic inflammation are increased in most patients with severe COVID-19, including lactate dehydrogenase level, ferritin, C-reactive protein, procalcitonin, and interleukin 6 (IL-6). Additionally, many reports have accumulated detailing the initial coagulopathy seen in severe COVID-19, which is identified by elevated von Willebrand factor (VWF) antigen, elevated D-dimer, and fibrin/fibrinogen degradation products; the prothrombin time, partial thromboplastin time, and platelet counts are usually unaffected initially (see Chapter 14). The entity, referred to as COVID-19–associated coagulopathy (CAC) has laboratory findings that differ from traditional DIC. In CAC, fibrinogen levels are higher and platelets levels are more often normal than with DIC. Mortality among hospitalized SARS-CoV-2–infected patients correlates with levels of VWF antigen as well as levels of soluble thrombomodulin, suggesting that an endotheliopathy occurs in critically ill patients.

C. Diagnostic Studies

COVID-19 diagnosis is established using nucleic acid testing. Molecular tests to detect SARS-CoV-2 were first developed in China in January 2020. Since then, many different types of SARS-CoV-2 tests have been developed in thousands of laboratories worldwide. In the United States, the FDA approved the first SARS-CoV-2 PCR test via EUA on February 4, 2020. The first EUA for a SARS-CoV-2 antigen test was issued on May 9, 2020. As of September 11, 2020, the FDA has approved 247 tests under EUAs, including 197 molecular tests, 46 antibody tests, and 4 antigen tests.

Importantly, standardization of these tests is far from finalized. On May 27, 2020, the FDA released a SARS-CoV-2 reference panel to be used as an independent performance validation step for molecular diagnostic tests. In general, the reverse transcriptase–polymerase chain reaction (RT-PCR) assays are the standard for diagnosis, and assays based on nucleic acid amplification technology (NAAT), rapid antigen assays, and laminar flow procedures are less sensitive. The laminar flow assays are available for home use; these assays, despite their lower sensitivity, may be useful for early illness when viral loads are high (and usually higher even before symptoms develop). The lateral flow Abbott assay has a 97.1% predictive for a positive test and a 98.5% predictive value for a negative test (note these values are not sensitivity and specificity) and the FDA has already expressed concern that the rate of false-negative tests is about 3%.

Currently, the sensitivity of nucleic acid tests from oral swabs is deemed low (35%); nasopharyngeal swabs (63%) or the more invasive bronchoalveolar lavage fluids (91%) are preferred. Sputum is theoretically preferred over oropharyngeal specimens, and the virus may be detectable longer in sputum than in other upper respiratory tract samples. Saliva tests are quickly gaining popularity due to their ease of collection, although they likely have decreased sensitivity compared to deeper respiratory tract specimens. Five saliva tests have received FDA EUAs to date. Most recently, the Yale School of Public Health’s “SalivaDirect” test was approved on August 15, 2020. This test is unique because it does not require a separate nucleic acid extraction step, thereby allowing for increased, rapid testing that has the potential to reduce the strain on available testing resources that is being experienced by many communities.

The use of duplicate “orthogonal” testing is recommended by CDC when clinical conditions support the diagnosis in the absence of a confirmed SARS-CoV-2 assay. A guideline to monitor decision making published by the CDC is available at https://www.whitehouse.gov/wp-content/uploads/2020/05/Testing-Guidance.pdf.

Isolation of the virus by nucleic acid assays more than 10 days after the onset of symptomatic infection (or 15 days after exposure on the average) is usually not associated with replicative, infectious particles. Immunosuppressed patients can have prolonged detection of replicative virus (viral shedding).

A variety of laboratories are producing antibody assays to determine immunity and facilitate decision making in return-to-work policies. On April 1, 2020, the first rapid lateral flow assay (Cellex) was approved by the FDA under EUA to detect IgM and IgG antibodies to SARS-CoV-2. Subsequently, many additional tests that can detect SARS-CoV-2 antibodies have received EUAs (https://www.fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations#covid19ivd). It is not clear whether these assays test for neutralizing antibodies. Importantly, because most of these assays are not standardized, the results should be interpreted with caution. Certain assays show cross-reactivity with common human coronaviruses, and most are insensitive early in the course of mild disease.

Currently, an unstandardized combination of clinical findings in conjunction with nucleic acid tests are used to make the diagnosis of COVID-19, recognizing that the wide spectrum of clinical findings and the false reassurance of assays are not fully sensitive or specific. At this time, the consensus, including that from a Cochrane Review, is that serologic assays should not be used in point-of-care settings and should not be used to determine back-to-work status. In the clinical setting, commercial serologic assays can be used to determine if a person has had past COVID-19, and these assays show public health utility in serosurveys.

Of note, the CDC is currently equivocal about testing asymptomatic individuals. Questions have been raised about whether there was political influence on the CDC to equivocate about its asymptomatic testing position, which is counter to the advice of the vast majority of infectious disease specialists who recognize the important role of asymptomatic disease in transmission (earlier modeling data, including those from the University of California, Berkeley, have emphasized the important role of asymptomatic individuals in transmission and the need to identify such persons if one is going to control the pandemic). Also, Harvard scientists recommend that SARS-CoV-2 assays be used to test asymptomatic individuals, that there should be regular and low cost testing of asymptomatic persons, and that those who test positive should be quarantined in an attempt to effectively control the pandemic.

D. Imaging

The American College of Radiology confirms clinicians’ earlier findings; neither chest radiographs nor chest CT scans provide diagnostic utility, since both may be normal, and the nonspecific findings overlap with those of many viral infections (including influenza, H1N1, and the SARS-1 and MERS coronaviruses). Later in the disease course, nonspecific diffuse ground glass opacities and/or multilobular infiltrates (which often progress to consolidation) become more common. Chest ultrasonography, MRI, and PET/CT findings tend to confirm the CT findings of an evolving organizing pneumonia.

Differential Diagnosis

The key element in the differential diagnosis is seasonal influenza infection, which can usually be ruled out by a nasal swab antigen assay. Concomitant infection with influenza or other respiratory pathogens is reported. Symptom onset tends to be more abrupt with influenza; however, the clinical manifestations overlap to a considerable degree, and it is difficult to use any symptom to distinguish between the two diseases. A useful Table comparing symptoms of an upper respiratory infection, influenza, and COVID-19 is available at https://www.medicalnewstoday.com/articles/coronavirus-vs-flu#symptoms.

Complications

Most patients have uncomplicated disease. In an early Chinese series, 81% of patients were asymptomatic or had mild disease, 14% had severe disease, and 5% were critically ill. In a New York City series, 14% of patients required ICU care, 12% required ventilation, 3% required renal replacement therapy, and 21% died.

One large Chinese study found that the independent predictors of a fatal outcome were age 75 years or greater, a history or coronary heart disease, cerebrovascular disease, dyspnea, procalcitonin levels over 0.5 ng/mL, and aspartate aminotransferase levels over 40 units/L. A large German study confirmed the role of age with an in-hospital mortality of 72% in those over 80 years, and it also showed that among ventilated patients who received dialysis, the mortality was 73%.

A clinical risk score calculator to predict critical illness in hospitalized patients with COVID-19 called COVID-GRAM has been validated (http://118.126.104.170/); predictors of clinical deterioration include presence of chest film abnormalities, older age, positive cancer history, increased number of comorbidities, presence of certain signs and symptoms (hemoptysis, dyspnea, and decreased consciousness), and presence of certain laboratory abnormalities (increased neutrophil to lymphocyte ratio, increased lactate dehydrogenase, and increased direct bilirubin). Severe COVID-19 likely occurs because of an intense and/or prolonged inflammatory reaction, often called a “cytokine storm” (a term that is criticized by some experts because cytokine levels in COVID-19 are far lower than those in ARDS), in the later phase of illness. Persistent immune activation in predisposed patients can lead to uncontrolled amplification of cytokine production (including IL-6), leading to multiorgan failure and death.

Some patients progress to ARDS akin to the coronavirus infections that cause SARS and MERS (but unlike the far more common “common cold” coronavirus infections); COVID-19–related ARDS is so commonly recognized now that it is referred to as “CARDS.” CARDS care requires the involvement of intensivists who can provide guidelines for respiratory support, including appropriate oxygen flow and ventilator parameters, prone positioning (which is also useful for nonventilated pulmonary patients), and hydration status. Several chemokine-receptor genes (CCR9, CXCR6, and XCR1) are associated with severe disease.

The spectrum of pulmonary pathology based on a review from Italy shows that the most common findings on postmortem examinations are diffuse alveoli congestion, hyaline membrane formation, pneumatocyte hyperplasia and necrosis, platelet-fibrin thrombi, interstitial edema, and squamous metaplasia with atypia. Such pathologic findings are seen in other organs as well at autopsy; pathologists note the four most common findings are the alveolar damage and thrombosis listed in the lung descriptions above as well as hemophagocytosis and lymphocyte depletion.

Many extrapulmonary complications are reported and most of these are likely related to SARS-CoV-2–induced inflammatory reactions. COVID-19–related coagulopathy is associated with a particular predisposition to pulmonary emboli and to thrombosis of renal vessels used for continuous renal replacement therapy and, less often, to thrombosis of extracorporeal membrane oxygenation–associated vessels. A fulminant myocarditis occurs in about 15% of ICU patients, which can be further complicated by heart failure, cardiac arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. Preliminary data from China suggested that acute kidney injury is not a complication of COVID-19, although the more recent reports of coagulopathic renal complications modify this finding. Skin manifestations are diverse and on occasion the presenting sign. These skin manifestations range from ill-defined rashes to petechial lesions and hemorrhagic edematous lesions in children and hardened red plaques on the ankles.

A large retrospective review from Wuhan showed that patients with type 2 diabetes who were taking metformin manifested higher rates of acidosis, heart failure, and inflammatory markers, although short-term (28-day) mortality was not impacted. It is recommended that kidney function and acid-base status be watched closely in diabetic patients with COVID-19.

Commonly reported neurologic complications are headaches; seizures; strokes; and more often, a loss of taste and smell (ageusia and anosmia). The loss of smell in the absence of significant rhinorrhea or nasal congestion suggests a neurotropism by this coronavirus. SARS-CoV-2–related meningitis as well as other neurologic complications including impairment of consciousness, Guillain-Barre syndrome, and acute hemorrhagic necrotizing encephalopathy are reported. While the presence of ACE receptors in brain tissue support direct CNS involvement, actual isolation of the virus from the CNS is not consistent and the CNS damage may occur via indirect mechanisms to be defined.

COVID-19 patients are at high risk for postoperative complications. In an international cohort study assessing postsurgical outcomes, postoperative severe acute respiratory problems occurred in 71.5% and the 30 days postoperative mortality was 23.8%.

Acute musculoskeletal pain is reported in nearly 20%. Hepatic and biliary injury, often acute, and DIC in advanced cases are reported from China. Conjunctivitis is reported from China in about one-third of cases. In the New York, British, and Italian experiences, a hyperinflammatory syndrome akin to atypical Kawasaki disease, called multisystem inflammatory syndrome in children (MIS-C) in the United States and Paediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2 (PIMS-TS) in Europe, was noted in children (see Kawasaki syndrome); the leading systems involved are gastrointestinal (the nonspecific symptoms have been diagnosed as appendicitis), cardiovascular, hematologic, mucocutaneous, and pulmonary. Central and peripheral nervous system findings are reported in children with this syndrome even in the absence of pulmonary disease, and such findings show a predilection for the corpus callosum.

Long-term sequelae of COVID-19 are described in an Italian study of nearly 200 COVID-19 survivors; 87.4% of patients reported persistent symptoms (including fatigue, dyspnea chest pain, and joint pain) about 30–60 days post-acute symptom onset, suggesting relatively long recovery times. Neurologists and psychiatrists express concern that long-term sequelae including encephalopathy, psychoses, and movement disorders may follow the pandemic (as they did after the influenza pandemic of 1918).

Recovery times are protracted, and the CDC reports from telephone surveys that 35% do not return to work 2–3 weeks after testing positive for COVID-19 and even among the young, 20% do not return to work within the same timeframe. Such prolonged recovery times will affect decisions regarding return to work and suggests that a consensus be worked out between the provider and the patient.

The full impact of COVID-19 on other chronic medical conditions is only beginning to be elucidated. For example, multiple sclerosis patients are at risk if they are neurologically compromised, obese, or elderly, while cancer patients seem to be compromised by the delays in “elective” surgical procedures.

The serious psychological sequelae of potentially dying alone, of restricted or impaired access to family or friends (especially in nursing homes), and limited funeral services are all relevant issues with which society is grappling. These important aspects require creativity to find tolerable, safe, and sustainable solutions.

Treatment

The WHO (https://www.who.int/publications-detail/clinical-management-of-covid-19), the NIH (https://www.covid19treatmentguidelines.nih.gov/whats-new/), and Infectious Diseases Society of America (IDSA) (https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/) have released guidance for the management of COVID-19 patients from screening to discharge. The Pediatric Infectious Diseases Society has also published guidelines for management of SARS-CoV-2 infections in children (https://academic.oup.com/jpids/article/doi/10.1093/jpids/piaa045/5823622). Most infections are mild and require no treatment or only supportive therapy. Because of the biphasic nature of advanced cases, the early course should be managed with antiviral agents, as they become available, and the later “cytokine storm” phase should be managed with anti-inflammatory agents.

Many medications for the treatment of COVID-19 are being evaluated in clinical trials. The two medications with most promising data to date are remdesivir and dexamethasone. Other promising therapies include inhaled interferon beta-1b and convalescent plasma therapy.

Remdesivir is a viral RNA-dependent RNA polymerase [RdRp] inhibitor with known in vitro but limited in vivo activity against the Ebola and Marburg viruses as well as RSV, Lassa virus, and Nipah virus. The preliminary results of the first remdesivir randomized controlled trials were released on April 29, 2020. One of these, a multicenter trial sponsored by the United States National Institute of Allergy and Infectious Diseases (NIAID) called the Adaptive COVID-19 Treatment Trial 1 (ACTT 1), studied 1063 hospitalized adult patients with advanced COVID-19 and lung involvement and found that those who received remdesivir recovered several days faster than similar patients who received placebo; no mortality benefit was noted however. Based on these data, remdesivir was approved by the FDA under EUA on May 1, 2020. Subsequently, a study comparing 5 days and 10 days of remdesivir showed no statistically significant difference in clinical status between the two treatment regimens. The rate of adverse events is about 40%, including renal toxicity, diarrhea, transaminitis, and rash. The drug must be administered intravenously in the hospital, usually in an intensive care unit. With a shortage of remdesivir, limitations based on data showing who responds best include restricting use to 5 days and giving it to patients who are hypoxic (oxygen saturation ≤94%) but not requiring high-flow oxygen or mechanical ventilation or extracorporeal membrane oxygenation (ECMO). Remdesivir, in combination with lopinavir/ritonavir and ribavirin, showed significant improvement in symptom duration, interval to viral clearance, and duration of hospital stay in a study from Hong Kong. Favipiravir is an additional RdRp inhibitor being studied for COVID-19 treatment.

A British trial (the Recovery Trial) indicated that dexamethasone reduces death in hospitalized patients with severe respiratory complications of COVID-19 (https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf). Dexamethasone is now recommended only for treatment of patients with severe disease (those who require supplemental oxygen and those who are mechanically ventilated or need ECMO). Because of potential long-term side effects, dexamethasone courses should be relatively short, such as 10 days or less. Patients without hypoxia, mechanical ventilation, or ECMO should not be given corticosteroids. While dexamethasone has shown promise, other corticosteroid treatments, such as methylprednisolone, have not shown benefit in trials to date.

With the recognition that type I interferon responses are impaired in COVID-19, a variety of trials are underway. Inhaled interferon-beta-1b (Synairgen plc® in the United Kingdom), was found to prevent progression to death and to lower death rate in one British study of hospitalized patients. Studies are planned to assess this agent as a preventive at-home strategy. The third iteration of the ACTT is assessing the combination of interferon beta-1b with remdesivir as a subcutaneous preparation.

Convalescent plasma (plasma from the blood of patients who have recovered from COVID-19) is being given to critically ill patients in many centers. A published study from China did not find a statistically significant difference in time to outcome at 28 days in patients who received convalescent plasma, although a negative PCR conversion rate was statistically higher among the plasma-treated patients, indicating that the therapy does have some antiviral activity. Larger clinical trials are ongoing in the United States and the United Kingdom (convalescent plasma is an additional arm of the Recovery trial). Despite the FDA issuing an EUA for convalescent plasma on August 23, 2020, neither the IDSA nor the NIH recommend that convalescent plasma be given outside of a clinical trial at this time because of the paucity of efficacy and safety data to support this therapy. Several individual SARS-CoV-2 monoclonal neutralizing antibody candidates are being developed for clinical use. A combination of neutralizing monoclonal antibodies (REGN3048 and REGN3051) is being studied in a first-in-human clinical trial sponsored by the NIAID. However, these monoclonal antibody therapies share (and amplify) the disadvantages of convalescent plasma therapy, namely that their production is complex and expensive.

“AeroNabs” is a new form of therapy under development at UCSF School of Medicine, with the goal of achieving safe and passive immunity to SARS-CoV-2. “AeroNabs” involves the inhalation of nanoparticles, an ultrahigh affinity synthetic nanobody (miniscule antigen-binding heavy chain fragments derived from camelids who do not make light chain) that binds the SARS-CoV-2 Spike protein and locks it into an inactive conformation. The agent would be easy to administer and provide therapy both prophylactically and therapeutically early in infection.

Treatments targeting the SARS-CoV-2–induced immune response, such as IL-6 receptor inhibitors (eg, tocilizumab and sarilumab), are being used based on anecdotal evidence for severe pneumonia and with the rationale that high levels of IL-6 are a key component of the “cytokine storm” associated with advanced SARS-CoV-2 infection. However, available data are discouraging for tocilizumab; in the COVACTA study, no difference was seen in clinical status, ventilator-free days, or death rate, but a shorter hospital stay was noted among those treated. Similar negative results have been found with the use of sarulimab, an analog of tocilizumab, where there have been no differences in clinical outcomes during its phase III trials. Both tocilizumab and sarilumab should therefore only be given as part of clinical trials. The large clinical Recovery trial remains underway in which tocilizumab is one arm.

Of the remaining re-purposed treatments that have been used or studied for management of COVID-19, none have shown as much promise as the therapies described above. Hydroxychloroquine, a drug used in several rheumatic conditions, was initially prescribed widely for COVID-19 and was being studied as part of the WHO’s Solidarity Trial, a large international trial comparing four study arms ([1] remdesivir, [2] lopinavir/ritonavir, [3] lopinavir/ritonavir plus interferon beta-1a, and [4] hydroxychloroquine to standard of care). Subsequently data from several studies suggested that the potential for adverse effects when hydroxychloroquine is used to treat patients with COVID-19 likely outweighs the small potential benefit of using the drug. For this reason, the hydroxychloroquine arm within the Solidarity Trial was discontinued. The use of hydroxychloroquine, particularly in combination with azithromycin, is potentially dangerous because of the untoward development of cardiac arrhythmias as well as optic neuritis, gastrointestinal intolerance, and anemia. The one “successful” trial reported in JAMA was a retrospective observational study unlike the other studies which were double-blind and placebo-controlled. The use of these agents should be limited to clinical trials.

The anti-HIV combination of lopinavir/ritonavir (Kaletra) was shown to have no clinical benefit by a group of Chinese investigators and in the Recovery trial. As a result, the lopinavir/ritonavir arm was discontinued from the WHO’s Solidarity Trial. The open-label Discovery trial compared adults receiving the triple combination of lopinavir-ritonavir, ribavirin, and interferon beta-1b to adults receiving lopinavir-ritonavir alone. Preliminary results showed that symptoms resolved faster, and duration of hospital stay was shorter in the combination group when medications were given within 7 days of symptom onset. Another anti-HIV combination, darunavir/cobicistat, is also under study. A study showing a lower incidence of hospitalization among HIV-infected individuals in Spain who were receiving prophylaxis with tenofovir disoproxil fumarate and emtricitabine (Truvada) needs confirmation because of potentially confounding variables. Currently, the IDSA does not recommend the use of HIV antivirals for COVID-19.

Additional agents under investigation include leronlimab (PRO 140; a CCR5 antagonist), galidesivir (BCX4430; a nucleoside RNA polymerase inhibitor), baricitinib (a Janus kinase [JAK] inhibitor), and Bruton tyrosine kinase (BTK) inhibitors. Baricitinib is being studied in combination with remdesivir during the second iteration of the ACTT (ACTT 2).

Ivermectin, an antiparasitic drug, has been used extensively for COVID-19 in Latin America. However, in vitro studies of ivermectin at doses much higher than those deemed safe in humans have failed to reduce SARS-CoV-2 viral loads. Both the Panamerican Health Organization (PAHO) and the WHO recommend against the use of ivermectin for COVID-19.

A retrospective review of COVID-19 cases at a New York hospital showed that the use of famotidine, but not protein pump inhibitors, is associated with a two-fold reduction in clinical deterioration leading to intubation or death. Famotidine inhibits 3-chymotrypsin-like protease (3CLpro), an enzyme needed for viral replication; its use is also associated with lower ferritin levels, suggesting a significant anti-inflammatory aspect. Further studies are under way.

ACE inhibitors and angiotensin receptor blockers do not have an impact on disease, and it is recommended that patients who take these medications for other indications continue taking them. No increased risk of COVID-19 exists among patients who take any particular class of antihypertensive agents.

Because pathogenesis includes the action of a serine protease TMPRSS2 with the ACE receptor, two inhibitors of TMPRSS2 are undergoing studies. Camostat mesylate is a TMPRSS2 inhibitor that is available in Japan for other indications (chronic pancreatitis and postoperative reflux esophagitis) and is undergoing study in phase I and II trials for COVID-19 in Denmark. A related TMPRSS2 inhibitor, nafamostat, is being studied in Germany.

Various vitamin and mineral supplements have been suggested for both the treatment and prevention of COVID-19, including vitamin C, vitamin D, and zinc supplements; of these, vitamin D has shown the most promising results to date.

The WHO does not recommend that patients who have or may have COVID-19 restrict the use of ibuprofen if it is needed, although the IDSA recommends that all NSAIDs need further study in the context of ongoing COVID-19.

VTE prophylaxis for COVID-19 patients is indicated and numerous guidelines are being published to assist with full anticoagulation (see Chapter 14). Guidelines published by the American Society of Hematology are available at https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation. Higher levels of anticoagulation may be needed in COVID-19 patients and weight-based anticoagulation is preferred.

Prevention

The usual precautions recommended to prevent SARS-CoV-2 infection include frequent handwashing with soap and water for at least 20 seconds, avoiding touching the face, wearing a cloth face covering in public (and, for healthcare workers, wearing an impermeable mask [eg, N95 mask] and face shield if exposure to patients with cough and/or respiratory secretions is anticipated), and isolating cases (in particular, removing infected patients from long-term–care facilities, such as nursing homes, and transportation structures, such as cruise ships). Physical distancing is also an important practice for control of the disease. Masking likely reduces the viral inoculum to which the mask-wearer is exposed. Specifically, cloth masks, if worn correctly, filter 65–85% of viral particles. For healthcare workers, a recent study indicated that correctly-sized but expired N95 masks with intact elastic bands and masks that had been subjected to sterilization procedures had unchanged fitted filtration efficiencies (FFEs) of more than 95%, while the performance of N95 masks of the wrong size resulted in decreased FFEs between 90% and 95%.

The first SARS-CoV-2 vaccine trials began in China in March 2020. Since then, many candidate vaccines have been launched into preclinical development using a variety of technologies (including DNA and RNA platforms, inactivated genes, live-attenuated genes, nonreplicating vectors, protein subunits, and replicating viral vectors). Over 250 vaccines are under development, and more than 30 vaccines are currently in various stages of clinical evaluation (more information about those vaccine candidates that are tracked by the WHO is available https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines). Two vaccines have already been released; one developed by the Chinese government and the firm CanSino that is being used for the Chinese military (it is an adenovirus-vectored recombinant protein found to be safe in clinical trials) and the other is a Russian vaccine based on a human adenovirus (what types of trials this vaccine was subjected to is unclear). Another Chinese vaccine, an inactivated whole virus vaccine, is currently in phase III trials, and preliminary analysis indicates that it caused a low rate of adverse reactions and demonstrated immunogenicity (ChiCTR2000031809).

The US government, in partnership with private initiatives, established Operation Warp Speed to develop and produce SARS-CoV-2 vaccines in the United States. Initially, six vaccines were chosen based on pre-vaccine technology, the likelihood of entering phase III trials in the fall of 2020 and production by early 2021, the ability to produce industrial quantities of vaccine, and the ability to use a platform technology likely to produce a safe and effective vaccine. Operation Warp Speed has chosen three vaccines for further development; they include the Moderna/NIAID mRNA vaccine, the Pfizer/BioNTech mRNA vaccine, and the AstraZeneca/Oxford live chimpanzee adenovirus vector vaccine (AZD1222, formerly ChAdOx). All three of these vaccines target the SARS-CoV-2 Spike protein, require two doses 3–4 weeks apart, and require refrigeration (particularly the mRNA vaccines, which require –70̊C storage). The Moderna and AstraZeneca vaccines were both safe and immunogenic during phase II trials and are currently undergoing phase III trials. However, the AstraZeneca vaccine phase III trial was put on hold on September 8, 2020, after a study participant developed transverse myelitis. The Pfizer vaccine completed phase I trials in August 2020 and is now being evaluated in phase II/III trials. Another replication-defective adenovirus vector vaccine by Janssen Pharmaceuticals (Ad26) will be entering phase III trials in the United States in the fall of 2020, a recombinant subunit adjuvanted protein vaccine by Novavax has undergone phase I trials in Australia and has pending phase III trials in the United States, and a recombinant Spike protein, oil adjuvant vaccine by Sanofi/GSK is planned to enter phase III trials in early 2021.

Data from animal models at the University of California, San Diego show that neutralizing antibodies isolated from patients recovering from COVID-19 protect mice but the protection is greater against receptor binding domains than the Spike protein. In other vaccine studies, neutralizing antibodies can be achieved in nonhuman primates with an mRNA vaccine encoding the prefusion stabilized Spike protein and protecting the animals from lung pathology.

The incidence of COVID-19 is curiously lower among those who report a history of BCG vaccination. In an analysis of European countries that use a BCG vaccine, a 10% increase in BCG deployment correlated with a 10% reduction in COVID-19 cases. Similar correlations were found in many but not all vaccine preventable diseases (no correlation was seen with meningococcal or typhoid vaccines). The latter finding may be due to either a specific immune-enhancing aspect of some BCG vaccine antigens or a broader “healthy user effect” among those who seek more medical care.

To achieve effective herd immunity in a population, vaccination uptake must be 70% or higher. However, studies on attitudes toward SARS-CoV-2 vaccine acceptance by the general population indicate that a significant portion of the adult population would not accept a SARS-CoV-2 vaccine (including more than 25% of French adults, nearly 15% of Australian adults, and more than 20% of US adults). This implies that considerable public education may be necessary to promote vaccine acceptance and thereby attain herd immunity from vaccination, especially among segments of the population with low health literacy.

As testing of potential SARS-CoV-2 vaccine candidates draws near completion, vaccine preparedness plans are starting to appear. In the United States, on September 4, 2020, the CDC distributed a document detailing SARS-CoV-2 vaccine distribution, storage, handling, and administration to health departments across the nation, suggesting that enough vaccine doses to cover 1 million people with the Pfizer and/or AstraZeneca vaccine would be available by October 2020. Under the CDC guidance, prioritized populations for the vaccine would include healthcare professionals, unspecified types of essential workers, national security populations, and long-term–care facility residents and staff. This announcement was thought to be premature by many health experts, since final testing of the three vaccines supported by Operation Warp Speed has not yet been completed.

Finally, promising data have been released about naturally acquired herd immunity, indicating that robust T- and B-cell immunity develops after asymptomatic or mild SARS-CoV-2 infection. Additionally, only a few cases of proven reinfection have been documented to date, suggesting that the post–SARS-CoV-2 immune response is effective at preventing subsequent disease. Areas of the world that experienced high infection rates earlier in 2020 (such as Italy, Sweden, New York) are now showing significantly fewer deaths per number of SARS-CoV-2 cases detected, indicating that herd immunity has likely been achieved in those communities. Greater population-level immunity, whether achieved naturally or via an effective vaccine, will significantly slow the spread of SARS-CoV-2. While awaiting a vaccine, widespread masking may be the safest way to both prevent severe infections and achieve herd immunity.

When to Refer

Even asymptomatic patients and those with atypical manifestations may be shedding and transmitting the virus. Patients in whom the disease is suspected should be tested with nasopharyngeal swabs that are sent for FDA-approved molecular testing if symptoms are consistent with SARS-CoV-2 infection. In the future, at-home antigen testing may be used.

Clinics and hospitals with the resources to screen or test outpatients for SARS-CoV-2 should set up a testing area that is isolated from other patient care areas (and outside or in an “open air” environment if possible). These facilities should also designate separate care areas for patients in whom SARS-CoV-2 infection is confirmed or suspected and provide the necessary personal protective equipment for staff who could potentially be exposed to patients infected with SARS-CoV-2.

When to Admit

The principal complications requiring admission for adults with COVID-19 are respiratory. Progression to respiratory failure and ARDS can be rapid, and any patient in a high-risk category for complications (eg, those with advanced age; immunosuppression; chronic diseases such as hypertension, obesity, and diabetes) or any patient with evident thrombotic, neurologic, or multiple system disease should be admitted for observation and placed under intensive care based on respiratory parameters.

General Considerations

Respiratory syncytial virus (RSV) is a paramyxovirus that causes annual outbreaks during the wintertime with usual onset of pulmonary symptoms between mid-October and early January in the continental United States (excluding Florida). Outside the United States, RSV usually peaks during wet months in areas with high annual precipitation and during cooler months in hot and dry areas. It occurs earlier in urban areas.

There are two major subtypes, A and B, and it appears that the A subtype is associated with disease severity. RSV is the leading cause of hospitalization in US children, with annual hospitalization rates of 6 per 1000 children younger than 5 years. Globally, the annual RSV hospitalization rates are 4 per 1000 children less than 5 years old, 19 among children less than 1 year old, 20 among children less than 6 months old, and 64 among premature children less than 1 year. Prematurity is a major risk factor for severe disease. Early RSV bronchiolitis in children, along with a family history of asthma, are associated with persistence of airway reactivity later in life.

RSV also causes upper and lower respiratory tract infection in adults, with the virus entering through contact with mucous membranes. RSV occurs with increasing severity in those with comorbid conditions, older adults (accounting for a rate of 4 per 1000 hospitalizations and 14,000 deaths annually), persons with severe combined immunodeficiency, and patients after lung or bone marrow transplantation (because CD8 T cells are not available for viral clearance). An interleukin-1 receptor polymorphism is shown to be associated with more severe bronchiolitis. Recurrences occur throughout life. The average incubation period is 5 days. Up to 10% of disease classified as invasive pneumococcal disease is thought to be RSV or influenza.

In immunocompromised patients, such as bone marrow transplant recipients, serious pneumonia can occur, and outbreaks with a high mortality rate (greater than 70%) are reported.

Other paramyxoviruses important in human disease include human metapneumovirus, parainfluenza virus, and Nipah virus.

Human metapneumovirus is a ubiquitous seasonal virus circulating during late winter to early spring. It is divided into subgroups A and B. Metapneumovirus accounted for 7.3% of childhood (younger than 16 years old) pneumonia in a Norwegian series of 3650 patients in which RSV accounted for 28.7%. Clinical presentations range from mild upper respiratory tract infections to severe lower respiratory tract infections (eg, bronchiolitis, croup, and pneumonia). Lower respiratory tract (sometimes severe) infections have been observed among immunocompromised and elderly adults, especially residents of nursing homes. In lung transplant recipients, human metapneumovirus is a common cause of respiratory illness and is thought to increase the risk of acute and chronic graft rejection. Ribavirin appears to be well tolerated in lung transplant recipients with metapneumovirus infection.

Human parainfluenza viruses (HPIVs) are commonly seen in children and are the most common cause of laryngotracheitis (croup). Four different serotypes are described, and they differ in their clinical presentations as well as epidemiology. HPIV-1 and HPIV-2 are responsible for croup. HPIV-3 is associated with bronchiolitis and pneumonia. HPIV-4 is a less frequently reported pathogen. Reinfections are common throughout life. HPIVs can also cause severe disease in older individuals, immunocompromised persons, and patients with chronic illnesses.

Nipah virus is a highly virulent paramyxovirus first described in 1999. Cases are concentrated mainly in Southeast Asia (Malaysia, Singapore, Bangladesh, and India). Fruit bats are identified as the natural host of the virus. An outbreak of 14 cases, 8 fatal, occurred in Bangladesh associated with drinking date palm sap between 2010 and 2014. Direct pig-human, cow-human, human-human, and nosocomial transmission are reported. Nipah virus causes acute encephalitis with a high fatality rate (67–92%), although respiratory symptoms are also described. Cranial nerve palsies, encephalopathy, and dystonia are among neurologic sequelae (15–32%) seen in infected individuals. Relapses occurring weeks and months after initial infection are described (3.4–7.5%).

Clinical Findings

A. Symptoms and Signs

In RSV bronchiolitis, proliferation and necrosis of bronchiolar epithelium develop, producing obstruction from sloughed epithelium and increased mucus secretion. Signs of infection include low-grade fever, tachypnea, and wheezes. Apnea is a common presenting symptom. Hyperinflated lungs, decreased gas exchange, and increased work of breathing are present. Pulmonary hemorrhage is reported. In children, RSV is globally the most common cause of acute lower respiratory infection and also a common cause of acute and recurrent otitis media. In patients with Down syndrome, RSV develops at a later age and is associated with more protracted hospitalizations.

B. Laboratory Findings

A rapid diagnosis of RSV infection is made by viral antigen identification of nasal washings using an ELISA or immunofluorescent assay, but PCR-based rapid tests are increasingly used. Coinfection with bacteria is relatively uncommon in industrialized countries although Clostridioides (formerly Clostridium) difficile–associated diarrhea is documented to occur after RSV infections in a Canadian study. Coinfection with Bordetella pertussis and other viruses occurs in a subset of patients hospitalized for RSV infection. Multiplex assays in conjunction with influenza A and B tests are available commercially. RSV viral load assay values at day 3 of infection may correlate with requirement of intensive care and respiratory failure in children.

Human metapneumovirus is best diagnosed by PCR. Tests for rapid detection of viral antigens with immunofluorescence or ELISA, and PCR techniques are also widely available for detection of HPIV. Culture may also be used. ELISA (serum and CSF) and PCR (urine and respiratory secretions but not blood) are both used for Nipah virus infection diagnosis.

Treatment & Prevention

Treatment of RSV consists of supportive care, including hydration, humidification of inspired air, antibiotic therapy (to reduce other respiratory morbidity), and ventilatory support as needed. Neither bronchodilating agents nor corticosteroids have demonstrated efficacy in bronchiolitis although individual patients with significant bronchospasm or history of asthma might respond to them. Oral antiviral agents remain under study.

The use of aerosolized ribavirin or RSV-enriched IVIG, or both, can be considered in high-risk patients, such as those with a history of bone marrow transplantation, and appears to lessen mortality. Pregnant women, including hospital staff, should avoid ribavirin exposure. Therapy with surfactant lacks evidence to make recommendations on its use. The prophylactic monoclonal antibody palivizumab, while recommended for and effective in high-risk infants (premature infants less than 32 weeks’ gestational age, as well as infants with congenital heart and lung diseases and Down syndrome), is not of proven efficacy among adults with RSV.

A 2017 clinical trial studied the administration of palivizumab to preterm infants to prevent long-term sequelae; palivizumab did not suppress the onset of atopic asthma but did result in a significantly lower incidence of recurrent wheezing. Azithromycin therapy during RSV infection has been shown to reduce the probability of recurrent wheezing during the subsequent year by approximately 50%. MEDI8897 is a recombinant human RSV monoclonal antibody that is being developed as RSV prophylaxis for infants (NCT02114268).

No RSV vaccine is currently commercially available. A vaccine composed of the RSV postfusion F protein with glucopyranosyl lipid adjuvant was found to be immunogenic but not to protect older adults from RSV. It is currently being evaluated in pregnant women in their third trimester, with the goal of passively protecting infants through transfer of RSV-specific maternal antibodies (NCT01960686). Other vaccines under development include a variety of live, attenuated vaccines and a variety of subunit vaccines for adults and infants. The use of RNA interference therapy in lung transplant patients may have some beneficial effects.

Prevention in hospitals entails rapid diagnosis, hand washing contact isolation, and perhaps passive immunization. (Passive immunization is costly but is associated with improved antiviral titers in hematologic stem cell transplant recipients). The use of conjugated pneumococcal vaccination appears to decrease the incidence of concomitant pneumonia associated with viral infections in children in some countries. Viral shedding averages 11 days and correlates inversely with age and directly with severity of infection.

Therapeutic modalities for human metapneumovirus and parainfluenza virus infections under investigation include intravenous ribavirin administration. Vaccines for human metapneumovirus and parainfluenza virus are in early stages of development. During the initial Nipah virus outbreak, ribavirin was used empirically, although its efficacy remains questionable.

General Considerations

Influenza (an orthomyxovirus) is a highly contagious disease transmitted by the respiratory route in humans. Transmission occurs primarily by droplet nuclei rather than fomites or direct contact. There are three types of influenza viruses that infect humans. While type A can infect a variety of mammals (humans, swine, horses, etc) and birds, types B and C almost exclusively infect humans. Type A viruses are further divided into subtypes based on the hemagglutinin (H) and the neuraminidase (N) expressed on their surface. There are 18 subtypes of hemagglutinin and 11 subtypes of neuraminidase.

Annual epidemics usually appear in the fall or winter in temperate climates, although sporadic cases occur as summer outbreaks in northern areas such as Alaska or the southern hemisphere. Up to 5 million cases of severe influenza are estimated by the WHO to occur annually, with up to 0.5 million annual deaths. Influenza epidemics affect 10–20% of the global population on average each year and are typically the result of minor antigenic variations of the virus, or antigenic drift, which occur often in influenza A virus. On the other hand, pandemics—associated with higher mortality—appear at longer and varying intervals (decades) as a consequence of major genetic reassortment of the virus (antigenic shift) or adaptation of an avian or swine virus to humans (as with the pandemic H1N1 virus of 1918). (https://www.who.int/influenza/surveillance_monitoring/updates/latest_update_GIP_surveillance/en/).

The highly pathogenic avian influenza subtypes are discussed in the next section. The novel swine-origin influenza A (pandemic H1N1) virus emerged in Mexico in 2009 and quickly spread throughout North America and the world causing a pandemic. This virus originated from triple-reassortment of North American swine, human, and avian virus lineages and Eurasian swine virus lineages and replaced the previous H1N1 seasonal virus.

Clinical Findings

A. Symptoms and Signs

Type A and B seasonal influenza viruses produce clinically indistinguishable infections, whereas type C usually causes mild illness. The incubation period is 1–4 days. In unvaccinated persons, uncomplicated influenza often begins abruptly. Symptoms range widely from nearly asymptomatic to a constellation of systemic symptoms (including fever, chills, headache, malaise, and myalgias) and respiratory symptoms (including rhinorrhea, congestion, pharyngitis, hoarseness, nonproductive cough, and substernal soreness). Gastrointestinal symptoms and signs may occur, particularly among young children with influenza B virus infections. Fever lasts 1–7 days (usually 3–5). Elderly patients especially may present with lassitude and confusion, often without fever or respiratory symptoms. Signs include mild pharyngeal injection, flushed face, and conjunctival redness. Moderate enlargement of the cervical lymph nodes and tracheal tenderness may be observed. The presence of fever (higher than 38.2°C) and cough during influenza season is highly predictive of influenza infection in those older than 4 years.

B. Laboratory Findings

Rapid influenza diagnostic tests for detection of influenza antigens from nasal or throat swabs are widely available, highly specific, and produce fast results but have low sensitivity leading to high false-negative results. Not all commercial rapid influenza diagnostic tests can differentiate between influenza A and influenza B, and none of the available rapid influenza diagnostic tests can provide information on influenza A subtypes. Newer digital immunoassays and rapid nucleic acid amplification tests are more sensitive than traditional rapid influenza diagnostic tests; however, the sensitivity of newer PCR techniques is compromised early in the season during low prevalence periods. A nasopharyngeal swab, nasal aspirate, combined nasopharyngeal swab with oropharyngeal swab, or material from a bronchoalveolar lavage can be tested for any influenza strain. When influenza pneumonia is suspected, lower respiratory tract specimens should be collected and tested for influenza viruses by RT-PCR or the above assays.

Differential Diagnosis

The differential diagnoses for influenza-like infections include a variety of viral respiratory infections (parainfluenza, RSV, atypical dengue, adenovirus, enterovirus, coronavirus) or other viral infections (flavivirus, CMV, EBV, acute HIV infection), as well as bacterial infections such as mycobacterial infection (atypical pneumonia), pertussis, and Legionnaire disease. Epidemiologic factors can suggest Legionnaire (elderly smokers). Chronicity of cough may suggest adenovirus, mycobacterial, or pertussis infection. Leukocytosis and lymphadenopathy are more often seen with CMV and EBV. Distinguishing influenza from dengue requires attention to rhinitis (influenza) and thrombocytopenia (dengue).

Complications

Hospitalization or ICU admission for influenza is often a consequence of diffuse viral pneumonitis with severe hypoxemia and sometimes shock. Patients with asthma, residents of nursing homes and long-term care facilities, adults aged 65 years or older, persons who are morbidly obese, and persons with underlying medical conditions (pulmonary, renal, cardiovascular, hepatic, hematologic, neurologic and neurodevelopmental conditions; and immune-deficient conditions, such as HIV, diabetes, and cirrhosis) are at high risk for complications. Infection during pregnancy increases the risk for hospitalization and may be associated with severe illness, sepsis, pneumothorax and respiratory failure, spontaneous abortion, preterm labor, and fetal distress.

Influenza causes necrosis of the respiratory epithelium, increased adherence of bacteria to infected cells, and ciliary dysfunction, which predispose to secondary bacterial infections due to pneumococci, staphylococci, or Haemophilus spp. In turn, bacterial enzymes (eg, proteases, trypsin-like compounds, and streptokinase) activate influenza viruses. Frequent complications are acute sinusitis, otitis media, purulent bronchitis, and pneumonia.

Cardiovascular diseases are a complication of influenza infection, in particular among older adults, and influenza is postulated to be a significant trigger for myocardial infarction, cerebrovascular disease, and sudden death. Several studies suggest that influenza vaccination has protective effect against major adverse cardiovascular events. Neurologic complications, including seizures and encephalopathy, may occur. Encephalopathic complications of influenza are uncommon.

Reye syndrome (fatty liver with encephalopathy) is a rare and severe complication of influenza (usually B type) and other viral diseases (especially varicella), particularly in young children. It consists of rapidly progressive hepatic failure and encephalopathy, and there is a 30% mortality rate. The pathogenesis is unknown, but the syndrome is associated with aspirin use in the management of viral infections.

Treatment

Treatment is supportive. Antiviral therapy should be considered for all persons with acute illness, in particular those at high risk for developing complications who have a suggestive clinical presentation or with laboratory-confirmed influenza. Clinical trials show a reduction in the duration of symptoms, hospital admissions, as well as secondary complications, such as otitis, sinusitis, or pneumonia, but not mortality when using these agents. Maximum benefit is expected with the earliest initiation of therapy. Although the benefit of antiviral therapy after 48 hours of illness is reduced, it should be initiated if the patient is hospitalized or critically ill. Benefit has been noted up to 4–5 days into illness.

The antiviral treatment of choice should be based on the susceptibility of the circulating virus. Currently, since high levels of resistance to the adamantanes (amantadine and rimantadine) persist among seasonal H1N1 and H3N2 influenza A viruses and these agents are not effective against influenza B viruses, amantadine and rimantadine are not recommended for treatment.

Three neuraminidase inhibitors are FDA approved for treatment of influenza A and B: oral oseltamivir, inhaled zanamivir, and intravenous peramivir. The CDC recommends treatment with oral oseltamivir (75 mg twice daily for 5 days) as the drug of choice for patients of any age, pregnant women, and patients who are hospitalized or have complicated infection. Absorption of oral oseltamivir is considered reliable, except in patients with impaired gastric motility or gastrointestinal bleeding.

Inhaled zanamivir (10 mg, 2 inhalations twice daily for 5 days) is indicated for uncomplicated acute influenza in patients 7 years and older, is relatively contraindicated among persons with asthma because of the risk of bronchospasm, and is not formulated for use in mechanically ventilated patients. Inhaled zanamivir lacks efficacy in pneumonia, probably due to poor bioavailability in the peripheral lungs.

Intravenous peramivir (600 mg in single dose) is used for outpatient treatment of uncomplicated infection in patients 18 years and older and is recommended when there is a concern about inadequate oral absorption of oseltamivir. The efficacy of peramivir in patients with severe illness and in patients with influenza B is not well established. Some studies demonstrated that repeated doses for up to 5 days of intravenous peramivir is safe, effective and shorten the duration of influenza illness.

Resistance to neuraminidase inhibitors (oseltamivir, zanamivir, and peramivir) can occur during or after prolonged use in immunocompromised patients, particularly in persons who have undergone hematopoietic stem cell transplant. Intravenous zanamivir is an investigational drug that could be requested for clinical use if there is a concern for oseltamivir-resistant influenza strain. Depending on the mutation conferring the resistance, the virus might develop resistance to oseltamivir but remain susceptible to zanamivir. Laninamivir is a long-acting inhaled neuraminidase inhibitor used for the treatment of seasonal influenza, including infection caused by oseltamivir-resistant virus. It is licensed in Japan and South Korea and is currently in phase III clinical trials in the United States.

Baloxavir (a selective inhibitor of influenza cap-dependent endonuclease that is given as a single oral dose) was approved by the FDA in 2018 for treatment of uncomplicated influenza A and B infections. Baloxavir is given as 40 mg or 80 mg orally once daily depending on weight (the higher dose for persons 80 kg or more) and should be given within the first 48 hours of infection. Its side effects include diarrhea and bronchitis, and to date, its effects in patients older than 65 years or younger than 12 years are not established. Baloxavir’s unique mechanism of action will likely make it useful as part of multidrug therapy for resistant disease. For complicated disease, especially in immunosuppressed patients, the combination of oseltamivir, amantadine, and ribavirin appears to produce faster viral clearance but no definite clinical improvement. Other drugs are being tested in vitro showing potent antiviral activity against multidrug-resistant influenza viruses.

The first class of organosilanes have potent antiviral activity against influenza A viruses that are resistant to amantadine and oseltamivir. Dapivirine, an FDA-approved HIV nonnucleoside reverse transcriptase inhibitor, has broad-spectrum antiviral against multiple strains of influenza A and B viruses. Iminosugars are also under study. Updated advice is available at http://www.cdc.gov/flu/index.htm.

Prognosis

The duration of the uncomplicated illness is 1–7 days, and the prognosis is excellent in healthy, nonelderly adults. Hospitalization typically occurs in those with underlying medical disease, at the extremes of age, and in pregnant women. Most fatalities are due to bacterial pneumonia although exacerbations of other disease processes, in particular cardiac diseases, occur. Pneumonia resulting from influenza has a high mortality rate among pregnant women and persons with a history of rheumatic heart disease. Mortality among adults hospitalized with influenza ranges from 4% to 8%, although higher mortality (greater than 10–15%) may be seen during pandemics and among immunocompromised individuals. At least 64% of pneumonia and influenza deaths occurred among elderly persons in the United States, who comprised only 15% of the population.

If the fever recurs or persists for more than 4 days with productive cough and white cell count over 10,000/mcL, secondary bacterial infection should be suspected. Pneumococcal pneumonia is the most common secondary infection, and staphylococcal pneumonia is the most serious. Major complications include viral myocarditis and viral encephalitis.

Prevention

Annual administration of influenza vaccine is the most effective measure for preventing influenza and its complications. Seasonal influenza vaccines can reduce influenza hospitalizations by an estimated 61%. Vaccination of healthcare workers is associated with decreased mortality among hospitalized patients and those in long-term care facilities. Vaccination prevents influenza illness among pregnant women and their infants during the first months of life.

The ACIP and the American College of Obstetricians and Gynecologists’ Committee recommend annual influenza vaccination for all persons over 6 months of age with no contraindications. Vaccination is emphasized for high-risk groups and their contacts and caregivers.

Several Cochrane database analyses have analyzed the efficacy of the influenza vaccines in select populations. The studied groups include patients with COPD (a documented reduction in exacerbations with inactivated vaccine), the elderly (where vaccination shows some efficacy), adults with cancer (weak evidence, some lower mortality and influenza-related outcomes), healthy adults (established efficacy with inactivated vaccine, but only modest effects in pregnant women and newborns), and healthy children (where both live and inactivated vaccines lower the rate of influenza infections).

Other reviews establish the efficacy and safety of influenza vaccination in patients with rheumatoid arthritis, asthma, or myasthenia gravis, and elderly nursing home patients. The obese have an impaired response to the influenza vaccine.

Multiple influenza vaccine products are licensed in the United States and available from different manufacturers. These include inactivated influenza vaccines (standard- or high-dose, trivalent [IIV3] or quadrivalent [IIV4], adjuvanted or unadjuvanted), recombinant vaccines (trivalent [RIV3] or quadrivalent [RIV4]), and live attenuated influenza vaccine (LAIV4). All trivalent vaccines contain antigens from one strain each of influenza A (H1N1), influenza A (H3N2), and influenza B. Quadrivalent vaccines include an additional influenza B strain. The CDC does not endorse one influenza vaccine product over another, although each influenza vaccine product has different age indications and contraindications. The CDC publishes its annual influenza recommendations in the late summer (www.cdc.gov/mmwr).

LAIV4 use, not recommended by the CDC for the last two seasons due to concerns about its effectiveness against influenza viruses in prior years, is currently considered an acceptable option for groups in whom it is indicated. The efficacy of including the fourth A/Slovenian strain is as yet unknown.

Adults over the age of 18 years, including pregnant women, can receive any influenza vaccine, with few exceptions. Patients 65 years or older should receive a high-dose trivalent inactivated influenza vaccine containing four times more hemagglutinin than standard dose, or Fluad, a trivalent inactivated influenza vaccine that contains an adjuvant (MF59), which enhances the immune response to the vaccine. Fluzone intradermal inactivated quadrivalent vaccine is equally immunogenic and safe but more expensive than the intramuscular vaccine and is not recommended for persons older than 65 years. Adults older than 65 years can use any IIV or RIV intramuscular vaccine; in a large randomized trial, high-dose IIV3 showed superior efficacy over standard-dose IIV3 and may provide better protection. Some data suggest intradermal vaccination is more effective than intramuscular vaccination in the elderly. The herpes zoster vaccine can be safely coadministered with the seasonal influenza vaccines in patients over 50 years of age, with similar immunogenicity.

For patients with cancer, chemotherapeutic regimens containing rituximab show persistent perturbations of B-cell and Ig synthesis, and these modifications decrease humoral responses to the influenza vaccine. Adjuvanted vaccine is efficacious but has resulted in brief disease exacerbation in persons with psoriatic arthritis taking TNF-alpha inhibitors.

Vaccination is contraindicated for persons with a history of severe allergic reaction to influenza. Precautions should be taken if patients report a history of Guillain-Barré syndrome 6 weeks following an influenza vaccine and if patients have a moderate to severe acute illness with or without fever until clinical improvement. Persons with a history of egg allergy with hives only may receive any recommended influenza vaccine. Those with more severe allergic reactions to eggs may receive any recommended vaccine under close observation in a health care facility under the supervision of a provider with experience treating severe allergic reactions. Only the recombinant vaccine is completely egg-free.

Additional vaccine information can be found at http://www.cdc.gov/flu/professionals/vaccination/index.htm.

When antiviral chemoprophylaxis is used, it prevents 70–90% of influenza infections. Chemoprophylaxis is not routinely recommended and is not recommended prior to exposure to prevent development of resistance. Chemoprophylaxis may be considered for persons at increased risk for complications from infection who are exposed to an infected patient within 2 weeks of vaccination, for persons unlikely to respond to vaccination because of immunosuppression after exposure to an infected person, for persons for whom vaccination is contraindicated and who are at high risk for complications after exposure to an infected person, and for prevention of infection in residents of institutions during an outbreak. Alternatively, a person can be monitored closely, and antiviral therapy initiated at the first onset of symptoms after exposure. Initiation of chemoprophylaxis is not recommended more than 48 hours after exposure. Patients taking chemoprophylaxis should seek urgent medical care if an influenza-like illness develops.

Chemoprophylaxis against influenza A and B is accomplished with daily administration of the neuraminidase inhibitors oseltamivir (75 mg/day, oral) or zanamivir (10 mg/day, inhaled) to continue through 7 days after last known exposure. For outbreak control in long-term care facilities and hospitals, a minimum of 2 weeks is recommended, including in vaccinated persons if the seasonal vaccine is not well matched to the circulating strain, to continue until 1 week after identification of the last known case. Zanamivir should not be given as chemoprophylaxis to asthmatic persons, nursing home residents, or children younger than 5 years.

Breakthrough infections with influenza occur with neuraminidase inhibitors (in a study with zanamivir) and with vaccination. The efficacy of chemoprophylaxis is proven for individuals and households but not community settings.

Hand hygiene and surgical facemasks appear to prevent household transmission of influenza virus isolates when implemented within 36 hours of recognition of symptoms in an index patient. Such nonpharmaceutical interventions assist in mitigating the spread of pandemic and interpandemic influenza to nonvaccinated persons. In one study, patients with seasonal H1N1 influenza infection were infectious from 1 day before to about 7 days following illness onset. Children and immunosuppressed persons exhibit prolonged viral shedding and may be infectious longer. Winter school breaks during periods of high influenza transmission appear to decrease rates of visits to primary care practitioners for influenza illness among children and adults.

The data are not currently sufficient to modify statin usage for influenza vaccination. There may be, however, some impaired effectiveness against the H3N2 influenza A component of vaccines from the immunomodulatory effects of statins.

Any hospital patient in whom the infection is suspected should be isolated in an individual room with standard and droplet precautions. CDC guidelines recommend the equivalent of N95 masks for aerosol generating procedures (eg, bronchoscopy, elective intubation, suctioning, administering nebulized medications). For such procedures, an airborne infection isolation room can be used, with air exhausted directly outside or recirculated after filtration by a high efficiency particulate air (HEPA) filter. Strict adherence to hand hygiene with soap and water or an alcohol-based hand sanitizer and immediate removal of gloves and other equipment after contact with respiratory secretions is essential. Precautions should be maintained until 7 days from symptom onset or until 24 hours after symptom resolution, whichever is longer. Postexposure prophylaxis or close monitoring and early treatment should be considered for close contacts of patients who are at high risk for complications of influenza and may be considered for health care personnel, public health workers, or first responders who experienced a recognized, unprotected close contact exposure to a person with influenza virus infection during that person’s infectious period.

A regimen of dose sparing vaccination (to 3.5 mcg) is advocated by some providers to address the extreme shortage of influenza vaccine, particularly in developing world countries, with adequate vaccination against all components except H3N2, where there is reduced seroconversion.

When to Admit

• Limited availability of supporting services.

• Pneumonia or decreased oxygen saturation.

• Changes in mental status.

• Consider with pregnancy.

General Considerations

Zoonotic influenza viruses are distinct from human seasonal influenza viruses and do not easily transmit between humans. In addition, a number of viral genetic changes are required for adaptation to humans. For avian influenza viruses, birds are the natural hosts. Around the world and in North America, avian influenza A outbreaks occur in poultry from time to time (including a 2016 outbreak in Dubois County, Indiana, with avian but no human cases), and the virus has become endemic in poultry in some countries, mostly in Southeast Asia and Egypt. Occasionally, avian influenza viruses may infect humans or other mammals, including domestic cats and dogs. Illness in humans ranges from mild disease to rapid progressive severe disease and death depending on the subtype.

The primary risk factor for human infection is direct or indirect exposure to infected live or dead poultry or contaminated environments, such as live bird markets. Slaughtering and handling carcasses of infected poultry are also risk factors.

The emergence of H5, H7, and H9 avian influenza virus subtypes in humans raises concern that the virus may undergo genetic reassortment or mutations in some of the genes and develop greater human-to-human transmissibility with the potential to produce a global pandemic. All fatal avian influenza virus infections acquire their internal gene segments from H9N2 viruses, the most widespread avian influenza subtype.

Human infections with H5N1 viruses have been reported to WHO from 16 countries, the first report in the Americas was in Canada in 2014, and approximately 60% of the cases have died. Infection with H7N9 avian influenza virus was first reported in China in 2013. Since then, many cases have been reported around the world with an average case fatality rate of 40%. Infections with other H7 avian influenza viruses (H7N2, H7N3, and H7N7) have occurred sporadically around the world. Rare human cases of influenza H9N2 are also reported.

Clinical Findings

A. Symptoms and Signs

Distinguishing avian influenza from regular influenza is difficult. History of exposure to dead or ill birds or live poultry markets in the prior 10 days, recent travel to Southeast Asia or Egypt, or contact with known cases should be investigated. Patients infected by H5N1 or H7N9 avian influenza A viruses have an aggressive clinical course. The symptoms and signs include fever followed by lower respiratory symptoms (cough, dyspnea). Upper respiratory tract symptoms are less common. Gastrointestinal symptoms are reported more frequently in H5N1 infections. Conjunctivitis is reported in influenza H7 infections. Other systems can also be involved leading to neurologic manifestations (encephalopathy, seizure) and liver impairment. Prolonged febrile states and generalized malaise are common. Respiratory failure, multiorgan dysfunction, and septic shock are the usual cause of death. Bacterial superinfections are reported.

For human infections with H7N7 and N9B2 avian influenza virus infections, most cases have been mild with a few cases hospitalized and very few reports of deaths resulting from infection.

B. Laboratory Findings

Current commercial rapid antigen tests are not optimally sensitive or specific for detection of H5N1 influenza and should not be the definitive test for influenza. More sensitive RT-PCR assays are available through many hospitals and state health departments. Diagnostic yield can be improved by early collection of samples, preferably within 7 days of illness onset. Throat swabs or lower respiratory specimens (such as tracheal aspirate or bronchoalveolar lavage fluid) may provide higher yield of detection than nasal swabs. When highly pathogenic strains, such as H5N1 influenza virus infections, are suspected, extreme care in the handling of these samples must be observed during preliminary testing. Positive samples must then be forwarded to the appropriate public health authorities for further investigation (eg, culture) in laboratories with the adequate level of biosafety (level 3).

Treatment

Persons with severe illness and confirmed and probable cases with mild disease should receive treatment as soon as possible. The current first-line recommendation is to use the neuraminidase inhibitor oseltamivir, 75 mg orally twice daily for 5 days administered within 48 hours from onset of illness. Longer courses of therapy (eg, 10 days) should be considered in hospitalized patients with severe illness and persistent viral shedding. Data are lacking for use of inhaled zanamivir or peramivir for severe avian influenza. Overall oseltamivir, by modeling, is associated with a 49% reduction in mortality from H5N1 avian influenza virus infections. As with seasonal influenza, enteric oseltamivir is well absorbed in critically ill persons without gastric stasis, known malabsorption, or gastrointestinal bleeding. Daily intravenous peramivir (600 mg, reduced to 200 mg for kidney dysfunction) for a minimum of 5 days and a maximum of 10 or more days (depending on severity of illness) or zanamivir (10 mg inhaled daily for 10 days) may be considered in such patients. Combination therapy with amantadine or rimantadine (in countries where H5N1 influenza virus A strains are likely to be susceptible to adamantanes) may be considered in patients with pneumonia or progressive disease. Resistance of avian H5N1 influenza strains to amantadine and rimantadine is present in most geographic areas. Resistance to neuraminidase inhibitors (oseltamivir, zanamivir, and peramivir) can occur with H5NA and H7N9 avian–infected patients. Successful treatment with administration of convalescent plasma is reported.

Prevention

The most effective method of prevention is avoidance of exposure. Persons who work with poultry should practice good hand hygiene and use appropriate personal protective equipment. These workers should also be vaccinated against seasonal influenza, since this can reduce the likelihood of coinfection with avian and seasonal influenza. Persons should avoid visiting live poultry markets when able and should avoid contact with ill birds. No risk exists for acquiring avian influenza through the consumption of well-cooked poultry products. The US government bans the importation of poultry from infected areas. Culling of animals has been effective in ending outbreaks of highly pathogenic avian influenza but is difficult with H7-infected poultry because most are asymptomatic. Policies regarding closure of live poultry markets during avian epidemics are controversial.

Persons with exposure should monitor themselves for 10 days after the last known exposure and should seek prompt medical attention if new fever or respiratory symptoms develop. Postexposure prophylaxis is not recommended in persons working with noninfected birds or who used appropriate personal protective equipment while working with infected birds. For persons with exposure to infected persons, postexposure prophylaxis is recommended for household and family members and may be considered for health care personnel with close unprotected contact. Postexposure prophylaxis regimens include 75 mg of oseltamivir orally or 10 mg inhaled zanamivir twice daily for 5 or 10 days from the last known exposure, depending on the length of the exposure. Careful surveillance for human cases and prudent stockpiling of medications with establishment of an infrastructure for dissemination are essential modalities of control. Nonpharmacologic means of control include masks, social distancing, quarantine, travel limitations, and infrastructure development, particularly for emergency departments.

Current vaccines do not provide cross-protection against strains of the H5, H7, and H9 influenza viruses. The United States government has prepandemic stockpiles of adjuvanted H5N1 vaccines and H7N9 vaccines that are not available to the public. The highly diverse genetic nature and the rapid evolution of the avian influenza viruses has resulted in the emergence of viruses that are distinct from stockpiled vaccines. New vaccine development is ongoing to generate vaccines against H7N9 and H5N1 with broadened protection against unmatched strains. Some of these vaccines are under study in preclinical and clinical trials; however, no vaccines are currently commercially available for humans.

Control of infection among the poultry population is key to prevention of human disease. Vaccination of poultry as a sole means of control is ineffective. Closing live poultry markets can interrupt outbreaks. Additional adjunctive measures, such as days where live markets are closed temporarily for disinfection (which can decrease viral loads in surrounding ground water) or separation of land-based poultry from waterfowl, are needed for improved control.

Because the potential for pandemic influenza for many of the new reassortment viruses is not fully known, continued surveillance is essential, and stockpiling of vaccines, adjuvant, and medications (oseltamivir and zanamivir) is warranted at the public health level.

General Considerations

SARS is a respiratory syndrome caused by a unique coronavirus, transmitted through direct or indirect contact of mucous membranes with infectious respiratory droplets. The virus is shed in stools, but the role of fecal-oral transmission is unknown. The natural reservoir appears to be the horseshoe bat (which eats and drops fruits ingested by civets, the earlier presumed reservoir and a likely amplifying host), which can carry a variety of different coronavirus strains.

The earliest cases were traced to a health care worker in Guangdong Province in China in late 2002, with rapid spread thereafter throughout Asia and Canada, considered a consequence of spread through travel. The last cases were reported in 2004. The 2003 outbreak involved 8098 probable cases from 29 countries, with 774 fatalities. Nine additional cases associated with a research laboratory were reported in China in 2004 with no further cases reported since then.

Clinical Findings

A. Symptoms and Signs

SARS is an atypical pneumonia that affects persons in all age groups. Severity ranges from asymptomatic disease to severe respiratory illness. Many subclinical cases probably go undiagnosed. Seasonality, as with influenza, is not established. The incubation period is 2–7 days, and it can be spread to contacts of affected patients for 10 days. The mean time from onset of clinical symptoms to hospital admission is 3–5 days. In all clinical cases, persistent fever is present; chills or rigors (or both), cough, shortness of breath, rales, and rhonchi are the rule. Headache, myalgias, and sore throat are common with watery diarrhea occurring in a subset of patients. Elderly patients may report malaise and delirium, without the typical febrile response.

B. Laboratory Findings and Imaging

Leukopenia (particularly lymphopenia) and low-grade disseminated intravascular coagulation are common. Modest elevations of ALT and creatine kinase are frequently seen. Arterial oxygen saturation less than 95% with associated nonspecific pulmonary infiltrates is evident in 80% of affected individuals. A high-resolution CT scan is abnormal in 67% of patients with initially normal chest radiographs.

Serum serologies, including enzyme immunoassays and fluorescent antibody assays, are available through public health departments at the state level, although seroconversion may not occur until 3 weeks after the onset of symptoms. The detection rates for the virus using conventional RT-PCR are generally low during the first week of illness. Urine, nasopharyngeal aspirate, and stool specimens are positive in 42%, 68%, and 97%, respectively, on day 14 of illness. Viral isolation is technically laborious and time-consuming.

Complications

ARDS, with extensive bilateral consolidation, occurs in about 16% of patients, and about 20–30% of patients require intubation and mechanical ventilation.

Treatment

Severe cases require intensive supportive management. Different agents including, lopinavir/ritonavir, ribavirin, interferon, IVIG, and systemic corticosteroids were used during the 2003 epidemic, but the treatment efficacy of these agents remains inconclusive. In vitro studies with ribavirin show no activity against the virus, and a retrospective analysis of the epidemic in Toronto suggests worse outcomes in patients who received the drug. A 2017 study of alisporivir, a nonimmunosuppressive cyclosporine A analog, alone and in combination with ribavirin, initially showed efficacy in vitro but then did not improve outcomes in a mouse model. A meta-analysis studying the use of Chinese herbs failed to show any efficacy in treating SARS. Studies using monoclonal antibodies are underway based on the response of some patients to immune convalescent sera of convalescent patients.

Prognosis

The overall mortality rate of identified cases is about 14%. Poor prognostic factors include advanced age (mortality rate greater than 50% in those over 65 years of age compared with less than 1% for those under 2 years of age), chronic hepatitis B infection treated with lamivudine, high initial or high peak lactate dehydrogenase concentration, high neutrophil count on presentation, diabetes mellitus, acute kidney disease, and low counts of CD4 and CD8 on presentation.

Prevention

Health care workers engaged in procedures that involve contact with respiratory droplets are at risk. Isolation of high-risk patients is essential, and simple hygienic measures may help reduce transmission.

Control measures include quarantining in the home for high-risk exposed persons and the use of facemasks for preventing hospital-acquired infections. The validity of using such masks in the community remains unsubstantiated. Continual reporting of suspected cases is crucial, as is awareness of restrictions on international travel. The most cautious modalities include monitoring for 10 days after the last potential exposure and confinement of recovering patients for a similar interval. Currently, there are two vaccine candidates in early stages of development. One is the 218-amino acid residue receptor-binding domain of SARS, expressed in yeast, and it is called RBD219-N1. The other is a single-plasmid DNA vaccine encoding the spike (S) glycoprotein of SARS; it has been shown to be safe in a phase I clinical trial (NCT00099463).

General Considerations

Middle East respiratory syndrome (MERS) is a syndrome associated with a coronavirus similar to the cause of severe acute respiratory syndrome (SARS). Patients with MERS have had a history of residence or travel in the Middle East, in particular Saudi Arabia, or contact with such patients. The virus is probably transmitted through direct or indirect contact of mucous membranes with infectious respiratory droplets. The virus is shed in stool, but the role of fecal-oral transmission is unknown. The earliest cases were identified in 2012 in the Kingdom of Saudi Arabia, and 75% of all cases have occurred there. Additional cases have occurred throughout the Middle East, Africa, and Europe, with a reported death rate of 36% (http://www.who.int/emergencies/mers-cov/en/). So-called super-spreaders are often responsible for propagating the pathogen in the early stages of an outbreak.

Person-to-person transmission can occur within families; hospital-associated cases comprise 25% of cases. The median incubation period is 5 days (range, 2–14) with the mean age of 50 (range 9 months to 99 years) and 65% occurring among men. Over 90% of patients have an underlying medical condition, including diabetes mellitus (68%), hypertension (34%), or chronic heart or kidney disease. Those with diabetes, kidney disease, chronic lung disease, or other immunocompromising conditions likely are at highest risk for severe disease.

Camels appear to be the principal reservoir, and several studies show that contact with dromedary herds of camels is greater among cases than controls. Raw camel milk is considered a potential source. Persons who work with camels are more likely to have antibody evidence of past infection.

Clinical Findings

A. Symptoms and Signs

MERS is an acute respiratory syndrome, with the most common symptoms being fever (98%), cough (83%), and dyspnea (72%). Chills and rigors are common (87%). Gastrointestinal symptoms may occur, with diarrhea being most common (26%), followed by nausea and abdominal pain, and may precede respiratory symptoms. Mild and asymptomatic cases are reported.

B. Laboratory Findings and Imaging

Hematologic findings in the largest series to date include thrombocytopenia (36%), lymphopenia (34%), and lymphocytosis (11%). Moderate elevations in lactate dehydrogenase (49%), AST (15%), and ALT (11%) are recognized. Chest radiograph abnormalities are nearly universal and include increased bronchovascular markings, patchy infiltrates or consolidations, interstitial changes, opacities (reticular and nodular) and pleural effusions, and total lung opacification. Ground-glass opacities and consolidation are most commonly seen. The findings mimic those of many other causes of pneumonia.

Serum serologies and RT-PCR are available through CDC (contact information below, on MMWR reference site). Highest viral loads are found in lower respiratory tract specimens, including bronchoalveolar lavage fluid, sputum, and tracheal aspirates. These samples are preferred for diagnosis. The CDC recommends sending lower respiratory tract specimens, nasopharyngeal and oropharyngeal swabs, and serum for testing. In confirmed cases, serial sample collection (perhaps every 2–4 days) from multiple sites is recommended to increase understanding of virus shedding kinetics. In cases in which symptom onset occurred more than 14 days prior and symptoms are ongoing, serum should be sent to the CDC for serologic testing and the above specimens should be sent for RT-PCR.

C. Case Definition

A patient with severe illness shows the following characteristics: fever (38°C, 100.4°F or higher) and pneumonia or ARDS (based on clinical or radiologic evidence); and either history of travel in or near the Arabian Peninsula within 14 days before symptom onset; or close contact with a symptomatic traveler in whom fever and acute respiratory illness (not necessarily pneumonia) developed within 14 days after traveling in or near the Arabian Peninsula (above); or is a member of a cluster of patients with severe acute respiratory illness (eg, fever and pneumonia requiring hospitalization) of unknown etiology in which MERS-CoV is being evaluated, in consultation with state and local health departments.

In milder illness, patients have fever and symptoms of respiratory illness (not necessarily pneumonia; eg, cough, shortness of breath) and history of having close contact with a confirmed MERS case as well as a history of being in a health care facility (as a patient, worker, or visitor) within 14 days of symptom onset in a country or territory within the Arabian Peninsula in which recent health care–associated cases of MERS have been identified.

Of note, fever may not be present in certain patients, including the very young, elderly persons, immunosuppressed individuals, or those taking certain medications.

Complications

Respiratory failure is such a common complication that in a series from Saudi Arabia, 89% of patients required intensive care and mechanical ventilation. Patients with MERS-CoV appear to advance faster to respiratory failure than do those with SARS.

Treatment

Respiratory support is essential. No vaccine or known antiviral therapy exists to combat MERS. Current therapies are adapted from SARS treatments, which include broad-spectrum antibiotics, corticosteroids, interferons, ribavirin, lopinavir-ritonavir, or mycophenolate mofetil. A small retrospective study found improved survival at 14 days with ribavirin and interferon-alpha but not at 28 days. A novel study is underway to investigate the safety of SAB-301, a fully human polyclonal anti-MERS IgG collected from transchromosomic cattle (cattle that produce fully human polyclonal IgG; NCT02788188). Further studies are necessary to evaluate the efficacy of these treatments.

Prognosis

The overall mortality rate of identified cases is about 36%. Advanced age is associated with a poor prognosis.

Prevention

Isolation and quarantine of cases is authorized by CDC. Strict infection control measures are essential as well as care and management of household contacts and hospital workers engaged in the care of patients. Travelers to Saudi Arabia (including the many pilgrims to the holy sites) should practice frequent hand washing and avoid contact with those who have respiratory symptoms. Evaluation of patients with suspect symptoms within 14 days of return from Saudi Arabia is essential. Because healthcare workers engaged in procedures that involve contact with respiratory droplets are at risk, isolation of high-risk patients is essential, as are simple hygienic measures. Control measures, including quarantining in the home for high-risk exposed persons and the use of facemasks for preventing hospital-acquired infections, are important. Assisting public health authorities with case reporting and surveillance is essential.

Camel workers including slaughterhouse and market workers, veterinarians, and racing personnel should wear facial protection and protective clothing and practice good personal hygiene, including frequent hand washing after touching animals. Family members of such personnel should not be exposed to work paraphernalia including clothing and shoes and workers should shower at the site of employment rather than the home. Avoid direct contact with camels (who may be asymptomatic but who can transmit the virus though nasal or ocular discharge, milk, urine, and feces). All infected animals should be kept off the market, including their meat products, and buried or destroyed.

Several MERS vaccines are under development, and most of these are based on MERS-CoV “spike” glycoprotein (NCT03615911). The most recent vaccine to enter phase I clinical trials is a biologic vaccine called ChAdOx1 (NCT03399578).