32-06: Common Viral Respiratory Infections

General Considerations

In late 2019, a novel coronavirus emerged, spreading quickly from 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.

Coronaviruses are a large family of viruses commonly found in humans as well as many other species of animals, including bats, camels, cattle, and cats. There are four genera of coronaviruses, of which only the alphacoronaviruses (coronavirus NL63 and 229E) and the betacoronaviruses affect humans. Like SARS-CoV-1, MERS-CoV, and the human common cold coronaviruses HC43 and HKU1, the SARS-CoV-2 virus is a betacoronavirus. SARS-CoV-1 and MERS-CoV were identified 7 and 17 years, respectively, before SARS-CoV-2 was identified. All coronaviruses likely originated in bats. 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 theory remains under investigation. Antibodies to SARS-CoV-2 have been identified in bats over a 4800 km range in Asia as well as in pangolins at a wildlife checkpoint station in southern Thailand. A WHO investigative team was unable to implicate a specific area of Wuhan as the origin of the outbreak and further geo-epidemiologic studies are needed. A potential role of mink is under study, with mink farms being a secondary and transmitting source of SARS-CoV-2 infections in the Netherlands; mink farms are recognized as potential sources of human infection in seven other European countries and the United States. Transmission to humans does not appear to regularly occur with cats and dogs, who are also secondarily infected by humans although a new coronavirus canine-feline recombinant is reported from a Malaysian patient with pneumonia.

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/map.html).

While SARS-CoV-2 antibodies have been identified in retrospective analysis of US blood donors as early as December 2019, 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 May 21, 2021, global cases surpassed 165 million, including over 3.4 million deaths from 220 countries and territories. The 10 most impacted countries are the United States, India (where high caseloads and deaths and poor reporting suggest that it may be the most impacted country), Brazil, France, Turkey, Russia, the United Kingdom, Italy, Germany, and Spain. The United States alone reports over 33 million cases and over 602,000 deaths. In the United States, the five states with the highest total cases are California, Texas, Florida, New York, and Illinois; the five states with the highest per capita cases are North Dakota, Rhode Island, South Dakota, Iowa, and Utah. The five states with the highest total deaths are California, New York, Texas, Florida, and Pennsylvania. Significant increases in deaths attributable to diabetes and heart disease are also being recorded since the advent of the pandemic. Accordingly, the CDC has identified “hotspot counties” where social vulnerability to COVID-19 is greater. Such counties show a higher proportion of racial and ethnic minorities, a greater density of housing units as well as more crowded housing (persons/room). These data imply that the actual number of deaths caused by COVID-19 may be up to 50% higher than reported. The excess number of deaths reported in October 2020 by the CDC show that nearly 101,000 excess deaths occurred between January 26 and October 3, 2020, with persons between the ages of 20 and 55 years and persons of Hispanic or Latinx heritage being particularly impacted. The average life expectancy for Americans is anticipated to be reduced by 1.13 years for 2020 with 2–3 times greater reduction in Black and Latinx populations than in Whites.

The relatively low prevalence among African countries is being evaluated by studies from Kenya, which show that seroprevalence based on blood donor surveys (as high as 8% in Mombasa) far exceed the rates detected by case-based surveillance. This is, in part, due to the relatively young age of African populations and the consequent paucity of older, vulnerable populations.

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). For the vaccinated as well as the unvaccinated, the CDC continues to recommend wearing a mask if traveling by mass transportation, that all unmasked persons without legitimate exemptions should be denied boarding, and that masks also be worn at all transportation hubs. 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 ongoing surge of cases in the United States. For example, Germany has reclosed its borders (except to France, Austria, and Switzerland) with concern about the impact of new variants and potential reduced vaccine coverage. The fully vaccinated can resume intimate social activities without distancing and masks (although a number of epidemiologists differ regarding this recommendation). Masks remain particularly necessary in the medical setting and schools. Major determinants in the need for masks are the community prevalence of SARS-CoV-2 infection and the percentage of vaccinated individuals.

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 biweekly 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

R₀ is the basic reproductive number signifying the number of contacts infected by one infectious individual. Calculations of R₀ for SARS-CoV-2 have varied but the true R₀ likely lies somewhere between 2 and 3. While the case-fatality rate was far higher with the 2003 SARS-CoV-1 and with the MERS virus, the rate of person-to-person spread and the number of infected cases is much higher with SARS-CoV-2 than with either the SARS or MERS viruses. The current reported rates of SARS-CoV-2 transmission are 5% for close contacts and 10–40% for household contacts. In a meta-analysis of 54 studies encompassing 77,758 COVID-19 cases, the household secondary attack rate was 16.6%. Transmission is particularly efficient within higher-density living facilities and employment settings. The interrelationship between high-risk areas and the surrounding community is evident in CDC reports that correlate nursing home rates with those of the surrounding community.

Presymptomatic spread accounts for many cases, and the viral load for SARS-CoV-2 is highest the day before symptoms develop. 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 incubation period for SARS-CoV-2 ranges from 2 to 24 days with an average of about 5 days. 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). Simply talking (or singing) in close quarters may efficiently spread the virus, as exemplified by a study of a choir in the state of Washington where 52 of 61 choir members became ill in March 2020. 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 health care settings principally for health care providers performing respiratory procedures (such as collecting induced sputum or intubating the patient). While aerosols have been considered a much less likely mode of transmission than respiratory droplets, modeling studies of the Diamond Princess cruise ship outbreak suggest that aerosols may have contributed up to 59% of transmission (with 41% from larger respiratory droplets).

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 persons) can play 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 300,000 cases throughout the globe. 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. In a study from the University of Colorado at Boulder, the role of “supercarriers” is also identified, with just 2% of infected individuals carrying 90% of the virions that circulate within the community. These persons may be superspreaders.

1. COVID-19 in health care personnel

The WHO estimates that about 14%, and in some cases as many as 35%, of all COVID-19 cases are among health care personnel. Early in the pandemic, hospital-related transmission to staff or other patients was reported in 41% of 138 hospitalized patients from Wuhan, China. A later study of more than 3000 symptomatic health care personnel in Seattle, WA, however, showed that the prevalence of positive SARS-CoV-2 tests among symptomatic “frontline” personnel was comparable to that of symptomatic non-frontline staff at about 5%.

As of April 22, 2021, the CDC reported 473,705 COVID-19 cases among health care personnel in the United States; most work in nursing and residential care facilities. Survival data are available for 376,720 of these health care personnel; 1559 have died. Seroprevalence studies suggest that many SARS-CoV-2 cases likely went undetected in health care personnel. Analysis of US COVID-19 hospitalization data by the CDC showed that 6% of adults hospitalized with COVID-19 were health care personnel. Of those hospitalized health care personnel, 36% were in nursing-related occupations and 73% were obese. Regarding severity of disease, 28% of these health care personnel were admitted to an intensive care unit, 16% required invasive mechanical ventilation, and 4% died. Health care personnel who have died of COVID-19 are disproportionately older, male, Asian, Black, and have underlying medical conditions. In a review from Glasgow, household members of patient-facing health care personnel are also shown to be at an increased risk for COVID-19 hospital admissions. The encouraging outcomes among health care workers with documented antibodies is discussed in the Vaccine section below.

2. Risk factors for COVID-19

Symptomatic disease appears to develop in men more often than in women. The coding of the angiotensin-converting enzyme 2 (ACE-2) receptor protein—the receptor used by SARS-CoV-2 to infect host cells—occurs on the X chromosome, and the presence of variants in this protein may explain some of the clinical variation based on sex. The presence of high titers of anti-receptor binding antibodies correlates with lesser disease severity and improved survival.

Children are just as susceptible to SARS-CoV-2 as adults, although they are much less likely to manifest symptoms (the role of preexisting immunity based on exposure to other coronaviruses is important and discussed below). Children have lower concentrations of ACE-2 receptors in lung tissue, which may explain their lower propensity toward severe infection. A study from Mississippi showed that children are more likely to acquire SARS-CoV-2 infection from gatherings, such as weddings, parties, playdates, or funerals, than at childcare or school. Nonetheless, data from early 2020 suggest a greater reduction in the rate of SARS-CoV-2 infection and COVID-19 mortality in states with school closure. As the 2020–21 school year began, 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, although the CDC recommends that schools be reopened in low incidence areas with appropriate safety precautions, including mask wearing by teachers and students and appropriate distancing. On March 19, 2021, the CDC released new guidelines based on a study from Massachusetts. The CDC reduced minimal social distancing recommendations in school classrooms from 6 feet to 3 feet with universal mask wearing and suggested that schools continue to ensure ventilation and filtration of air as economically and technically feasible. A school mitigation program in New Jersey showed that biweekly testing, masking, and distancing (6 feet at time of study), and a Bluetooth-enabled personal contact tracing system was effective in identifying cases as they arose (with only 7% of cases found to be transmitted on campus) and preventing larger outbreaks. The CDC’s easing of mask recommendations for vaccinated adults in social situations does not appear to include school settings.

The modeling of the effects of school closure and the loss of education by one group of Seattle investigators suggest that the net impact of school closures will be a reduction in life expectancy for the impacted children. Accordingly, controls that are effective can ease restrictions. In studies from Duke University, the use of pooled specimens for testing, for example, is proving to be an effective modality of control at the college level. The CDC reports that COVID-19 experience surveys show that children exposed to virtual learning only, rather than in-person experiences, have higher risks related to parental and child mental and emotional health.

With the advent of COVID-19, the CDC reports a fall in immunization rates for the vaccine preventable diseases of childhood. The WHO reports that 117 million children in 37 countries will be missing a measles vaccine in the wake of COVID-19–associated changes in health care. SARS-CoV-2 is associated with unique complications among children, which are discussed below.

US data emphasize that the rate of infection is highest among young and middle-aged adults, with 23.8% of confirmed cases occurring in persons aged 20–29, and 20.6% of cases in those aged 50–64. Data from the southern United States show increases in incidence among persons aged 20–39 precedes the increases among those over age 60 by 4–15 days. COVID-19 mortality rates are distinctly higher over the age of 50. New data show that older individuals often have lower levels of concomitant antibodies to benign cold coronaviruses, and the presence of such antibodies in younger individuals may protect them from symptomatic SARS-CoV-2 infection.

Besides the elderly, SARS-CoV-2 infection is particularly serious in those with 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 a 113% increased risk of hospitalization and a 43% increased risk of death. While the infection shows a predilection for pulmonary tissues, data regarding susceptibility of persons with asthma are unclear. A reduced frequency of asthma exacerbations during the COVID-19 pandemic is not understood and may in part be a consequence of increased anxiety regarding seeking care. Smokers in a British international collaborative study have an increased risk of developing symptomatic COVID-19 infection. In a European multicenter study, sleep deprivation is identified as a risk factor, particularly in health care workers, given that an extra hour of sleep per night lowered the risk of acquiring COVID-19 by 12%.

Preliminary evidence is mixed regarding the risk of SARS-CoV-2 infection in immunosuppressed patients (including those immunosuppressed due to rheumatologic conditions). In one review, the subgroups of cancer patients who had disproportionately high COVID-19 mortality included those 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 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 study of 286 people with HIV in whom SARS-CoV-2 infection developed, 57.3% 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. In a British study, HIV was independently associated with a small increase in mortality among COVID-19 patients, while in a review of the New York State experience of HIV-infected individuals, the rates of diagnosis were similar although mortality was decidedly higher (standardized rate ratio, 1.23) among those with HIV. Black and Latinx individuals were more likely to be diagnosed with COVID-19 than White people with HIV, but hospitalization was more likely to be associated with advancing HIV status regardless of race. Anecdotally, it appears that patients with cancers and immunosuppressive states show clinical recrudescences of COVID-19 infection despite good initial responses. The outpatient experience from South Africa shows that the pandemic lockdown has been associated with a significant reduction in HIV testing and in antiretroviral therapy initiation but not in maintenance.

3. COVID-19 in pregnancy

While pregnancy is not clearly associated with an increased risk of acquisition, pregnant women develop complications at a higher rate than nonpregnant women. SARS-CoV-2–infected pregnant women are less likely to show fever or myalgia than noninfected women. In the United States, approximately 50% of pregnant women hospitalized (for any reason) and tested for SARS-CoV-2 are asymptomatic. Most pregnant women hospitalized with COVID-19 are in their third trimester and are Latinx or Black. British studies document an increased risk of ICU admission and invasive ventilation among pregnant women infected with SARS-CoV-2 compared with pregnant women who are not infected. The risk factors for severe disease among pregnant women, besides other predisposing conditions, are advanced maternal age and high body mass index (BMI). Pregnant and recently pregnant women experience fevers and myalgias with infection less frequently than do nonpregnant women of reproductive age. Preterm birth rate data among pregnant women infected with SARS-CoV-2 are diverse, with data from Canada and Scandinavia failing to show an increase in preterm births or stillbirths, with the confounding factor possibly being the effect of strict lockdown procedures. However, in a large multinational cohort study, COVID-19 during pregnancy is shown to be associated consistently and substantially with higher maternal morbidity and mortality including not only increased preterm births, but also preeclampsia and eclampsia, severe maternal infections, maternal ICU admissions, and maternal and neonatal as well as perinatal complications. Stillbirth data show an increased rate compared with before the pandemic, but the effect of SARS-Co-V-2 in this regard is not clear. Pregnancy losses occur in 2% of women infected with SARS-CoV-2 (69% of whom were asymptomatic), emphasizing the need for continued observation for SARS-CoV-2 among pregnant women and for vaccination.

In utero transmission of SARS-CoV-2 is reported from Italy (2 of 31 pregnancies) and Dallas, Texas, but it appears to be rare. The duration of IgM to coronavirus in potentially infected neonates is much shorter than that seen with other neonatal viral infections. In general, the virus does not appear to be transmitted in breastmilk, but anti-SARS-CoV-2 antibodies are transmitted. Among the vaccinated, antibodies appear in breast milk by 2 weeks after vaccination and persist for 7 weeks. 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).

4. Genetic susceptibility to COVID-19

There are several human genes that may increase an individual’s susceptibility to SARS-CoV-2. Several ACE-2 mutations appear to confer altered host sensitivity to SARS-CoV-2, and these mutations show racial differences. Two specific gene clusters are identified as genetic susceptibility loci for respiratory failure in patients with COVID-19. Gene cluster 3p21.31 encodes a protein, LZTFL1, which is a protein transporter that regulates ciliary action (the second, 9q34.2, is discussed below). Another site of genetic susceptibility exists with the TMPRSS2 gene, which codes for a serine protease and is required for SARS-CoV-2 entry. Expression of TMPRSS2 is increased among Black individuals. Several chemokine-receptor genes (CCR9, CXCR6, and XCR1) are associated with severe disease.

Antibodies to interferon (IFN), including autoantibodies as part of an inborn error of metabolism, are an important area of investigation. Among patients with such antibodies, cases of severe COVID-19 appear disproportionately represented. In a multicenter series based in France and the United States, among 987 patients with severe COVID-19 infection, 101 showed antibodies of diverse types to IFN-I (anti-IFN-omega, -IFN-alpha, both, or three other IFNs). It is thought that a cycle of self-sustaining inflammatory reactions occurs among patients with such functional interferon deficiencies. Similarly, loss of function at 13 loci associated with TLR3- and IFN7-dependent type I IFN immunity are strongly associated with COVID-19 pneumonia. These diverse findings emphasize the role of genetic factors in the development of severe complications from SARS-CoV-2 infection and require confirmation in diverse ethnic and geographic settings. Importantly, despite these genetic findings, the greatest determinants of COVID-19 severity to date are patient factors and not viral genetic factors.

5. SARS-CoV-2 variants

In the spectrum of existing RNA viruses, SARS-CoV-2 mutates relatively infrequently. Nonetheless several SARS-CoV-2 genetic variants have been identified to date. The ability of coronaviruses to develop mutations with deletions accelerates the rate of mutations and many of the new SARS-CoV-2 variants involve deletions. Most SARS-CoV-2 variants now carry the Spike protein amino acid change D614G, though variants with a new Spike protein mutation, G614, are becoming more prevalent, suggesting that variants with G614 may have a fitness advantage. Two specific SARS-CoV-2 variants have become particularly notorious. The UK variant B.1.1.7, named by the WHO as Variant of Concern (VOC)-202012/01 (VOC defined below), was first identified in the United Kingdom in September 2020 and is now the dominant variant in the United Kingdom. It is associated with enhanced transmissibility as well as an increased reproductive number of 0.4 or greater and increased transmissibility of usually 30% but to up to 70%. Secondary attack rates are higher if the index case has VOC-202012/01. In a matched cohort study from the United Kingdom, a 64% higher mortality was seen in patients with VOC-202012/01. This variant has 23 mutations, 8 of which are in the SARS-CoV-2 Spike protein gene, including D614G, the 69-70 deletion, P681H (which facilitates new Spike protein formation) and N501Y. VOC-202012/01 has spread to at least 80 different countries and is broadly circulating in Europe and the United States. The mRNA vaccines appear to be effective against this variant.

The South African variant (which is also known as the B.1.351 variant and contains the D614G, N501Y, K417N, and E484K mutations, among others) was first identified in South Africa in December 2020 and has also been associated with enhanced transmissibility. It has been detected in more than 40 countries, including the United States.

A variant known as P.1 was first identified in December 2020 in Brazilian travelers and is associated with 17 unique mutations (including the N501Y mutation). This variant is also circulating in the United States. A number of mutations are being recognized in the receptor binding domain as well as the N-terminal domain of the Spike protein, including several near the Y144 site. Variants with such mutations are thought to be responsible for surging case numbers in Brazil, complicated by the absence of governmental masking and lockdown policies.

Three B.1.617 lineage variants (B.1.617.1, .2, and .3) are identified and the variant B.1.617.2 is now dominant in several Indian states and, along with low vaccination rates, may be responsible for the rampant nature of the outbreak there. Public Health England in the United Kingdom currently lists this new variant as a Variant of Concern. VOC is defined as a variant with evidence of an increase in transmissibility, more severe disease (eg, increased hospitalizations or deaths), significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnostic detection failures). Currently, there are six such VOCs identified (including B.1.1.7 [mentioned above], P.1 (identified first in Japan and Brazil), B1.351 (identified first in the Republic of South Africa), B.1.427 and 1.429 (both identified first in California). The classification is not uniform and the CDC and WHO continue to list the B.1.617 as a Variant of Interest (one that warrants monitoring with increase in transmissibility but with an unclear impact on immunity or severity).

The transmissibility of variant B.1.617 is 40–50% greater than B.1.1.7, and its impact in India emphasizes the need for vaccine distribution, patent waivers, judicious border controls, continued testing, surveillance, and caution, and continued emphasis on aerosolized ventilation.

The WHO is recommending against the use of geographic descriptors for variants as they may be stigmatizing and these descriptors will be removed from this chapter as possible, although the common usage of such terms limits their full elimination currently. (See comments on Global Initiative on Sharing Avian Influenza Data [GISAID] below).

A variant that originated in Denmark, containing the L452R mutation, is now dominant in California (45% of isolates show this mutation, and the rate is higher in the Los Angeles area); it appears to be more transmissible but not more pathogenic.

Importantly, although variant strains exist, SARS-CoV-2 has a relatively low variation rate, and identified variant strains do not seem to reduce the recognition of the Spike protein epitopes important for antibody neutralization. Early study suggests that the Pfizer-BioNTech vaccine prevents infection with some strains containing the N501Y and E484K mutations. The AstraZeneca, Johnson & Johnson, and Novavax vaccines are less effective against the South Africa and Brazilian variants (see the Vaccine section for specifics).

A global scientific database initiated originally for avian influenza, entitled GISAID, is now a repository for COVID-19 genetic data and can be accessed online at https://www.gisaid.org/. Ten wealthy nations account for 82% of the 1.4 million sequences in the GISAID database. Less than 0.1% of case isolates are reported from major countries such as Brazil, Russia, or India.

Particular needs related to the presence of circulating and potentially increasing numbers of variants include (1) identification of the viral characteristics of SARS-CoV-2 isolated from vaccinated individuals (who may be infected with a recognized or new variant), (2) establishing a national and international repository for identification and surveillance for such variants, (3) maintaining serum repositories of vaccinated individuals for testing against new variants as they emerge, and (4) adjusting the vaccines as new variants emerge.

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 (this is especially important and is described as “smokeless fires” which cannot be extinguished without strong surveillance); (5) increased attention to minority populations, particularly Black and Latinx populations, since they are at high risk for infection and complications (due to socioeconomic risk factors); (6) guidelines for nursing home safety and support including frequent screening of residents and staff and use of antibody testing when daily testing is not feasible; (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; (10) vaccine research, including the identification of markers of protection and the role of mucosal immunity; (11) the assistance of the mental health community in addressing mass nonadherence to medical advice; and (12) establishing means for dealing with the as yet poorly defined long-term complications of COVID-19, including occupational support and rehabilitation services.

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 method of contact tracing, including the use of digital contact procedures, and (4) a documented decline in incidence of COVID-19 for at least 14 days.

A multinational analysis shows the most effective social distancing measures include closure of schools, closure of workplaces, restrictions of mass gatherings, and lockdowns and are associated with a reduction in incidence of COVID-19. These measures appear to be more effective at mitigating SARS-CoV-2 transmission than stay-at-home orders. A factor correlating with infection and mitigated by lockdown is pollen concentrations. An increase in pollen concentration by 100 pollen/m³ is associated with a 4% increase in COVID-19 infection rates.

Regarding community activities, the CDC first 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, avoiding gathering of more than 10 individuals, and cleaning “high touch” surfaces. Close exposures that put someone at risk for acquiring SARS-CoV-2 are defined as 15 minutes or longer within 6 feet over a 24-hour interval based on epidemiologic studies of intermittent exposure by prison personnel in Vermont. Of note, the American Academy of Pediatrics (AAP) strongly advocates for in-person learning. Despite these measures, significant concern exists regarding whether schools should go forward with virtual versus in-person classes.

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. Modeling data of environmental and seasonal elements currently show that a significant variable is exposure to UV radiation, which can lower growth rate of the virus over ensuing weeks. Temperature and humidity do not appear to influence the virus. The effects of UV radiation remain modest, however, in comparison with the impact of physical distancing.

Regarding travel, public health authorities recommend that passengers observe standard physical distancing precautions and undergo judicious pre-departure and post-arrival testing (and provide contact information in case follow up is needed). Masks are mandatory on planes, buses, trains, and other forms of public transportation in the United States. Two reports of military outbreaks on the USS Theodore Roosevelt and among marines on Parris Island raise the possibility that the quarantine period, based on periods of infectivity, may on occasion need to be longer than 2 weeks, and show the importance of molecular virologic and serologic testing in documenting transmissions and outcome.

The mandating of vaccines is deemed important in certain occupational, educational, or social settings where the risk of transmission is high. The widespread use of vaccine mandates in the community, however, is generally not deemed a wise policy with risks of backlash and a multitude of factors associated with transmission in society.

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 typically begin 2–14 days after exposure to SARS-CoV-2. Symptomatic patients may have cough, fever, chills/rigors, or myalgias. The presence of dyspnea is variable, but it is common in severe infection. No one symptom should be used as a discriminant for disease. Less frequent symptoms include rhinitis, pharyngitis, abdominal symptoms such as nausea and diarrhea, headaches, anosmia and cacosmia, and ageusia and cacogeusia. It appears that 15–20% of adults with SARS-CoV-2 infection 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 (especially in infants) 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, ferritin, C-reactive protein, procalcitonin, and interleukin 6 (IL-6). A coagulopathy often is 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

Diagnosis of SARS-CoV-2 infection 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 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 April 20, 2021, the FDA had approved 367 tests and sample collection devices under EUAs, including 269 molecular tests, 75 antibody tests, and 23 antigen tests. These include 49 molecular tests that can be used with home-collected samples.

Importantly, standardization of 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 reading of rapid diagnostic tests can be improved by artificial intelligence programs such as a smartphone application (xRCovid) associated with a 99.3% precision and the ability to remove ambiguity in reading. A rapid antigen assay (BinaxNOW COVID-19 Ag Card) is shown to be useful in nursing homes in identifying contagious indivduals early in the course of infection.

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; one meta-analysis indicated that saliva testing (using nucleic acid amplification testing or NAAT) is as sensitive as nasopharyngeal swabs (also with NAAT), although it may be less sensitive than deeper respiratory tract specimen testing. Saliva testing is useful for detecting asymptomatic individuals with higher viral loads, does not require swabs or viral transport media for collection, and may help improve voluntary screening compliance.

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. To prevent unnecessary quarantines, it is recommended that patients not be re-tested for COVID-19 for about 90 days after their initial infection. There are few instances in which persistent PCR positivity indicates presence of infectious virus: (1) reinfection, which may require advanced testing to distinguish persistence from new infection, and (2) immunosuppressed patients can have prolonged detection of replicative virus (viral shedding).

A number of MIT investigators now document that SARS-CoV-2 RNA can be integrated into the genome of infected cells. Such chimeras are documented in patient-derived tissues, and this may explain why some patients continue to produce viral RNA after recovery from infection. Only subgenomic material is integrated and infectious virus cannot be produced from such sequences. But this finding also suggests that such integration may allow for persistence of immunity or development of autoimmunity and also that the use of extremely sensitive PCR tests may not always reliably reflect the potential of treatment regimens to suppress viral replication.

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. The first test that detects SARS-CoV-2 neutralizing antibodies received an FDA EUA on November 6, 2020. Importantly, because most anti-SARS-CoV-2 antibody 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. Instead, serologic assays can be used to determine if a person has had past SARS-CoV-2 infection and to evaluate population immunity.

D. Imaging

Early in the disease course, neither chest radiographs nor chest CT scans provide diagnostic utility, since both may be normal, and the nonspecific findings overlap with those of many respiratory viral infections. 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. Serial imaging may be useful in identifying the progression of COVID-19–associated pulmonary aspergillosis (discussed below).

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 (eg, tachycardia) tends to be more abrupt with influenza than with COVID-19, and influenza tends to have a shorter duration (7–9 days for influenza versus 12 days for symptomatic COVID-19). Nonetheless, the clinical manifestations overlap to a considerable degree, and it is difficult to use any symptom to distinguish between the two diseases. Influenza immunization is shown in the United Kingdom to be associated with a 15–24% lower odds of severe COIVD-19 outcomes (hospitalization or all-cause mortality). 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.

A disease that can be triggered by or associated with SARS-CoV-2 infection and mimics severe COVID-19 is secondary hemophagocytic lymphohistiocytosis. The features include cytopenia, hyperferritinemia, DIC, ARDS, multiorgan dysfunction, excessive expansion of T lymphocytes, and bone marrow histiocytic hyperplasia with hemophagocytosis with aggregates of interstitial CD8+ lymphocytes. Ferritin levels with COVID-19 do not appear to show a predictive benefit in predicting in whom secondary hemophagocytic lymphohistiocytosis develops.

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.

In a review of 1648 patients admitted to 38 community hospitals in Michigan with COVID-19 infection, the mortality was 24.2%, with another 6.7% dying within 60 days after discharge. The mortality was particularly high (63.5%) for those who had received ICU care. The 60-day rehospitalization rate was 15%. Complications included cardiopulmonary symptoms (in 32% of respondents to a phone survey) and psychiatric problems (reported by 48.7% of respondents). In a larger CDC series (126,137 infected hospitalized patients), the 60-day readmission rate was 9%, and the risk factors for readmission were obesity and other comorbidities associated with increased COVID-19 risk, recent hospitalization, and discharge to a nursing home or use of home health care. In a multicenter VA study of 678 patients with COVID-19 at 132 VA hospitals, the readmission rate was 27% for survivors during the 60 days after discharge—a rate lower than that for survivors of heart failure or pneumonia; although in the immediate 10 days after discharge, this rate was comparatively higher. These data suggest that clinical deterioration usually occurs during a relatively short acute interval post discharge for COVID-19.

One large Chinese study found that the independent predictors of a fatal outcome were age 75 years or greater, a history of 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 particularly strong association exists between acute pancreatitis and SARS-CoV-2 infection. In a prospective international multicenter study based at Newcastle upon Tyne, patients with acute pancreatitis and coexisting SARS-CoV-2 infection are at increased risk for severe pancreatitis, ICU admission, local complications, organ failure, prolonged hospital stay, and higher 30-day mortality.

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). A British predictive scale suggests that eight variables be used at the time of hospitalization to assess the likelihood of death: age, gender, number of comorbidities, respiratory rate, peripheral oxygen saturation, Glasgow coma scale, serum urea level, and C-reactive protein. The scale is available at https://www.bmj.com/content/370/bmj.m3339 (Table 2).

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 lower than those in patients with ARDS and lower than those in patients with bacterial sepsis), 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. Approximately 17–23 days after infection is identified as a critical point when a unique inflammatory response occurs in critically ill patients whose outcomes are fatal.

The most common system involved with complications of severe COVID-19 is pulmonary. Some patients progress to ARDS akin to the coronavirus infections that cause SARS and MERS. In a large Veterans Affairs database, the risk for such progression was 19-fold greater among COVID-19 patients than among influenza patients. COVID-19–related ARDS is so commonly recognized 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.

The spectrum of pulmonary pathology based on a review from Italy shows that the most common findings on postmortem examinations are diffuse alveolar congestion, hyaline membrane formation, pneumocyte 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 vessels used for continuous renal replacement therapy and, less often, to thrombosis of extracorporeal membrane oxygenation–associated vessels. The reported incidence of DVT among ICU patients with COVID-19 infection is 6.3% and the incidence of a major bleed 2.8%. Male sex and high D-dimer levels on day 1 are associated with greater likelihood of thrombotic complications. The presence of antiphospholipid antibodies in over half of patients hospitalized with COVID-19 suggests that autoantibodies may promote coagulation. A component of cell membranes, phosphatidylserine, is thought to have a significant role in the induction of thromboinflammation. Such inflammatory cell remnants are referred to as neutrophil extracellular traps, and preliminary studies suggest that dipyridamole may show both immunomodulatory and antiviral properties and stimulate type I interferon responses. A trial is underway at the University of Michigan to assess the role of dipyridamole in hospitalized COVID-19 patients. Leflunomide, an agent active against rheumatoid arthritis, its metabolite teriflunomide, and brequinar are well-known inhibitors of human dihydroorotate dehydrogenase and may become future therapies for SARS-CoV-2 infection. The benefits and risks of anticoagulants in patients hospitalized with COVID-19 are being actively studied and current management recommendations are available at https://www.covid19treatmentguidelines.nih.gov/antithrombotic-therapy/.

Cardiac involvement is unique among coronaviruses pathogenic for humans, with only rare cases of cardiac complications with MERS or SARS and none with human cold viruses. In a multicenter US cohort study, myocardial infarctions occurred in 14% of patients; survival was infrequent (2.9%) in those with infarction who were older than 80 years. A fulminant myocarditis occurs in about 15% of ICU patients, which can be further complicated by heart failure, cardiac arrhythmias, acute coronary syndrome, stress cardiomyopathy (tako-tsubo syndrome), cardiac aneurysms, vasculitis, and sudden death. Increased plasma ACE-2 concentration is associated with an increased risk of major cardiovascular events. In the small percentage of children in whom severe COVID-19 develops (or who have multisystem inflammatory syndrome [MIS-C], see further description below), cardiac complications are common enough that the AAP recommends treating these children as though they have myocarditis, so they should be restricted from exercise and sports participation for 3–6 months.

Acute kidney injury occurs in approximately 12% of patients hospitalized with COVID-19. Of these, more than 20% require renal replacement therapy, which portends mortality (89–100%). Additionally, a collapsing glomerulopathy has been associated with COVID-19, termed “COVID-19–associated nephropathy” or COVAN, which specifically affects individuals with polymorphisms in the apolipoprotein L1 (APOL1) gene.

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 to a comatose state, Guillain-Barré syndrome, and acute hemorrhagic necrotizing encephalopathy are reported. The presence of such neurologic manifestations are associated with higher in-hospital mortality.

While the presence of ACE receptors in brain tissue supports direct CNS involvement, actual isolation of the virus from the CNS is not consistent, and the CNS damage may occur via indirect mechanisms. The NIH has established a databank/biobank to document and track neurologic involvement in COVID-19 infection (the NeuroCOVID Project).

Acute psychiatric diagnoses occurring at increased frequency include anxiety, depression, substance use disorder, and posttraumatic stress disorders. The CDC currently reports that either anxiety or depression have increased in prevalence from 36.4% to 41.5% with highest rates among adults 18–29 and those with less than high school education. Psychoses otherwise do not appear at increased rates, although eventual development of psychosis among people with no prior or family history is reported among some patients after COVID-19. Suicidal behavior appears to occur in about 6% of patients, and this rate is the same among health care professionals. Data from Australia suggest that the suicide rate is not impacted by COVID-19. 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). Opioid use disorders are increasing because of the outbreak and are attendant with a decrease in outpatient visits for management and a possible decrease in access to naloxone.

Skin manifestations are diverse and on occasion the presenting sign. Approximately 5–20% of patients with COVID-19 are found to have dermatologic symptoms. One review of patients with COVID-19 identified acral lesions as the most common rash type, followed by erythematous maculopapular rashes, vesicular rashes, urticarial rashes, and many others. Such skin manifestations typically last no longer than 2 weeks, although rarely COVID-19–related rashes are reported to last 2–4 weeks.

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.

A hyperinflammatory syndrome is akin to atypical Kawasaki disease (KD) and is 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 (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. MIS-C can be distinguished from KD by the T cell subsets involved (CD4+ higher in KD) and the levels of IL-17A (higher in KD). Inflammatory complications weeks after mild or asymptomatic SARS-CoV-2 infection in adults, a syndrome termed MIS-A, are increasingly recognized. A retrospective French analysis shows a better response (faster resolution of fever and a lower rate of treatment failure) with the use of methylprednisolone (at varying doses) with intravenous gamma globulin (IVIG) at 2 g/kg, compared with IVIG alone.

Regarding infectious complications, one systematic review found that approximately 8% of patients hospitalized with COVID-19 have bacterial coinfection or secondary infection. The higher complication rates among patients who have COVID-19 compared with patients who have influenza include risks for pneumonia, ventilator dependence, pneumothorax, acute myocarditis, stroke, cardiogenic shock, sepsis, and pressure injuries but not for acute myocardial infarctions, unstable angina, or heart failure. As has been well-documented in influenza patients, a unique form of pulmonary aspergillosis, referred to as COVID-19–associated pulmonary aspergillosis (CAPA), is recognized to increase the morbidity and mortality of patients infected with SARS-CoV-2. However, due to the difficulty distinguishing airway colonization with Aspergillus from CAPA, debate about many features of this entity remains. CAPA usually responds to voriconazole or isavuconazonium, although in some azole-resistant cases, amphotericin is needed. Diagnosis is facilitated by galactomannan assays when available. Clinicians in India are currently reporting an increased incidence of mucormycosis, and public health advisories caution against the use of smearing of cow dung and urine over the bodies of COVID-19 patients.

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-day postoperative mortality was 23.8%.

A host of endocrine abnormalities are reported including diabetic ketoacidosis, subacute thyroiditis with clinical thyrotoxicosis, and new-onset Graves disease, or autoimmune (Hashimoto) thyroiditis. In addition, malnutrition occurs in up to 45% of patients with COVID-19 and significant deficits in a variety of quality of life and functional capacity measures are reported 6 months after infection.

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 that timeframe. Such prolonged recovery times will affect decisions regarding return to work and suggests that a consensus be worked out between the clinician and the patient.

The long-term sequelae of COVID-19 are being described; a diversity of syndromes appears to characterize these long-term sequelae and are in the process of further definition. A compilation of nine studies of post-acute COVID-19 syndrome from the United States, Europe, and China shows that a male preponderance (52–67%) and an age range veered toward upper middle age (mean, 45–63.2, median 56–70.5, not all studies giving both values), with the most common symptoms being fatigue and dyspnea. More recently, a prospective cohort of 507 symptomatic outpatients undergoing SARS-CoV-2 PCR testing in Switzerland indicated that 53% of patients with SARS-CoV-2 infection reported persistent symptoms between 3 and 10 months after diagnosis compared to 37% of patients who tested negative. About 20% of patients who tested positive consulted a clinician for persistent symptoms, and the most common symptoms were fatigue (32%), smell or taste disorder (22%), dyspnea (16%), headache (12%), memory impairment (11%), hair loss (10%), and sleep disorder (10%). Among patients who tested positive for SARS-CoV-2, female sex (aOR = 1.7) and overweight/obesity (aOR = 1.7) predicted persistent symptoms. The British refer to such complications as “long COVID” and attest to a relapsing and remitting nature to the entity as well as a multisystem nature with pulmonary, dermatologic, gastrointestinal, and neurologic symptoms all variably involved. A classification system based on time of exposure and severity of disease is emerging in the literature. The most common neurologic symptoms among long-term patients are cognitive dysfunction, headache, and paresthesias.

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. In one series, multiple sclerosis patients who had received recent anti-CD20 therapy or methylprednisolone were at increased risk for severe COVID-19 infection with increased risk magnitudes of 2.4 and 5.2, respectively. Commercial laboratories are available to assess for antibody levels in patients with potentially reduced levels. The role of monoclonal antibodies in such patients is under study.

Other reported delays exist in emergency care and cardiac surgery. When elective surgery is performed, it should be delayed to about 7 weeks after acute COVID-19 infection since the mortality rate declines from 9.1% in the first 2 weeks following infection to 2% after 7 weeks have passed following acute infection. Similarly, with infectious diseases, malaria patients are anticipated to suffer disruptions of care and an increase in mortality, nearly double in some models, is predicted.

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 the 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, and the later inflammatory phase should be managed with anti-inflammatory agents. Many medications for the treatment of COVID-19 are being evaluated in clinical trials. The medications with most promising data to date, at least for severe disease, are remdesivir, dexamethasone, tocilizumab, and baricitinib.

A. RNA Polymerase Inhibitors

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. Remdesivir was approved by the FDA in the United States on October 22, 2020 for the treatment of COVID-19 requiring hospitalization. It was the first medication approved by the FDA for the treatment of COVID-19; monoclonal antibodies are also now approved under limited circumstances and are listed below.

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 granted EUA by the FDA 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. Remdesivir 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 for patients who are hypoxic (oxygen saturation 94% or less on room air) requiring supplemental oxygen. Patients requiring mechanical ventilation or ECMO could be given a 10-day course of remdesivir. However, the WHO, in reporting its interim Solidarity Trial results, is not recommending use of remdesivir in hospitalized patients due to the costs and feasibility of administration in much of the world as well as the insufficient data in multiple studies; remdesivir has shown no effect on outcomes, including survival, need for mechanical ventilation, and time to clinical improvement. 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. Remdesivir given with the Janus kinase inhibitor baricitinib is associated with a reduced recovery time and accelerated clinical improvement, especially in patients receiving high-flow oxygen or noninvasive ventilation, and the combination shows fewer adverse effects than with remdesivir alone. Favipiravir is an additional RdRp inhibitor being studied for COVID-19 treatment.

B. Corticosteroids

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 recommended only for treatment of patients with severe disease (eg, 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, preferably 10 days or less. Patients without hypoxia and who do not require mechanical ventilation or ECMO should not be given corticosteroids. If dexamethasone is not available, the NIH COVID-19 treatment guidelines do recommend using alternative glucocorticoids, including prednisone, methylprednisolone, or hydrocortisone.

A trial in Germany using a cytokine adsorber among patients undergoing ECMO was not associated with any fall in serum IL-6 levels and was associated with a reduced 30-day survival.

C. IL-6 Receptor Inhibitors

Treatments targeting the SARS-CoV-2–induced immune response, such as IL-6 receptor inhibitors (eg, tocilizumab and sarilumab) were initially used for treatment of severe COVID-19 using the rationale that high levels of IL-6 are a key component of the “cytokine storm” associated with advanced SARS-CoV-2 infection. 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 with tocilizumab. In a randomized, open label trial in Brazil, among patients with severe or critical COVID-19 infection, tocilizumab plus standard care was not superior to standard care at 156 days and the combination appeared to increase mortality. Similar negative results have been found with the use of sarilumab, an analog of tocilizumab, where there have been no differences in clinical outcomes during its phase 3 trials. Tocilizumab is being studied in one arm of the Recovery trial, and the REMDACTA trial is evaluating tocilizumab in combination with remdesivir. The combination of tocilizumab and dexamethasone has a survival benefit among patients with rapid respiratory decompensation due to COVID-19; thus, adding tocilizumab to dexamethasone therapy is recommended for patients with rapidly increasing respiratory needs and those within 24 hours of admission to the ICU.

D. Interferon Therapies

With the recognition that type I IFN responses are impaired in COVID-19, a variety of trials are underway to evaluate IFN treatments in COVID-19 patients. A Canadian study of pegylated lambda interferon given subcutaneously in mild-to-moderate disease shows a decrease in viral load and an increase in the virus clearance by day 7. Thus, pegylated lambda interferon is thought to have potential activity in preventing community transmission by lowering viral loads. Inhaled IFN-beta-1b (Synairgen plc® in the United Kingdom), was found to shorten recovery time and 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 IFN-beta-1b with remdesivir as a subcutaneous preparation.

E. Convalescent Plasma

Convalescent plasma (plasma from the blood of patients who have recovered from COVID-19) is being given to patients in many centers, though data on its efficacy are mixed. A 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. Recent studies have found that hospitalized patients who receive high-titer convalescent plasma have a lower 30-day mortality rate when compared to patients receiving low-titer convalescent plasma. Additionally, in a study of older adults treated within 3 days of symptom onset, COVID-19 progression occurred in significantly fewer patients who received high-titer convalescent plasma (16%) compared to those in the placebo arm (31%). In a retrospective review of patients who received convalescent plasma a mean of 4 days after diagnosis, those who received higher titer antibodies had a lower 30-day mortality, although this effect was not seen among patients on a ventilator. The significant variables in these studies include the stage of disease, the timing of administration, and underlying clinical demographics. The FDA issued an EUA for convalescent plasma on August 23, 2020; however, because overall randomized clinical trial data show no significant benefits of convalescent plasma independent of antibody titers, neither the IDSA nor the NIH recommend its use. Additionally, the FDA EUA for convalescent plasma was revised on February 4, 2021 to reflect that it covers only high-titer convalescent plasma. UK review of patients treated with high-titer convalescent anti-SARS-CoV-2 antibodies, showed no improvement in 28-day survival or in progression to mechanical ventilation or death among those not receiving invasive mechanical ventilation at the time of randomization.

F. SARS-CoV-2 Directed Monoclonal Antibody Therapies

Monoclonal antibody therapies share (and amplify) the disadvantages of convalescent plasma therapy, namely that their production is complex and expensive and usually requires intravenous administration (although subcutaneous administration is being used in some locales). Additionally, viral mutations that escape the effect of monoclonal antibodies are already identified in circulating SARS-CoV-2 variants. Continued surveillance for such mutations with testing of monoclonal antibodies against new viral variants at central repositories is needed. Even with these caveats, certain monoclonal antibody combination therapies (specifically, bamlanivimab plus etesevimab or casirivimab plus imdevimab) are thought to have clinical benefit during early disease, and thus are recommended for outpatients with mild to moderate COVID-19 who are at high risk for disease progression.

Several individual SARS-CoV-2 monoclonal neutralizing antibody candidates are being developed for clinical use. The monoclonal antibody combination casirivimab/imdevimab made by Regeneron Pharmaceuticals (also known as REGEN-COV2) is given intravenously and has received FDA EUA for treatment of COVID-19 patients with mild to moderate disease who are at risk for progression to severe disease. The recommendations are based on improvements in viral load at 7 days, although data on percentages requiring medically attended visits showed a difference (15% vs 6%, placebo versus the two combined groups with different dosage monoclonal antibody combinations, decrease in hospitalization and deaths from the 3–5% to the 1% range). The regimen should not be given to patients requiring oxygen or inpatient hospitalization due to safety concerns and an unfavorable risk/benefit profile among such patients. The casirivimab/imdevimab combination currently does appear to work against most variants. The current FDA EUA permits the use of REGEN-COV2 in confirmed cases of COVID-19 among patients older than 12 years of age and weighting at least 40 kg with a high risk of progression to severe COVID-19, with risk factors defined at the FDA’swebsite (https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs). The agents should not be used for hospitalized patients, for those who require oxygen, or who require an increase in baseline oxygen flow rate due to non-COVID-19–related comorbidity.

Eli Lilly in conjunction with Canadian firm AbCellera Biologics reported early success with bamlanivimab, a single agent IgG₁ monoclonal antibody (earlier known as LY-CoV555), which binds to the Spike protein and blocks attachment to the main ACE-2 receptor. In their phase 2 interim analysis, bamlanivimab appeared to accelerate the natural decline in viral load by day 11. Bamlanivimab use was stopped by Eli Lilly in hospitalized patients, however, out of concern that the medication was unlikely to help, and currently its use as a monotherapy is not recommended. Bamlanivimab combined with etesevimab, a second anti-Spike monoclonal antibody which binds at a different site, shows a better response than bamlanivimab alone, with a statistically significant different viral load reduction. This combination was initially studied in China (Junshi Biosciences). In the United States, the FDA has granted an EUA for the combination in the treatment of mild to moderate COVID-19 in adults and pediatric patients 12 years of age and older who weigh at least 40 kg, has a positive SARS-CoV-2 assay, and are deemed at high risk for progression to severe disease and/or hospitalization (a list of conditions placing one at risk are available at the FDA’s website). The IDSA accordingly limits the recommendations of the use of such monoclonal antibodies and emphasizes that they not be given to either hospitalized patients or those requiring oxygen therapy or those who require increases in oxygen basal flow rates as described above for REGEN-COV2. The complex administrative regimen for this combination is also available at the FDA’s website. The bamlanivimab and bamlanivimab/etesevimab monoclonal antibodies do not work against the new variants, except the B.1.1.7 variant.

New developments in monoclonal antibodies include a cocktail of two anti-SARS-CoV-2 monoclonal antibodies by AstraZeneca called AZD7442 and a broad-spectrum monoclonal antibody by Adagio Therapeutics, Inc, called ADG-2, with action against SARS-related coronaviruses. The monoclonal antibody mavrilimumab (against the granulocyte-macrophage colony stimulating factor [GM-CSF]) failed to show favorable outcome data (off oxygen therapy at day 14) among patients hospitalized with pneumonia or systemic hyperinflammation not requiring ventilation.

A current multicenter study, ACTIV-2/A5401 is assessing the relative value of monoclonal antibodies (intravenous and intramuscular), bovine-derived monoclonal antibodies, oral camostat (see below), and beta-1-interferon (see below) in preventing hospitalization and death from COVID-19. The website for further information is https://www.riseabovecovid.org/en/.

“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. Further development of multivalent nanobodies is ongoing in Germany.

G. Therapies Discarded or Early in Development

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 IFN-beta-1a, and [4] hydroxychloroquine). 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 in over 10,000 patients with rheumatic diseases was not associated with a protective effect against the development of SARS-CoV-2 infection. In a Spanish review of asymptomatic healthy contacts of people confirmed to have SARS-CoV-2 infections, postexposure prophylaxis with hydroxychloroquine did not prevent either SARS-CoV-2 infection or symptomatic COVID-19 disease. 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, in contrast to the other studies which were double-blinded and placebo controlled. The FDA reports a higher-than-expected incidence in adverse drug reactions with the use of these agents. Accordingly, the use of these agents for the treatment of SARS-CoV-2 infections should be avoided or limited to clinical trials.

Medications traditionally used as antiretroviral therapies have been investigated for use in SARS-CoV-2 treatment. Lopinavir, ritonavir, and nelfinavir are three such medications that potentially inhibit the SARS-CoV-2 C30 endopeptidase. The 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 IFN-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 antiretroviral therapies for COVID-19.

Ivermectin, an antiparasitic medication, has been used extensively for COVID-19 in Latin America. In vitro studies of ivermectin at doses much higher than those deemed safe in humans have failed to reduce SARS-CoV-2 viral load. In a study from Barcelona, however, the agent did improve anosmia and cough with a tendency to reduce viral loads. Oral disease does not attain the levels needed for anti-COVID-19 activity and the high doses used in veterinary formulations are toxic and associated with overdoses. Accordingly the IDSA, the Panamerican Health Organization (PAHO) and the WHO all 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 underway; in the meantime it should only be used as part of a clinical trial.

The human interleukin-1 receptor antagonist anakinra was studied in patients with mild-to-moderate pneumonia via a large French randomized controlled trial without any significant change in outcome.

Because SARS-CoV-2 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 1 and 2 trials for COVID-19 in Denmark. A related TMPRSS2 inhibitor, nafamostat, is being studied in Germany.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been thought not to have an impact on disease; however, a cohort study using a national sample of US patients showed that treatment with ACE inhibitors, as well as statins and calcium channel blockers, was associated with a decreased risk of death (the risk was increased in this same series with azithromycin and hydroxychloroquine use). Also, a study of patients on ACE inhibitors or ARBs shows no significant difference in days alive and out of the hospital among those who discontinued versus continued these medications. It is thus 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 class of antihypertensive agents. The potential role of a preventive effect with ACE inhibitors has been postulated.

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.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, though a Brazilian randomized control trial evaluating 240 hospitalized patients with moderate to severe COVID-19 did not significantly reduce hospital length of stay in patients who received a single dose of 200,000 international units of vitamin D₃ compared to placebo. Vitamin D does not reduce COVID severity, mortality, ICU care, length of stay, the need for an ICU, or prevent COVID transmission to household contacts. It is not recommended among current NIH guidelines for therapy. An immune boosting natural product with some legitimacy in controlling inflammation for respiratory infections in saffron (Crocus sativas) although its exact role in SARS-CoV-2 infection remains under study.

Additional agents under investigation include aspirin (which was added as an arm of the Recovery trial on November 6, 2020), colchicine (an additional arm of the Recovery trial; notably colchicine alone does not have significant activity against SARS-CoV-2 and is associated in one study with an increase in pulmonary emboli), dimethyl fumarate (an additional arm of the Recovery trial), leronlimab (PRO 140; a CCR5 antagonist), galidesivir (BCX4430; a nucleoside RNA polymerase inhibitor), baricitinib (a Janus kinase [JAK] inhibitor being studied in combination with remdesivir during the second iteration of the ACTT [ACTT 2]) (see above), Bruton tyrosine kinase (BTK) inhibitors, selective serotonin reuptake inhibitors (eg, fluvoxamine was found to bind to the sigma-1 receptor on immune cells leading to reduced production of inflammatory cytokines, but data to date are insufficient to support its use in treating COVID-19), the transmembrane receptor protein neuropilin-1 (recently identified as another potential mode of inhibition in the binding of SARS-CoV-2 to cells), ribonucleoside analog inhibitor MK-4482/EIDD-2801 (molnupiravir; shown to both treat and block SARS-CoV-2 transmission in an animal model), dalbavancin (a lipoglycopeptide antibiotic that directly binds to ACE-2 receptors); small interfering RNA molecules (the nonstructural protein 1, NSP1, of COVID competes with mRNA by inhibiting translation), and plitidepsin (an elongation factor host inhibitor that interacts with several coronaviruses and marketed in Europe for acute lymphoblastic leukemia therapy and Australia for plasma cell myeloma therapy and active in vivo in a mouse model). Importantly, many of these agents target host factors rather than viral proteins and thus the likelihood of resistance developing is lower.

VTE prophylaxis for COVID-19 patients is indicated and numerous guidelines are available 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. The final answers are not available regarding anticoagulation and in an emulation study of critically ill adults with COVID-19 infection, early anticoagulation did not affect survival. On the other hand, a US VA-based national cohort study of 4297 patients showed a decreased 30-day mortality rate and no risk of serious bleeding events with the use of prophylactic anticoagulation among patients admitted with COVID-19 infection. Dipyridamole is being studied as a means to control the release of neutrophil extracellular traps associated with infection.

Rarely, patients with severe COVID-19 undergo curative lung transplantation.

Prevention

A. Personal and Public Health Measures

The recommended precautions 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 health care personnel, wearing an impermeable mask [eg, N95 mask] and face shield if exposure to patients with cough and/or respiratory secretions is anticipated), practicing social distancing of at least 6 feet when in public, and isolating cases (in particular, removing infected patients from long-term-care facilities, such as nursing homes, and transportation structures, such as cruise ships). Using eye protection (including wearing eyeglasses daily) provides protection from SARS-CoV-2 as well.

Masking likely reduces the viral inoculum to which the mask-wearer is exposed but more importantly prevents transmission of the virus to others if the wearer is infected. For health care personnel, correctly sized but expired N95 masks with intact elastic bands and masks 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%. In Wuhan, the strict use of personal protective equipment (PPE) among 420 health care personnel was associated with no new cases of COVID-19 and no seropositive 2 weeks after potential exposures. A study of mandatory masking in Jena, Germany concluded that masks reduced the infection rate by 15–75% (mean, 47%) over a 20-day interval. Similarly, CDC data from 10 states with mask mandates showed a decline in weekly COVID-19 hospitalization rates by up to 5.5% among adults aged 18–64 years compared with growth rates preceding such mandates. A review of university mandates by CDC describes the potential of direct observation and rapid feedback programs for mandating mask wearing. This is especially important if the wearer is infected. Cloth masks, if worn correctly, filter 65–85% of viral particles.

When masking is needed, the CDC has recommended double masking with a cloth mask covering a medical procedure mask and modifying the medical procedure mask by knotting its ear loops at the mask edges and then tucking in and flattening the extra material close to the face (a so-called “knotted and tucked mask,” with video instructions available here: https://www.youtube.com/watch?v=UANi8Cc71A0&feature=youtu.be). A cloth mask over a filter mask is considered one of the more comfortable options.

For social activities among vaccinated individuals, an easing of masking precautions can be recommended. Masking is still needed for medical and educational settings and is still recommended for transportation settings.

B. Vaccines

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, nonreplicating vectors, protein subunits, and replicating viral vectors). Over 300 vaccines are under development, including at least 90 vaccines in various stages of clinical evaluation and another 184 in active animal studies (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).

As of May 20, 2021, 15 vaccines have received at least preliminary regulatory authorization and begun to be distributed in one or more countries. These vaccines are listed in eTable 32–1.

Notably, one concern for both the Pfizer and Moderna mRNA vaccines is the need for a cold chain; the Pfizer vaccine requires storage at –70°C and the Moderna vaccine can be stored at 2°C to 8°C for up to 30 days after thawing from frozen (between –25°C and –15°C). Most other vaccines are kept at 4°C. The equipment for a cold chain, especially with the current Pfizer product, is particularly burdensome for the developing world. The Moderna vaccine can be maintained for a month if stored at appropriately cold temperatures. The available adenovirus vectored vaccines generally have more flexible storage conditions.

Distribution of the Pfizer and Moderna vaccines began in the United States in December 2020. The first groups allowed to receive the vaccine were health care workers (including administrators and support personnel) followed by those living or working in closed populations (nursing homes, prisons, packing plants, schools, Native American populations, and populations with psychiatric illness). The criteria used to explain the ethics of distribution include those at risk for acquiring infection from their environment (the above groups), those who are at greatest risk for morbidity and mortality (the elderly, nursing home residents, those with COVID-19 risk factors), those required to provide essential tasks (frontline workers), and those who are at high risk for transmission to others. As of April 2021 all people 16 years and older without contraindications are eligible to be vaccinated free of charge in the United States. Those with prior infection should still undergo vaccination since immune responses to mild or moderate infections are not always durable (although those with prior infection mount a stronger response to vaccination).

Because eggs are not used in production, a history of egg allergy is not a contraindication for receiving the vaccine.Commonly reported side effects post-mRNA vaccine administration include nausea, low-grade fevers, injection site soreness (shown for the Moderna vaccine to be a local delayed hypersensitivity reaction and not a contraindication for further vaccination), headaches (4.5%, both vaccines), and fatigue (as high as 9.7% with the Moderna vaccine, 3.8% with the Pfizer vaccine). Local injection site reactions, fatigue, headache, fever, and muscle pains also are common for the AstraZeneca and Johnson & Johnson vaccines. Concomitant administration of anti-inflammatory agents, such as paracetamol or ibuprofen, is not recommended because antibody responses may be blunted. Nonetheless, British data find that ibuprofen decreases pulmonary edema and may reduce the severity of ARDS. NSAID use in a multicenter British study was not associated with higher mortality or increased severity of COVID-19. Thus, the final recommendations for NSAID usage require further analysis.

When Pfizer and AstraZeneca vaccines were mixed for the two doses, the incidence of mild side effects (fever, chills, aches) was more common than when a single agent was used for both doses. Delaying the second dose in one model is associated with reduced cumulative mortality in those under age 65.

A small number of cases of Bell palsy are reported among recipients of the mRNA vaccines, especially the Moderna vaccine, and a Norwegian report cites an increase in death in the elderly after vaccination. Both findings require firm establishment of the background rates.

Rare side effects associated with the adenovirus-vectored vaccines, specifically the AstraZeneca vaccine and the Johnson & Johnson vaccine, include thrombotic and hemorrhagic events and thrombocytopenia. Several European countries report such complications among AstraZeneca vaccine recipients, including cerebral venous thrombosis, although the findings do not necessarily meet the epidemiologic requirement that the rate is higher than expected. Use of the vaccine was suspended temporarily in early 2021 but has since resumed. AstraZeneca considers the rate of thrombotic complications from their surveillance no greater than expected, and the European Medicines Agency concurs that the vaccine is safe. As of April 30, 2021, 12 cases of vaccine-associated thrombotic disease had been reported in Johnson & Johnson vaccine recipients. Johnson & Johnson vaccine administration was paused in the United Kingdom and the United States in April 2021 while this complication was investigated; however, it has since resumed in both countries (on April 23, 2021, the CDC recommended that the FDA include a warning label for women under the age of 50).

Characteristics of cases include nearly uniform presence of heparin-platelet factor 4, and thrombocytopenia, and a predilection for cerebral venous sinus thrombosis but also a lower rate of intracerebral hemorrhages. The outcomes are highly variable ranging from complete recover to persistent ICU or non-ICU care to recovery (with numbers too small to definitively make individual prognostic assessments at this time).

One theory is that adenovirus-vectored vaccines may trigger autoimmune phenomena directed at platelet activators, which may render recipients of these types of vaccines unusually susceptible to thrombotic disease. The clinical syndrome of vaccine associated thrombotic disease in the setting of thrombocytopenia has been termed “vaccine-induced immune thrombotic thrombocytopenia” (VITT).

Continued surveillance for vaccine-associated complications is important. The CDC has developed a smartphone-based post-vaccination monitoring system called v-safe. Many in the medical community remember the untoward effects of past vaccines, such as Guillain-Barré syndrome associated with the influenza H1N1 [“swine flu”] vaccine in 1976. Such complications have occurred at rates lower (1 per 100,000) than that detectable with current surveillance of early marketed vaccines (detecting major adverse events at 1 per 20,000). The full safety of current vaccines will not be established until a few million doses are administered. The elderly reportedly showed good responses to both mRNA vaccines. Documentation of vaccine serostatus using current antibody technology prior to vaccination is not recommended.

The CDC reports that as of May 19, 2021, at least 48% of the United States population (159 million people) have received one dose and 38% (125 million) are considered fully vaccinated. Considerable regional variation exists with the highest full vaccination rates in New England and the lowest in the South.

Globally, Israel has been particularly successful in vaccination, a consequence of good supplies, a strong health infrastructure, and a low rate of vaccine hesitancy. According to one report, 2 months after the start of Israel’s Pfizer vaccination campaign, the number of cases declined by 77%, the percentage of positive tests declined by 45%, and the number of hospitalizations declined by 68%. The European nations are having difficulty with vaccine distribution in part complicated by the temporary pause in AstraZeneca vaccine use because of safety concerns (see above) and a surge in the purchase and use of the Pfizer BioNTech vaccine is reported.

Duration of protection post-SARS-CoV-2 vaccination has not been fully elucidated. One study of 33 people who had received both doses of the Moderna vaccine observed that vaccine-induced antibody activity remained high in all study participants at 6 months post-vaccination.

A comparison of vaccine efficacy nonetheless is complicated by the differences in vaccines, types of placebos, underlying disease incidence and study populations, durations of exposures, endpoints, and statistical methods. A table is available in an attempt to compare relative risk reduction and number needed to vaccinate to prevent one case of COVID-19, assessing the Pfizer/BioNTech, Moderna, Gamaleya, Johnson & Johnson, and AstraZeneca-Oxford vaccines and is available in the reference by Olliaro below. A community setting review comparing the Pfizer/BioNTech and AstraZeneca/Oxford vaccines showed that both had side effects at rates lower than in phase 3 trials and both decreased the risk of SARS-CoV-2 infection at 12 days.

“Breakthrough” SARS-CoV-2 infections have been reported post-vaccination. A recent article published in Morbidity Mortality Weekly Report described 22 possible breakthrough SARS-CoV-2 infections among fully vaccinated (with either mRNA vaccine) nursing home residents and staff members across 75 skilled nursing facilities in the Chicago, Illinois area. While more than 65% of the infections described were asymptomatic, several severe cases and one death occurred. Another recent article published in Morbidity Mortality Weekly Report indicated that unvaccinated residents and health care personnel at a Kentucky skilled nursing facility had a 3- to 4-fold higher risk of SARS-CoV-2 infection compared to those who were vaccinated with the Pfizer vaccine during an outbreak of the R.1 variant (which contains the E48K mutation among others within the Spike protein) in March 2021. During this outbreak, 18 fully vaccinated individuals were shown to have SARS-CoV-2 infection; even so, vaccination proved to be over 85% protective against symptomatic illness. While partial vaccination is protective, the full protection is provided by two-dose vaccination.

Similarly, two cases of mild SARS-CoV-2 infection were recently reported in a cohort of 417 people who had received their second dose of Pfizer or Moderna vaccine at least 2 weeks prior (one 19 days post-vaccination and the other 36 days post-vaccination). Both cases were infected with SARS-CoV-2 variants (mutation E484K was identified in one case and mutations T95I, del142–144, and D614G were identified in both cases). Both mRNA vaccines appear to adequately cover the UK B.1.1.7 variant, although greater concern is expressed about the potential for the South African B.1.351 strain to escape protection (only 64% with the AstraZeneca, 60.1% with the Novavax vaccine). The efficacies against the B.1.1.7 variant and sometimes the B.1.351 variants are still higher than that seen commonly with the annual influenza vaccine.

Since both variants are more infectious, the public implementation of the vaccine programs is all the more important. Continued surveillance and genomic sequencing are essential to continue to provide comprehensive vaccine coverage and to assess the potential need for booster doses in the future.

Even though immunocompromised patients, such as those with inflammatory bowel disease taking anti-TNF agents, may show diminished immune responses to vaccination, the benefits outweigh such concerns, and it is generally recommended that such patients receive the vaccine.

Preliminary vaccine registry data indicate that mRNA vaccines are safe in pregnant people, thus pregnant people and those planning pregnancy should be targeted for vaccination with the mRNA vaccines. Lactating people should also be offered the vaccines, with the recognition that studies of their efficacy did not include either pregnant or lactating people.

The role of the vaccine in diminishing asymptomatic shedding or preventing community transmission is not known. To achieve effective herd immunity in a population, vaccination uptake must be 70% or higher (though some experts now cite a 60% threshold). Studies on attitudes toward SARS-CoV-2 vaccine acceptance by the general population, however, 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. Vaccine hesitancy research in late 2020 by the CDC showed that highest nonintent to receive vaccines exists among younger adults; women; non-Hispanic Black adults; adults in nonmetropolitan areas; and adults who are less educated, have lower income, and do not have health insurance. Measures advocated to increase vaccine acceptance by the public include making the vaccine free and accessible, establishing conditions dependent on vaccination (school entry, employment maintenance, flight requirements as has been done by Qantas), announcing public endorsement by trusted leaders, encouraging public documentation of vaccination (stickers), and facilitating access with early sign-up periods. In March 2021, about 13% of the US population stated that did not intend to receive any COVID vaccine.

Models show that prioritization of the vaccine for adults age 20–40 will most likely interrupt transmission (as do animal studies and recognition of elevated levels of IgG and IgA in mucosal secretions) while prioritization for those over age 60 will minimize the number of years of life lost. With limited supplies, recognizing the balance between these approaches can be used to establish policy. A CDC multisite test-negative design vaccine effectiveness study among health care personnel confirms that a single dose of either mRNA vaccine was 82% effective against COVID-19 and the administration of two doses was 94% effective.

C. Immunity to SARS-CoV-2

Promising data have been released about naturally acquired immunity to SARS-CoV-2, indicating that robust T- and B-cell immunity develops even after asymptomatic or mild SARS-CoV-2 infection. Several studies indicate that anti-SARS-CoV-2 antibodies are produced in most people recovered from SARS-CoV-2 infection and last for at least several months after exposure. A study of anti-SARS-CoV-2 antibody responses in New Yorkers showed that more than 90% of individuals who experienced mild-to-moderate COVID-19 have robust IgG antibody responses against the SARS-CoV-2 Spike protein and that these antibody titers are relatively stable for about 5 months. Data from Iceland show persistence of antibody for 4 months after acute infection. They also showed that anti-Spike antibody titers correlate with SARS-CoV-2 neutralization. The half-life of CD4 and CD8 cells in cohorts of patients from California and New York is 3–5 months. Early declines in immunologic reactivity do not necessarily indicate loss of immunity, since serologic and T cell memory may be maintained. More recent European studies (Sweden and Italy) confirm persistence of protective adaptive immunity following natural SARS-CoV-2 infection for at least 6–8 months and memory B and T cell responses persisted throughout a 6- to 8-month period of follow-up. The antibody and T cell responses tend to correlate with one another.

A key component distinguishing mild and severe COVID-19 illness is the presence of early bystander CD8 T cells and strong plasmablast responses among those with mild disease. Those with more severe disease show pronounced systemic inflammation at early presentation and these inflammatory immunologic abnormalities persist for 60 or more days.

The lack of a vaccine response among patients on certain medications (B-cell depleting therapies such as rituximab and high-dose corticosteroids deplete antibody levels more than JAK inhibitors, antimetabolites, or TNF inhibitors) or with certain malignancies and immunosuppressive states (especially B-cell disorders) and even autoimmune states should be considered as equivalent to being unvaccinated. In such patients, the antibody responses are often considerably lower than in healthy vaccinees. Patients with solid organ transplants do appear to show good responses to two doses of vaccine, but less so to one dose of vaccines. The type of vaccine that should be administered is not fully known although the mRNA vaccine, in providing two doses, are preferred by some specialists.

The best assay to determine the response to vaccine among cancer and immunosuppressed patients is the anti-Spike protein IgG (these are available through Quest^® or LabCorp,^® with T cell assays typically not commercially available). The kinetics of the IgG immune responses are not well established and decisions regarding boosters, increased dosing, and delaying underlying disease therapy are individual decisions between a provider and a patient with no firm answers to date. Persistent immune responses are documented at 6 months for dialysis patients after infection. It is important that family and contacts of immunocompromised vaccines be vaccinated and that such vaccines should receive doses before receiving immunosuppressive therapy if possible.

Preexisting antibodies among SARS-CoV-2 uninfected individuals (based on likely community exposures to human cold coronaviruses) are now recognized especially in children and young adults, and these may provide relative protection to these populations. Cases of proven reinfection are documented to date, suggesting that the post–SARS-CoV-2 immune response is effective at preventing subsequent disease. A Danish population-based observational study of PCR-tested persons experiencing the two main surges of the outbreak during 2020 demonstrated that prior infection provides about 80% protection in those younger than 65 years but only 50% in those aged 65 years or older.

These data are countered by experience from 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 either new viral isolates show modified virulence or that some degree of herd immunity was achieved in those communities. Additionally, studies from Oxford of health care personnel show the presence of positive anti-Spike or anti-nucleocapsid IgG antibodies are associated with a reduced risk of SARS-CoV-2 reinfection. Greater population-level immunity, whether achieved naturally or via an effective vaccine, will significantly slow the spread of SARS-CoV-2.

The immunodominant epitopes, which induce robust antibody responses, do not significantly overlap with those that induce T cell responses, and the dominant epitopes are associated with HLA binding with CD8 responses dependent on the available repertoire of HLA alleles (explaining perhaps some of the ethnic differences in predilection to severe disease and vaccine responses). Immunodominant epitopes also differ between the earliest and subsequent prevalent variants (early in the pandemic, variants with D614 mutations dominated in China, while those with G614 mutations dominated in European and the United States). The T cell responses of SARS-CoV-2 immunity recognize 30–40 epitopes that do not overlap with the antibody response epitopes and correlate with a repertoire of HLA class I alleles. The presence of early-induced T cells is associated with rapid viral clearance and mild disease. Some experts believe that the currently available vaccines will be able to protect against new SARS-CoV-2 variants because of the relatively slow kinetics of coronaviruses. In general, thus, the production of variants requires a growth of the outbreak, so general containment measures (vaccine and social) will limit the development of variants.

The successful vaccine rates and low prevalence in some areas such as California, anticipate the early development of herd immunity in such areas, although in a mobile and internationally-oriented society, it is too early to foretell the development of such immunity.

Curiously, the incidence of COVID-19 is 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.

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 appropriately and quarantined or triaged based on the severity of their symptoms.

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 organ 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. Infections occur 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. 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 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 (over 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 are 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 may increase the risk of acute and chronic graft rejection. Ribavirin appears to be well tolerated in lung transplant recipients with metapneumovirus infection. The control of RSV infection in modeling studies reduces the incidence of human 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 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; PCR-based rapid tests are also 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. An Xpert assay is one such reliable and sensitive assay. 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, ELISA, and PCR techniques are 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 show efficacy in bronchiolitis although individual patients with significant bronchospasm or history of asthma may respond to them. At least eight 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.

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. Techniques are under development to distinguish native from vaccine-associated antibodies, using antibodies in lymphocyte supernatants.

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. Because of this, the CDC recommends empirically treating patients in whom influenza is suspected. Testing is not necessary unless the patient is ill enough to require admission to the hospital. 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. Pneumococcal pneumonia is the most common secondary infection, and staphylococcal pneumonia is the most serious. Haemophilus spp infections also occur. Other frequent complications are acute sinusitis, otitis media, and purulent bronchitis.

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 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 but not in the United States.

Baloxavir (a selective inhibitor of influenza cap-dependent endonuclease that is given as a single oral dose) is FDA-approved for treatment of uncomplicated influenza A and B infections. It 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.

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 examined 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 (see Table 30–8). 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 (which was not recommended by the CDC during the 2016–2017 and 2017–2018 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.

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 (Fluzone High Dose), or Fluad, a trivalent inactivated influenza vaccine that contains an adjuvant (MF59), which enhances the immune response to the vaccine. 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 US 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 not covered by 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 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 healthcare 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. A 29-base pair deletion evolved during the course of human-to-human transmission, and it is thought to be responsible in part for the abeyance of the outbreak.

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. The tourist industry, in particular hotels with attention to hygiene and quarantine, were significant places for control measure in the past outbreak.

While facemasks are useful for preventing hospital acquired infection, their validity 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 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 transmitted between humans 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. It is also recognized more often that asymptomatic cases are frequent, especially among children, and they may contribute to disease transmission.

Person-to-person transmission can occur within families; hospital-associated cases comprise 10–25% 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 (especially female 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 (https://www.cdc.gov/coronavirus/mers/lab/index.html). 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 interferons, ribavirin, lopinavir-ritonavir, or mycophenolate mofetil. The use of macrolides is not associated with a reduction in mortality. 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%. Factors associated with mortality include the use of corticosteroids and also the use of continuous renal replacement therapy. A set of radiographic criteria (diffuse involvement, fibrosing sequela) are associated with a worse prognosis and the need for intubation. Advanced age is associated with a poor prognosis. Functional outcomes of survivors are similar to those of other non-MERS severe acute respiratory virus illnesses.

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. Limiting the number of hospital contacts and visits is important. 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. Postexposure prophylaxis with ribavirin and lopinavir/ritonavir for health care workers is associated with a 40% decrease in the risk of acquiring infection.

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 and receive education about the syndrome. 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. Avoidance of direct contact with camels (who may be asymptomatic but who can transmit the virus though nasal or ocular discharge, milk, urine, and feces) is important. Infected camels should be segregated from other livestock and kept off the market, including their meat products, and buried or destroyed.

Current vaccine candidates include subunits to the RBD (receptor binding domain), whole DNA, viral vectors, and inactivated or live attenuated whole virus vaccines.

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).