#54151: The Coronavirus Disease (COVID-19) Pandemic

Human coronavirus (HCoV) was first identified in 1965, isolated from a patient with what was described as the common cold [3]. Subsequently, four types of HCoV have been detected frequently in respiratory secretions from children and adults in scattered regions of the globe, labeled HCoV-229E, -NL63, -OC43, and -HKU1. These agents are a common cause of mild-to-moderate upper respiratory illness, including common cold, bronchitis, bronchiolitis in infants and children, and asthma exacerbation. Rarely, HCoVs have been implicated in lower respiratory tract infection (viral pneumonia), a complication more common to persons with underlying cardiopulmonary disease or weakened immune systems.

In addition to the seasonal infections caused by the ambient, adaptive HCoVs described, widespread outbreaks of novel coronavirus infection have occurred in each of the past two decades, and the 2019–2020 Wuhan, China, outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale [1,4]. The epidemiologic feature common to these outbreaks is an initial point source cluster of zoonotic infection followed by secondary spread of the virus via human-to-human transmission. Among the factors thought to be conducive to the emergence of such outbreaks are the following: genomic recombination in an animal CoV capsid that renders the virus better adapted to human infection (and perhaps more virulent); and dietary practices and cultural determinants that bring humans into close contact with livestock or raw meat and carcasses of wild animals and birds, thereby facilitating transmission from an infected animal host to humans. After infection is established, secondary viral transmission occurs through close person-to-person contact by way of droplet nuclei propelled into the air during coughing and sneezing. The first two known novel coronavirus outbreaks, severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, are considered to be zoonotic in origin and were associated with serious, sometimes fatal illness.

Severe Acute Respiratory Syndrome (SARS-CoV)

Infection with SARS-CoV was first recognized in China in November 2002, and signs of an outbreak in Asia were evident by February 2003 [3]. Epidemiologic investigation found that early cases of SARS-CoV were zoonotic infection involving transmission from civet cats to humans. Over the next several months, SARS-CoV spread to countries in North America, South America, Europe, and other parts of Asia before the global outbreak was contained later in the same year.

SARS-CoV infection began with fever, headache, malaise, and arthralgia/myalgia followed in two to seven days by cough, shortness of breath, and signs of pneumonia [3].

According to the World Health Organization (WHO), the 2002–2003 outbreak caused 8,098 probable cases of SARS worldwide and 774 deaths. Just eight cases were identified in the United States. Since 2004, no additional known cases of SARS-CoV infection have been reported anywhere in the world [3].

In response to the 2003 global SARS outbreak, the Centers for Disease Control and Prevention (CDC), working in concert with the WHO, developed a strategy for controlling the epidemic that included the following elements [3]:

This experience informed the rapid public health response to the 2019–2020 coronavirus outbreak in China.

Middle East Respiratory Syndrome (MERS-CoV)

MERS-CoV was first reported in Saudi Arabia in 2012, and all cases to date have been linked to countries in or near the Arabian Peninsula. Travel-associated cases of MERS-CoV infection have been reported in many countries, including two imported cases diagnosed in the United States in 2014 involving unlinked healthcare providers recently returned from Saudi Arabia. Two modes of transmission have been identified: zoonotic infection from an animal reservoir to humans (with camels acting as the intermediate host), and person-to-person transmission via close contact with an index case, as described in association with a family case cluster and a nosocomial outbreak [5,6,7].

Most persons with confirmed MERS-CoV infection have had moderately severe respiratory illness manifest by fever, cough, and shortness of breath, often complicated by pneumonia and respiratory failure. The case-fatality rate approaches 40%. Most deaths have been in patients with pre-existing chronic conditions such as diabetes, cancer, or heart, lung, or renal disease. Sporadic cases of MERS-CoV continue to appear in various parts of the Middle East [3].

For purposes of risk stratification and prioritization of care, adults with COVID-19 can be grouped into the following severity of illness categories:

Persons of all ages are at risk for SARS-CoV-2 infection and severe COVID-19. The likelihood of severe disease is greater for children younger than 4 years and adults older than 65 years of age, those living in nursing home or long-term care facilities, those with multiple comorbidities, and those unvaccinated against COVID-19. Individual risk factors for severe disease include advanced age, obesity (body mass index ≥30), cardiovascular disease, diabetes, cancer, and chronic obstructive pulmonary disease (COPD). Of more than 70,000 cases reported in China the first two months of the pandemic, 87% occurred in persons 30 to 79 years of age [23]. The proportion of case fatalities among patients 70 to 79 years of age was 8%, among those 80 years of age or older, the rate was 14.8%. The case fatality rate for patients with comorbidities was elevated as well, specifically those with cardiovascular disease (10.5%), diabetes (7.3%), chronic respiratory disease (6.3%), hypertension (6%), and cancer (5.6%). Only 2% of cases in persons younger than 20 years of age were fatal, and no deaths were reported in those younger than 10 years of age.

In June 2020, the CDC issued an epidemiologic report on 1,320,488 laboratory-confirmed COVID-19 cases in the United States and territories, reported to CDC between January 22 and May 30, 2020 [55]. Cumulative incidence (403.6 cases per 100,000 persons) was similar among males (401.1) and females (406.0), highest among persons 80 years of age or older (902.0), and lowest among children younger than 9 years of age (51.1). Among 599,636 cases with known information on both race and ethnicity, 36% were non-Hispanic White, 33% were Hispanic, 22% were Black, 4% were Asian, and 1.3% were American Indian or Alaska Native. Among 287,320 cases with sufficient data on underlying health conditions, the most frequently reported comorbidities were cardiovascular disease (32%), diabetes (30%), and chronic lung disease (18%). Overall, 14% were hospitalized, 2% admitted to an ICU, and 5% died. The rate of hospitalization was six times higher among patients with underlying health conditions (45.4%) than among those without reported underlying comorbidities (7.6%). The mortality rate was 12 times higher among patients with reported underlying conditions (19.5%) compared with those reporting none (1.6%). Approximately 4% of reported cases were asymptomatic. Among 373,833 cases with data on individual symptoms, 70% noted fever, cough, or shortness of breath; 35% experienced muscle aches and/or headache; 8% reported loss of taste or smell [55].

During the course of the pandemic in the United States, obesity has been identified as an important independent risk factor for severe COVID-19, especially among adult patients younger than 60 years of age. Multiple reports, ranging from single-center studies to analyses of records from large patient care networks, have found that severe obesity (body mass index >35) is associated with higher rates of hospitalization, respiratory failure, and mortality from COVID-19 [77,78]. The risk varies directly with degree of obesity and is independent of obesity-associated comorbidities. The impact is more striking among men than women. There are multiple mechanisms by which obesity may contribute to adverse outcomes in patients with COVID-19. In addition to obstructive pulmonary physiology, severe obesity is associated with immune dysfunction (depression of anti-inflammatory signaling and increased pro-inflammatory signaling), alterations in vascular endothelium, and renin-angiotensin stimulation, which together may worsen lung inflammation and alveolar damage [78].

Hospitalized patients with advanced COVID-19 may have laboratory signs of a coagulopathy and increased risk for arterial and venous thromboembolic complications [15,39,40]. The pathogenesis is unknown but likely involves some combination of systemic inflammation, endothelial dysfunction, platelet activation, immobility, and stasis of blood flow [40]. The earliest abnormalities are elevated D-dimer levels and mild thrombocytopenia; with disease progression, fibrin degradation products are elevated and prothrombin time becomes prolonged. Laboratory measure of coagulation factors in a patient hospitalized with COVID-19 provides a way to track disease severity. The presence of an elevated D-dimer on admission carries a poor prognosis and has been associated with increased risk of requiring mechanical ventilation, ICU admission, and mortality [40,41]. The most frequently reported complications of COVID-19 coagulopathy are deep venous thrombosis (DVT) and pulmonary emboli (PE). In a prospective study of 150 critically ill patients from two centers in France, 25 patients developed PE and 3 developed DVT despite prophylactic anticoagulation [42]. In a report of 184 patients with severe COVID-19 from three centers in the Netherlands, the cumulative incidence of venous thromboembolism was 27%, including PE in 80% of the cases affected [43]. Other centers have reported lower rates. Among 393 patients from New York, venous thromboembolism was diagnosed in only 13 patients (3.3%), 10 of whom were on mechanical ventilation [44]. These differences point to the need for studies that control for clinical severity, underlying comorbidities, prophylactic regimen, and COVID-19-related therapies. At present, there are limited data available to inform clinical management around prophylaxis or treatment of venous thromboembolic complications in patients with COVID-19 [15]. One source of interim guidance recommends regularly monitoring hemostatic markers—namely D-dimer, prothrombin time, and platelet count—in all patients presenting with COVID-19 and prophylactic use of low-molecular-weight heparin in all hospitalized patients, unless there are contraindications [40]. Clinical guidance on use of antithrombotic therapy for patients with COVID-19 is provided by the National Institutes of Health (NIH) at https://www.covid19treatmentguidelines.nih.gov/therapies/antithrombotic-therapy.

In summary, the clinical features of COVID-19 range from self-limited upper respiratory syndrome to pneumonia and rapid-onset respiratory insufficiency to vascular complications and critical organ dysfunction. Older patients and those with comorbidities are at significant risk for severe disease. Among patients with COVID-19 who progress to pneumonia, the median time from initial symptoms to onset of dyspnea is 5 to 8 days, to ARDS is 8 to 12 days, and to ICU admission is 10 to 12 days. Therefore, in monitoring at-risk patients, clinicians should bear in mind the anticipated period of rapid clinical deterioration is 7 to 8 days after onset of symptoms. Data from clinical series show that in patients hospitalized for COVID-19, 26% to 42% require ICU admission; in those admitted to ICU, 65% to 85% develop ARDS [15]. Reported mortality rates among patients requiring ICU admission range from 39% to 72%. The median length of hospitalization for survivors is 10 to 13 days.

Multiple cohort studies and meta-analyses have found that vertical transmission of SARS-CoV-2 is rare, though severe maternal COVID-19 has been associated with SARS-CoV-2 infection in newborn infants. The majority of SARS-CoV-2 infections reported in newborns result from exposure to maternal COVID-19 at the time of birth or shortly after. One systemic review and meta-analysis found that 1.8% of newborn infants from mothers with SARS-CoV-2 infection tested positive for the virus [177]. In a subset of 592 SARS-CoV-2-positive infants with data on time of exposure and testing, 7 had evidence of confirmed mother-to-child transmission in utero. Risk factors associated with neonatal SARS-CoV0-2 infection in offspring included severe maternal COVID-19, maternal admission to ICU, maternal death, and postnatal maternal COVID-19 [177].

Several small clinical series have reported fetal demise or stillbirth following maternal COVID-19, resulting from placental SARS-CoV-2 infection without evidence of intrauterine transmission to fetus. Data from a prospective clinicopathologic study of placentas from unvaccinated pregnant individuals affected by COVID-19 were used to examine the placental pathology associated with autopsy findings in six stillbirth cases [178]. In all six stillbirths, the maternal placentas showed extensive inflammation and massive perivillous fibrinoid deposition with trophoblast damage, associated with the presence of virions on electron microscopy and positive immunostaining for SARS-CoV-2 spike protein. Thus, severe "placentitis," with near 75% obliteration of the maternal intervillous space, accounted for intrauterine fetal death. Complete fetal autopsy examination found signs of tissue asphyxia as mode of death and no evidence of viral transmission to the fetus [178]. The interval between maternal COVID-19 diagnosis and fetal death ranged from 3 to 15 days.

As of January 2023, there is no highly effective, safe, and easily administered antiviral therapy for routine treatment of COVID-19. Remdesivir, which must be administered intravenously, is the only drug approved by FDA for treatment of COVID-19. Two oral antiviral drugs, ritonavir-boosted nirmatrelvir (Paxlovid) and molnupiravir, have received EUA from the FDA for early treatment in nonhospitalized patients with mild-to-moderate COVID-19 who are at risk of progressing to severe illness. Recommendations for use of antiviral therapies apply to adults and children (of certain age and weight limitations). The NIH Panel guidelines recommend selecting from the following antiviral agents, in order of preference [57]:

Remdesivir

Remdesivir is a nucleotide analog RNA polymerase inhibitor having in-vitro activity against SARS-CoV-2 [15]. A multinational study at the onset of the pandemic described favorable outcomes when hospitalized patients were given a 10-day course of intravenous remdesivir as part of a compassionate use program [26]. The study enrolled patients from the United States, Canada, Europe, and Japan with confirmed SARS-CoV-2 infection and signs of lower respiratory tract disease severe enough to require oxygen supplementation and/or ventilatory support. Of 53 patients in the data analysis, 32 (68%) showed significant improvement in oxygenation with use of remdesivir. Mortality at 18 days follow-up was 13% overall, 18% among patients who required invasive ventilation, and 5% among those who had received noninvasive ventilation. The authors observed that although this was not a randomized study and patients were not directly comparable, observed mortality was considerably less than that reported contemporaneously in other COVID-19 case series and reports [26].

Remdesivir is approved by the FDA for treatment of adults and pediatric patients with COVID-19. The approval was supported by three randomized, controlled clinical trials showing that remdesivir reduces risk of disease progression and shortens the time to recovery in adult patients hospitalized with moderate-to-severe COVID-19 [90]. The analysis included data from a double-blind, placebo-controlled trial that enrolled 1,062 patients, randomized to receive either intravenous remdesivir or placebo. The primary outcome was time to recovery, defined by discharge from hospital or resolution of need for clinical care (hospitalization for infection-control purposes only). The median time to recovery was 10 days for the remdesivir group, compared with 15 days for the placebo group [35]. In an analysis of secondary outcomes, patients who received remdesivir were more likely than those who received placebo to have clinical improvement at day 15. The proportion of serious adverse events related to respiratory failure and the need for higher levels of ventilatory support were lower among patients in the remdesivir group. Kaplan-Meier estimates of mortality showed a trend in favor of the treatment group: 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% versus 15.2% by day 29 [35].

The NIH Panel recommends remdesivir for treatment of COVID-19 in hospitalized patients with SpO₂ <94% on ambient air, or require supplemental oxygen, and for those who require noninvasive or mechanical ventilation [57]. The duration of treatment recommendation, including advisability of combining remdesivir with a glucocorticoid such as dexamethasone, depends on severity of illness and level of ventilatory support. For patients who require supplemental oxygen but have no need for delivery of oxygen through a high-flow device, the recommended regimen is remdesivir 200 mg IV for one day, followed by 100 mg daily for four days or until hospital discharge, whichever comes first. The duration of remdesivir therapy may be extended up to 10 days when there is no substantial clinical improvement by day 5 (57).

The FDA has approved the use of remdesivir (three-day regimen) in nonhospitalized patients with COVID-19 who are at risk of severe disease in settings where intravenous therapy and close patient monitoring are feasible. In a randomized, placebo-controlled clinical trial among nonhospitalized adults (mean age: 50 years) with symptomatic COVID-19 and at least one risk factor for disease progression, a three-day course of remdesivir resulted in an 87% lower risk of hospitalization or death than placebo [165]. COVID-19-related hospitalizations and deaths from any cause occurred in 2 patients (0.7%) in the remdesivir group and 15 patients (5.3%) in the placebo group.

Remdesivir is indicated for treatment of mild-to-moderate COVID-19 in adults and children (28 days of age and older and weighing at least 3 kg), whether hospitalized or not hospitalized, who are at risk for progression to severe disease, hospitalization, or death [57]. The recommended dosage for adults and pediatric patients weighing at least 40 kg is a single loading dose of 200 mg, followed by once-daily doses of 100 mg, administered by intravenous infusion. For younger/smaller pediatric patients weighing 3 kg to less than 40 kg, the initial dosage is 5 mg/kg, followed by 2.5 mg/kg daily. For nonhospitalized patients, the total duration of therapy is 3 days; for hospitalized patients, duration of therapy is 5 or 10 days, determined by severity of respiratory insufficiency (need for mechanical ventilation) and clinical response.

Ritonavir-Boosted Nirmatrelvir (Paxlovid)

Nirmatrelvir is a protease inhibitor active against a constitutive protein (protease) essential for virus replication. It has demonstrated antiviral activity against all human coronaviruses [57]. Nirmatrelvir is used in combination with ritonavir, a pharmacokinetic booster required to increase nirmetrelvir concentration into therapeutic range. A randomized, placebo-controlled clinical trial of nirmatrelvir-riyonavir (Paxlovid) was conducted among unvaccinated, nonhospitalized high-risk adults with symptomatic COVID-19. The incidence of disease progression to hospitalization or death was 89% lower in the treatment group than in the placebo group [166]. The incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths.

The available formulation uses nirmatrelvir 300 mg plus ritonavir 100 mg administered orally twice daily for five days in patients older than 12 years of age and weighing more than 40 kg. Treatment should be initiated as soon as possible and within five days of symptom onset. The NIH Panel recommends nirmatrelvir-riyonavir for high-risk, nonhospitalized patients with mild-to-moderate COVID-19 [57]. Because ritonavir is a potent P450 3A4 inhibitor, it may increase blood concentrations of certain concomitant medications and the potential for serious drug toxicities. Many potential drug-drug interactions can be safely managed (e.g., with certain statins, calcium channel blockers, or direct oral anticoagulants) [57]. Before using nirmatrelvir-ritonavir, clinicians should review the patient's concomitant medications and consider consulting with a pharmacist. The following online resources are available to assist in identifying and managing drug-drug interactions:

There are reports of SARS-CoV-2 viral rebound and clinical relapse of COVID-19 in some patients who have completed treatment with nirmatrelvir-ritonavir [57,176]. These patients reportedly have had mild, self-limited symptoms without illness progression or need of additional treatment. Viral rebound and recurrence of COVID-19 symptoms also occurs in patients who have not been treated with nirmatrelvir-ritonavir. Patients with suspected COVID-19 rebound following treatment should be advised to re-isolate for at least five days to prevent further transmission of the virus.

Molnupiravir

Molnupiravir is the prodrug of a ribonucleoside that exhibits antiviral activity against RNA viruses, including SARS-CoV-2. Uptake by viral RNA-dependent RNA polymerases causes mutations that are lethal to the virus. In clinical trials, 800-mg molnupiravir twice daily for five days reduced the rate of hospitalization or death among patients with COVID-19 by 30% compared with placebo [57]. Molnupiravir is not recommended for use in pregnant patients due to concerns about potential fetal toxicity. The NIH Panel recommends using molnupiravir as an alternative when nirmatrelvir-ritonavir and remdesivir are not available, not feasible to use, or clinically inappropriate [57]. Molnupiravir appears to have lower clinical efficacy than the other treatment options.

Several other approaches to antiviral therapy have been explored for the treatment of COVID-19, with poor results. Hydroxychloroquine and ivermectin are of historical interest, have been evaluated in multiple clinical trials, and therefore are discussed in detail below. The NIH guidelines for the treatment of COVID-19 recommend against the use of nitazoxanide, lopinavir/ritonavir, and other HIV protease inhibitors to manage or prevent COVID-19 outside of clinical trials [57].

Hydroxychloroquine

In-vitro studies show that chloroquine phosphate and hydroxychloroquine sulphate (commonly used to treat malaria) interfere with the replication cycle of coronaviruses, including SARS-CoV-2, and thus may offer some therapeutic efficacy for treatment of COVID-19 [21]. Randomized controlled clinical trials of hydroxychloroquine are underway in the United States. Based on small case studies and anecdotal reports of possible efficacy, many clinicians have been inclined to administer hydroxychloroquine to patients with COVID-19 who are so ill as to require hospitalization and having risk factors for severe disease (i.e., age older than 65 years, underlying medical conditions, and/or signs of viral pneumonia). On March 28, 2020, the FDA issued an EUA that allowed chloroquine phosphate or hydroxychloroquine sulphate to be used for the treatment of patients hospitalized with COVID-19 when clinical trials are not available or participation is not feasible [36]. However, this letter was revoked in June 2020 [58]. If used, hydroxychloroquine is generally preferred as it is better tolerated. The suggested dosage regimen is hydroxychloroquine sulphate administered orally in a loading dose of 400 mg twice daily (for one day) then 200 mg twice daily for four days [22]. Potential adverse effects include cardiac conduction QT-prolongation and a number of drug-drug interactions.

An observational study examined the association between hydroxychloroquine use and clinical outcomes, analyzing data from 1,376 consecutive patients with COVID-19 admitted to a clinical center in New York City between March 7 and April 8, 2020 [37]. To assess potential benefit or detrimental effect, the primary end point selected was a composite of intubation or death in a time-to-event analysis, comparing outcomes in patients who received hydroxychloroquine with those who did not. A total of 811 patients (59%) were treated with hydroxychloroquine for a median of five days, 60% of whom also received azithromycin. After adjusting for severity of illness, the investigators found no significant difference in the rate of the composite end point of intubation or death over a median follow-up of 22.5 days. Thus, the risk of intubation or death was not significantly different among hospitalized patients with COVID-19 who received hydroxychloroquine than among those who did not [37].

Randomized, controlled clinical trials to assess efficacy of hydroxychloroquine in patients hospitalized with COVID-19 have not shown a benefit. A multicenter study of hospitalized patients with mild-to-moderate COVID-19 found that hydroxychloroquine, alone or in combination with azithromycin, was no more effective than standard care in improving clinical status at 15 days [70]. Preliminary analysis of data from a multicenter, randomized trial in the United Kingdom found no reduction in 28-day mortality among those treated with hydroxychloroquine when compared with the control group [71]. Hydroxychloroquine use was associated with increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation. An NIH-sponsored, controlled clinical trial was halted (after the fourth interim analysis) because hydroxychloroquine was found unlikely to be beneficial to hospitalized patients with COVID-19 [72]. As of November 2021, multiple randomized, controlled trials have failed to demonstrate any significant benefit for hydroxychloroquine in outpatient treatment of mild COVID-19 or as primary or secondary prophylaxis against SARS-CoV-2 infection.

On June 15, 2020, the FDA revoked the EUA that allowed for chloroquine and hydroxychloroquine donated to the Strategic National Stockpile to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was not available or feasible [58]. This decision was based on an ongoing analysis of emerging data indicating that these drugs are unlikely to be effective for patients hospitalized with COVID-19. As of December 28, 2022, the NIH Panel continues to recommend against the use of hydroxychloroquine or chloroquine with or without azithromycin [57].

Ivermectin

Ivermectin is an antiparasitic drug approved by the FDA for the treatment of several tropical diseases (e.g., onchocerciasis, helminthiases, scabies) and under investigation for the prevention of malaria transmission. Ivermectin is poorly absorbed from the intestinal tract, which enhances its effectiveness against parasitic infections confined largely to the intestinal tracts of humans and large mammals (e.g., sheep, cattle, horses). Reports from in vitro studies suggest that ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host's antiviral response. In addition, ivermectin docking may interfere with the attachment of the SARS-CoV-2 spike protein to the human cell membrane. Although ivermectin inhibits SARS-CoV-2 replication in vitro (cell culture), the effect is dose-dependent, meaning that inhibition is observed when the concentration of ivermectin is raised to a certain level. Furthermore, the ivermectin concentration required for in vitro inhibition of SARS-CoV-2 is 50 to 60 times higher than can be achieved in humans by standard oral doses of the drug. Pharmacokinetic and pharmacodynamic studies suggest that achieving the plasma concentrations necessary for the antiviral efficacy detected in vitro would require administration of doses up to 100-fold higher than those approved for use in humans.

In 2021, ivermectin dispensing by retail pharmacies increased dramatically, as did the use of available over-the-counter veterinary formulations not intended for human consumption. The number of ivermectin prescriptions dispensed in the United States increased from 3,600 per week at the pre-pandemic baseline to more than 88,000 per week in August 2021 [167]. During the same period, state poison control centers across the country reported a fivefold increase in consultations for human exposures to ivermectin [167,168]. Misuse of prescription ivermectin by excess dosage or duration can have adverse effects. Veterinary formulations intended for use in horses and cattle are often highly concentrated and unsafe for ingestion by humans. Clinical signs of ivermectin toxicity include gastrointestinal upset, confusion, ataxia, hypotension, disturbances of vision, hallucinations, seizures, and coma.

Ivermectin is neither authorized nor approved by FDA for prevention or treatment of COVID-19. Clinical studies regarding the use of ivermectin to treat or prevent COVID-19 have been conflicting, and many studies had incomplete information and significant methodological limitations. Among 400 patients with mild COVID-19, a double-blind, randomized, placebo-controlled trial of ivermectin 300 mg/kg twice daily for five days found that ivermectin had no significant effect on time to resolution of symptoms compared with placebo [169]. A larger, double-blind, randomized, placebo-controlled trial of early ivermectin treatment for COVID-19 (679 patients in each comparator group) found that ivermectin did not lower the rate of hospitalization (progression of disease) or duration of time required for emergency department observation [170]. In a randomized, placebo-controlled trial among patients hospitalized with mild-to-moderate COVID-19, treatment with ivermectin on admission had no beneficial effect on the rate of disease progression (21.6%) compared with standard care (17.3%) [171]. The rates of COVID-19-associated ICU admission, mechanical ventilation, and mortality were not significantly different for the ivermectin group than the control group. Due to the lack of reliable and accurate data, the NIH Panel does not recommend either for or against the use of ivermectin for the treatment of COVID-19 [57].

Severe SARS-Cov-2 infection results in progressive interstitial-alveolar pneumonia and respiratory failure. Disease pathogenesis is linked to activation of the innate immune system and dysregulation of adaptive immune responses, with release of proinflammatory cytokines and chemokines. Death from COVID-19 is often preceded by signs of a hyperimmune inflammatory response ("cytokine storm") that leads to ARDS, multi-organ dysfunction, and circulatory collapse. Laboratory markers of heightened inflammation include elevated C-reactive protein, ferritin, and interleukin-6. Novel approaches to clinical treatment attempt to modify disease progression and prevent or ameliorate pulmonary and systemic complications of cytokine storm, thereby reducing mortality from COVID-19.

COVID-19 Convalescent Plasma

In the past, passive immunization with plasma obtained from surviving patients has been used to treat life-threatening infections absent specific therapy. Early in the COVID-19 pandemic, before emergence of SARS-CoV-2 variants that evade neutralizing antibody, studies demonstrated that intravenous transfusion of convalescent plasma with high-titer antibody directed against SARS-CoV-2 was effective in reducing mortality in hospitalized patients with COVID-19 pneumonia. In a preliminary, uncontrolled case series of five critically ill Chinese patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in clinical status, including resolution of ARDS in four patients at 12 days after transfusion [27].

A study from the Mayo Clinic Expanded Access Protocol (EAP) involving 35,322 registered patients found that plasma infusion was safe and reduced COVID-19 mortality if administered early after hospitalization [76]. A subset analysis showed a gradient of mortality in relation to IgG antibody levels in transfused plasma. The risk of dying from COVID-19 was lower among patients who had received convalescent plasma units containing high titer anti-SARS-CoV-2 antibody than among those who received plasma containing low antibody levels. The pooled relative risk reduction among patients transfused with high antibody level plasma units versus low-level antibody plasma was 35% at 7 days and 23% at 30 days. The Mayo EAP report is an analysis of registry data and not a randomized controlled study.

On August 23, 2020, the FDA granted an EUA to COVID-19 convalescent plasma for treatment of patients hospitalized with COVID-19 [73]. This decision was based on historical evidence derived from the use of plasma in prior outbreaks of respiratory virus infection, small case series, and non-randomized clinical trials conducted during the current outbreak. The only double-blind, placebo-controlled clinical trial of convalescent plasma failed to demonstrate a reduction in mortality or improvement in other clinical outcomes [93]. This study enrolled 333 patients with severe COVID-19 pneumonia, randomized in a 2:1 ratio to receive convalescent plasma (228 subjects) or placebo (105 subjects). Of the total, 68% were men and 65% had a coexisting condition at entry into the trial. The median time from onset of COVID-19 symptoms to enrollment was eight days. More than 90% were receiving oxygen and glucocorticoids at the time of entry into the trial. The infused convalescent plasma had a median titer of 1:3,200 of total SARS-CoV-2 antibodies. At 30 days, the clinical status of patients in the convalescent plasma group did not differ significantly from that of patients in the placebo group. The proportion of ICU admissions and invasive ventilatory support requirements were similar in both groups. Overall mortality was 11.43% in the placebo group and 10.96% in the convalescent plasma group. In a subset analysis, no differences favoring convalescent plasma were noted in a group of 39 patients who received the intervention within 72 hours of symptom onset [93]. Of note, all patients in this study had signs of severe pneumonia; thus, no firm conclusion can be drawn as to the potential efficacy of COVID-19 convalescent plasma initiated at an earlier stage of illness.

Convalescent plasma therapy is not beneficial for hospitalized patients with COVID-19 pneumonia; however, high-titer convalescent plasma administered within three to five days of symptom onset was shown to reduce the risk of disease progression caused by strains of SARS-CoV-2 circulating early in the pandemic. Evidence for this comes from a randomized, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV-2 administered to older adults within 72 hours after onset of mild COVID-19 symptoms. In a subset of patients who received high-titer plasma therapy, 13 of 80 (16%) patients progressed to severe respiratory disease, compared with 25 of 80 patients (31%) who received placebo [109]. This corresponds to a relative risk reduction of 48%. The study population consisted of adults 75 years of age or older, or between 65 and 74 years of age with at least one coexisting condition.

The FDA has subsequently revised the EUA to limit authorization to the use of COVID-19 convalescent plasma with high titers of anti-SARS-CoV-2 antibodies for treatment of COVID-19 in patients with immunosuppressive disease or immunosuppressive treatment [179]. The FDA also issued new guidance for healthcare providers and investigators, with recommendations on pathways for use of investigational convalescent plasma, collection of convalescent plasma, and record keeping [179].

Monoclonal Antibody to SARS-CoV-2

Modern immunologic techniques enable the identification of pathogen-specific memory B cells and recovery of immunoglobulin genes that can be expressed to produce monoclonal antibodies [85]. FDA-approved monoclonal antibody products are available to treat or prevent respiratory-syncytial virus, anthrax, and Clostridioides difficile. Memory B cells harvested from patients recovering from COVID-19 have been used to produce anti-SARS-CoV-2 monoclonal antibodies directed against the surface spike glycoprotein, preventing entry of virus into host cells. Monoclonal antibody infusions have potential for preventing COVID-19 in vulnerable people and for blocking disease progression in patients at risk for severe illness. Given the long half-life of immunoglobulin (approximately three weeks), a single monoclonal antibody infusion should suffice for either prevention or treatment of COVID-19 [85]. A phase 2 randomized study among outpatients with mild or moderate COVID-19, during circulation of the original strain SARS-CoV-2, found that infusion of bamlanivimab (a monoclonal neutralizing antibody) was followed by a rapid decline in viral load and reduced need for further medical attention [94]. Subsequent COVID-related hospitalization or emergency department care was required in 1.6% of patients in the monoclonal antibody group, compared with 6.3% in the placebo group.

Four monoclonal antibody products (bamlanivimab plus etexevemab, casirivimab plus imdevimab, sotrovimab, and bebtelovimab) have received EUAs from the FDA for treatment of outpatients with mild-to-moderate COVID-19. Placebo-controlled clinical trials performed during the first year of the pandemic found that treatment with anti-SARS-CoV-2 monoclonal antibodies reduced the risk of hospitalization or death 70% to 85% [57]. Following emergence of the Omicron variant in early 2022, soltrovimab was recommended over other products when studies demonstrated that only sotrovimab exhibited acceptable activity against the Omicron subvariants in circulation at that time.

Outpatient monoclonal antibody therapy is useful during periods when the dominant SARS-CoV-2 variant in circulation shows little evidence of immune evasion. This mode of therapy is reserved for at-risk symptomatic patients and should be administered soon after confirmation of SARS-CoV-2 infection, within 7 to 10 days of symptom onset. Patients with symptomatic COVID-19 who meet one of the following criteria are eligible for treatment:

The NIH guidelines provide updated guidance on current efficacy, patient selection criteria, authorized dosage, and treatment precautions. As of February 2023, the NIH Panel recommends against using anti-SARS-CoV-2 monoclonal antibody for the treatment of COVD-19 because current Omicron subvariants in circulation are not expected to be susceptible to these products [57].

Dexamethasone

A large multicenter therapeutic trial demonstrated that dexamethasone (a glucocorticoid) improves survival in patients hospitalized with COVID-19 who require supplemental oxygen and/or some degree of ventilatory support [63]. In this study platform, patients were randomly assigned to a group of different therapies and efficacy was assessed using a single endpoint: mortality within 28 days after randomization. In total, 2,104 patients were assigned to receive dexamethasone at a dose of 6 mg daily, and 4,321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1,110 patients (25.7%) in the usual care group died within 28 days after randomization. The observed differences in mortality varied in relation to the level of respiratory support patients required upon entry to the study. Among patients receiving mechanical ventilation, the 28-day mortality was significantly lower in the dexamethasone group (29.3%) than that in the usual care group (41.4%). Among patients receiving supplemental oxygen without mechanical ventilation, the observed benefit was less pronounced but also significant, 23.3% in the dexamethasone group and 26.2% in the usual care group. There was no demonstrable benefit from dexamethasone treatment in patients who did not require oxygen.

The NIH Panel recommends using dexamethasone (at a dose of 6 mg per day for up to 10 days) for the treatment of COVID-19 in patients who are mechanically ventilated and in patients who only require supplemental oxygen (not mechanical ventilation) [57]. If dexamethasone is not available, equivalent doses of another glucocorticoid may be used, such as prednisone 40 mg/day or methylprednisolone 32 mg/day. Dexamethasone is the preferred glucocorticoid to use in pregnant women with COVID-19 who require respiratory support, because of the potential benefit of decreased maternal mortality and the known low risk of fetal adverse effects associated with short-course maternal dexamethasone therapy [57]. Patients receiving dexamethasone at the time of hospital discharge should be given a prescription to complete the specified 10-day course. The NIH Panel recommends against the use of dexamethasone in patients with COVID-19 who do not require supplemental oxygen.

Potential adverse effects of glucocorticoid use include hyperglycemia and opportunistic infection. Clinicians should be mindful of Strongyloides hyperinfection syndrome as a complication of modest-dose and short-duration dexamethasone regimens [75]. Patients at risk are those who have previously resided in South America, the Caribbean, the Middle East, Africa, or Asia. Clinical indicators of possible subclinical or unrecognized Strongyloides infection include peripheral eosinophilia and unexplained gram-negative bacteremia [75].

Tocilizumab and Baricitinib

Patients hospitalized with COVID-19 and worsening hypoxemia despite high-flow supplemental oxygen and/or ventilatory support plus dexamethasone often have signs of ongoing systemic inflammation. Clinical trials have demonstrated that these patients benefit from combining dexamethasone with an additional immunomodulator, such as an interleukin (IL)-6 inhibitor (e.g., tocilizumab) or Janus kinase (JAK) inhibitor (e.g., baricitinib, tofacitinib) [57]. The NIH Panel recommends baricitinib or tofacitinib in addition to dexamethasone in hospitalized COVID-19 patients on high-flow oxygen or noninvasive/mechanical ventilation, who have evidence of systemic inflammation and increasing oxygen needs [57].

Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, can be effective in mitigating the cytokine storm associated with COVID-19 hyperinflammatory states. A retrospective cohort study of hospitalized patients requiring ICU support found that treatment with tocilizumab was associated with reduced mortality [74]. Of 630 patients selected for analysis, 358 (57%) died—102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. The primary multivariable Cox regression analysis showed an association between receipt of tocilizumab and reduction in hospital-related mortality. This association was also noted among subgroups requiring mechanical ventilation and with baseline C-reactive protein of 15 mg/dL or higher. In contrast to findings from this and other observational studies of COVID-19 pneumonia, randomized clinical trials have not demonstrated a mortality benefit with tocilizumab therapy [91]. Tocilizumab has been reported to reduce the requirement for mechanical ventilation in some patient populations, thereby alleviating the burden on ICU-level care for management of severe COVID-19. A published editorial assessment concluded that newly released randomized trials suggest a potential role for tocilizumab in COVID-19 but do not show clear evidence of efficacy [91].

JAK inhibitors interfere with phosphorylation of key proteins required for signal transduction that promotes immune activation and inflammation (e.g., the cellular response to proinflammatory cytokines such as IL-6) [57]. The FDA has issued an EUA for baricitinib to treat COVID-19 in hospitalized adults and in pediatric patients 2 to 17 years of age requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO [175]. The recommended dosage of baricitinib under the EUA is 4 mg once daily for patients 9 years of age and older or 2 mg once daily for patients 2 to 8 years of age. Treatment should continue for 14 days or until hospital discharge, whichever occurs first [175].

Before initiating therapy, baseline glomerular filtration rate, liver enzyme level, and complete blood count should be assessed, as modifications in approach are necessary with abnormalities in any of these values. Baricitinib is not recommended for patients with active tuberculosis, who are on dialysis, have end-stage renal disease, or have acute kidney injury [175].

The CDC advises that the decision to monitor a patient in the outpatient or inpatient setting should be made on a case-by-case basis. Important considerations are the patient's clinical status, reliability, need of clinical monitoring, and options for home isolation to reduce risk of secondary transmission. General guidance on patient isolation and transmission precautions for people with COVID-19 is available at https://www.cdc.gov/coronavirus/2019-ncov/your-health/isolation.html.

The CDC recommends that for most patients with confirmed SARS-CoV-2 infection, the decision to discontinue transmission-based precautions should be made using a symptom-based strategy [88]. Patients with mild-to-moderate COVID-19 may discontinue isolation five days after onset of illness if respiratory symptoms have improved and at least 24 hours have passed since resolution of fever (without the use of fever-reducing medications). For patients who were asymptomatic throughout their infection, precautions may be discontinued when at least five days have passed since the date of the first positive viral diagnostic test. A well-fitted face mask should be worn by symptomatic and asymptomatic persons during the period of isolation and for five additional days when around others and in public. Additional considerations, including extending the period of isolation precautions to 10 days or more, apply to patients who have sustained severe or critical illness and to those who are significantly immunocompromised [88].

Early side effects, such as soreness at injection site, fatigue, and headache, occur in about 50% of vaccine recipients; feverishness is less common, and all side effects usually resolve in 12 to 36 hours. Immediate, severe allergic reactions (anaphylaxis) do occur rarely within 15 minutes after injection, as with influenza vaccine. Anaphylaxis was not observed during clinical trials, in part because potential participants who had experienced reactions to vaccines were excluded. However, according to a review of SARS-CoV-2 vaccine safety, several cases of anaphylaxis associated with the Pfizer mRNA vaccine were reported following vaccination of 2 million healthcare workers in the United States [102]. For most vaccines in common use, vaccine-associated anaphylaxis has been a rare event, at about one case per million injections. The estimated risk of anaphylaxis associated with use of the Pfizer mRNA vaccine is 1 in 100,000 inoculations—10 times higher [102]. The explanation for this is unclear. One component unique to mRNA vaccines is a polyethylene glycol (PEG) 200 lipid conjugate used to stabilize the nanoparticle carrier system. PEG is a stabilizing compound commonly used in medications and other products and has been implicated in IgE-mediated reactions and recurrent anaphylaxis [102]. This has raised concern that individuals sensitized by past exposure to PEG (or its polysorbate derivative) in commercial products may be at risk of anaphylactic reactions from mRNA vaccination. Anaphylaxis is an acute allergic reaction that can lead to upper airway obstruction, bronchospasm, and circulatory collapse. Prompt recognition and treatment with epinephrine is necessary to prevent life-threatening complications.

A detailed discussion of contraindications and precautions to be observed with mRNA vaccine administration is included in the guidance provided by the CDC [101]. The history of any one of the following reactions is considered a contraindication to vaccination with either the Pfizer-BioNTech or Moderna COVID-19 vaccines [101]:

Persons with an immediate allergic reaction to the first dose of an mRNA vaccine should not receive additional doses of either of the mRNA COVID-19 vaccines [101]. Healthcare providers who participate in mRNA vaccine administration should be familiar with signs and symptoms of hypersensitivity reactions and have access to medications and supplies needed for assessing and managing anaphylaxis. The CDC has provided interim guidance on preparation for the potential management of anaphylaxis after COVID-19 vaccination [103].

Delayed-onset local reactions have been reported after mRNA vaccination in some individuals beginning a few days through the second week after the first dose [101,114]. The suspected cause is delayed-type or T-cell-mediated hypersensitivity, and reactions resolve within a few days. In a small series report, the recurrence rate following the second dose was less than 50% [114]. Vaccinees with only a delayed-onset local reaction (e.g., erythema, induration, pruritis) around the injection site do not have a contraindication or precaution to the second dose of vaccine. The CDC recommends these individuals receive the second dose using the same vaccine product as the first dose at the recommended interval, preferably in the opposite arm [101].

On April 13, 2021, after more than 6.8 million doses of the Janssen COVID-19 vaccine had been administered in the United States. the FDA placed a pause on use of this vaccine while the CDC investigated reports of severe intravascular clotting events in six vaccine recipients within two weeks following vaccination [127]. A rare form of blood clot (cerebral venous sinus thrombosis) combined with thrombocytopenia was observed between the 6th and 13th day after vaccination. All cases were women 18 to 48 years of age, one of whom died. The pause was for purposes of further analysis and so health professionals could become familiar with the diagnostic and management implications. Treatment of this clotting disorder is different from heparin anticoagulant typically administered for treatment of blood clots. Administration of heparin may be dangerous, and alternative therapies are needed for management of COVID-19 vaccine-associated thrombotic complications [127]. The risk of cerebral venous thrombosis following Jenssen COVID-19 vaccination was approximately 1 in 1,000,000 vaccinees.

AstraZenica COVID-19 vaccine, the other primate adenovirus-vectored vaccine used in Europe, has also been linked to thrombotic events in vaccinees. In two separate reviews (11 cases from Germany and Austria, and 5 cases from Norway), patients presented 5 to 16 days after vaccination with thrombocytopenia and signs of vascular thrombosis at unusual sites [128,129]. In patients with one or more thrombotic events, there were 13 instances of cerebral venous thrombosis, 4 of splanchnic-vein thrombosis, 2 of pulmonary embolism, and 4 involving other sites. The patient age range was 22 to 54 years, and 13 of 16 cases were women. The timing of events and character of clinical features were similar to that observed in cases of severe autoimmune heparin-induced thrombocytopenia, suggesting an antibody-mediated thrombotic thrombocytopenia triggered by the vaccine. All patients in each series had high levels of antibodies directed against antigenic complexes of platelet factor 4 (PF4). None of the patients had previously received heparin. This disorder is thought to represent vaccine-induced immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4 [128,129].

These reports, and the action taken by the FDA and the CDC, have important implications for health professionals. Surveillance data from millions of vaccine doses administered indicate that the risk of thrombotic events is extremely low. The risk may be highest in women younger than 50 years of age. Vaccinees who are beyond three weeks from date of vaccination are not considered at risk of thrombotic complications. Individuals who develop any of the following new-onset symptoms within three weeks of vaccination should be evaluated for possible thrombotic complications: severe headache, abdominal pain, swelling or pain in the leg, chest pain, or shortness of breath. The evaluation should include a platelet count and imaging studies appropriate to clinical exam findings. A screening immunoassay for antibodies against PF4-heparin, or an enzyme-linked immunosorbent assay for antibodies against PF4-polyanion should be ordered. Hematology consultation is advisable. Patients with thrombocytopenia and suspicion of a thrombotic event should not be treated initially with a heparin product. Potential treatment options include high-dose immunoglobulins and non-heparin anticoagulants [128,130].

Guillain-Barré syndrome (GBS) has also been reported after Janssen COVID-19 vaccination. As of June 2021, approximately 12.6 million doses of Janssen COVID-19 vaccine had been administered in the United States, with 100 reports of GBS with disease onset 3 to 42 days after vaccination [145]. The median age of reported cases was 57 years, and 61 were male. The GBS reporting rate for all recipients was 7.8 cases per million doses administered; among men 50 to 64 years of age, the rate is 15.6 cases per million doses [145].

Myocarditis and pericarditis have been reported more frequently than expected following receipt of either the Pfizer or Moderna mRNA COVID-19 vaccine, usually within seven days after the second dose of vaccine. The majority were male adolescents or young adult, and most cases were mild, responded well to treatment, and improved rapidly without evident long-term effects. Because a background level of seasonal myocarditis/pericarditis is associated with several common viral infections, at issue is whether and how many additional (excess) cases are precipitated by COVID vaccination. Following a nationwide vaccination program, a one-to-one comparison study with 800,000 subjects each in the vaccinated and control groups found that mRNA COVID-19 vaccine was associated with an excess risk of myocarditis (2.7 events per 100,000 persons) [146]. SARS-CoV-2 infection in the same time period was associated with a higher incidence of myocarditis (11 events per 100,000 persons). The estimated incidence of vaccine-associated myocarditis among males 16 to 29 years of age was 10 events per 100,000 vaccinees; among females 16 to 29 years of age, 0.3 events per 100,000 vaccinees; and among men 30 years of age or older, 2 events per 100,000 [153].

Data from a network of 40 healthcare systems (subserving 15 million people) found the risk of cardiac complications (myocarditis/pericarditis) was significantly higher after SARS-CoV-2 infection than after mRNA COVID-19 vaccination in all age groups evaluated. For example, among males 12 to 17 years of age, the incidence rate of myocarditis/pericarditis was 50 to 65 cases per 100,000 after infection, 2 to 3 cases per 100,000 after the first dose of vaccine, and 22 to 36 after the second dose; among males 18 to 29 years of age, the corresponding incidence rates (cases per 100,000) were 55 to 100 after infection, to -8 after the first and 7 to 15 after the second dose of vaccine. Among young children 5 to 11 years of age, the incidence of myocarditis/pericarditis was considerably lower. After infection, the rate was 13 to 18 cases per 100,000 among males and 5 to 11 cases per 100,000 among females; after COVID-19 vaccination, the rate was 0 to 4 cases per 100,000 among males and 0 cases among females [173]. These findings show that the risk of myocarditis/pericarditis in adolescent and young adult males is 5 to 8 times higher after SARS-CoV-2 infection than after mRNA COVID-19 vaccination.

On July 22, 2021, the ACIP reviewed updated benefit-risk analyses after Janssen and mRNA COVID-19 vaccination and concluded that the benefits of COVID-19 vaccination outweigh the risks for rare serious adverse events after COVID-19 vaccination [145]. In reaching this conclusion, the ACIP reviewed population-level considerations, including that COVID-19 cases were rising in the United States, the predominance of the highly transmissible Delta variant, and the importance of providing options for the type of COVID-19 vaccines offered in relation to epidemiologic considerations. The Department of Health and Human Services, American Academy of Pediatrics, American Heart Association, and other health professional organizations issued a joint statement concurring with the ACIP findings and recommended COVID-19 vaccination of all eligible persons [147].

In late 2020, variant strains of SARS-CoV-2 began to appear in countries with high COVID-19 case rates. Widespread circulation of SARS-CoV-2 combined with spontaneous mutations in the genome increases the probability that mutations affecting transmissibility will lead to emergence of a variant strain. The CDC's national genomic surveillance program identifies SARS-CoV-2 variants and tracks the proportion and distribution of COVID-19 cases attributable to variants [123,124]. SARS-CoV-2 variants circulating in the United States are characterized as variants of concern (VOC) or variants of interest (VOI). In spring 2021, three VOCs accounted for 40% of COVID-19 cases in the United States: B.1.1.7, B.1.351, P.1, and California (B.1.351, 427/429) [123]. The defining characteristics of VOC include increased transmission (B.1.1.7), increased disease severity (B.1.1.7), and decreased neutralization by monoclonal antibody therapeutics (evasion of immunity) (P.1, B.1.351, 427/429). By June/July 2021, these variants had been superseded by a single highly transmissible VOC: B.1.617.2 (Delta) variant [132].

Delta Variant

Compared with the original SARS-CoV-2 strain, Delta variant was more infectious, spread faster, and caused more severe illness in unvaccinated people than previous variants [132]. First detected in December 2020, the Delta variant spread rapidly to 43 countries across six continents. In spring 2021, the COVID-19 surge in the United States had receded to the lowest point of the pandemic; the seven-day moving average of daily new cases was 12,000. By mid-July, the daily average of new cases had again surged to more than 60,000, of which 98% were caused by the SARS-CoV-2 Delta variant [132].

During the period of Delta predominance, breakthrough infection (usually asymptomatic or mild) occurred in vaccinated persons, but the majority of hospitalizations and deaths caused by Delta variant COVID-19 were in unvaccinated people. During the summer COVID-19 surge in Los Angeles County, unvaccinated individuals were five times more likely to acquire Delta variant infection and 29 times more likely to be hospitalized than persons who had been fully vaccinated [158]. The principal risk of secondary household and community transmission was also attributable to unvaccinated people, who were much more likely to become infected and thus shed the virus. Fully vaccinated individuals with breakthrough Delta infection did spread virus to others, but to a lesser degree and for a shorter period of time [132]. An investigation of virologic characteristics among healthcare workers with Delta variant breakthrough COVID-19 found that illness was uniformly mild; shedding of virus from the nose and throat was either unmeasurable or rapidly dissipated within one to three days [115].

Omicron Variant and Subvariants

In mid-November 2021, a new SARS-CoV-2 strain (the Omicron variant) emerged in South Africa among children, college students, and international travelers. By December, Omicron COVID-19 cases were identified in 50 countries, indicating a high level of transmission. Initial cases of SARS-CoV-2 Omicron in the United States were reported in December 2021; by end of month, Omicron replaced Delta as the predominant variant and principal cause of COVID-19 in the United States [123,124]. Omicron SARS-CoV-2 was unique because for the number of genomic mutations and substitutions identified—50 overall, with more than 30 in the spike protein, some associated with reduced susceptibility to monoclonal antibody therapeutics and reduced neutralization by convalescent and vaccinee sera [123]. Epidemiologic studies demonstrated the Omicron variant had a 13-fold increase in infectivity and was three times more infectious than Delta variant [29]. Clinical reports indicated Omicron-associated COVID was mild (e.g., nasal congestion, cough, and fatigue); rates of hospitalization were less than half than with Delta variant. Apparent moderation in disease severity and lower rates of hospitalization for COVID-19 could be misleading, as many early Omicron patients were children and vaccinated adults, in whom illness would is expected to be mild. However, in vitro studies have found that, in hamsters, the Omicron variant was less likely to infect the lungs, and in human alveolar cells, the replication rate was lower, compared with the Delta variant [29].

It was expected that the Omicron variant might evade immune protection gained from prior SARS-CoV-2 infection or COVID-19 vaccination. Studies showed that two-dose mRNA vaccine (Pfizer, Moderna) efficacy in prevention of Omicron COVID-19 waned after four to six months, though protection against severe illness and hospitalization was preserved. Evasion of vaccine immunity was reversed following receipt of a booster dose in persons who previously received the primary COVID-19 vaccine series; an interval-appropriate third (booster) dose increased neutralizing antibody levels 25- to 60-fold, reducing the risk of breakthrough infection by 75% and providing >90% protection against severe illness and hospitalization.

Continued, wide-spread circulation of SARS-CoV-2 has led to new lineages of the Omicron variant and subvariants more transmissible than the previous strain. The BA.5 and BA.4.6 lineages emerged in mid-2022, replaced by XBB subvariant and XBB.1.5 in January 2023. XBB.1.5 is a combination of two earlier Omicron lineages and became the predominant Omicron lineage in the United States, accounting for an estimated 66.4% of cases the week ending February 3, 2023 [124]. Apart from heightened transmissibility and risk of reinfection, the severity of COVID-19 caused by current subvariants is unchanged and the degree of protection against hospitalization and serious outcomes derived from natural and boosted vaccine immunity appears similar to that with prior SARS-CoV-2 strains.

The emergence and subsequent surges of Delta and Omicron COVID-19 demonstrate that SARS-CoV-2 variants can impact transmission, disease severity, risk of reinfection, and vaccine efficacy. At issue is whether and to what extent adaptive immunity (CD4+ and CD8+ T cell responses) acquired from prior infection and/or vaccination recognizes conserved epitopes on new SARS-CoV-2 variants of concern. Fortunately, studies to date have demonstrated that SARS-CoV-2 T cell epitopes are not appreciably affected by mutations found in newly described variants [125,126]. Overall, CD4+ and CD8+ T cell responses in convalescing COVID-19 patients and COVID-19 mRNA vaccinees remain active against VOC circulating in the United States in 2023, including Delta and Omicron variants.

Following initial rollout in December 2020, COVID-19 vaccines were 94% effective in preventing SARS-CoV-2 infection and nearly 100% effective against severe disease, hospitalization, and death. Six months later, after emergence of the Delta variant in May/June 2021, vaccine protection against severe outcomes remained high (92% to 95%) while efficacy against infection (70%) had declined. From January to May 2021, 100 million adults were vaccinated against SARS-CoV-2; an analysis of COVID-19 hospitalizations for the same period found that 600 previously vaccinated adults had been hospitalized for breakthrough COVID-19. Of this group, 74% were older than 65 years of age and 130 died (all patients 71 to 89 years of age) [154].

By mid-2021, vaccine effectiveness against SARS-CoV-2 infection was gradually diminishing among healthcare and other frontline workers, most likely because of decreased immune protection and greater infectiousness of the Delta variant. Clinical trials demonstrated that administration of a COVID-19 vaccine booster dose enhanced significantly the anti-SARS-CoV-2 immune response in previously immunized participants [131]. In response, CDC/ACIP recommended that all persons 5 years of age and older receive an interval-appropriate COVID-19 vaccine booster dose; specifically, six months after having received either a Pfizer or Moderna mRNA primary series, or two months after receiving Johnson & Johnson vaccine. Choice of vaccine booster was left open, meaning that one may "mix and match" vaccine selected for the booster dose; however, selecting one of the mRNA vaccines was preferred. In April 2022, a second interval-appropriate COVID-19 vaccine booster dose was recommended for vaccinees 50 years of age and older, and for others at risk of severe illness because of underlying medical conditions.

Efficacy of COVID-19 vaccine booster against SARS-CoV-2 variants was demonstrated in an analysis of data from a multistate hospital network comprising 7,544 patients enrolled between March 11, 2021, and January 24, 2022. This study found that two or three doses of COVID-19 mRNA vaccine conferred 90% protection against COVID-19-related invasive mechanical ventilation or in-hospital death [172]. Vaccine effectiveness against adverse outcomes was consistent throughout the periods of Delta and Omicron predominance; protection against mechanical ventilation and death (94%) in the Omicron period was higher in patients with COVID-19 who had received a third (booster) dose. In a large cohort study of nursing home residents, receipt of a second mRNA COVID-19 booster dose during circulation of Omicron subvariants was 74% effective at 60 days against severe COVID-19-related outcomes (including hospitalization and death) and 90% against death alone compared with receipt of a single booster [180].

Following emergence in November 2021, Omicron SARS-CoV-2 has evolved into multiple sublineages, accumulating additional mutations that facilitate evasion of neutralizing antibody activity elicited by both natural infection and COVID-19 vaccination. SARS-CoV-2 circulation persisted in the general population, new cases of COVID-19 continued, and reports of reinfection increased among persons previously infected or vaccinated. In order to bring the pandemic under better control, the CDC/ACIP recommended replacing monovalent mRNA vaccine boosters with a newly developed Pfizer bivalent mRNA vaccine composed of Omicron BA.4/BA.5 spike and ancestral SARS-CoV-2 spike protein. Beginning September 2022, bivalent mRNA vaccine replaced the monovalent vaccine for COVID-19 booster dose vaccination in the United States and other countries.

During the intervening period, September 2022 to January 2023, studies of bivalent mRNA COVID-19 vaccine effectiveness demonstrated greater immunogenicity and additional benefit against Omicron subvariants when compared with monovalent COVID-19 vaccine. A comparison study found that neutralizing antibody titers elicited against all Omicron sublineages (including XBB.1) were several times higher with bivalent vaccine compared to monovalent vaccine when administered as a fourth booster dose [181]. Participants with a history of prior SARS-CoV-2 infection exhibited higher titers to bivalent vaccination than those without prior history of infection. CDC surveillance data from a healthcare network demonstrated that bivalent boosters provided significant additional protection against symptomatic SARS-CoV-2 infection in participants who had received at least two prior monovalent vaccines. Relative benefits increased with time since receipt of the most recent monovalent vaccine dose [182]. In another report, bivalent boosters provided substantial additional protection against Omicron COVID-19 disease severity and hospitalization, higher (59%) than monovalent boosters (25%) [183]. An observational cohort study in Great Britain found that people 65 years of age and older who received the bivalent vaccine had lower COVID-19 hospitalization and mortality rates than non-recipients up to 70 days after vaccination. Of the 622,700 participants in the study, 85,300 (14%) received a bivalent booster during the 70-day study period. Hospitalization due to COVID-19 occurred in 6 bivalent vaccine recipients and 297 non-recipients, corresponding to 80% effectiveness against hospitalization for bivalent vaccine. Death from COVID-19 occurred in 1 bivalent booster dose recipient and 73 non-recipients of bivalent vaccine booster [184]. In a January 2023 early release, CDC investigators reported that receipt of bivalent mRNA booster dose provided additional protection against symptomatic XBB/XBB.1.5 subvariant infection for at least three months after vaccination in persons who had previously received two to four monovalent vaccine doses [185]. These finding indicate the importance of continued monitoring of vaccine effectiveness and the value of staying up to date with recommended COVID-19 vaccines, including receiving a bivalent booster dose when eligible.

The CDC uses public health surveillance data from participating health departments, hospitals, and long-term care facilities to monitor rates of COVID-19 cases, hospitalizations, and deaths by vaccination status. Participating jurisdictions represent a large proportion of the United States population and all regions of the country. Age-standardized weekly rates of COVID-19 cases and deaths are displayed by vaccination status, including receipt of an updated booster (bivalent) dose [124]. As of December 2022, all age-matched vaccinated groups had lower rates of dying from COVID-19 and lower rates of testing positive for SARS-CoV-2 compared with those who were unvaccinated. People who were vaccinated with an updated (bivalent) booster dose had lower rates of dying and testing positive compared with those vaccinated but who had not received an updated (bivalent) booster dose. People 5 years of age and older who were vaccinated with an updated (bivalent) booster had 3.1 times decreased risk of testing positive for SARS-CoV-2 and 12.7 times decreased risk of dying from COVID-19. In people 65 to 79 years of age, the death rate from COVID-19 was 24 times lower among those vaccinated and (bivalent) boosted (0.3 per 100,000 population) compared with those unvaccinated (8 per 100,000) [124].

As of January 2023, COVID-19 vaccines have been in use in the United States for two years; more than 665 million COVID-19 vaccine doses have been administered and 229.5 million people have completed a primary series, comprising 69% of the total population [124]. In people 65 years of age and older, 71.4% have completed a primary series and received at least one booster dose. Approximately 52% of the eligible general population have received a primary COVID-19 series and an interval-appropriate booster dose. The efficacy of COVID-19 vaccines in reducing the incidence of symptomatic SARS-CoV-2 infection and protecting against severe outcomes (hospitalization and death) has been demonstrated in clinical trials and confirmed by real-world observational studies.

The CDC's surveillance program maintains a COVID-19 Data Tracker and Weekly Review of reported COVID-19 cases, hospitalizations, and deaths in the United States [124]. This website also provides updated information on COVID-19 vaccination rates, prevalence of SARS-CoV-2 variant strains in circulation, and the current community levels of COVID-19 by county, district, and territory. As of February 1, 2023, the seven-day average of weekly new cases (40,130) decreased 6.7% compared with the previous week, and the Omicron lineage (e.g., XBB.1.5, BQ.1, XBB) accounted for 100% of new cases. The seven-day daily average of new hospital admissions was 3,319, a decrease of 8.4% from the prior week. The seven-day average of new COVID-19 deaths (493) decreased 9% compared with the previous seven-day average. Overall, about 229.7 million people (69.2% of the population) have completed a primary COVID-19 vaccine series. Approximately 71% of people >65 years of age have completed a primary COVID-19 vaccine series followed by at least one interval-appropriate booster. About 111 million people (49% of the eligible population) have completed a primary series plus one additional booster dose of COVID-19 vaccine. More than 42.1 million people, or 20% of the eligible population 5 years of age and older, have received an updated (bivalent) booster dose [124].

The CDC recommends use of their COVID-19 Community Levels site to determine the impact of COVID-19 on communities, the local risk of exposure, and advisable precautions. As of February 3, 2023, 4% of counties, districts, or territories had a high COVID-19 Community Level, 25% had a medium Community Level, and 71% had a Low Community Level [124]. Compared with the prior week, the number of counties in the high and medium levels increased by 1.5%.

The CDC website also provides updated COVID-19 clinical guidance for providers, laboratories and health facilities, and public health officials [124]. Included are recommendations for the evaluation of persons/patients under investigation, laboratory specimen transport, and protection of healthcare workers and transmission precautions in clinical settings. Recommendations for patient assessment and care in hospitals, clinics, and other healthcare facilities emphasize the importance of adherence to isolation and barrier precautions, including proper use of personal protective equipment (PPE). Selected materials from the CDC website, including recommendations for travelers, are reproduced in the following sections. Please note that language and/or cultural barriers may impede assessment of risk and patient education on the topics pertaining to transmission of infection and public safety; using interpreters and translated materials are recommended, when appropriate.

The CDC provides updated information and guidance on domestic and international travel precautions [13]. The CDC recommends being up to date with COVID-19 vaccines before travel and checking COVID-19 community level at destination. Vaccinated and unvaccinated individuals who travel should observe the following precautions [13]:

Unvaccinated persons should consider obtaining a SARS-CoV-2 nasopharyngeal swab test one to three days before the trip, and repeat the viral test three to five days after return from destinations with medium or high COVID-19 activity. Returning travelers from any destination are encouraged to observe standard precautions, monitor health, and follow state, territorial, tribal, and local recommendations or requirements after travel [13].

As of May 2022, the CDC recommends that persons who are up to date with COVID-19 vaccination can travel with low risk to themselves and others [13]. Up-to-date COVID-19 vaccination status is defined as having received the initial primary series and an interval-appropriate booster dose. Such persons can travel safely within the United States without the need for pre-travel testing or post-travel self-quarantine if they continue to take COVID-19 precautions while traveling.

CDC guidance specifies who should be tested for COVID-19 and encourages clinicians to use clinical judgment in determining whether a patient with signs and symptoms compatible with COVID-19 should be tested [14]. Symptoms to be considered include fever, chills, cough, sore throat, muscle aches, shortness of breath, new loss of taste or smell, and vomiting or diarrhea. As noted, SARS-CoV-2 can cause asymptomatic, pre-symptomatic, and minimally symptomatic infection, leading to virus shedding that may result in transmission to others who are particularly vulnerable to severe disease and death. Special attention should be paid to older adults and to patients with underlying conditions or immunosuppressed states. Even mild signs and symptoms of COVID-19 should be evaluated among potentially exposed healthcare personnel because of their extensive contact with vulnerable patients in healthcare settings.

The CDC has established priorities for COVID-19 diagnostic testing [14]. High priority for testing applies to hospitalized patients with compatible clinical features, healthcare facility workers and those who work in congregate living settings with symptoms, and residents in long-term care facilities (including prisons and shelters) with symptoms. Priority designation for testing applies to any person in the community with symptoms of potential COVID-19. In addition, persons without symptoms may be prioritized by health departments or clinicians for reasons such as public health monitoring, sentinel surveillance, or screening purposes.

Clinicians should work with their local and state health departments to coordinate testing through public health laboratories or work with commercial or clinical laboratories using SARS-CoV-2 diagnostic tests granted an Emergency Use Authorization by the FDA. Patients should be evaluated and discussed with public health departments on a case-by-case basis if their clinical presentation or exposure history is equivocal.

Other considerations that may guide testing include epidemiologic factors (e.g., close contact with an individual who in the past 14 days has tested positive for SARS-CoV-2) and the occurrence of local transmission or a cluster of COVID-19 within a specific community setting (e.g., nursing home, manufacturing facility) [14]. Close contact is defined as one of the following:

Any patient with fever and severe acute lower respiratory illness (e.g., pneumonia, ARDS) requiring hospitalization and without alternative explanatory diagnosis (e.g., influenza) should be evaluated for COVID-19, even if no source of exposure has been identified [14].

Symptomatic patients should be provided a surgical mask and placed on respiratory isolation, preferably in an airborne isolation negative pressure room. Caregivers should observe enhanced precautions (i.e., wear gloves, gown, eye protection device [other than prescription eye glasses], and N95 respirator). For information on the management of patients with COVID-19, see https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/clinical-considerations-index.html.

The CDC recommends that healthcare providers should immediately notify both infection control personnel at their healthcare facility and their local or state health department in the event of a newly diagnosed or suspected case of COVID-19.

Confirmation of COVID-19 is performed using the RT-PCR assay for SARS-CoV-2 on respiratory specimens (which can include nasopharyngeal or oropharyngeal aspirates or washes, nasopharyngeal or oropharyngeal swabs, bronchoalveolar lavage, tracheal aspirates, or sputum) and serum. The FDA has worked to expedite the availability of tests through emergency authorization of commercial laboratories that have developed SARS-CoV-2 testing capability. Information on specimen collection, handling, and storage is available at https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html. After initial confirmation of COVID-19, additional testing of clinical specimens can help inform clinical management, including discharge planning. Additional guidance for collection, handling, and testing of clinical specimens is available at the CDC website [12].

Infection with both SARS-CoV-2 and with other respiratory viruses has been reported, and detection of another respiratory pathogen does not rule out COVID-19 [15].

The CDC and NIH websites provide updated clinical guidance and additional resources for clinicians caring for patients with COVID-19 [15,57]. Clinical management entails prompt implementation of recommended infection prevention and control measures, and resources to support patients with complications, including advanced organ support if indicated [15]. Healthcare personnel should care for patients in an airborne infection isolation room. Isolation Precautions should be used when caring for the patient. For detailed recommendations, see the CDC's Interim Infection Prevention and Control Recommendations for Patients with Suspected or Confirmed Coronavirus Disease 2019 (COVID-19) in Healthcare Settings at https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.html. The NIH and the Infectious Diseases Society of America provide updated COVID-19 management guidelines, including specific recommendations for the use of remdesivir and dexamethasone in hospitalized patients [10,57].