ESSENTIALS OF DIAGNOSIS
Wide spectrum of symptoms.
Asymptomatic in at least 20–35% of adults.
Adults have upper respiratory tract illness with fever and cough most often when symptomatic.
The clinical triad of cough, fever, and dyspnea is infrequent (less than 15%).
Advanced pulmonary complications (pneumonia, acute respiratory distress syndrome [ARDS]) with fulminant disease.
Mortality of 1–21% (varied by geographic area and strain).
High predilection for the elderly, the immunocompromised, those with chronic diseases, those living in crowded conditions.
In late 2019, a novel coronavirus emerged, spreading quickly from its origin in China across the globe. The virus was initially named “novel coronavirus 2019” (2019-nCoV), accounting for the year of discovery, its status as a “novel” virus, and its family name (coronavirus, CoV). The CDC-recommended terminology for the virus is SARS-CoV-2, and the illness caused by this virus is called “Coronavirus Disease 2019” or COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/summary.html).
Coronaviruses are a large family of viruses commonly found in humans as well as many other species of animals, including bats, camels, cattle, and feral cats. Like SARS-CoV and MERS-CoV as well as human common cold coronaviruses HC43 and HKU1, the SARS-CoV-2 virus is a betacoronavirus, which is one of the four genera of coronaviruses (only the alphacoronaviruses [coronavirus NL63 and 229E] and betacoronaviruses affect humans). All these coronaviruses have their origins in bats. SARS-CoV-1 and MERS- CoV were identified 7 and 17 years before SARS-CoV-2 was identified. The spread of SARS-CoV-2 from bats was perhaps amplified by pangolins, an Asian anteater whose scales are traded on black markets for circulatory problems, although this latter theory remains under investigation.
SARS-CoV-2 appears to have made its transition from bats to humans in late 2019 at a wet market in Wuhan, the capital of the Chinese province of Hubei. Early in the outbreak, most fatalities were from Wuhan and other parts of the Hubei province. As cases were reported from other countries, COVID-19 was declared a pandemic by the WHO on March 11, 2020. By early March 2020, case numbers outside of China were growing faster than inside China (see the Johns Hopkins Coronavirus Resource Center website for specifics at a given time https://coronavirus.jhu.edu/).
The earliest known case in the United States was documented on January 21, 2020, in a man who had recently returned to the state of Washington from China. The first US case that was not associated with travel or contact with infected travelers was identified on February 26, 2020 in Solano, California, although community transmission likely began in late January or early February (three cases that occurred in February and early March 2020 from Santa Clara County, California, were identified as COVID-19 by postmortem examination).
As of September 11, 2020, global cases surpassed 28.2 million, including over 911,000 deaths. The ten most impacted countries are the United States, India, Brazil, Russia, Peru, Colombia, Mexico, the Republic of South Africa, Spain, and Argentina. The United States reports the largest number of recognized cases in a single country at over 6.43 million and over 192,000 deaths. China, the original epicenter of the emerging pandemic now ranks 37th in number of total cases among the 188 world nations reporting infections. In the United States, the five states with the highest total cases are California, Texas, Florida, Georgia, and Illinois; the five states with the highest per capita cases are Louisiana, Florida, Mississippi, Alabama, and Georgia, and the five states with the highest total deaths are New York, New Jersey, California, Texas, and Florida.
Since April 2020, the CDC has recommended that travelers avoid nonessential international travel, restrict domestic travel, and stay at home as much as possible, especially if sick. The CDC website continues to provide a complex set of guidelines and suggestions regarding travel (www.cdc.gov). All travelers should be aware of the likelihood of evolving quarantine regulations both abroad and on return based on origin and destination of travel. Most nations are currently restricting American travel in the wake of the recent surge of cases in the United States. A case tally and other current information are available through the WHO website (https://www.who.int/emergencies/diseases/novel-coronavirus-2019) and, with an interactive map, through The Johns Hopkins University Coronavirus Resource Center website (https://coronavirus.jhu.edu/map.html). Highly informative weekly University of California, San Francisco (UCSF) Medical Grand Rounds focused entirely on COVID-19 since March 19, 2020 can be found on YouTube.
A. Clinical Epidemiology and Transmission
SARS-CoV-2 shows a higher rate of person-to-person spread than the 2003 SARS-CoV-1 virus. Some COVID-19 strains from Western Europe have enhanced transmissibility as a function of a modified Spike protein. Specifically, a SARS-CoV-2 variant carrying the Spike protein amino acid change D614G, initially the most prevalent form in the global pandemic, has been superseded by a new SARS-CoV-2 variant, G614, suggesting that the G614 variant may have a fitness advantage. A pattern of mutations is being described as phylodynamic and three main groups comprise current global strains, with ongoing efforts underway to identify new variants as they emerge.
A number of angiotensin-converting enzyme–2 (ACE-2) mutations appear to confer altered host sensitivity to COVID-19. A specific gene cluster (3p21.31) has also been identified as a genetic susceptibility locus for respiratory failure in patients with COVID-19. A deletion in the toll-like receptor 7 (TLR7, involved in interferon production) is recognized to be associated with progressive COVID-19 disease in a small cohort of young individuals.
R0 is the basic reproductive number signifying the number of contacts infected by an infected individual. Calculations of R0 for SARS-CoV-2 have varied but the true R0 likely lies somewhere between 2 and 3. Transmission has been shown to be extremely efficient within higher-density living facilities (such as nursing homes, homeless encampments, jails and prisons, some Native American reservations, and certain employment settings [such as meat packing plants]). Simply talking (or singing) in close quarters may efficiently spread the virus, as shown by a study of a choir in the state of Washington where 52 of 61 choir members became ill in March 2020.
Superspreading events (ie, when a person infected with SARS-CoV-2 is at the most infectious stage [usually around day 4 of infection] and infects a disproportionate number of susceptible person[s]) are increasingly recognized as playing an important role in SARS-CoV-2 transmission. One example of a superspreading event was a biopharmaceutical executive meeting that was held in Boston in February 2020 where the disease developed in 28 of the 175 participants; through genomic analysis, it was determined that subsequent superspreading was responsible for over 20,000 cases (2.7% of all American cases) throughout the United States, including cases among homeless shelter clients in Boston. Conversely, certain variants of SARS-CoV-2 did not appear to be as likely to induce widespread dissemination. Nonetheless, the importance of venues outside the home for spreading infection is evident from a Japanese review in which 61% of all national cases were traceable to clusters outside the home, including restaurants, bars, event venues, and workplaces.
While the case-fatality rate was higher with the 2003 SARS-CoV-1, the number of infected cases is much higher with SARS-CoV-2 than with either the SARS or MERS viruses. The incubation period for SARS-CoV-2 ranges from 2 to 24 days with an average of about 5 days. Presymptomatic spread accounts for a large number of cases, and the viral load for SARS-CoV-2 is highest in the presymptomatic phase. A CDC telephone survey of infected individuals showed that only 46% reported contact with a known case, and among the known contacts, the most common were family members (46%) or work colleagues (34%).
The principal mode of transmission is respiratory droplets, which can be propelled 6 feet or more by sneezing or coughing (and have been documented to be propelled as far as 27 feet). Studies of SARS-CoV-2 aerosolization during loud talking have brought into question the adequacy of the “6 feet/1.8 meter” rule currently recommended for physical distancing. The degree that SARS-CoV-2 is aerosolized during coughing and respiratory procedures, the transmission potential of aerosolized particles containing live virus, and the inactivation potential of UV-C light all remain under study. The CDC currently recommends that airborne precautions be used in healthcare settings principally for healthcare providers performing respiratory procedures (such as collecting induced sputum or intubating the patient). Nonetheless, aerosols are considered a much less likely mode of transmission than respiratory droplets. The current reported rates of transmission are 5% for close contacts and 10–40% for household contacts.
Hospital-related transmission to staff or other patients was reported in 41% of 138 hospitalized patients from Wuhan, China. A study of more than 3000 symptomatic healthcare workers in Seattle, WA, however, showed that the prevalence of positive SARS-CoV-2 tests among symptomatic “frontline” workers was comparable to that of symptomatic non-frontline staff (about 5%).
As of September 11, 2020, the CDC reported that 158,519 healthcare personnel had become infected in the United States. Survival data are available for 112,361 of these healthcare personnel; 697 had died. Non-CDC sources show even higher death tolls for healthcare worker; the Manchester Guardian and the Kaiser Family Foundation maintain a database of healthcare-associated mortality, and as of August 27, 2020, the healthcare deaths had increased to 1087 in the United States with nurses being the group at highest risk. The reported prevalence of SARS-CoV-2–infected clinical personnel at a large Houston hospital was 5.4%. Recent seroprevalence studies suggest that a large number of SARS-CoV-2 cases likely went undetected in healthcare workers.
Reviews of death data imply that reported deaths from COVID-19 only capture about two-thirds of all excess deaths that are reported late or misattributed to other respiratory and nonrespiratory illnesses. In the New York outbreak, cardiac causes were responsible for most of these excess deaths.
Severe disease seems to develop in adults much more often than in children, and symptomatic disease appears to develop in men more often than in women. The coding of the ACE receptor protein occurs on the X chromosome and the presence of variants in this protein may explain some of the clinical variation based on sex.
SARS-CoV-2 certainly can infect children and may be able to spread efficiently in children in close contact settings, such as schools. As the 2020–21 school year begins, some schools and universities that opened for in-person classes in August 2020 have since closed or restricted student movement due to increasing case numbers. Children have lower concentrations of ACE-2 receptors in lung tissue, which may explain their lower propensity toward severe infection. With the advent of COVID-19, the CDC reports a fall in immunization rates for the vaccine preventable diseases of childhood. The unique complications of SARS-CoV-2 among children are discussed below.
SARS-CoV-2 infection is particularly serious in the elderly and in those with comorbid conditions of immunocompromise (including post-organ transplant) or chronic diseases (diabetes; obesity; hypertension; chronic heart, lung, or kidney disease; and prior stroke). In one large multiethnic cohort study of adults hospitalized with COVID-19, obesity was associated with an increased risk of death or intubation independent of age, sex, race/ethnicity, and comorbid conditions. While the infection shows a predilection for pulmonary tissues, data regarding susceptibility of persons who smoke cigarettes and those with asthma are unclear.
Preliminary evidence is mixed regarding the risk of SARS-CoV-2 infection in immunosuppressed patients (including those immunosuppressed due to rheumatologic conditions). In one recent review, the subgroups of cancer patients who had disproportionately high mortality from COVID-19 included individuals with lung cancer (case fatality rate [CFR] 18–55%) and those with hematologic malignancy (CFR 33–41%). Recent active therapy for cancer (including immunotherapy and tyrosine kinase inhibitors) has been associated with worse outcomes. Studies of people living with HIV suggest that their risk of developing COVID-19 is just as high if not higher than that of the general population (see Chapter 31). In one recent study of 286 people living with HIV, 57.3% of patients were hospitalized, 16.5% required ICU care, and the overall mortality rate was 9.4%. As in the general population, older age, chronic lung disease, and hypertension were associated with worse outcomes.
The full spectrum of complications associated with pregnancy is unknown. Reports of in utero transmission from Italy (2 of 31 pregnancies) require confirmation. The duration of IgM to coronavirus in potentially infected neonates is much shorter than that seen with other neonatal viral infections. The virus does not appear to be transmitted in breast milk. A team based at UCSF (the Priority study) is assessing prospectively the complications associated with pregnancy, delivery, and breastfeeding. (See https://www.nejm.org/coronavirus for review of cases and https://obgyn.ucsf.edu/block/theme-priority-study for enrollment of women in the above categories). Among pregnant women with SARS-CoV-2 infection, CDC studies document an increased risk of hospitalization, ICU admission, and mechanical ventilation but not death.
B. Public Health Concerns
Among many COVID-19–related US public health concerns, the most urgent needs include the following: (1) widespread implementation of (and adherence to) containment measures (physical distancing and self-quarantining) to prevent spread of the disease in vulnerable populations; (2) increased availability of masks, personal protection equipment, and ventilators; (3) standardization of nucleic acid (and making available easy-to-use home kits for early infection) and serologic assays and broadened surveillance to help control infection and determine duration of natural immunity; (4) continued surveillance to determine the relative importance of asymptomatic transmission; (5) increased attention to minority populations, particularly black and Latinx populations, since they are at high risk for infection and complications (importantly, the most recent analysis shows that these minority populations are at higher risk for COVID-19–associated mortality because of concomitant socioeconomic risk factors rather than genetic factors); (6) guidelines for nursing home safety and support; (7) standardization of state-by-state data reporting; (8) improving data-based guidelines for children and staff to safely return to schools and policies for universities to provide a safe learning environment for students and faculty; (9) emergence of antibiotic resistance exacerbated by the inappropriate use of antibiotics for COVID-19; and (10) vaccine research, including the identification of markers of protection and the role of mucosal immunity.
At this time, lockdown and physical distancing restrictions have been relaxed or modified in many parts of the United States. Four benchmarks developed by a panel of US governmental and academic advisors to recommend the readiness of jurisdictions to ease restrictions include (1) the ability of hospitals to safely care for patients without requiring a crisis standard of care, (2) the ability of a state to test all who have symptoms, (3) a robust system of contact tracing, and (4) a documented decline in incidence of COVID-19 for 14 days. Unfortunately, the reopening of businesses without strict requirements to maintain physical distancing standards has led to increasing case numbers in many US cities, particularly in the American South and Southwest, and subsequently the American Midwest. Consequently, many communities are evaluating ways to estimate the incidence and prevalence of SARS-CoV-2 infection to inform decision-making (ie, integrated community and seroepidemiologic surveys combined with modeling approaches). In an attempt to address the increasing need for rapid diagnostic community testing in the United States, the FDA issued the first emergency use authorization (EUA) for sample pooling in COVID-19 diagnostic testing on July 18, 2020.
The CDC has published guidelines for workplaces, schools, childcare centers, and other entities (https://www.cdc.gov/coronavirus/2019-ncov/community/index.html) in July 2020. These guidelines include wearing face coverings in public, maintaining physical distancing measures, and cleaning “high touch” surfaces. Further suggestions based on data to suppress the spread of aerosolized SARS-CoV-2 inside public buildings include engineering controls such as implementation of effective ventilation with air filtration and disinfection and avoidance of air recirculation and overcrowding. On June 26, 2020, the American Academy of Pediatrics released a statement strongly advocating for in-person learning. Despite these measures, significant concern exists regarding whether grade schools should go forward with virtual versus in-person classes. The many issues attendant with testing for return to work include the day-to-day variability in exposure and positivity, the needs for informed consent for those tested and for employers to learn results, the nonreplicative nature of late positive tests, and the unreliability of many assays.
Most infected individuals are asymptomatic, although the ratio of asymptomatic to symptomatic infection remains unclear and changes as more individuals are tested. Adults can manifest a wide range of symptoms from mild to severe illness that begin 2–14 days (the mean is 5 days) after exposure to SARS-CoV-2. The CDC reports that symptomatic patients may have any of the following: cough, fever, chills/rigors, or myalgias. The presence of dyspnea is variable, but it is the most common symptom among patients with life-threatening infection and is highly prevalent in advanced, severe infection. No one symptom should be used as a discriminant for disease. Less common symptoms include rhinitis; pharyngitis; abdominal symptoms, including nausea and diarrhea; headaches; anosmia; and ageusia. It appears that 15–20% of adults with COVID-19 require hospitalization and 3–5% require critical care. “Classic” respiratory manifestations of COVID-19 develop in few children; unless immunocompromised or younger than 1 year old, children typically have asymptomatic or only mild disease after SARS-CoV-2 exposure. Symptomatic disease in children is more likely to present with gastrointestinal symptoms and less likely to present with respiratory symptoms.
Hematologic findings include neutrophilia, absolute lymphopenia, and an increased neutrophil to lymphocyte ratio. As disease advances, blood chemistry findings often include elevated liver biochemical tests and total bilirubin. Serum markers of systemic inflammation are increased in most patients with severe COVID-19, including lactate dehydrogenase level, ferritin, C-reactive protein, procalcitonin, and interleukin 6 (IL-6). Additionally, many reports have accumulated detailing the initial coagulopathy seen in severe COVID-19, which is identified by elevated von Willebrand factor (VWF) antigen, elevated D-dimer, and fibrin/fibrinogen degradation products; the prothrombin time, partial thromboplastin time, and platelet counts are usually unaffected initially (see Chapter 14). The entity, referred to as COVID-19–associated coagulopathy (CAC) has laboratory findings that differ from traditional DIC. In CAC, fibrinogen levels are higher and platelets levels are more often normal than with DIC. Mortality among hospitalized SARS-CoV-2–infected patients correlates with levels of VWF antigen as well as levels of soluble thrombomodulin, suggesting that an endotheliopathy occurs in critically ill patients.
COVID-19 diagnosis is established using nucleic acid testing. Molecular tests to detect SARS-CoV-2 were first developed in China in January 2020. Since then, many different types of SARS-CoV-2 tests have been developed in thousands of laboratories worldwide. In the United States, the FDA approved the first SARS-CoV-2 PCR test via EUA on February 4, 2020. The first EUA for a SARS-CoV-2 antigen test was issued on May 9, 2020. As of September 11, 2020, the FDA has approved 247 tests under EUAs, including 197 molecular tests, 46 antibody tests, and 4 antigen tests.
Importantly, standardization of these tests is far from finalized. On May 27, 2020, the FDA released a SARS-CoV-2 reference panel to be used as an independent performance validation step for molecular diagnostic tests. In general, the reverse transcriptase–polymerase chain reaction (RT-PCR) assays are the standard for diagnosis, and assays based on nucleic acid amplification technology (NAAT), rapid antigen assays, and laminar flow procedures are less sensitive. The laminar flow assays are available for home use; these assays, despite their lower sensitivity, may be useful for early illness when viral loads are high (and usually higher even before symptoms develop). The lateral flow Abbott assay has a 97.1% predictive for a positive test and a 98.5% predictive value for a negative test (note these values are not sensitivity and specificity) and the FDA has already expressed concern that the rate of false-negative tests is about 3%.
Currently, the sensitivity of nucleic acid tests from oral swabs is deemed low (35%); nasopharyngeal swabs (63%) or the more invasive bronchoalveolar lavage fluids (91%) are preferred. Sputum is theoretically preferred over oropharyngeal specimens, and the virus may be detectable longer in sputum than in other upper respiratory tract samples. Saliva tests are quickly gaining popularity due to their ease of collection, although they likely have decreased sensitivity compared to deeper respiratory tract specimens. Five saliva tests have received FDA EUAs to date. Most recently, the Yale School of Public Health’s “SalivaDirect” test was approved on August 15, 2020. This test is unique because it does not require a separate nucleic acid extraction step, thereby allowing for increased, rapid testing that has the potential to reduce the strain on available testing resources that is being experienced by many communities.
The use of duplicate “orthogonal” testing is recommended by CDC when clinical conditions support the diagnosis in the absence of a confirmed SARS-CoV-2 assay. A guideline to monitor decision making published by the CDC is available at https://www.whitehouse.gov/wp-content/uploads/2020/05/Testing-Guidance.pdf.
Isolation of the virus by nucleic acid assays more than 10 days after the onset of symptomatic infection (or 15 days after exposure on the average) is usually not associated with replicative, infectious particles. Immunosuppressed patients can have prolonged detection of replicative virus (viral shedding).
A variety of laboratories are producing antibody assays to determine immunity and facilitate decision making in return-to-work policies. On April 1, 2020, the first rapid lateral flow assay (Cellex) was approved by the FDA under EUA to detect IgM and IgG antibodies to SARS-CoV-2. Subsequently, many additional tests that can detect SARS-CoV-2 antibodies have received EUAs (https://www.fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations#covid19ivd). It is not clear whether these assays test for neutralizing antibodies. Importantly, because most of these assays are not standardized, the results should be interpreted with caution. Certain assays show cross-reactivity with common human coronaviruses, and most are insensitive early in the course of mild disease.
Currently, an unstandardized combination of clinical findings in conjunction with nucleic acid tests are used to make the diagnosis of COVID-19, recognizing that the wide spectrum of clinical findings and the false reassurance of assays are not fully sensitive or specific. At this time, the consensus, including that from a Cochrane Review, is that serologic assays should not be used in point-of-care settings and should not be used to determine back-to-work status. In the clinical setting, commercial serologic assays can be used to determine if a person has had past COVID-19, and these assays show public health utility in serosurveys.
Of note, the CDC is currently equivocal about testing asymptomatic individuals. Questions have been raised about whether there was political influence on the CDC to equivocate about its asymptomatic testing position, which is counter to the advice of the vast majority of infectious disease specialists who recognize the important role of asymptomatic disease in transmission (earlier modeling data, including those from the University of California, Berkeley, have emphasized the important role of asymptomatic individuals in transmission and the need to identify such persons if one is going to control the pandemic). Also, Harvard scientists recommend that SARS-CoV-2 assays be used to test asymptomatic individuals, that there should be regular and low cost testing of asymptomatic persons, and that those who test positive should be quarantined in an attempt to effectively control the pandemic.
The American College of Radiology confirms clinicians’ earlier findings; neither chest radiographs nor chest CT scans provide diagnostic utility, since both may be normal, and the nonspecific findings overlap with those of many viral infections (including influenza, H1N1, and the SARS-1 and MERS coronaviruses). Later in the disease course, nonspecific diffuse ground glass opacities and/or multilobular infiltrates (which often progress to consolidation) become more common. Chest ultrasonography, MRI, and PET/CT findings tend to confirm the CT findings of an evolving organizing pneumonia.
The key element in the differential diagnosis is seasonal influenza infection, which can usually be ruled out by a nasal swab antigen assay. Concomitant infection with influenza or other respiratory pathogens is reported. Symptom onset tends to be more abrupt with influenza; however, the clinical manifestations overlap to a considerable degree, and it is difficult to use any symptom to distinguish between the two diseases. A useful Table comparing symptoms of an upper respiratory infection, influenza, and COVID-19 is available at https://www.medicalnewstoday.com/articles/coronavirus-vs-flu#symptoms.
Most patients have uncomplicated disease. In an early Chinese series, 81% of patients were asymptomatic or had mild disease, 14% had severe disease, and 5% were critically ill. In a New York City series, 14% of patients required ICU care, 12% required ventilation, 3% required renal replacement therapy, and 21% died.
One large Chinese study found that the independent predictors of a fatal outcome were age 75 years or greater, a history or coronary heart disease, cerebrovascular disease, dyspnea, procalcitonin levels over 0.5 ng/mL, and aspartate aminotransferase levels over 40 units/L. A large German study confirmed the role of age with an in-hospital mortality of 72% in those over 80 years, and it also showed that among ventilated patients who received dialysis, the mortality was 73%.
A clinical risk score calculator to predict critical illness in hospitalized patients with COVID-19 called COVID-GRAM has been validated (http://22.214.171.124/); predictors of clinical deterioration include presence of chest film abnormalities, older age, positive cancer history, increased number of comorbidities, presence of certain signs and symptoms (hemoptysis, dyspnea, and decreased consciousness), and presence of certain laboratory abnormalities (increased neutrophil to lymphocyte ratio, increased lactate dehydrogenase, and increased direct bilirubin). Severe COVID-19 likely occurs because of an intense and/or prolonged inflammatory reaction, often called a “cytokine storm” (a term that is criticized by some experts because cytokine levels in COVID-19 are far lower than those in ARDS), in the later phase of illness. Persistent immune activation in predisposed patients can lead to uncontrolled amplification of cytokine production (including IL-6), leading to multiorgan failure and death.
Some patients progress to ARDS akin to the coronavirus infections that cause SARS and MERS (but unlike the far more common “common cold” coronavirus infections); COVID-19–related ARDS is so commonly recognized now that it is referred to as “CARDS.” CARDS care requires the involvement of intensivists who can provide guidelines for respiratory support, including appropriate oxygen flow and ventilator parameters, prone positioning (which is also useful for nonventilated pulmonary patients), and hydration status. Several chemokine-receptor genes (CCR9, CXCR6, and XCR1) are associated with severe disease.
The spectrum of pulmonary pathology based on a review from Italy shows that the most common findings on postmortem examinations are diffuse alveoli congestion, hyaline membrane formation, pneumatocyte hyperplasia and necrosis, platelet-fibrin thrombi, interstitial edema, and squamous metaplasia with atypia. Such pathologic findings are seen in other organs as well at autopsy; pathologists note the four most common findings are the alveolar damage and thrombosis listed in the lung descriptions above as well as hemophagocytosis and lymphocyte depletion.
Many extrapulmonary complications are reported and most of these are likely related to SARS-CoV-2–induced inflammatory reactions. COVID-19–related coagulopathy is associated with a particular predisposition to pulmonary emboli and to thrombosis of renal vessels used for continuous renal replacement therapy and, less often, to thrombosis of extracorporeal membrane oxygenation–associated vessels. A fulminant myocarditis occurs in about 15% of ICU patients, which can be further complicated by heart failure, cardiac arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. Preliminary data from China suggested that acute kidney injury is not a complication of COVID-19, although the more recent reports of coagulopathic renal complications modify this finding. Skin manifestations are diverse and on occasion the presenting sign. These skin manifestations range from ill-defined rashes to petechial lesions and hemorrhagic edematous lesions in children and hardened red plaques on the ankles.
A large retrospective review from Wuhan showed that patients with type 2 diabetes who were taking metformin manifested higher rates of acidosis, heart failure, and inflammatory markers, although short-term (28-day) mortality was not impacted. It is recommended that kidney function and acid-base status be watched closely in diabetic patients with COVID-19.
Commonly reported neurologic complications are headaches; seizures; strokes; and more often, a loss of taste and smell (ageusia and anosmia). The loss of smell in the absence of significant rhinorrhea or nasal congestion suggests a neurotropism by this coronavirus. SARS-CoV-2–related meningitis as well as other neurologic complications including impairment of consciousness, Guillain-Barre syndrome, and acute hemorrhagic necrotizing encephalopathy are reported. While the presence of ACE receptors in brain tissue support direct CNS involvement, actual isolation of the virus from the CNS is not consistent and the CNS damage may occur via indirect mechanisms to be defined.
COVID-19 patients are at high risk for postoperative complications. In an international cohort study assessing postsurgical outcomes, postoperative severe acute respiratory problems occurred in 71.5% and the 30 days postoperative mortality was 23.8%.
Acute musculoskeletal pain is reported in nearly 20%. Hepatic and biliary injury, often acute, and DIC in advanced cases are reported from China. Conjunctivitis is reported from China in about one-third of cases. In the New York, British, and Italian experiences, a hyperinflammatory syndrome akin to atypical Kawasaki disease, called multisystem inflammatory syndrome in children (MIS-C) in the United States and Paediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2 (PIMS-TS) in Europe, was noted in children (see Kawasaki syndrome); the leading systems involved are gastrointestinal (the nonspecific symptoms have been diagnosed as appendicitis), cardiovascular, hematologic, mucocutaneous, and pulmonary. Central and peripheral nervous system findings are reported in children with this syndrome even in the absence of pulmonary disease, and such findings show a predilection for the corpus callosum.
Long-term sequelae of COVID-19 are described in an Italian study of nearly 200 COVID-19 survivors; 87.4% of patients reported persistent symptoms (including fatigue, dyspnea chest pain, and joint pain) about 30–60 days post-acute symptom onset, suggesting relatively long recovery times. Neurologists and psychiatrists express concern that long-term sequelae including encephalopathy, psychoses, and movement disorders may follow the pandemic (as they did after the influenza pandemic of 1918).
Recovery times are protracted, and the CDC reports from telephone surveys that 35% do not return to work 2–3 weeks after testing positive for COVID-19 and even among the young, 20% do not return to work within the same timeframe. Such prolonged recovery times will affect decisions regarding return to work and suggests that a consensus be worked out between the provider and the patient.
The full impact of COVID-19 on other chronic medical conditions is only beginning to be elucidated. For example, multiple sclerosis patients are at risk if they are neurologically compromised, obese, or elderly, while cancer patients seem to be compromised by the delays in “elective” surgical procedures.
The serious psychological sequelae of potentially dying alone, of restricted or impaired access to family or friends (especially in nursing homes), and limited funeral services are all relevant issues with which society is grappling. These important aspects require creativity to find tolerable, safe, and sustainable solutions.
The WHO (https://www.who.int/publications-detail/clinical-management-of-covid-19), the NIH (https://www.covid19treatmentguidelines.nih.gov/whats-new/), and Infectious Diseases Society of America (IDSA) (https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/) have released guidance for the management of COVID-19 patients from screening to discharge. The Pediatric Infectious Diseases Society has also published guidelines for management of SARS-CoV-2 infections in children (https://academic.oup.com/jpids/article/doi/10.1093/jpids/piaa045/5823622). Most infections are mild and require no treatment or only supportive therapy. Because of the biphasic nature of advanced cases, the early course should be managed with antiviral agents, as they become available, and the later “cytokine storm” phase should be managed with anti-inflammatory agents.
Many medications for the treatment of COVID-19 are being evaluated in clinical trials. The two medications with most promising data to date are remdesivir and dexamethasone. Other promising therapies include inhaled interferon beta-1b and convalescent plasma therapy.
Remdesivir is a viral RNA-dependent RNA polymerase [RdRp] inhibitor with known in vitro but limited in vivo activity against the Ebola and Marburg viruses as well as RSV, Lassa virus, and Nipah virus. The preliminary results of the first remdesivir randomized controlled trials were released on April 29, 2020. One of these, a multicenter trial sponsored by the United States National Institute of Allergy and Infectious Diseases (NIAID) called the Adaptive COVID-19 Treatment Trial 1 (ACTT 1), studied 1063 hospitalized adult patients with advanced COVID-19 and lung involvement and found that those who received remdesivir recovered several days faster than similar patients who received placebo; no mortality benefit was noted however. Based on these data, remdesivir was approved by the FDA under EUA on May 1, 2020. Subsequently, a study comparing 5 days and 10 days of remdesivir showed no statistically significant difference in clinical status between the two treatment regimens. The rate of adverse events is about 40%, including renal toxicity, diarrhea, transaminitis, and rash. The drug must be administered intravenously in the hospital, usually in an intensive care unit. With a shortage of remdesivir, limitations based on data showing who responds best include restricting use to 5 days and giving it to patients who are hypoxic (oxygen saturation ≤94%) but not requiring high-flow oxygen or mechanical ventilation or extracorporeal membrane oxygenation (ECMO). Remdesivir, in combination with lopinavir/ritonavir and ribavirin, showed significant improvement in symptom duration, interval to viral clearance, and duration of hospital stay in a study from Hong Kong. Favipiravir is an additional RdRp inhibitor being studied for COVID-19 treatment.
A British trial (the Recovery Trial) indicated that dexamethasone reduces death in hospitalized patients with severe respiratory complications of COVID-19 (https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf). Dexamethasone is now recommended only for treatment of patients with severe disease (those who require supplemental oxygen and those who are mechanically ventilated or need ECMO). Because of potential long-term side effects, dexamethasone courses should be relatively short, such as 10 days or less. Patients without hypoxia, mechanical ventilation, or ECMO should not be given corticosteroids. While dexamethasone has shown promise, other corticosteroid treatments, such as methylprednisolone, have not shown benefit in trials to date.
With the recognition that type I interferon responses are impaired in COVID-19, a variety of trials are underway. Inhaled interferon-beta-1b (Synairgen plc® in the United Kingdom), was found to prevent progression to death and to lower death rate in one British study of hospitalized patients. Studies are planned to assess this agent as a preventive at-home strategy. The third iteration of the ACTT is assessing the combination of interferon beta-1b with remdesivir as a subcutaneous preparation.
Convalescent plasma (plasma from the blood of patients who have recovered from COVID-19) is being given to critically ill patients in many centers. A published study from China did not find a statistically significant difference in time to outcome at 28 days in patients who received convalescent plasma, although a negative PCR conversion rate was statistically higher among the plasma-treated patients, indicating that the therapy does have some antiviral activity. Larger clinical trials are ongoing in the United States and the United Kingdom (convalescent plasma is an additional arm of the Recovery trial). Despite the FDA issuing an EUA for convalescent plasma on August 23, 2020, neither the IDSA nor the NIH recommend that convalescent plasma be given outside of a clinical trial at this time because of the paucity of efficacy and safety data to support this therapy. Several individual SARS-CoV-2 monoclonal neutralizing antibody candidates are being developed for clinical use. A combination of neutralizing monoclonal antibodies (REGN3048 and REGN3051) is being studied in a first-in-human clinical trial sponsored by the NIAID. However, these monoclonal antibody therapies share (and amplify) the disadvantages of convalescent plasma therapy, namely that their production is complex and expensive.
“AeroNabs” is a new form of therapy under development at UCSF School of Medicine, with the goal of achieving safe and passive immunity to SARS-CoV-2. “AeroNabs” involves the inhalation of nanoparticles, an ultrahigh affinity synthetic nanobody (miniscule antigen-binding heavy chain fragments derived from camelids who do not make light chain) that binds the SARS-CoV-2 Spike protein and locks it into an inactive conformation. The agent would be easy to administer and provide therapy both prophylactically and therapeutically early in infection.
Treatments targeting the SARS-CoV-2–induced immune response, such as IL-6 receptor inhibitors (eg, tocilizumab and sarilumab), are being used based on anecdotal evidence for severe pneumonia and with the rationale that high levels of IL-6 are a key component of the “cytokine storm” associated with advanced SARS-CoV-2 infection. However, available data are discouraging for tocilizumab; in the COVACTA study, no difference was seen in clinical status, ventilator-free days, or death rate, but a shorter hospital stay was noted among those treated. Similar negative results have been found with the use of sarulimab, an analog of tocilizumab, where there have been no differences in clinical outcomes during its phase III trials. Both tocilizumab and sarilumab should therefore only be given as part of clinical trials. The large clinical Recovery trial remains underway in which tocilizumab is one arm.
Of the remaining re-purposed treatments that have been used or studied for management of COVID-19, none have shown as much promise as the therapies described above. Hydroxychloroquine, a drug used in several rheumatic conditions, was initially prescribed widely for COVID-19 and was being studied as part of the WHO’s Solidarity Trial, a large international trial comparing four study arms ( remdesivir,  lopinavir/ritonavir,  lopinavir/ritonavir plus interferon beta-1a, and  hydroxychloroquine to standard of care). Subsequently data from several studies suggested that the potential for adverse effects when hydroxychloroquine is used to treat patients with COVID-19 likely outweighs the small potential benefit of using the drug. For this reason, the hydroxychloroquine arm within the Solidarity Trial was discontinued. The use of hydroxychloroquine, particularly in combination with azithromycin, is potentially dangerous because of the untoward development of cardiac arrhythmias as well as optic neuritis, gastrointestinal intolerance, and anemia. The one “successful” trial reported in JAMA was a retrospective observational study unlike the other studies which were double-blind and placebo-controlled. The use of these agents should be limited to clinical trials.
The anti-HIV combination of lopinavir/ritonavir (Kaletra) was shown to have no clinical benefit by a group of Chinese investigators and in the Recovery trial. As a result, the lopinavir/ritonavir arm was discontinued from the WHO’s Solidarity Trial. The open-label Discovery trial compared adults receiving the triple combination of lopinavir-ritonavir, ribavirin, and interferon beta-1b to adults receiving lopinavir-ritonavir alone. Preliminary results showed that symptoms resolved faster, and duration of hospital stay was shorter in the combination group when medications were given within 7 days of symptom onset. Another anti-HIV combination, darunavir/cobicistat, is also under study. A study showing a lower incidence of hospitalization among HIV-infected individuals in Spain who were receiving prophylaxis with tenofovir disoproxil fumarate and emtricitabine (Truvada) needs confirmation because of potentially confounding variables. Currently, the IDSA does not recommend the use of HIV antivirals for COVID-19.
Additional agents under investigation include leronlimab (PRO 140; a CCR5 antagonist), galidesivir (BCX4430; a nucleoside RNA polymerase inhibitor), baricitinib (a Janus kinase [JAK] inhibitor), and Bruton tyrosine kinase (BTK) inhibitors. Baricitinib is being studied in combination with remdesivir during the second iteration of the ACTT (ACTT 2).
Ivermectin, an antiparasitic drug, has been used extensively for COVID-19 in Latin America. However, in vitro studies of ivermectin at doses much higher than those deemed safe in humans have failed to reduce SARS-CoV-2 viral loads. Both the Panamerican Health Organization (PAHO) and the WHO recommend against the use of ivermectin for COVID-19.
A retrospective review of COVID-19 cases at a New York hospital showed that the use of famotidine, but not protein pump inhibitors, is associated with a two-fold reduction in clinical deterioration leading to intubation or death. Famotidine inhibits 3-chymotrypsin-like protease (3CLpro), an enzyme needed for viral replication; its use is also associated with lower ferritin levels, suggesting a significant anti-inflammatory aspect. Further studies are under way.
ACE inhibitors and angiotensin receptor blockers do not have an impact on disease, and it is recommended that patients who take these medications for other indications continue taking them. No increased risk of COVID-19 exists among patients who take any particular class of antihypertensive agents.
Because pathogenesis includes the action of a serine protease TMPRSS2 with the ACE receptor, two inhibitors of TMPRSS2 are undergoing studies. Camostat mesylate is a TMPRSS2 inhibitor that is available in Japan for other indications (chronic pancreatitis and postoperative reflux esophagitis) and is undergoing study in phase I and II trials for COVID-19 in Denmark. A related TMPRSS2 inhibitor, nafamostat, is being studied in Germany.
Various vitamin and mineral supplements have been suggested for both the treatment and prevention of COVID-19, including vitamin C, vitamin D, and zinc supplements; of these, vitamin D has shown the most promising results to date.
The WHO does not recommend that patients who have or may have COVID-19 restrict the use of ibuprofen if it is needed, although the IDSA recommends that all NSAIDs need further study in the context of ongoing COVID-19.
VTE prophylaxis for COVID-19 patients is indicated and numerous guidelines are being published to assist with full anticoagulation (see Chapter 14). Guidelines published by the American Society of Hematology are available at https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation. Higher levels of anticoagulation may be needed in COVID-19 patients and weight-based anticoagulation is preferred.
The usual precautions recommended to prevent SARS-CoV-2 infection include frequent handwashing with soap and water for at least 20 seconds, avoiding touching the face, wearing a cloth face covering in public (and, for healthcare workers, wearing an impermeable mask [eg, N95 mask] and face shield if exposure to patients with cough and/or respiratory secretions is anticipated), and isolating cases (in particular, removing infected patients from long-term–care facilities, such as nursing homes, and transportation structures, such as cruise ships). Physical distancing is also an important practice for control of the disease. Masking likely reduces the viral inoculum to which the mask-wearer is exposed. Specifically, cloth masks, if worn correctly, filter 65–85% of viral particles. For healthcare workers, a recent study indicated that correctly-sized but expired N95 masks with intact elastic bands and masks that had been subjected to sterilization procedures had unchanged fitted filtration efficiencies (FFEs) of more than 95%, while the performance of N95 masks of the wrong size resulted in decreased FFEs between 90% and 95%.
The first SARS-CoV-2 vaccine trials began in China in March 2020. Since then, many candidate vaccines have been launched into preclinical development using a variety of technologies (including DNA and RNA platforms, inactivated genes, live-attenuated genes, nonreplicating vectors, protein subunits, and replicating viral vectors). Over 250 vaccines are under development, and more than 30 vaccines are currently in various stages of clinical evaluation (more information about those vaccine candidates that are tracked by the WHO is available https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines). Two vaccines have already been released; one developed by the Chinese government and the firm CanSino that is being used for the Chinese military (it is an adenovirus-vectored recombinant protein found to be safe in clinical trials) and the other is a Russian vaccine based on a human adenovirus (what types of trials this vaccine was subjected to is unclear). Another Chinese vaccine, an inactivated whole virus vaccine, is currently in phase III trials, and preliminary analysis indicates that it caused a low rate of adverse reactions and demonstrated immunogenicity (ChiCTR2000031809).
The US government, in partnership with private initiatives, established Operation Warp Speed to develop and produce SARS-CoV-2 vaccines in the United States. Initially, six vaccines were chosen based on pre-vaccine technology, the likelihood of entering phase III trials in the fall of 2020 and production by early 2021, the ability to produce industrial quantities of vaccine, and the ability to use a platform technology likely to produce a safe and effective vaccine. Operation Warp Speed has chosen three vaccines for further development; they include the Moderna/NIAID mRNA vaccine, the Pfizer/BioNTech mRNA vaccine, and the AstraZeneca/Oxford live chimpanzee adenovirus vector vaccine (AZD1222, formerly ChAdOx). All three of these vaccines target the SARS-CoV-2 Spike protein, require two doses 3–4 weeks apart, and require refrigeration (particularly the mRNA vaccines, which require –70̊C storage). The Moderna and AstraZeneca vaccines were both safe and immunogenic during phase II trials and are currently undergoing phase III trials. However, the AstraZeneca vaccine phase III trial was put on hold on September 8, 2020, after a study participant developed transverse myelitis. The Pfizer vaccine completed phase I trials in August 2020 and is now being evaluated in phase II/III trials. Another replication-defective adenovirus vector vaccine by Janssen Pharmaceuticals (Ad26) will be entering phase III trials in the United States in the fall of 2020, a recombinant subunit adjuvanted protein vaccine by Novavax has undergone phase I trials in Australia and has pending phase III trials in the United States, and a recombinant Spike protein, oil adjuvant vaccine by Sanofi/GSK is planned to enter phase III trials in early 2021.
Data from animal models at the University of California, San Diego show that neutralizing antibodies isolated from patients recovering from COVID-19 protect mice but the protection is greater against receptor binding domains than the Spike protein. In other vaccine studies, neutralizing antibodies can be achieved in nonhuman primates with an mRNA vaccine encoding the prefusion stabilized Spike protein and protecting the animals from lung pathology.
The incidence of COVID-19 is curiously lower among those who report a history of BCG vaccination. In an analysis of European countries that use a BCG vaccine, a 10% increase in BCG deployment correlated with a 10% reduction in COVID-19 cases. Similar correlations were found in many but not all vaccine preventable diseases (no correlation was seen with meningococcal or typhoid vaccines). The latter finding may be due to either a specific immune-enhancing aspect of some BCG vaccine antigens or a broader “healthy user effect” among those who seek more medical care.
To achieve effective herd immunity in a population, vaccination uptake must be 70% or higher. However, studies on attitudes toward SARS-CoV-2 vaccine acceptance by the general population indicate that a significant portion of the adult population would not accept a SARS-CoV-2 vaccine (including more than 25% of French adults, nearly 15% of Australian adults, and more than 20% of US adults). This implies that considerable public education may be necessary to promote vaccine acceptance and thereby attain herd immunity from vaccination, especially among segments of the population with low health literacy.
As testing of potential SARS-CoV-2 vaccine candidates draws near completion, vaccine preparedness plans are starting to appear. In the United States, on September 4, 2020, the CDC distributed a document detailing SARS-CoV-2 vaccine distribution, storage, handling, and administration to health departments across the nation, suggesting that enough vaccine doses to cover 1 million people with the Pfizer and/or AstraZeneca vaccine would be available by October 2020. Under the CDC guidance, prioritized populations for the vaccine would include healthcare professionals, unspecified types of essential workers, national security populations, and long-term–care facility residents and staff. This announcement was thought to be premature by many health experts, since final testing of the three vaccines supported by Operation Warp Speed has not yet been completed.
Finally, promising data have been released about naturally acquired herd immunity, indicating that robust T- and B-cell immunity develops after asymptomatic or mild SARS-CoV-2 infection. Additionally, only a few cases of proven reinfection have been documented to date, suggesting that the post–SARS-CoV-2 immune response is effective at preventing subsequent disease. Areas of the world that experienced high infection rates earlier in 2020 (such as Italy, Sweden, New York) are now showing significantly fewer deaths per number of SARS-CoV-2 cases detected, indicating that herd immunity has likely been achieved in those communities. Greater population-level immunity, whether achieved naturally or via an effective vaccine, will significantly slow the spread of SARS-CoV-2. While awaiting a vaccine, widespread masking may be the safest way to both prevent severe infections and achieve herd immunity.
Even asymptomatic patients and those with atypical manifestations may be shedding and transmitting the virus. Patients in whom the disease is suspected should be tested with nasopharyngeal swabs that are sent for FDA-approved molecular testing if symptoms are consistent with SARS-CoV-2 infection. In the future, at-home antigen testing may be used.
Clinics and hospitals with the resources to screen or test outpatients for SARS-CoV-2 should set up a testing area that is isolated from other patient care areas (and outside or in an “open air” environment if possible). These facilities should also designate separate care areas for patients in whom SARS-CoV-2 infection is confirmed or suspected and provide the necessary personal protective equipment for staff who could potentially be exposed to patients infected with SARS-CoV-2.
The principal complications requiring admission for adults with COVID-19 are respiratory. Progression to respiratory failure and ARDS can be rapid, and any patient in a high-risk category for complications (eg, those with advanced age; immunosuppression; chronic diseases such as hypertension, obesity, and diabetes) or any patient with evident thrombotic, neurologic, or multiple system disease should be admitted for observation and placed under intensive care based on respiratory parameters.
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