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 of 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 the 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 July 31, 2020, globally recognized cases surpassed 17.3 million, including over 673,000 deaths. The United States reports the largest number of recognized cases in a single country at over 4.5 million and over 154,000 deaths). Other highly impacted countries include Russia, India, the Republic of South Africa, the United Kingdom, Iran, Brazil, Mexico, Peru, and Chile are all among the top 10 impacted nations. Increasing case numbers are also prominent in Spain, Columbia, Bangladesh, and Saudi Arabia (where restrictions on gathering for the annual Hajj are underway). China, the original epicenter of the emerging pandemic now ranks 26th in number of total cases among the 188 world nations reporting infections. The formerly highly impacted European nations of Germany, France, Italy, and Turkey have stabilized their numbers although Japan has seen an upsurge.
Since April 2020, the CDC has recommended that travelers avoid nonessential international travel, restrict domestic travel, and stay at home as much as possible. The CDC website provides 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 through July 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 specific gene cluster (3p21.31) has recently been identified as a genetic susceptibility locus in patients with COVID-19 with respiratory failure. The differential blood group susceptibility (lower for type O, higher for type A) may be related only to the likelihood of testing positive (greater for B/AB/RH+, lower for O) but not for likelihood of intubation or death.
R0 is the basic reproductive number signifying the number of persons 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.
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 probably 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 likely 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 recommended for social 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 health care providers performing respiratory procedures (such as collecting induced sputum or intubating the patient). The absence of a massive outbreak from China suggests that areosrolization did not occur there in the early outbreak.
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 July 17, 2020, the CDC reported that 101,789 health care personnel had become infected in the United States. Survival data are available for 67,669 of these health care personnel. The Guardian has reported 879 deaths among US health care personnel as of July 23, 2020. A preliminary study from Birmingham, England shows that among hospital personnel, the highest rates of disease are encountered among housekeeping staff and physicians on acute medicine (but not emergency medicine) and general medicine services. More recent studies emphasize the risks attendant to frontline workers.
Reviews of death data suggest 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 angiotensin-converting enzyme (ACE) receptor protein on the X chromosome and the presence of variants in this protein may explain some of the clinical variation seen.
Children appear to be infected primarily by older family members and less so by school interactions, although these data are preliminary. Children have lower concentrations of ACE-2 receptors in lung tissue, which may explain their lower propensity toward 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 COVID-19 among children are discussed below.
COVID-19 infection is particularly serious in the elderly and in those with comorbid conditions of immunocompromise (including post-organ transplant) or chronic diseases (diabetes; hypertension; chronic heart, lung, or kidney disease; and prior stroke). While the infection shows a predilection for pulmonary tissues, data regarding susceptibility of persons who smoke cigarettes and those with asthma are unclear. The comorbid conditions are referred to by some as “twin epidemics.”
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. Small prospective 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). To date, there have been multiple case series of people living with HIV in whom COVID-19 develops; in these series, 25–100% of patients were hospitalized, 11–56% required ICU care, and the mortality rate ranged between 0 and 28%.
The full spectrum of complications associated with pregnancy is unknown. Reports of in utero transmission are not confirmed; 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 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 (4) increased attention to minority populations, particularly black and Latino 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); (5) guidelines for nursing home safety and support; (6) standardization of state-by-state data reporting; (7) evolving guidelines for reasonable dates for children and staff to return to schools and policies for universities to provide a safe learning environment for students and faculty; (8) emergence of antibiotic resistance exacerbated by the inappropriate use of antibacterial antibiotics for COVID-19; and (9) vaccine research, including the identification of markers for protection and the role of mucosal immunity.
At this time, lockdown and social 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 social 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.
As populations begin to return to work and school, the CDC has published guidelines for workplaces, schools, childcare centers, and other entities (https://www.cdc.gov/coronavirus/2019-ncov/community/index.html). These guidelines include wearing face coverings in public, maintaining social 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. Even so, significant concern exists about children returning to school in the fall of 2020. Much controversy exists regarding whether grade schools should go forward with virtual versus in-person classes. On June 26, 2020, the American Academy of Pediatrics released a statement strongly advocating for in-person learning.
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 July 17, 2020, the FDA has approved 184 tests under EUAs, including 152 molecular tests, 30 antibody tests, and 2 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 diagnostic tests. 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. Some tests convert from negative to positive during the course of acute illness.
In general, the reverse transcriptase–polymerase chain reaction (RT-PCR) assays are the gold standard, and assays based on nucleic acid amplification technology (NAAT), rapid antigen assays, and laminar flow procedures are less sensitive. The laminar flow assays area available to be used at home, and their lower sensitivity may be useful for early illness when viral loads are high (and usually higher even before symptoms develop).
The use of duplicate “orthogonal” testing is recommended by CDC when clinical conditions support the diagnosis in the absence of a confirmed COVID-19 assay. A guideline to monitor decision making published by 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. Prolonged detection of replicative virus occurs on occasion among patients with other immunosuppressive illnesses.
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, several 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 or if neutralizing antibodies are sufficient for control of infection; T cell responses may also be needed. The length of time that IgM and IgG antibodies to SARS-CoV-2 persist post-infection also remains unclear. It is likely that some patients with mild infection do not mount adequate antibody responses for long-term protection from reinfection. 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. Unfortunately, at this time, the consensus, including that from a Cochrane Database of Systematic Reviews, is that serologic assays should not be used in point-of-care settings. Assays should not be used to determine back-to-work status. In the clinical examination room, commercial assays can be used to determine if a person has had past COVID-19 illness, and the assays show public health utility in serosurveys.
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. The 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 authors because cytokine levels in COVID-19 infection 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.
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.
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 infection, although the more recent reports of coagulopathic renal complications modify this finding.
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.
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, termed multisystem inflammatory syndrome in children (MIS-C), was noted in children (see Kawasaki syndrome); the leading systems involved are gastrointestinal, 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 after COVID-19 infection 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 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 and a third, inhaled interferon beta-1b, shows promise.
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 (ACTT), 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). Favipiravir is an additional RdRp inhibitor being studied for COVID-19 treatment.
A recent 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 immunosuppressive long-term 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.
With the recognition that type I interferon responses are impaired in COVID-19 infections, 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. An NIH study is assessing the combination of interferon beta-1b with remdesivir as a subcutaneous preparation. 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.
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. The current 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. Convalescent plasma (ie, plasma from the blood of patients who have recovered from COVID-19) is being used for the critically ill in many centers. Several small series have reported success with the use of convalescent plasma, and the results of the first clinical trial of convalescent plasma (an open-label, multicenter Chinese clinical trial of 103 patients with severe COVID-19) showed some positive signals. Larger clinical trials are ongoing in the United States (for the US center and patient enrollment, visit www.uscovidplasma.org) and the United Kingdom (convalescent plasma is an additional arm of the Recovery trial). Convalescent plasma should not be given outside a clinical trial.
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 in the United States) needs confirmation because of potentially confounding variables. Currently, the IDSA does not recommend the use of HIV antivirals for COVID-19 infection.
A combination of neutralizing monoclonal antibodies (REGN3048 and REGN3051) is being studied in a first-in-human clinical trial sponsored by the NIAID. Additional agents under investigation include leronlimab (PRO 140; a CCR5 antagonist) and galidesivir (BCX4430; a nucleoside RNA polymerase inhibitor). Other agents under evaluation include immunomodulators, such as Janus kinase (JAK) inhibitors (baricitintib) and Bruton tyrosine kinase (BTK) inhibitors.
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 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; as of yet, no data support their use.
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 infection.
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 health care 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 living/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.
The first SARS-CoV-2 vaccine trials began 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 40 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). The only vaccine that has already been released is one developed by the Chinese government and the firm CanSino; it is being used for the Chinese military. The vaccine comprises an Ad5-vectored recombinant protein and is safe in clinical phase I and II trials. Two other vaccines report successful phase I data. A recombinant vaccine, produced by Moderna Inc®, consists of modified RNA encoding the SARS-CoV-2 receptor binding domain; this vaccine has been shown to be safe and immunogenic in a phase II trial. An AstraZeneca adenovirus vaccine has also been reported to be safe and immunogenic in a phase II study.
The US government has chosen three vaccine candidates to fund for phase III trials: the Moderna vaccine, The University of Oxford and AstraZeneca’s AZD1222 vaccine, and Pfizer and BioNTech’s BNT162 vaccine. Current estimates are that an effective vaccine may be available by mid-2021.
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 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 COVID-19 acceptance by the general population indicated that a significant portion of the adult population would not accept a COVID-19 vaccine (including more than 25% of French adults and nearly 15% of Australian 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.
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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