Transmission Data from the Military
Letizia AG, Ramos I, Obla A, et al. SARS-CoV-2 Transmission among Marine recruits during quarantine. N Engl J Med. 2020;383:2407-2416.
Kasper MR, Geibe JR, Sears CL, et al. An outbreak of Covid-19 on an aircraft carrier. N Engl J Med. 2020;383:2417-2426.
Michael NL. SARS-CoV-2 in the U.S. military - lessons for civil society. N Engl J Med. 2020;383:2472-2473.
Young adults appear to be at significant risk for the transmission of coronavirus disease 2019 (COVID-19). The Department of Defense is an ideal setting to investigate the dynamics of transmission among young adults because large numbers of healthy young adults episodically work in close proximity where the risk of transmission is increased. Two recent studies provide important data in this regard. First is the evaluation of a large group of Marine recruits who entered a training facility in South Carolina after a 14-day quarantine at home followed by a supervised 14-day quarantine at a college campus, which was used exclusively for this purpose. Recruits were examined at the time of presentation to the training facility and instructed to wear face covering and maintain appropriate social distancing. Groups of 350 to 450 recruits arrived each week. These groups were divided into platoons of 50 to 60 recruits, and independent assignment of pairs of recruits used double occupancy rooms with sinks. Recruits ate in shared dining facilities and used shared bathrooms. All rooms were cleaned daily. Recruits had no contact with nonmilitary personnel during this time. Routine quantitative polymerase chain reaction (qPCR) testing was performed using nasal swabs to identify the appearance of COVID-19. Over 1,800 recruits agreed to permit clinical data collection for research during their participation in isolation procedures and during initial intake procedures. At the time of enrollment, only 16 of over 1,800 study participants tested by qPCR were positive for COVID-19. These participants stated that procedures before enrollment had been followed.
After rigorous collection of viral genome data, 6 independent transmission clusters were defined by distinct mutations relative to sampled data from US and global data sets. These strains were ultimately found in 18 of the studied recruits. Epidemiologic data showed that infected roommate pairs and the cluster strains correlated with platoon assignments and provided supporting evidence for the transmission of the virus at the supervised quarantine location. In all, in a group of young male military recruits, approximately 3% (51 recruits) became positive for COVID-19 as determined by qPCR testing during a 2-week strictly enforced quarantine on base. Multiple independent virus clusters were identified. Living conditions were associated with positive tests. Study participants with positive qPCR results were asymptomatic for the most part, and all cases among participants were identified as the result of scheduled testing rather than testing performed based on daily screening for symptoms.
A more dramatic data set comes from an outbreak of COVID-19 on a nuclear-powered aircraft carrier with a crew of over 4,700. The majority of crewmembers were young males in good health who met Navy standards for sea duty. Over the course of an outbreak lasting several weeks, over 1,200 crewmembers testing positive for COVID-19 were confirmed by real-time reverse transcription polymerase chain reaction testing, and more than 1,000 infections were identified within 5 weeks of the first positive laboratory testing. Among crewmembers with laboratory-confirmed infection, 77% of these individuals had no symptoms at the time that they tested positive, and 55% of the infected crewmembers had symptoms develop at some point during the clinical course. Ultimately, 23 members of the crew were hospitalized, 4 crewmembers received intensive care, and one 41-year-old man died. Working in confined spaces was associated with an increased risk of infection.
Navy investigators reported that all crewmembers were evaluated, tested, placed in isolation, and monitored on a daily basis to assure good overall health if symptoms were identified. The ship had been at sea for 13 days when the first 3 crewmembers presented with symptoms suggestive of COVID-19. These crewmembers were subsequently tested and found positive for COVID-19. Over the next 24 hours, additional symptomatic crewmembers and approximately 400 close contacts were identified by contact tracing. Four days after the first positive test was reported, the affected crewmembers were placed in isolation when the ship reached port. COVID-19 cases were evenly distributed across sex, race, and crew roles. Enlisted personnel were more likely than officers to present with clinical COVID-19. Crewmembers working in tighter spaces, such as the reactor department, appeared more likely to have confirmed COVID-19 than those working in open-air conditions such as deck crew. Medical workers who wore protective equipment had an attack rate of 16.7%, which was lower than the nonmedical crew. Presenting symptoms were cough, headache, altered sense of taste or smell, and shortness of breath. In discussing these results, investigators were concerned by episodic limitation in the quality of records obtained, particularly in the early days of the COVID-19 outbreak. Although a relatively small number of crewmembers required hospitalization, these findings support the observation that young, healthy individuals can contribute to community spread of infection, frequently without symptoms.
Several observations from these 2 reports were made. First was the suggestion that longer periods of quarantine before working in close quarters is necessary. The standard of waiting for 2 weeks appears insufficient. An extended quarantine period could prevent further transmission before personnel enter prolonged training on a base or work in other situations in which distancing is far more difficult because of military operations. Second, the increased use of molecular diagnostic testing and careful correlation of findings to clinical outcomes are essential to obtain better data regarding disease transmission patterns. Data from shipboard and land-based training operations are relevant to shared living situations, such as college dormitories, prisons, residential care facilities, and sports training environments. Additional data are also needed to understand the durability of natural immunity and immunity from vaccination or immunotherapy when these data are available.
National Institutes of Health on Transmission, Detection, and Prophylaxis
Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 vaccines at pandemic speed. N Engl J Med. 2020;382:1969-1973.
Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020;383:517-525.
Mitjá O, Corbacho-Monné M, Ubals M, et al. A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19. N Engl J Med. 2021;384:417-427.
The currently used estimated incubation interval for COVID-19 is up to 14 days from the time of exposure, with a median incubation interval of 4 to 5 days. The spectrum of illness can range from asymptomatic infection to severe pneumonia with acute respiratory distress syndrome and death. Consistent with earlier reports, a National Institutes of Health (NIH) panel suggests that up to 81% of cases of COVID-19 are mild (without obvious pulmonary process), 14% were severe (defined as shortness of breath, respiratory rate ≥ 30 breaths/min, oxygen saturation ≤ 93%, and a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen < 300 mmHg and/or lung infiltrates within 24-48 hours), and 5% were critical (respiratory failure, septic shock, and possibly with multiple organ dysfunction or multiple organ failure). Multifocal opacity on a chest x-ray is the most common imaging finding. Computed tomographic imaging of the chest also reveals bilateral peripheral changes. Noting data provided by the military earlier, it may be necessary to revisit the criteria for the duration of incubation, particularly in relation to the varied severity of disease presentation for COVID-19.
Testing to diagnose COVID-19 may be performed using a nucleic acid amplification test based on the identification of viral genetic material or testing for antigens that may appear on the surface of viral particles in individuals with high-risk exposure or repeated exposure thought possibility related to COVID-19. Another screening test that may be used identifies antibody development in patients exposed to COVID-19. Antibody testing is positive in individuals with recent COVID-19 infection. The NIH panel does not currently recommend the use of antibody testing as the basis for diagnosing COVID-19 infection. The panel also notes that the detection technologies listed previously may yield false-negative results, thus stimulating the use of confirmatory antibody testing. Using antibody testing in combination with nucleic acid amplification testing or testing for viral surface particles may provide confirmatory diagnostic results. However, it may take 21 days or longer after the onset of symptoms to identify antibodies to COVID-19, thus increasing the risk of transmission of the virus before positive confirmatory testing. Finally, antibody testing is not recommended at this time to determine whether an individual is immune to COVID-19.
The transmission of COVID-19 is thought to occur through respiratory droplets transmitted from an infected person to those within 6 feet of that individual. Less commonly, airborne transmission of small droplets or particles of the virus that are suspended in air can result in transmission to those who are more than 6 feet from an infected individual. Infection may also occur in individuals who pass through a room that was previously occupied by an infected person. COVID-19 infection from airborne transmission of small particles may occur after exposure for greater than 30 minutes to an infected person in an enclosed space with poor ventilation. Basic prevention of COVID-19 transmission includes covering coughs and sneezes and maintaining a 6-foot distance from others. Face covering and frequent handwashing are also important. Health care workers are advised to use Centers for Disease Control and Prevention recommendations for infection control and the use of personal protective equipment. As noted earlier, further examination of data provided by the military may allow greater clarity in prevention practices.
Vaccination for COVID-19 is currently being aggressively pursued. Multiple new products are under evaluation and seeing initial clinical application.
Several trials have taken place for pre-exposure prophylaxis to COVID-19. At present, the NIH panel recommends against the use of any agent for COVID-19 pre-exposure prophylaxis, except in a clinical trial. The agent that has seen the greatest evaluation in clinical trials for pre-exposure prophylaxis is hydroxychloroquine. Trials in health care workers have been compromised by low rates of infection and concerns regarding the applicability of study findings to other populations. Hydroxychloroquine administration was frequently associated with nausea and other gastrointestinal upset. Hydroxychloroquine has been investigated for postexposure prevention of COVID-19. This practice is not recommended because recent trials have been unsuccessful.
Critical Care Guidance from the NIH and More
Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020;383:2451-2460.
Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48:e440-e469.
The common initial symptoms of COVID-19 are cough, fever, fatigue, headache, muscle ache, and diarrhea. Severe illness typically begins 1 week after the onset of symptoms. Shortness of breath is the most common symptom of severe disease and is often observed with hypoxemia. Progressive respiratory failure develops in many patients with severe COVID-19 infection soon after the onset of dyspnea and hypoxemia. These patients frequently meet the criteria for acute respiratory distress syndrome, which is typically defined as the acute onset of bilateral pulmonary infiltrates on chest imaging, severe hypoxemia, and pulmonary edema that is not fully explained by heart failure or fluid overload. The majority of patients with severe COVID-19 have reduced lymphocyte counts, thromboembolic complications, and disorders of the central or peripheral nervous systems. Severe COVID-19 may also lead to cardiac, renal, and liver injury, in addition to cardiac rhythm changes, muscle breakdown, coagulopathy, and shock. Organ failure may be associated with clinical and laboratory signs of inflammation, which is sometimes termed cytokine storm, including high fevers, thrombocytopenia, elevated ferritin, and increased levels of C reactive protein and interleukin 6.
The most important risk factor for death or critical illness in the setting of COVID-19 infection is the age of the patient. The risk of mortality or evolution of critical illness with COVID-19 increases with each decade. Chronic health conditions including cardiovascular disease, diabetes, immunosuppression, and obesity increase the likelihood of critical illness associated with COVID-19. Severe disease is more common among men than women. The risk is reported to be increased among specific racial and ethnic groups such as blacks and Hispanics. Social determinants of health have a significant influence on the risk of severe disease with COVID-19. Consistent with the epidemiologic data described earlier from the military, a common presentation of COVID-19 is the sudden appearance of a large number of affected patients within a geographic area or among a social or work cohort. Local health care resources may be strained in the setting of a sudden influx of patients resulting in a shortage of trained and experienced staff, equipment, or intensive care beds. Of the 3 components of management needed for the critically ill patient, the shortage of trained staff seems to be the most acute problem.
Infection control is found in the initial set of recommendations from the NIH regarding care of the patient with COVID-19 in the setting of critical illness. These recommendations are focused on airborne disease, the common transmission pathway of COVID-19. The NIH panel recommends that health care workers performing aerosol-generating procedures on patients with COVID-19 use an N95 respirator rather than typical surgical masks along with other personal protective equipment such as gloves, gowns, and eye protection. Aerosol-generating procedures include endotracheal intubation and extubation, induction of sputum, bronchoscopy, bronchoalveolar lavage, suctioning of airways, manual ventilation, ventilator disconnection, noninvasive ventilation, cardiopulmonary resuscitation, and possibly nebulizer use or high-flow oxygen delivery. N95 respirators block 95% to 99% of aerosol particles. Optimal fit must be determined for the type of N95 respirator used. A second recommendation is a reduction in the use of aerosol-generating procedures on intensive care unit patients with COVID-19 unless a negative pressure room or other airborne infection isolation room is available. Rooms equipped for airborne infection isolation reduce the risk of cross contamination among rooms and the risk of infection for staff and patients outside the room when aerosol-generating procedures are performed. Clinical data support airborne infection isolation rooms for preventing virus spread on the unit during the COVID-19 pandemic. High-efficiency particulate air filters may also reduce virus transmission. Even in the setting of procedures that are not typically associated with aerosol generation, bedside staff are advised to wear N95 respirators because of the ever-present risk of inadvertent aerosol exposure. The NIH does report a recent systematic review of randomized controlled trials comparing the protective effect of medical masks with N95 respirators demonstrating that the use of medical masks did not increase laboratory-confirmed viral infection including respiratory illness. Unfortunately, unplanned failure of secretion control, a significant risk for the health worker wearing only a surgical mask during care for a COVID-19 patient when the N95 respirator is optimally used, cannot be reliably predicted.
Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48:e440-e469.
Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378:829-839.
Bednarczyk JM, Fridfinnson JA, Kumar A, et al. Incorporating dynamic assessment of fluid responsiveness into goal-directed therapy: a systematic review and meta-analysis. Crit Care Med. 2017;45:1538-1545.
The NIH obtains many of its hemodynamic care recommendations from the Surviving Sepsis Campaign sponsored by the Society of Critical Care Medicine. At present, the NIH panel recommends that patients requiring fluid resuscitation or hemodynamic management for shock should be cared for in accordance with septic shock guidelines with a small number of exceptions. For example, in caring for adults with COVID-19 and evidence of shock, COVID-19 recommendations from the management panel of the NIH include using dynamic parameters such as skin temperature variation, capillary refill time, and change in lactate levels over static parameters (such as central venous pressure or mean arterial pressure) to determine the need to administer fluid. Other approaches that could be used include the assessment of organ function and hemodynamic response to a fixed bolus of fluid or straight leg elevation, which is equivalent to 300 or more milliliters of blood transmitted to the central circulation. The panel admits that no direct evidence addresses the optimal resuscitation strategy for patients with COVID-19 and shock. A review of clinical trials involving shock in non–COVID-19 patients revealed that dynamic assessment to guide fluid therapy reduced mortality, intensive care unit length of stay, and duration of mechanical ventilation. Passive leg raising followed by the evaluation of changes in pulse pressure or a monitor of cardiac stroke volume appeared to predict fluid responsiveness with the greatest accuracy. Static parameters included in these trials were central venous pressure and mean arterial pressure. The resuscitation of non–COVID-19 patients based on changes in serum lactate levels also was associated with a reduction in mortality and decreased resource consumption.
In another departure from common care, the NIH panel recommends using buffered or balanced crystalloids over unbalanced crystalloids. Intravenous electrolyte solutions (or crystalloids) are commonly given in critical care, but, until recently, the question of whether specific crystalloid composition affects outcome was unclear. Historically, 0.9% sodium chloride or saline has been the most commonly administered intravenous fluid. However, there is evidence to suggest that intravenous saline may be associated with hyperchloremic metabolic acidosis, acute kidney injury secondary to renal vasoconstriction, and increased risk of death, particularly with large-volume resuscitation. Crystalloid solutions with an electrolyte composition closer to that of plasma (balanced crystalloids such as lactated Ringer's solution or other custom solutions) represent an appropriate alternative to saline. A variety of trials have demonstrated that balanced crystalloids are associated with a lower rate of acute kidney injury, renal replacement therapy, and death. In non–COVID-19 sepsis, balanced crystalloids were associated with a reduction in mortality, fewer days requiring vasoactive drugs, and less need for renal replacement therapy. Although all trials do not support these results, adverse effects of balanced crystalloid solutions were not noted in comparison with saline.
The third recommendation from the panel was the avoidance of albumin for initial resuscitation of COVID-19 patients with shock. The panel notes that trials supporting the use of albumin in the setting of sepsis can be identified. However, when the higher cost of albumin is considered and the lack of definitive clinical benefit is identified, routine use of this product for initial resuscitation of patients with COVID-19 and shock is not recommended.
Several recommendations are made by the NIH panel based on what they describe as “general principles of critical care.” Details of these principles are included in the references cited previously. Among resuscitation fluids, the panel recommends that hydroxyethyl starches be avoided for intravascular volume replacement in the setting of shock. Norepinephrine, consistent with other guidelines, is the first-choice vasoactive drug. Vasopressin may be added to norepinephrine or epinephrine if needed to raise blood pressure. Vasopressin may also be used to reduce norepinephrine dosage. If norepinephrine is available, the panel recommends against using dopamine for patients with COVID-19 and shock. Dopamine is also not to be used for renal protection. The avoidance of dopamine has been a long-standing recommendation despite earlier studies that suggested improved renal perfusion with the administration of low-dose dopamine. Dobutamine may be used in patients demonstrating cardiac dysfunction and reduced perfusion despite adequate fluid administration as identified earlier and the use of vasopressor agents. Corticosteroid therapy may be used, in addition to vasoactive drugs in patients with COVID-19 and refractory shock. The typical corticosteroid dose in COVID-19 patients with septic shock is intravenous hydrocortisone given at 200 mg/d as an infusion or intermittent doses. Finally, the panel recommends that patients who are receiving corticosteroids for COVID-19 are also receiving sufficient steroid replacement therapy that they do not require additional steroid administration for other conditions typically treated with steroids.
Recent data from the military suggest that simple 2-week quarantine and the absence of symptoms are not adequate to rule out the risk of COVID-19. More aggressive use of molecular testing is also required even in the absence of symptoms in high-risk groups. Young people are highly likely to carry the virus with minimal symptoms.
A variety of molecular techniques including nucleic acid amplification and antigen testing are acceptable in patients exposed to COVID-19. Antibody testing may be used as a confirmatory test. Prophylaxis with exposure to COVID-19 is currently not recommended.
Health care workers involved in aerosol-generating procedures on patients with COVID-19 should use the N95 respirator mask rather than typical surgical masks. Other protective equipment should also be worn. Helpful technologies include negative airflow rooms and high-efficiency particulate air filters. In general, the N95 respirator should be emphasized in the presence of patients with known COVID-19 infection.
The majority of hemodynamic care recommendations for COVID-19 come from pre-existing guidelines. For example, norepinephrine is the recommended vasoactive drug. Vasopressin may also be used as a second vasoactive drug.
In departures from standard care, an NIH guidance panel recommends the use of balanced crystalloids, the restriction of albumin, and the avoidance of starches in resuscitation.
For hemodynamic assessment during resuscitation, the NIH panel recommends the use of dynamic assessment such as hemodynamic change with straight leg raising and evaluation of serial changes in capillary refill or lactate to guide fluid administration. Static parameters such as central venous pressure are to be avoided.