Coronavirus Disease 2019: From Intensive Care Unit to the Long Haul—Part 2

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). Intensive Care Med. 2020;46: 854-887.

Coppo A, Bellani G, Winterton D, et al. Feasibility and physiological effects of prone positioning in non-intubated patients with acute respiratory failure due to COVID-19 (PRON-COVID): a prospective cohort study. Lancet Respir Med. 2020;8: 765-774.

Dries DJ. High-flow nasal cannula: where does it fit? Respir Care. 2018;63:367-370.

The common initial symptoms of coronavirus disease 2019 (COVID-19) are cough, fever, fatigue, headache, muscle ache, and diarrhea. Severe illness usually begins approximately 1 week after the onset of symptoms. The most common symptom of severe disease is shortness of breath often accompanied by hypoxemia. Progressive respiratory failure develops in patients with severe COVID-19 soon after the onset of dyspnea and hypoxemia. These patients frequently meet the criteria for acute respiratory distress syndrome (ARDS). This syndrome is defined as acute onset of bilateral pulmonary infiltrates, severe hypoxemia, and lung edema not fully explained by cardiac failure or fluid overload. Other complications described with severe COVID-19 are lymphopenia, thromboembolic complications, and neurologic disorders. Acute cardiac, renal, and liver injury is often seen in addition to cardiac rhythm changes, muscle breakdown, coagulopathy, and shock. Elevated markers of inflammation include elevated ferritin, C-reactive protein, and interleukin 6.

From the standpoint of epidemiology, severe COVID-19 in adults is defined as shortness of breath with a respiratory rate of 30 or more breaths/min, blood oxygen saturation of 93% or less, and a ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen (Pao₂/Fio₂) of less than 300 mm Hg. In survey data described previously, for patients with COVID-19, 81% had mild disease, 14% had severe disease, and 5% of COVID-19 patients became critically ill with organ failure and a mortality rate of approximately 50%. Age is the most important factor for death or critical illness, and individuals with chronic health conditions such as cardiovascular disease, diabetes mellitus, immunosuppression, and obesity are more likely to become critically ill from COVID-19. Severe disease is more common in men than women. Racial and ethnic groups such as blacks and Hispanics are also at increased risk. Patients meeting the criteria for severe COVID-19 should be hospitalized for careful monitoring. Strict infection control and the use of personal protective equipment (PPE) by caregivers are essential. Avoidance of any unnecessary aerosol-generating procedures is recommended. If aerosol generation is possible, N95 respirators, PPE, and eye protection are minimum requirements. Negative pressure rooms or filter systems are extremely valuable. Patients with severe COVID-19 have a substantial risk of prolonged critical illness and death. Clinicians should review advanced care directives, identify surrogate decision makers, and establish goals of care. Because infection control measures may limit family visitation during critical illness, plans for communication with patient families and surrogate decision makers are necessary.

Patients should be monitored carefully by observation and pulse oximetry. Oxygen should be supplemented by the use of a nasal cannula or a face mask system to keep oxygen saturation of hemoglobin between 92% and 96%. Deciding whether or not to intubate is a critical decision for those caring for seriously ill patients with COVID-19. Clinicians must weigh the risks of intubation against the risk of sudden respiratory decompensation with a chaotic emergency intubation, which exposes staff to a greater risk of infection. A simple list of clinical indications for endotracheal intubation includes evidence of airway obstruction that is progressive, unsustainable work of breathing, progressive and refractory hypoxemia, hypercapnia or acidemia, and mental status changes contributing to inadequate airway protection. Other considerations are the pattern of illness trajectory and whether difficulties in endotracheal intubation are anticipated. These factors should motivate early controlled, preplanned intubation. Hemodynamic instability is another factor indicating the value of intubation. Early intubation is valuable to improve the safety of patient transportation or any planned bedside procedure. Finally, improved infection control and staff safety may motivate intubation.

If a patient does not require intubation but remains hypoxemic based on the criteria given earlier, a high-flow nasal cannula system can improve oxygenation and may prevent intubation in selected patients. The use of noninvasive positive-pressure ventilation by mask should be restricted to patients with COVID-19 who have respiratory insufficiency due to chronic obstructive pulmonary disease, cardiogenic pulmonary edema, or obstructive sleep apnea in addition to COVID-19. Patients treated with high-flow nasal cannula or noninvasive ventilation require careful monitoring for indications that may reflect the need for invasive mechanical ventilation. For example, patients receiving noninvasive ventilation must have the ability to communicate and protect the airway. Awake patients should be able to turn to the prone position while they breathe high concentrations of supplemental oxygen. This may improve oxygenation in patients with severe COVID-19. A variety of prospective studies support this approach. However, the use of prone positioning does not guarantee that intubation may be prevented with severe COVID-19. Because it is difficult to provide rescue ventilation to patients who are in the prone position, respiratory support of the prone patient should be avoided when the patient's condition may rapidly deteriorate.

COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed February 19, 2021.

Bouadma L, Lescure FX, Lucet JC, et al. Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists. Intensive Care Med. 2020;46:579-582.

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). Intensive Care Med. 2020;46: 854-887.

Wiersinga WJ, Rhodes A, Cheng AC, et al. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324:782-793.

Approximately 17% to 35% of hospitalized patients with COVID-19 are treated in an intensive care unit (ICU), most commonly due to hypoxemic respiratory failure. Among patients in the ICU with COVID-19, 30% to 90% will require invasive mechanical ventilation. In addition to respiratory failure, hospitalized patients may develop acute kidney injury (9%), liver dysfunction (19%), bleeding and coagulation complications (10%-25%), and septic shock (6%). COVID-19 has also been associated with myocarditis, cardiomyopathy, ventricular rhythm changes, and hemodynamic instability. Cerebrovascular disease and encephalitis are observed with severe illness. Venous and arterial thromboembolic events occur in 10% to 25% of patients hospitalized with COVID-19. However, in the ICU, venous and arterial thromboembolic events occur much more frequently in up to 30% to 60% of patients with COVID-19.

Severe illness in COVID-19 requires decisions on oxygenation targets. Patients with severe disease will rapidly require supplemental oxygen and should be monitored for respiratory deterioration. The optimal oxygen saturation in patients with COVID-19 is unclear. However, a target oxygen saturation of 92% to 96% is logical, considering that indirect evidence in patients without COVID-19 suggests that values above and below this range may be harmful. A recent trial randomly assigned ARDS patients without COVID-19 to either a conservative oxygen therapy with a saturation target of 88% to 92% or a liberal oxygen strategy with a target oxygen saturation greater than or equal to 96%. The trial stopped early because of futility, and the conservative oxygen group experienced increased mortality at 90 days and a trend toward increased mortality at 28 days. A meta-analysis of 25 randomized trials involving patients without COVID-19 found that a liberal oxygen strategy with a mean arterial saturation greater than 96% was associated with an increased risk of in-hospital mortality compared with a lower oxygen saturation target threshold.

High-flow nasal cannula is preferred over other forms of noninvasive positive-pressure ventilation in patients with acute hypoxemic respiratory failure based on limited clinical trial data in patients without COVID-19 experiencing acute hypoxemia. In this limited work, participants were randomized to high-flow nasal cannula, conventional oxygen therapy, or other forms of noninvasive positive-pressure ventilation. Patients in the high-flow nasal cannula group had more ventilator-free days than those receiving conventional oxygen therapy or other forms of noninvasive positive-pressure ventilation. Ninety-day mortality was lower in the high-flow nasal cannula group than in either the conventional oxygen therapy group or the group receiving conventional noninvasive positive-pressure ventilation. In the subgroup of patients who experienced severe hypoxemia (Pao₂/Fio₂ ≤ 100-200 mm Hg), the intubation rate was lower with the high-flow nasal cannula than for either conventional oxygen therapy or noninvasive positive-pressure ventilation. These findings were supported by a meta-analysis of 8 trials with over 1,000 patients enrolled. It should be noted that noninvasive positive-pressure ventilation may generate aerosol spread of COVID-19, thus increasing nosocomial transmission of infection. We do not have strong data concerning whether a high-flow nasal cannula creates a lower risk of nosocomial COVID-19 transmission than other noninvasive positive-pressure ventilation modalities.

Prone positioning has been shown to improve oxygenation and outcomes in patients with moderate to severe ARDS who are intubated and receiving mechanical ventilation. There is less evidence regarding the benefit of prone positioning in awake patients who require supplemental oxygen without mechanical ventilation. In a recent small study from New York, awake prone positioning improved the overall median oxygen saturation of the evaluated patients. However, awake prone positioning did not eliminate the potential need for intubation due to respiratory failure. Unfortunately, the short-term benefit in oxygenation with prone positioning may not be sustained in many patients when they are returned to the supine position. Overall, despite some promising data, it is unclear whether hypoxemic patients without intubation having COVID-19 pneumonia will benefit in the long run from prone positioning and how long prone positioning should be continued. A clear survival benefit has also not been demonstrated. Appropriate candidates for awake prone positioning are those who can adjust their position independently and tolerate lying prone. Awake prone positioning is contraindicated in patients with respiratory distress or who may need immediate intubation. Hemodynamic instability, recent abdominal surgery, and unstable spine disease are also contraindications to prone positioning. Prone positioning is acceptable and feasible for pregnant patients and can be performed in the left lateral decubitus position or in the fully prone position with adequate padding.

At present, there is no consistent evidence that ventilator management of patients with hypoxemic respiratory failure due to COVID-19 should differ from ventilator management of patients with hypoxemic respiratory failure from other causes. Therefore, the National Institutes of Health (NIH) panel recommends the use of low tidal volume ventilation (4-8 mL/kg of predicted body weight) over higher tidal volume ventilation (tidal volume > 8 mL/kg). Similar to ARDS recommendations, plateau pressure less than 30 cm H₂O is recommended along with the use of a conservative fluid strategy in these patients. The routine use of a pulmonary vasodilator, nitric oxide, is not recommended. Pulmonary vasodilator therapy may be considered as a rescue intervention. When patients are intubated and mechanically ventilated for COVID-19, prone ventilation for 12 to 16 hours per day is recommended over avoidance of prone ventilation.

The NIH panel made multiple recommendations regarding the use of positive end-expiratory pressure (PEEP) in COVID-19 patients with hypoxemia. In general, higher PEEP strategies were recommended over the use of lower PEEP. PEEP was seen as beneficial due to the prevention of alveolar collapse, improvement in oxygenation due to increased mean airway pressure, reduction of atelectasis, and, ultimately, reduced mortality in studies in which PEEP was used in patients without COVID-19 who had ARDS with Pao₂/Fio₂ ≤ 100 to 200 mm Hg (moderate or severe ARDS). The NIH panel acknowledges that the definition of a high level of PEEP is not clear. Limited data from COVID-19 patients suggest that respiratory failure in this group is a heterogeneous process, and assessment for responsiveness to higher PEEP levels (defined as > 10 cm H₂O) should be determined by serial evaluation of hemodynamics, oxygenation, and lung compliance. The side effects of high PEEP including hypotension from reduced venous return and lung injury due to airway pressure should be monitored. The panel also suggests the use of intermittent boluses of neuromuscular blocking agents or a continuous neuromuscular blocker infusion to facilitate protective lung ventilation. Indications for neuromuscular blocker administration include dyssynchrony of the patient and ventilator or cases in which an intubated patient requires deep sedation, prone ventilation, or persistently high airway pressures. A continuous neuromuscular blocker infusion for up to 48 hours is appropriate if patient anxiety and pain are adequately monitored and controlled.

Finally, the NIH panel discussed the value of “recruitment maneuvers” on the improvement of oxygenation in severe ARDS due to COVID-19. These interventions use a brief increase of airway pressure in an attempt to open or “recruit” occluded airways or collapsed alveoli. Data from COVID-19 patients are unavailable. Analysis of multiple trials of various recruitment maneuvers in non–COVID-19 patients with ARDS found that the appropriate use of recruitment maneuvers reduced mortality, improved oxygenation, and decreased the need for other rescue therapies. Recruitment maneuvers should be performed with care because lung injury and hypotension may occur. With any sign of patient decompensation during recruitment maneuvers, the maneuver should be stopped immediately. A clear trend in data with recruitment maneuvers cannot be found that supports improvement in hospital mortality in patients without COVID-19 for whom data are available.

Two other comments on organ support are appropriate here. The NIH recommends the use of continuous renal replacement therapy in patients with renal insufficiency associated with COVID-19. This approach to renal support minimizes the hemodynamic effects of the attachment of the patient to the machine and allows for better ICU staffing because a dedicated hemodialysis nurse frequently is not required. Finally, because thromboembolic vascular disease appears to contribute to many of the complications of COVID-19, prophylaxis with subcutaneous low–molecular-weight heparin is recommended for all hospitalized patients. Research continues on the optimal means to titrate anticoagulation based on coagulation parameters.

McWilliams D, Weblin J, Hodson J, et al. Rehabilitation levels in patients with COVID-19 admitted to intensive care requiring invasive ventilation. An Observational Study. Ann Am Thorac Soc. 2021;18:122-129.

Carfì A, Bernabei R, Landi F, Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after acute COVID-19. JAMA. 2020;324:603-605.

Rubin R. As their numbers grow, COVID-19 "long haulers" stump experts. JAMA. 2020;324:1381-1383.

Siegelman JN. Reflections of a COVID-19 long hauler. JAMA. 2020;324:2031-2032.

Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397:220-232.

Since the initial detection of the virus, more than 17 million cases have been detected worldwide, with the most severe cases requiring admission to the ICU for mechanical ventilation and other organ support. These patients have a high mortality rate with a prolonged stay in the ICU. Many ICU patients will require deep sedation and neuromuscular blockade with prone positioning for oxygenation. All of these practices have been identified as significant risk factors for the development of ICU-acquired weakness. In patients with ARDS and multiple organ failure, there is substantial muscle wasting within the first week of critical illness with loss of up to 20% of muscle mass by day 7. Survivors have longer-term physical, psychological, and cognitive morbidity, lasting for months to years, termed post–intensive care syndrome. Patients with COVID-19 also have complex organ support needs for a prolonged period, resulting in a high incidence of neuromuscular weakness with associated loss of well-being and delirium. This is predicted to create significant rehabilitation requirements in both the short- and long-term. Early structured rehabilitation during critical care has been shown to be safe and when implemented is associated with improvement in physical and emotional outcome. There are limited data, at present, regarding the overall outcome associated with this practice.

An acute care center in Birmingham, UK, provides some of the early data regarding rehabilitation experience in ICU patients affected by COVID-19. In all, this study evaluated 177 patients admitted to the ICU with confirmed COVID-19 infection. Sixty-two percent of these patients (100) survived to ICU discharge. Patients who died during the ICU stay were significantly older with a higher incidence of comorbidities and higher frailty scores. The mean age of patients surviving to ICU discharge was 53 years. Seventy-five percent of patients discharged were male, and the majority were of white origin or Asian ethnic backgrounds. Although there was a low incidence of frailty, the majority of this cohort was characterized as overweight or obese. Chronic medical conditions were common in this critically ill population, with 45% of the studied patients having hypertension and 31% of these individuals having diabetes mellitus. All patients in this trial of rehabilitation therapy required mechanical ventilation with a mean duration of mechanical ventilation of approximately 20 days. The duration of mechanical ventilation was as short as 2 days and as long as 59 days. A tracheostomy was placed in 77% of patients, and 67% of patients were placed in the prone position on 1 or more occasions. All patients were sedated for a mean duration of approximately 13 days, and 90% of these patients received neuromuscular blockade for a median duration of 7 days. Renal failure requiring continuous venovenous hemofiltration developed in 34% of patients. Delirium screens were positive in 69% of patients, and ICU-acquired weakness was present on awakening in all patients studied. The mean length of stay in the ICU was 22 days. All patients were mobilized in the ICU with a mean time until mobilization of 14 days. At the time of ICU discharge, 50% of patients were able to step transfer or walk.

One of the patients surviving ICU stay died in the hospital after ICU discharge due to cardiac arrest on the ward. Two patients were readmitted to the ICU after initially being transferred off this service, both as a result of respiratory decompensation secondary to hospital-acquired pneumonia. Patients were discharged from hospital a median of 11 days after being transferred from the ICU. Fifty percent of patients were discharged home without further rehabilitation, whereas 42% of patients required further rehabilitation at home and 7% of patients required ongoing inpatient rehabilitation therapy. At the time of hospital discharge, the majority of patients were able to step transfer or walk, with 83% of the studied individuals able to walk greater than 30 m independently. The time required to first mobilize these patients was significantly increased with body mass index from a mean of 10 days to 18 days for those with a body mass index of 20 to 24 versus 40. Frailty also predicted significant residual deconditioning at the time of discharge from acute hospitalization.

In summary, these patients required prolonged mechanical ventilation with high use of neuromuscular blockade and prone positioning. The incidence of delirium was high, and all patients presented with ICU-acquired weakness when sedation was reduced. Despite this, the Birmingham group observed that early rehabilitation was feasible with all patients mobilized at least once before ICU discharge and half of the patients regaining the ability to stand and transfer to a chair before discharge from the ICU to a hospital ward. Patients in this study demonstrated the significant impact of COVID-19 and the necessity for prolonged periods of mechanical ventilation and critical care support. The authors noted concerns regarding the insertion of tracheostomies because of the risk of airborne pathogens to health care workers. Despite this, 77% of patients studied had tracheostomy performed to support weaning from mechanical ventilation and rehabilitation. Tracheostomy was typically placed after 10 days of mechanical ventilation. As detailed earlier, essentially all patients required neuromuscular blockade, and two thirds were placed in the prone position. Although patients with COVID-19 were delayed in starting mobilization, the Birmingham group was able to mobilize patients in this trial within 24 hours of stopping sedation. The first mobilization took place 5 days before patients had been fully weaned from mechanical ventilation. Although all patients presented with ICU-acquired weakness, these workers suggest that commencing mobilization earlier allowed patients to begin to regain strength and mobility while still in the ICU.

Because of the nature of this pandemic, there is danger that rehabilitation, particularly in the ICU, is not seen as a priority. The constant need to free capacity to meet the demand of new admissions to the hospital may lead to a primary focus on stability, survival, and early discharge from both the ICU and hospital wards. The consequence of this practice is patients being discharged home at a lower functional level with a lack of community resources available to promote recovery. These individuals with prolonged ICU stay and profound ICU-acquired weakness are often left with significant physical, cognitive, and mental health impairment. Optimizing survivorship of patients with COVID-19 requires the implementation of early and structured rehabilitation, which begins in the ICU and continues after discharge. ICU patients with COVID-19 have additional risk for the development or exacerbation of delirium and psychological distress. These patients encounter staff wearing PPE, relatives who are unable to visit, and the use of common spaces, which potentially exposes patients to scenes that may be distressing. The broad impact of the COVID-19 pandemic and worsening patient delirium are expected to increase the risk for long-term cognitive impairment. This problem requires ongoing evaluation and investigation.

Multiple reports describe the initial symptoms of patients experiencing COVID-19 infection. Information is limited on the symptoms persisting after recovery from acute COVID-19 exposure. An early report on prolonged COVID-19 symptoms comes from Italian investigators based in Rome. The Italian team established a postacute outpatient service for individuals discharged from the hospital after recovery from COVID-19. Patients included in the clinic met World Health Organization criteria for discontinuation of quarantine and were followed on an ongoing basis. To be followed, patients had to have a negative reverse transcriptase polymerase chain reaction test reaction for COVID-19. Patients followed were offered comprehensive medical assessment with detailed history and physical examination and collection of data on all clinical characteristics including medication history, lifestyle, vaccination status, and body measurements. In particular, data on specific symptoms potentially correlated with COVID-19 were obtained using a standardized questionnaire that was administered when patients were enrolled. Early in the COVID-19 pandemic, nearly 200 patients were identified as eligible for follow-up. Ultimately, 143 patients were studied for prolonged symptoms. The mean age of these patients was 56 years, and 37% of patients were women. During hospitalization, 73% of patients had evidence of interstitial pneumonia. The mean length of hospital stay was 13.5 days, with 21 patients receiving noninvasive ventilation and 7 patients receiving invasive ventilation. In all, the majority of these patients were not acutely ill.

Patients were assessed a mean of 60 days after the onset of COVID-19 symptoms. At the time of evaluation, 12.6% of patients were completely free of COVID-19–related symptoms. Thirty-two percent of patients had 1 or 2 symptoms related to COVID-19, and 55% of patients had 3 or more symptoms related to this viral illness. None of the patients had fever or any signs or symptoms of acute COVID-19 illness. Worsened quality of life was observed among 44.1% of patients. A high proportion of patients followed reported fatigue (53%), shortness of breath (43%), joint pain (27.3%), and chest pain (21.7%). In all, 87.4% of patients who recovered from COVID-19 reported the persistence of at least 1 symptom associated with viral illness, particularly fatigue and shortness of breath. The authors note that other problems such as community-acquired pneumonia may have some of the persistent symptoms reported here for patients who had passed the acute phase of COVID-19 infection.

As the COVID-19 pandemic continues, it is becoming obvious that for some patients COVID-19 may be described as the “unwelcome houseguest” who will not leave. Anecdotal data suggest that a large number of individuals have postviral syndromes that become incapacitating for many weeks after so-called recovery and clearing of the virus. A similar experience was reported with the first severe acute respiratory syndrome (SARS) outbreak, which presented in 2002 and was also caused by a coronavirus. A number of patients who were hospitalized with SARS had impaired pulmonary function for 2 years after the initiation of symptoms. It is likely that this problem received limited attention because less than 9,000 people were diagnosed with SARS worldwide, a small fraction of the number of cases reported for COVID-19 in the United States alone.

Adults with severe illness who spend weeks in intensive care, often intubated, can experience long-lasting symptoms. This is not unique to patients with COVID-19 experiencing prolonged symptoms, now called “long haulers,” in that many affected individuals initially had mild to moderate symptoms that did not require lengthy hospitalization, if any, let alone intensive care. Many patients with prolonged symptomatology after COVID-19 were not hospitalized. They were unwell but able to stay at home. Another study of so-called long haulers revealed that more than a third of these individuals had not returned to usual health 2 to 3 weeks after testing positive for the virus. Older patients were more likely to report that their pre–COVID-19 health did not return. Even the youngest patients, aged 18 to 34 years, had a 25% rate of failure to rapidly regain prior health. Initial speculation proposes prolonged immune effects in target organs even after the virus can no longer be detected. The large number of COVID-19 cases occurring simultaneously creates a significant responsibility to investigate long-term consequences and potential disabilities that survivors may encounter. Autonomic nervous system dysregulation is another possible explanation for some of the problems experienced by long haulers, such as tachycardia, significant fatigue, and other persistent symptoms. The autonomic nervous system is of interest because it controls many involuntary processes such as heart rate, blood pressure, respiration, and digestion. Another symptom of long haulers is what investigators call “brain fog.” The etiology of this problem remains unclear. An important concern of long haulers is that society and medical professionals may not take them seriously. Patients affected with prolonged symptoms admit frustration that the medical community does not respond more directly to their complaints. One physician who experienced the long-haul phenomenon stated a need for validation and acceptance of symptoms rather than a dismissive approach or minimization of the patient experience.

One of the largest studies of the long-term outcome of patients discharged from the hospital after COVID-19 comes from Wuhan in China. In a review of over 1,700 patients followed for at least 6 months, most patients endorsed at least 1 symptom, particularly fatigue or muscle weakness, sleep difficulty, and anxiety or depression. More severely ill patients had increased risk of prolonged pulmonary dysfunction along with fatigue, anxiety, or depression. These findings are similar to long-term follow-up of SARS patients. The duration of symptoms in patients with SARS was reported to last over 3 years. Up to 50% of COVID-19 patients studied had lingering pulmonary dysfunction. Psychiatric consequences were believed to be multifactorial and inclusive of the direct effects of infection, therapies, ICU stay, social isolation, and stigma. Not surprisingly, more severe symptoms on follow-up were associated with greater acuity of symptoms during hospitalization.

The author gratefully acknowledges the assistance of Ms. Sherry Willett in preparation of this series for Air Medical Journal.