COVID-19 Pulmonary Management

At the end of 2019, a novel coronavirus started as an emerging pathogen for humans and resulted in a pandemic. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus causing coronavirus disease 2019 (COVID-19), is a positive-stranded RNA virus, similar to other coronaviruses. Ubiquitous in the environment, these viruses can infect several types of animals, including other mammals and birds. The roots of the current pandemic have been traced back to a wild live animal market in the Huanan Seafood Wholesale market in Wuhan, a city in the Hubei province of China. From there, the virus spread across the globe, with cases being reported from every continent except Antarctica.

The virus was initially isolated from the bronchoalveolar lavage of three patients who were admitted to a hospital in Wuhan. All three patients reported direct exposure to the Huanan Seafood market. The virus showed 85% shared identity with the bat SARS-like coronavirus (SARS-CoV), raising the possibility of animal-to-human transmission. ^[1] Since then, cases without direct exposure to the seafood market have been identified. This validates ongoing human-to-human transmission, likely occurring via respiratory droplets. 

The National Institute of Allergy and Infectious Disease evaluated the aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV. Virus aerosols were generated using a three-jet collision nebulizer and fed into the Goldberg drum to create an aerosolized environment. They reported detecting viable virus aerosols for up to 3 hours. The virus sustained for long periods, up to 72 hours, on plastic and stainless steel surfaces. This makes aerosol- and fomite-mediated transmission of virus plausible. ^[2]

Based on data from Wuhan, the China Center for Disease Control (China-CDC) reports the incubation period to be 3-7 days. The mean incubation period was reported to be 5.2 days, and the 95% percentile of the distribution was up to 12.5 days.

Although dynamic, the basic reproduction number (R₀ /R naught) is an epidemiologic entity that helps predict the expected number of cases from exposure to a single case, assuming all the individuals in the given population are susceptible. The R₀ of measles is 12-18, by far the highest known to humankind. The R₀ of seasonal influenza is around 0.9-2.1. Based on the data available so far, the R₀ of COVID-19 is 1.4-3.9.

The novel coronavirus has garnered unparalleled media attention, overwhelmed health systems, and caused the adoption of social distancing at the cost of major economic disruption. This review will summarize the pulmonary impact and management of COVID-19.

Long COVID

COVID-19 is most often an acute illness. However, numerous cases of “long COVID” have been reported. By one definition, long COVID is the persistence of symptoms at least 28 days after initial diagnosis. Also known as post-COVID syndrome and persistent post-COVID syndrome, ^[3] the most common symptoms include fatigue, shortness of breath, persistent alterations in smell and taste, and confusion/difficulty focusing, colloquially called “brain fog.” ^[4]

According to a review by Nalbandian et al, common pulmonary symptoms of long COVID most often include ground glass opacities on radiography, reduced diffusion capacity, dyspnea, and hypoxia. ^[5]  Post-COVID pulmonary fibrosis, particularly in elderly patients, has also been reported. ^[6]

As with acute COVID-19, obesity and prior pulmonary problems appear to be primary risk factors for long COVID. ^[7] Other risk factors include advanced age, positive smoking history, diabetes mellitus, and hypertension. ^[4]

Pulmonary management of inpatient COVID-19 cases should include follow-ups at 4-6 weeks and 12 weeks after discharge. Patients with persistent dyspnea or requiring supplemental oxygen should be assessed with pulmonary function tests, 6-minute walk tests, chest imaging, and pulmonary embolism screening. ^[5]

Also see Guidelines.

Please see Coronavirus Disease 2019 (COVID-19) and for continuously updated clinical guidance concerning COVID-19 and Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies for updated drug information.

Virology

Coronaviruses are a family of RNA viruses, named for their crownlike appearance. Human disease is caused by viruses belonging to the Orthocoronavirinae subfamily. This subfamily is further classified into four genera, alpha-coronavirus (alphaCoV), beta-coronavirus (betaCoV), gamma-coronavirus (gammaCoV), and delta-coronavirus (deltaCoV). To date, seven different coronaviruses have been identified to infect humans. 229E, NL63 (genus alpha), OC43, and HKU1 (genus beta) are the most common coronaviruses. ^[8]

In the past, zoonotic spread of other beta-coronaviruses led to MERS-CoV (coronavirus causing Middle Eastern respiratory syndrome) and SARS-CoV (coronavirus causing severe acute respiratory syndrome). The novel coronavirus SARS-CoV-2 was found to be genetically distinct but with some similarities to previously identified beta-coronavirus. Phylogenetically, the virus causing COVID-19 is classified under the subgenus Sarbecovirus. ^[9]

Since the SARS outbreak in 2002-2003, many coronaviruses have been discovered, mainly in bats and a few in humans. SARS-CoV-2 has genomic sequences up to 96% identical to a beta-coronavirus RaTG13, isolated from bats of the species Rhinolophus affinis. SARS-CoV-2 encodes four major structural proteins: the spike (S) protein, the nucleocapsid (N) protein, the membrane (M) protein, and the envelope (E) protein. The receptor-binding domain (RBD) of the S protein of SARS-CoV-2 is similar to a coronavirus isolated from Malayan pangolins (Manis javanica). This analysis strengthens the theory that the zoonotic origin of SARS-CoV-2 is likely bats and pangolins. Human infection and spread is likely explained by natural selection in humans following zoonotic transfer. ^[10]

Pathogenesis of lung injury

The RBD of the S protein of SARS-CoV-2 specifically recognizes the host angiotensin-converting enzyme 2 (ACE2) receptor. It is optimized for binding to the human receptor ACE2.

Similarly to SARS-CoV-2, SARS-CoV also binds with the ACE2 receptor to gain entry into human cells. Upon binding, host serine protease TMPRSS2 cleaves the S protein and results in the fusion of the viral and cellular membranes. The S protein of SARS-CoV-2 and SARS-CoV have almost identical three-dimensional structures, and, given this, researchers hypothesize that SARS-CoV-2 likely uses a similar mechanism.

The ACE2 receptor is expressed in type 2 alveolar epithelial cells in the lungs, heart, kidney, and gastrointestinal tract. However, the lungs seem to be particularly vulnerable to SARS-CoV-2 because of their large surface area and because alveolar epithelial type 2 cells seemingly act as a reservoir for virus replication. Direct injury to the lung tissue from a viral infection–mediated local inflammatory response is one of the proposed mechanisms behind the pulmonary manifestations of COVID-19. ^[11]

Cytokine storm and the systemic inflammatory response

Cytokine storm syndrome (CSS) is an accentuated immune response to triggers such as viral infections. Macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (sHLH) are two clinically similar CSSs. MAS is a CSS that is usually seen in the context of rheumatological diseases. HLH can be seen in patients with severe infection. It results from an excess of proinflammatory and inadequate anti-inflammatory stimuli. Some of the proinflammatory stimuli include foreign antigens, cytokines such as interleukin (IL)–1β, IL-2, IL-6, IL-7, IL-12, IL-18, tumor necrosis factor (TNF)–α, interferon (IFN)–γ, and granulocyte colony-stimulating factor (GCSF). Some of the anti-inflammatory stimuli include regulatory T cells, cytokines such as IL-10, transforming growth factor (TGF)–β, and IL-1ra. ^[12]

Increased production of IFNγ by hematopoietic stem cells in response to viral infections is thought to trigger CSS. CSS is characterized by unremitting fever and multiorgan involvement, including acute respiratory distress syndrome (ARDS) and acute cardiac and renal injury. Laboratory abnormalities include cytopenias, increased ferritin, D-dimer, and increased serum levels of proinflammatory cytokines.

Evidence gathered to date shows that CSS is directly related to the severity of the disease process. Laboratory analysis of confirmed COVID-19 patients showed leukopenia and increased serum levels of proinflammatory cytokines such as IL-2, IL-6, IL-7, TNFα, IFNγ, and GCSF, similar to that observed in sHLH, suggesting a possible mechanism for tissue injury. ^[13]

A retrospective multicenter study from Wuhan, China of COVID-19 patients showed statistically significant increased mortality in patients with elevated ferritin (>1200 ng/mL) and elevated IL-6 levels. ^[14]

Data from China showed that about 80% of patients with COVID-19 had a mild infection. Among the remaining 20% of patients, a fraction of the patients developed severe disease with multiorgan failure necessitating ICU level of care. The pathogenesis behind this severe manifestation of disease appears to be related to overwhelming inflammatory response as seen in sHLH/CSS. The predilection to develop CSS is unclear and is thought to be related to host factors such as underlying immunodeficiency or genetic factors.

Similar to SARS-CoV, clinical characteristics of COVID-19 include fever, cough, and gastrointestinal symptoms. Symptoms typical of a viral upper respiratory tract infection, including cough, sore throat, nasal congestion, and even conjunctivitis, have been reported. Further, gastrointestinal symptoms of nausea, vomiting, and diarrhea are also common with COVID-19. Anecdotal reports of anosmia (loss of smell) and ageusia (loss of taste) have been described, although the incidence of these symptoms is currently unknown. Further, anecdotal reports describe variable skin manifestations, including petechiae, red rashes, urticaria, perniolike purplish-red discoloration of the fingers and toes (particularly in younger people), and chickenpoxlike vesicles.

A wide range has been reported for patients presenting with dyspnea. For example, dyspnea was reported in 55% of the initial cohort from Wuhan; however, the ensuing report from Wuhan suggested dyspnea in 19% of all hospitalized patients. In Washington State, dyspnea was reported as the presenting complaint in 88% of the patients. ^[15]

When comparing severe with nonsevere cases, patients in the severe disease cohort were older and more likely to have comorbid conditions. ^[16] In Washington State, where chronic medical conditions were common, 58% of the patients had diabetes, another 21% had chronic kidney disease, and 14% had asthma. ^[15]

ARDS is a feared complication of COVID-19. ARDS is defined by the Berlin criteria by the presence of acute hypoxic respiratory failure with bilateral infiltrates without a known etiology in the presence of a known insult within 7 days. Hypoxia is graded in these patients by the means of a PaO₂/FiO₂ ratio, which is the ratio of the partial pressure of arterial oxygen divided by the fraction of oxygen inspired. ^[17] Although not included in the definition, decreased lung compliance, calculated as the tidal volume divided by the plateau pressure minus the positive end-expiratory pressure, is a prominent feature. However, initial reports from Italy seem to suggest an atypical form of ARDS in patients with COVID-19. In an editorial report of 16 patients with ARDS secondary to COVID-19, the respiratory lung compliance was 50 ±14.3 mL/H₂O but with significant hypoxia as evidenced by a shunt fraction of 0.50 ±0.11. ^[18]

Please see Coronavirus Disease 2019 (COVID-19) for continuously updated clinical guidance concerning COVID-19.

Laboratory findings

Common across several cohorts, leukopenia, especially lymphocytopenia and thrombocytopenia, may be seen on hemography. Patients also had elevated levels of C-reactive protein, greater than 10 mg/L in 81% of severe patients and 56% of nonsevere patients. ^[16] Procalcitonin, typically associated with bacterial pneumonia, remains in the normal range in most COVID-19 patients. Other abnormal laboratory findings include transaminitis, elevated lactate dehydrogenase (LDH), elevated creatinine, elevated creatinine kinase, and an elevated D-dimer. Of these, an elevated LDH may be associated with more severe disease.

Imaging

As with other respiratory diseases, chest radiography is often the first diagnostic test performed. For COVID-19 in Wuhan, 274 of 1,099 patients received chest radiographs. Positive findings, including ground-glass opacities, local or bilateral patchy shadows, and interstitial abnormalities, were seen in 59%. ^[16] In comparison, CT scans were positive in 86% of all patients. Patients who were symptomatic and had severe disease were more likely to have positive findings on chest radiographs. ^[16]

CT scans performed from both Washington State and Wuhan most commonly showed ground-glass opacities. ^{[15, 16]} Other CT scan findings include consolidations, nodular opacities, and reticulations. ^[19] Furthermore, these CT scans seem to represent a spectrum, with asymptomatic patients showing a predominance of ground-glass opacities and those with symptoms more likely to have consolidations. ^[20] Interestingly, from the Wuhan cohort, 18% of patients with nonsevere disease and 3% with severe disease did not have any findings on CT scans. ^[16]

Lung ultrasound, a relative new modality in chest imaging, has also shown potential in the diagnosis of COVID-19. Although the widespread use of point-of-care ultrasonography remains limited, a small report of 20 patients suggests that pleural-line irregularities, a "B-line" pattern, and consolidations are suggestive of COVID-19. ^[21] Lung ultrasonography has been frequently shown to be more sensitive than chest radiography, and the major advantages of lung ultrasonography over CT scanning include portability, limiting radiation exposure, and expense.

Microbiology

Like other viral respiratory illnesses, a specific polymerase chain reaction (PCR) can be obtained from the nasopharynx. As with other nasopharyngeal swabs, the results of this test are operator dependent and obtaining a deep nasopharyngeal sample is essential.

Several groups, including the American Association for Bronchoscopy and Interventional Pulmonology, recommend against inducing sputum or bronchoscopy in these patients because of the high risk of aerosolization. ^[22]

Please see Coronavirus Disease 2019 (COVID-19) for continuously updated clinical guidance concerning COVID-19.

Like other respiratory viral infections, unfortunately, there is no established treatment for COVID-19. The initial steps in the management of this pandemic are personal protection and social distancing. For patients who have already been infected, appropriate triage and supportive management are of paramount importance. Finally, in critically ill patients, the investigation of several experimental therapies is underway.

Please see Coronavirus Disease 2019 (COVID-19) for continuously updated clinical guidance concerning COVID-19 and Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies for updated drug information.

Personal protection

It is hypothesized that COVID-19, like influenza and other viral respiratory illnesses, is transmitted by large droplets. Preventing the spread of large droplets can be mediated through use of a surgical mask. Based on this, current recommendations from the World Health Organization (WHO) include giving patients suspected of having COVID-19 a facemask at the time of first interaction and separating these patients from others by at least 1 meter. ^[23]

It is unclear if experimental models properly simulate the aerosolization power generated by human cough or sneeze. They do, however, indicate possible aerosolization during high-risk procedures such as intubation, extubation, and bronchoscopy. Hence, the WHO recommends droplet precautions for all COVID-19 patients and recommends use of airborne precautions such as respirator masks when performing potentially aerosolizing procedures. In addition, the US Centers for Disease Control and Prevention (CDC) and the Australian and New Zealand Critical Care Society also recommend airborne precautions for all critically ill patients with COVID-19. ^{[24, 25]}

Given the prolonged surface viability of SARS-CoV-2, hand washing and disinfecting surfaces that may have accidentally been exposed is crucial. Further, because of the potential for fomites in the transmission, contact precautions are also recommended.

Oxygen delivery devices

Although no randomized control trial exists, the current paradigm is to support hypoxia up to a level of 92-96%. Several options for oxygen delivery exist. These can include a simple nasal cannula, which can provide up to 6 L or approximately 44% FiO₂. Further oxygen demand can be met by a nonrebreather mask, which can increase flow to 6-10 L while providing 100% FiO₂.

Currently, the use of noninvasive ventilation in COVID-19 patients is under intense debate. High-flow nasal cannula (HFNC) and noninvasive positive-pressure ventilation (NIPPV) have become standards of care in the ICU for patients with hypoxic respiratory failure and are known to help prevent endotracheal intubation. However, in COVID-19, the risk of intubation needs to be balanced against the potential risk of aerosolization of the virus and potentially increasing the exposure to healthcare workers. Currently, no guidelines exist to guide management in these patients; however, an initial report from Hong Kong recommended against the use of HFNC and NIPPV in COVID-19 patients. ^[26] A retrospective review from China examined a small cohort of 27 patients who developed severe acute respiratory failure after being diagnosed with COVID-19. ^[27] Of these, 63% were initially treated with HFNC. Interestingly, 41% of those treated with HFNC (n=7) developed further respiratory failure necessitating NIPPV and even intubation. Some indicators for HFNC included a PaO₂/FiO₂ ratio of less than 200 mm Hg and worsening tachypnea. ^[27] The Society of Critical Care Medicine (SCCM) suggests the use of HFNC over NIPPV (weak strength). Similarly, the SCCM also suggests using NIPPV with close monitoring, if HFNC is not available and the patient is not in emergent need of intubation (weak strength). ^[28]

Mechanical ventilation

Endotracheal intubation in COVID-19 patients is a high-risk procedure. Care must be taken to minimize aerosolization of the virus and protect the healthcare workers present. First, if possible, all intubations should be conducted in negative-pressure rooms. An attempt should be made to minimize bag-mask ventilation, and intubation should be performed by an experienced practitioner using rapid sequence intubation to maximize first-pass intubation. Further, the balloon should be inflated immediately after intubation to prevent further leakage of the virus. ^[26]

As with other causes of respiratory failure and ARDS, patients intubated secondary to COVID-19 should be treated with lung-protective ventilation with a tidal volume of 6 mL/kg ideal body weight and maintaining the plateau pressure under 30 cm H₂0. ^[29] As with ARDS from other causes, the respiratory rate is then increased to maintain minute ventilation. Some groups have also proposed using other nontraditional modes of mechanical ventilation modes such as airway pressure release ventilation.

Further, although no specific evidence exists, higher positive end-expiratory pressure, the use of prone positioning, neuromuscular blockade, inhaled vasodilators, and maintaining a net negative fluid balance of 0.5-1 L/day might improve respiratory failure. ^[30]

Extracorporeal membrane oxygenation

Extracorporeal membrane oxygenation (ECMO) can be used in patients with severe ARDS. To date, the largest series of 1035 patients from the Extracorporeal Life Support Organization (ELSO) registry has shown that patients undergoing ECMO support had an in-hospital 90-day mortality rate of 37.4% (95% confidence interval, 34.4-40.4%). ^[31] ELSO guidelines recommend to maximize conventional ARDS therapy such as prone positioning, neuromuscular blockade, and appropriate positive end-expiratory pressure therapy prior to initiating ECMO therapy. ECMO is indicated for patients with PaO₂/FiO₂ ratio of less than 60 mm Hg for more than 6 hours or less than 50 mm Hg for more than 3 hours. ECMO support should be instituted within 7 days of severe ARDS. ^[32]

Antibiotics

Although there is no role for antibiotics in the treatment of coronavirus infection, 58% of patients in Wuhan were started on antibiotics. ^[16] Further, the use of empiric antibiotics is endorsed by the WHO to cover bacterial superinfections. ^[23]

The use of azithromycin along with hydroxychloroquine has been described in an open-label trial.

Hydroxychloroquine/chloroquine 

Both chloroquine and hydroxychloroquine are antimalarial drugs that have been used in the treatment and prophylaxis of malaria as well as autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Both of these drugs have also shown efficacy against viruses such as HIV, Zika virus, and even SARS-CoV. ^[33] Based on this, hydroxychloroquine and chloroquine have been used in SARS-CoV-2 infection. ^[34]

In the Recovery trial, hospitalized patients randomized hydroxychloroquine had a 27% mortality rate at 28 days as compared with 25% in the usual care group. ^[35] Patients assigned to the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days and had a higher rate of mechanical ventilation need or death as compared with the usual care group. In the Solidarity trial, hydroxychloroquine was not associated with improvement in mortality as compared with the usual care group. ^[36]

In another randomized controlled trial of hospitalized mild-to-moderate COVID-19 patients (with no oxygen requirement or maximal oxygen requirement up to 4 liters), hydroxychloroquine with or without azithromycin was not associated with improvement in clinical status at 15 days as compared with standard care. ^[37]

Skipper et al studied the effect of hydroxychloroquine in nonhospitalized adults with early COVID-19. ^[38] In this randomized controlled trial, hydroxychloroquine did not reduce symptom severity when compared with placebo.

In a randomized controlled trial for postexposure prophylaxis after moderate-to-high–risk exposure, hydroxychloroquine use within 4 days after the exposure did not prevent illness compatible with COVID-19. ^[39]

Based on the available literature, the Infectious Diseases Society of America (IDSA) strongly recommends against the use of hydroxychloroquine for patients with COVID-19 infection. ^[40]

Remdesivir

Remdesivir, a nucleotide analog, has shown efficacy against SARS-CoV-2 in vitro. ^[33] In the randomized controlled Adaptive COVID-19 Treatment Trial-1 (ACTT-1), remdesivir was superior in reducing median recovery time to 10 days as compared with 15 days in the placebo arm. ^[41] In another randomized controlled trial, for patients not requiring mechanical ventilation, there was no statistically significant difference between 5 days and 10 days of remdesivir use. ^[42] However, in another randomized controlled trial, remdesivir was not associated with any improvement in mortality, initiation of mechanical ventilation, and duration of the hospital stay. ^[36] The US Food and Drug Administration (FDA) has approved remdesivir for the treatment for hospitalized COVID-19 patients aged 12 years and older and weighing at least 40 kg (88 lbs). Remdesivir is given by intravenous infusion. Adverse effects include nausea, vomiting, and transaminitis. An IDSA panel suggests remdesivir for hospitalized patients with severe COVID-19 pneumonia. ^[40] For patients not on mechanical ventilation or ECMO, IDSA guidelines suggest remdesivir use for only 5 days. ^[40] For patients without the need of oxygen and an oxygen saturation of greater 94% on room air, the IDSA panel suggests against the use of remdesivir. ^[40]  

Lopinavir-ritonavir

Lopinavir, an antiviral used in the treatment of HIV infection, was initially shown to have in vitro activity against SARS in 2003. Ritonavir is added to lopinavir to increase the plasma half-life through the inhibition of cytochrome P-450. Despite initial enthusiasm, a randomized controlled trial failed to show a mortality benefit. ^[43] For hospitalized patients with COVID-19, IDSA guidelines recommend against the use of lopinavir-ritonavir. ^[40]

IL-6 inhibitor

Tocilizumab, a recombinant humanized monoclonal antibody against the IL-6 receptor, is used in the treatment of rheumatoid arthritis. It was approved in 2017 for the management of cytokine storm syndrome in patients receiving chimeric antigen receptor (CAR) T-cell therapy. As mentioned, patients with COVID-19 may develop an intense inflammatory condition that may respond to the inhibition of IL-6–dependent inflammation. A multicenter cohort study of 3924 patients with COVID-19 pneumonia requiring ICU admission showed that patients who were treated with tocilizumab within 2 days of ICU admission had lower in-hospital mortality as compared with patients whose treatment did not include the early use of tocilizumab. ^[44] In a randomized controlled trial by Stone et al, tocilizumab use in moderately ill hospitalized patients did not prevent intubation or death as compared with placebo. ^[45] Salvarani et al randomized 126 patients with a PaO₂/FiO₂ ratio of 200-300 mm of Hg. ^[46] This study did not find any benefit of tocilizumab in reducing risk of clinical worsening. Preliminary results from the COVACTA trial showed that as compared with placebo, use of tocilizumab in the hospitalized patients with severe COVID-19 pneumonia did not result in improvement in a seven-category ordinal scale at week four. ^[47]

In a randomized controlled trial conducted by Hermine et al in hospitalized patients with moderate-to-severe COVID-19 pneumonia, tocilizumab use led to a reduction in the need for mechanical and noninvasive ventilation at day 14. ^[48] However, there was no reduction in mortality at day 28. Preliminary data from the EMPACTA trial have shown that use of tocilizumab in hospitalized patients was associated with a 44% less likelihood of progression to mechanical ventilation or death. ^[49] However, the study did not demonstrate any benefit in reducing 28-day mortality as compared with placebo. For hospitalized patients with COVID-19, IDSA guidelines recommend against the use of tocilizumab. ^[40]

Convalescent plasma

The use of plasma from individuals who have recovered from COVID-19 has the potential to provide passive immunity through the transfer antibodies. Preliminary data from the largest observational study by the Mayo Clinic showed that hospitalized patients who were transfused within 3 days of diagnosis of COVID-19 had significantly lower 7- and 28-day mortality rates compared with patients transfused 4 or more days after the diagnosis. ^[50] In addition, the study demonstrated that a higher titer of antibodies in plasma was associated with lower 7- and 30-day mortality. Three randomized controlled trials did not show any mortality benefit. The first randomized controlled trial by Li et al was stopped early. ^[51] Simonvich et al. also randomized 334 patients with severe COVID-19 pneumonia to receive either convalescent plasma or placebo. ^[52] Median time from the onset of symptoms to enrollment in the study was 7 days in this study. Therefore, it is harder to make any conclusion about mild-to-moderate COVID-19 patients or the benefit of plasma given very early in the course of the disease. The PLACID trial enrolled patients with moderate COVID-19 pneumonia and randomized them to receive either placebo or convalescent plasma. ^[53] Four-hundred sixty-four patients were enrolled in this study. Convalescent plasma did not reduce composite outcome of progression to severe disease or all-cause mortality at 28 days. However, the study was limited by an inability to measure the titer of antibodies in convalescent plasma. For hospitalized patients with COVID-19, IDSA guidelines recommend to use plasma only in the context of clinical trials. ^[40]

Corticosteroids

In March 2020, the WHO recommended against routine use of systemic corticosteroids in patients with ARDS secondary to SARS-CoV2 infection, unless otherwise indicated. This recommendation was largely based on data available on the use of corticosteroids in the management of Middle East respiratory syndrome, severe acute respiratory syndrome, seasonal influenza, and respiratory syncytial virus infections. ^[54]

Later, the controlled, open-label Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with COVID-19 was published. This trial was conducted on hospitalized patients across 176 National Health Service organizations. Patients were randomized to receive 6 mg of oral or intravenous dexamethasone for 10 days versus the usual care. Among patients hospitalized for SARS-CoV2 infection, use of dexamethasone resulted in lower 28-day mortality in patients on oxygen supplementation or invasive mechanical ventilation. No benefit and a possibility of harm was noted in patients not on oxygen supplementation at the time of randomization. Patients with longer duration of symptoms (>7 days) had greater benefit from dexamethasone therapy. It was also shown to reduce the median duration of hospital stay and clinical progression to respiratory decompensation in patients on supplemental oxygen. ^[55]

Patients treated with corticosteroids in the setting of Middle East respiratory syndrome, severe acute respiratory syndrome, and influenza showed slower viral clearance. ^{[56, 57, 58]} The clinical implication of this finding is unknown. However, in SARS-CoV2 infection, the viral shedding tends to decline over time and use of dexamethasone is likely more beneficial at a stage of the disease process dominated by immunopathological effects than active viral replication. ^[55]

Baricitinib

Baricitinib is a selective inhibitor Janus kinase 1 and 2. It is given orally. It inhibits the intracellular signalling pathway of cytokines such as IL-2, IL-6, IL-10, interferon-γ, and granulocyte macrophage colony-stimulating factor. It has been also shown to improve the lymphocyte count and prevent entry of the virus into the cell. In the Adaptive COVID-19 Treatment Trial-2 (ACTT-2), patients were randomized to receive either baricitinib or placebo. ^[59] Both groups received remdesivir. This randomized controlled trial showed that the combination of baricitinib and remdesivir was associated with a reduction in the time to recover, as well as acceleration in improvement in clinical status as compared with the combination of remdesivir and placebo. It was approved by the FDA as a medication to be used under an Emergency Use Authorization (EUA).

Vitamin C

The oxidative stress from ARDS generates free radicals and cytokines, leading to cellular malfunction, damage, and organ failure. On this front, use of antioxidative agents in the management of this pathophysiology is gaining popularity. One such modality is intravenous high-dose vitamin C. Although vitamin C is known to have antioxidant effects, the clinical implication of its use in the setting of ARDS from viral pneumonia is not established. There are reports of the use of high-dose intravenous vitamin C as part of treatment for ARDS associated with SARS-CoV2 infection, but there are no randomized controlled trials or concrete evidence to support its use. ^[60]

Vitamin D

Vitamin D receptor signaling has shown to play a role in decreasing the storm of cytokines and chemokines, modulating neutrophil activity and the renin angiotensin system, and maintaining the pulmonary epithelial barrier. ^[61] In animal studies, vitamin D receptor knockout mice experienced more severe lung injury than wild mice. ^[61] There are currently several ongoing observational and interventional studies evaluating the use of vitamin D for the prevention and/or management of ARDS in the setting of COVID-19.

Zinc

Zinc is an essential micronutrient factoring in anti-inflammatory and antioxidant functions. In vitro, zinc deficiency is related to enhanced IL-6 and IL-1β production, thereby translating to a pronounced inflammatory response. Hence, there are various ongoing studies to evaluate the role of zinc in antiviral immunity. The recommended dietary allowance for zinc is 11 mg/day in men and 8 mg/day in women. There are concerns for impaired intestinal absorption of copper and suppression of the immune system with long-term intake of high-dose zinc. ^[62]

Fluvoxamine

Fluvoxamine is a selective serotonin reuptake inhibitor. It has a strong affinity for the S1R receptor. It is an endoplasmic reticulum chaperone protein involved in the regulation of cytokine production. A double-blind placebo-controlled trial compared fluvoxamine with placebo in the outpatient treatment of patients with SARS-CoV2 infection on self-quarantine. Patients in the treatment arm received escalating doses of fluvoxamine. About 8% of patients in the placebo arm experienced clinical deterioration. The study has several limitations, such as small sample size (n=152), limited geographic involvement (subjects residing in the greater St. Louis area), loss of about 20% of the subject population to follow-up, and short follow-up duration. If fluvoxamine is proven to be effective in the treatment of COVID-19, further clarification on the exact mechanism of action is needed. ^[63]

Anticoagulation

Based on observational data, there appears to be a higher risk for venous thromboembolism (VTE) in patients with COVID-19. Based on the American Society of Hematology, reports of lower extremity deep vein thrombosis (DVT) range from 1.1% in no ICU patients to 69% in critically ill patients. Based on these observations, several institutions have developed anticoagulation protocols for patients infected with SARS-CoV-2. Unfortunately, at this time, no randomized controlled trials guide the empiric use of therapeutic anticoagulation in COVID-19 patients. ^[64]

The consensus from the Society of Critical Care Medicine and the American Society of Hematology does offer some recommendations. VTE prophylaxis is recommended for all COVID-19 patients in the absence of contraindications. Although higher D-dimers are associated with mortality in COVID-19, it is not known if therapeutic anticoagulation mitigates this risk and improves outcomes. Currently, where possible, a definitive diagnosis of VTE should be sought and parenteral therapeutic anticoagulation is not recommended at this time. ^[65]

One of the unique aspects of the SARS-CoV-2 pandemic has been the rapid pace at which a vaccine has been developed. The usual time frame for the development of a vaccine ranges from 3-9 years. ^[66] However, during this unprecedented time, from the time of SARS-CoV-2 sequencing, the completion of phase 1 trials took only 6 months. At this time, there are several vaccines available. These include the Pfizer-Biotech COVID-19 vaccine, Moderna COVID-19 vaccines, AstraZeneca COVID-19 vaccine, and Jansen COVID-19 vaccine. Further, other countries, including Russia (Sputnik V vaccine), China (Sinopharm vaccine) and others, are also available.

The two FDA-approved vaccines are described in detail below.

Pfizer-Biotech (BNT162b2)

The initial phase 1 trial reporting the efficacy of BNT162b2, a lipid nanoparticle–formulated, modified RNA particle encoding the SARS-CoV2 full-length spike was published in the New England Journal of Medicine in December 2020. ^[67] Since then, the vaccine, which was administered as two 30-μg doses given 21 days apart, demonstrated 95% efficacy. From July 2020 to November 2020, 43,448 patients were randomized in a 1:1 distribution at 150 sites worldwide. Demographically, these cohorts included 51% males and 82.9% Whites. Also of note, approximately 58% of the patients were aged 16-58 years. Currently, 37,706 patients are at least 2 months post receiving the second dose, and adverse events up to 14 days after the second data were described. ^[68] These data were self-reported by means of an electronic diary and subdivided into local or systemic adverse events. More patients in the vaccine group reported adverse events (27% vs 12%). Further, four patients in the vaccine group reported severe adverse events necessitating withdrawal from the trial. Two patients in the vaccine group and four in the placebo died, but these were thought to be unrelated to the effects of the vaccine. Interestingly, there were no COVID-19–related deaths in either cohort.

Based on these data, the FDA issued an Emergency Use Authorization for the vaccine on December 11, 2020.

Moderna (mRNA-1273)

Analogous to the BNT162b2 vaccine, the mRNA-1273 encodes the SARS-CoV-2 spike protein. After being tested on mice and rhesus macaques, the phase 1 trial of this vaccine was reported on two doses of the vaccine given 28 days apart. This report, published on November 12, 2020,  was an open-label trial with 45 patients comparing the 25-μg and the 100-μg dose. In this phase 1 clinical trial, the major adverse effects included fatigue, chills, headache, myalgia, and injection site pain. No major adverse events were noticed. More recently, on December 17, 2020, the original trial was expanded to include an additional 40 patients who were aged 56-70 years or older than 71 years. Again, no severe adverse events were noted and it seemed that more moderate systemic adverse events were associated with the 100-μg dose. ^[69]

Although the results of the phase 3 trial are pending publication in a peer-reviewed journal, the preliminary release shows the Moderna vaccine is 94.1% effective against SARS CoV-2 infection and 100% effective in preventing severe COVID-19.

The FDA issued an Emergency Use Authorization for the vaccine on December 18, 2020.

Pregnancy

The response to the unique maternal immune system to SARS-CoV-2 is not known. The maternal immune system must protect against microbial infections while simultaneously developing tolerance to fetal allogeneic antigens. In the respiratory tract, estrogen-mediated edema limits lung expansion and may predispose pregnant women to respiratory pathogens. ^[70]

Currently, there is no evidence of vertical transmission of SARS-CoV-2 as per two small studies from China. ^{[71, 72]} Detectable SARS-CoV-2 RNA has not been isolated from amniotic fluid, placenta, or breast milk. Owing to the limited number of reported cases of COVID-19 in the first trimester, it is still unclear if the viral infection impacts embryogenesis leading to a congenital anomaly. ^[73] However, in the third trimester of pregnancy, COVID-19 may result in a severe inflammatory response. This cytokine storm–mediated inflammatory response increases maternal serum levels of IL-17a, IL-2, and IL-7, among others, and can pose an indirect risk to fetal brain development, leading to neuronal dysfunction. ^[70]

The current situation warrants further research and large-scale studies into the risks, clinical manifestations, management, and complications of COVID-19 in pregnancy.

Chronic lung disease

Patients with chronic lung disease are at an increased risk of severe respiratory illness owing to alterations in the local/systemic immune response, host microbiome, excessive mucous production, and poor pulmonary reserve. ^[74]

The CDC states that patients with moderate-to-severe asthma are at a higher risk for severe respiratory illness when infected with SARS-CoV-2. ^[75]

Patients with chronic obstructive pulmonary disease (COPD) are known to have increased levels of ACE2, the host receptor for SARS-CoV-2, thereby theoretically increasing the risk of severe lung disease. A meta-analysis of seven studies that included approximately 1,592 patients showed up to five times increased risk of severe disease in patients with COPD. ^[74]

The prevalence of chronic respiratory diseases and diabetes was studied in COVID-19 patients in China and was compared with data available for SARS from China, Canada, and Hong Kong. ^[76] Chronic respiratory diseases are surprisingly underrepresented. However, it is possible that there might be a higher number of patients with undiagnosed respiratory disease.

A meta-analysis of eight studies that included approximately 46,000 infected patients showed the most prevalent comorbidities in severe COVID-19 disease were hypertension and diabetes, followed by cardiovascular disease and chronic respiratory disease. ^[77] Further studies are needed to investigate the actual risk of disease acquisition, severity, and management in these vulnerable populations.

Currently, there is no evidence to suggest that the use of inhaled corticosteroids increases the risk of COVID-19 acquisition. Hence, the recommendation is to continue the use of long-term inhaler therapy for patients with asthma or COPD.

Diabetes mellitus

Longstanding diabetes mellitus and hyperglycemia impairs innate immunity, thereby rendering patients susceptible to increased severity of infections. Innate immunity is the first line of defense against any infection, especially viral infections such as COVID-19. ^[78] A study of 174 patients with COVID-19 from China showed diabetes to be an independent predictor of the severity of illness. The patients were at higher risk of severe pneumonia and had higher serum levels of proinflammatory markers such as C-reactive protein, IL-6, ferritin, and D-dimer. ^[79]

Concomitant use of ACE inhibitors, pioglitazone, and liraglutide in patients with diabetes mellitus leads to the up-regulation of ACE2 receptors in animal studies. This can lead to increased viral intrusion and increased severity of illness. ^[78]

Please see Coronavirus Disease 2019 (COVID-19) for continuously updated clinical guidance concerning COVID-19.

In February 2022, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published guidelines for the assessment of long COVID. The end result was a paucity of recommendations, but conditional guidance includes the consideration of routine chest imaging, blood tests, and pulmonary functions tests for patients with respiratory symptoms persisting at least 3 months after COVID-19 diagnosis. Other than physical and respiratory rehabilitation as appropriate, no management recommendations were made. ^[80]

The European Respiratory Society (ERS) and the American Thoracic Society (ATS) taskforces jointly recommend that patients be encouraged in low-intensity exercise, such as daily activities, for the first 6-8 weeks after hospital discharge. The taskforces recommend against high-intensity exercise during this time period. ^[6]