COVID-19 Pulmonary Management

Updated: Apr 16, 2020
  • Author: Setu K Patolia, MD, MPH; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Overview

Overview

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 attempt to summarize the pulmonary impact and management of COVID-19.

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.

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Pathogenesis of COVID-19

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. [3]

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. [4]

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. [5]

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. [6]

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. [7]

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. [8]

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. [9]

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.

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Clinical Features of COVID-19

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. [10]

When comparing severe with nonsevere cases, patients in the severe disease cohort were older and more likely to have comorbid conditions. [11] 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. [10]

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. [12] 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. [13]

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

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Diagnosis of 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. [11] 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%. [11] 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. [11]

CT scans performed from both Washington State and Wuhan most commonly showed ground-glass opacities. [10, 11] Other CT scan findings include consolidations, nodular opacities, and reticulations. [14] 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. [15] Interestingly, from the Wuhan cohort, 18% of patients with nonsevere disease and 3% with severe disease did not have any findings on CT scans. [11]

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. [16] 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. [17]

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

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Treatment of 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. [18]

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. [19, 20]

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. [21] A retrospective review from China examined a small cohort of 27 patients who developed severe acute respiratory failure after being diagnosed with COVID-19. [22] 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. [22] 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). [23]

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. [21]

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. [24] 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. [25]

Extracorporeal membrane oxygenation

The role of extracorporeal membrane oxygenation (ECMO) in the treatment of ARDS is controversial, but there appears to be a role in patients with refractory hypoxemia. [26] At present, there are no robust data to guide the use of ECMO in patients with COVID-19. Per the WHO, ECMO should only be offered to patients with refractory hypoxia at an expert center. [18] The use of ECMO is very staff-intensive and runs the risk of potentially exposing multiple members of the treating team to SARS-CoV-2.

Antibiotics

Although there is no role for antibiotics in the treatment of coronavirus infection, 58% of patients in Wuhan were started on antibiotics. [11] Further, the use of empiric antibiotics is endorsed by the WHO to cover bacterial superinfections. [18]

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. Based on this, hydroxychloroquine and chloroquine have been used in SARS-CoV-2 infection. [27]

Chloroquine was shown to reduce viral replication in vitro and block infection by increasing the endosomal pH and by blocking glycosylation of the cellular receptor of SARS-CoV-2. [28] At this time, substantial evidence for the use of chloroquine is lacking; however, Chinese experts recommend treating patients with COVID-19 with 500 mg of chloroquine twice a day. [29]

Hydroxychloroquine, an analog of chloroquine, was further evaluated in an open-label trial from France. Twenty patients were treated with 600 mg of hydroxychloroquine once daily. Of note, several of these patients were also treated with azithromycin. The authors of this trial concluded there was improved reduction of the viral load in patients treated with hydroxychloroquine and azithromycin. The added advantage of hydroxychloroquine is a better safety profile and fewer drug interactions. [30] Large-scale randomized controlled trials are underway. However, caution is warranted regarding the potential adverse effects of hydroxychloroquine in the absence of randomized controlled trials showing beneficial effects. QTc prolongation is a known adverse effect of hydroxychloroquine. A clinical trial to evaluate the safety and effectiveness of hydroxychloroquine for the treatment of adults hospitalized with COVID-19 has begun with 10-12 centers in the United States (ORCHID study: Outcomes Related to COVID-19 treated with hydroxychloroquine among In-patients with symptomatic Disease study). [31]

Remdesivir and lopinavir-ritonavir

Remdesivir, a nucleotide analog, has shown efficacy against SARS-CoV-2 in vitro. [28] At this time, several randomized controlled trials are underway evaluating the use of remdesivir in COVID-19 patients, and it is only available through those trials or for compassionate use. Adverse effects include nausea, vomiting, and transaminitis.

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 control trial failed to show a mortality benefit. [32]

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 CSS in patients receiving CAR-T (chimeric antigen receptor-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 retrospective study observing the efficacy of tocilizumab in the treatment of severe COVID-19 is underway and yet to be published, but it has shown promising results. [27] A phase III trial was also approved by the US Food and Drug Administration.

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.

Corticosteroids

Based on data from SARS-CoV (2002-2003), MERS, influenza, and respiratory syncytial virus, the WHO issued interim guidance in January 2020 against the routine use of corticosteroids in the treatment of COVID-19. However, as with ARDS, there is a possible role for corticosteroid administration as it suppresses tissue inflammation in the lungs but runs the risk of delaying clearance of SARS-CoV-2. [27, 33]

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Special Populations

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. [34]

Currently, there is no evidence of vertical transmission of SARS-CoV-2 as per two small studies from China. [35, 36] 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. [37] 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. [34]

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. [38]

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. [39]

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. [38]

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. [40] 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. [41] 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. [42] 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. [43]

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. [42]

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

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