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Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.
The phases of COVID 19
COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).
The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.
The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.
The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.
The virus is actively replicating during the asymptomatic and at the beginning of the viral phase. The severity of symptoms varies according to the viral load and patient comorbidities [mild-moderate (81%), severe (14%), and critical (5%)]. The disease course is characterized by dysregulated immunity, profound inflammatory response, and dysregulated coagulation. By distinguishing these phases, clinicians can start interventions that would aim at the main cause of the derangement at each specific phase. For example, antiviral agents seem more appropriate in the early phases of the disease, while anti-inflammatory medications could target the inflammatory response that occurs in the pulmonary phase (Figure 1).
The tools in our toolbox: Timing is paramount
Remdesivir
The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.
Convalescent plasma
Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).
The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.
Corticosteroids
Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.
Self-proning
Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change.
What about thromboembolic events?
Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.
The available evidence is helpful but not definitive making it difficult to have a clear pathway to effectively treat the systemic effects of COVID-19. One should consider remdesivir and convalescent plasma during the viral phase before hypoxia ensue. Anti-inflammatory interventions (dexamethasone or methylprednisolone) should be given as soon as the pulmonary manifestations start (hypoxia). The type, optimal dose, and duration of corticosteroids vary from trial to trial and no evidence suggests that higher doses are associated with more benefit. It is not only important to choose the right treatment but also the phase when such treatment is most likely to be effective!
Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.
Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.
The phases of COVID 19
COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).
The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.
The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.
The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.
The virus is actively replicating during the asymptomatic and at the beginning of the viral phase. The severity of symptoms varies according to the viral load and patient comorbidities [mild-moderate (81%), severe (14%), and critical (5%)]. The disease course is characterized by dysregulated immunity, profound inflammatory response, and dysregulated coagulation. By distinguishing these phases, clinicians can start interventions that would aim at the main cause of the derangement at each specific phase. For example, antiviral agents seem more appropriate in the early phases of the disease, while anti-inflammatory medications could target the inflammatory response that occurs in the pulmonary phase (Figure 1).
The tools in our toolbox: Timing is paramount
Remdesivir
The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.
Convalescent plasma
Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).
The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.
Corticosteroids
Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.
Self-proning
Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change.
What about thromboembolic events?
Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.
The available evidence is helpful but not definitive making it difficult to have a clear pathway to effectively treat the systemic effects of COVID-19. One should consider remdesivir and convalescent plasma during the viral phase before hypoxia ensue. Anti-inflammatory interventions (dexamethasone or methylprednisolone) should be given as soon as the pulmonary manifestations start (hypoxia). The type, optimal dose, and duration of corticosteroids vary from trial to trial and no evidence suggests that higher doses are associated with more benefit. It is not only important to choose the right treatment but also the phase when such treatment is most likely to be effective!
Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.
Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.
The phases of COVID 19
COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).
The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.
The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.
The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.
The virus is actively replicating during the asymptomatic and at the beginning of the viral phase. The severity of symptoms varies according to the viral load and patient comorbidities [mild-moderate (81%), severe (14%), and critical (5%)]. The disease course is characterized by dysregulated immunity, profound inflammatory response, and dysregulated coagulation. By distinguishing these phases, clinicians can start interventions that would aim at the main cause of the derangement at each specific phase. For example, antiviral agents seem more appropriate in the early phases of the disease, while anti-inflammatory medications could target the inflammatory response that occurs in the pulmonary phase (Figure 1).
The tools in our toolbox: Timing is paramount
Remdesivir
The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.
Convalescent plasma
Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).
The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.
Corticosteroids
Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.
Self-proning
Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change.
What about thromboembolic events?
Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.
The available evidence is helpful but not definitive making it difficult to have a clear pathway to effectively treat the systemic effects of COVID-19. One should consider remdesivir and convalescent plasma during the viral phase before hypoxia ensue. Anti-inflammatory interventions (dexamethasone or methylprednisolone) should be given as soon as the pulmonary manifestations start (hypoxia). The type, optimal dose, and duration of corticosteroids vary from trial to trial and no evidence suggests that higher doses are associated with more benefit. It is not only important to choose the right treatment but also the phase when such treatment is most likely to be effective!
Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.