SUMMARY

COVID-19 infection can progress to severe respiratory infection and have high mortality rates. Several pathophysiological factors are observed in fatal cases, with mortality related to multiple organ failure, in addition to the evolution with high levels of serum ferritin, D-dimer, and C-reactive protein. These severe cases often meet the criteria for macrophage activation syndrome with changes in the host’s inflammatory response and an inadequate resolution phase. In the present study, the bundle for COVID-19 sepsis is proposed, including early recognition; protection, handwashing and isolation measures; oxygen therapy; early invasive mechanical ventilation; treatment aimed at modifying the clinical course. This strategy may be useful in the control of children with severe COVID-19 cases, as already demonstrated with the implementation of bundles in sepsis and other etiologies.

KEYWORDS:
COVID-19; Sepsis; Infections; Respiratory Distress Syndrome; Respiratory tract infections

INTRODUCTION

Several pathophysiological factors have been found in COVID-19 fatal cases, which may explain its severe behavior¹1. World Health Organization. Coronavirus disease 2019 (COVID-19): situation report. Geneva: World Health Organization; 2020. [cited on August 2, 2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
https://www.who.int/emergencies/diseases... . People with greater comorbidities⁴4. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. https://doi.org/10.1016/S0140-6736(20)30566-3
https://doi.org/10.1016/S0140-6736(20)30... ,⁵5. Al-Hajjar S, McIntosh K. Pediatric COVID-19: an update on the expanding pandemic. Int J Pediatr Adolesc Med. 2020;7(2):61-3. https://doi.org/10.1016/j.ijpam.2020.05.001
https://doi.org/10.1016/j.ijpam.2020.05.... , such as heart disease, diabetes, hypertension, or obesity have been noted to present a greater risk of death. Mortality has been related to multiple organ failure as the common final pathway of pneumonia, sepsis, and acute respiratory distress syndrome (ARDS) (Figure 1).

Figure 1
Various pathways leading to MAS and MOFS in COVID-19 infection.

Patients with this outcome have been found to have higher serum ferritin, D-dimer, and C-reactive protein (CRP) levels than those who survive⁵5. Al-Hajjar S, McIntosh K. Pediatric COVID-19: an update on the expanding pandemic. Int J Pediatr Adolesc Med. 2020;7(2):61-3. https://doi.org/10.1016/j.ijpam.2020.05.001
https://doi.org/10.1016/j.ijpam.2020.05.... . These findings have been seen in other severe viral infections, especially in children, due to the activation of some signaling pathways by increased interleukin 6 (IL-6), interleukin 1 (IL-1), and tumor necrosis factor alpha (TNF-α)⁶6. Zimmerman O, Rogowski O, Aviram G, Mizrahi M, Zeltser D, Justo D, et al. C-reactive protein serum levels as an early predictor of outcome in patients with pandemic H1N1 influenza A virus infection. BMC Infect Dis. 2010;10(1):288. https://doi.org/10.1186/1471-2334-10-288
https://doi.org/10.1186/1471-2334-10-288... . These severe cases often meet the criteria for macrophage activation syndrome (MAS), which is characterized by a disorderly inflammatory response in the host with an inadequate resolution phase. One of the defining criteria for MAS has been ferritin >500 mg/dL, which has also been seen in patients with severe COVID-19 infection⁵5. Al-Hajjar S, McIntosh K. Pediatric COVID-19: an update on the expanding pandemic. Int J Pediatr Adolesc Med. 2020;7(2):61-3. https://doi.org/10.1016/j.ijpam.2020.05.001
https://doi.org/10.1016/j.ijpam.2020.05.... ,⁷7. Shakoory B, Carcillo JA, Chatahm WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44(2):275-81. https://doi.org/10.1097/CCM.0000000000001402
https://doi.org/10.1097/CCM.000000000000... ,⁸8. Lachmann G, Knaak C, Vorderwülbecke G, La Rosée P, Balzer F, Schenk T, et al. Hyperferritinemia in critically ill patients. Crit Care Med. 2020;48(4):459-65. https://doi.org/10.1097/CCM.0000000000004131
https://doi.org/10.1097/CCM.000000000000... . This virus, in a septic patient scenario, can release damage-associated molecular patterns (DAMP) and pathogen-associated molecular proteins (PAMPs), which lead to severe inflammation with microcirculation injury, thrombosis, and fibrinogen consumption, coinciding with the increased D-dimer seen in patients who die from COVID-19⁵5. Al-Hajjar S, McIntosh K. Pediatric COVID-19: an update on the expanding pandemic. Int J Pediatr Adolesc Med. 2020;7(2):61-3. https://doi.org/10.1016/j.ijpam.2020.05.001
https://doi.org/10.1016/j.ijpam.2020.05.... ,⁹9. Carcillo JA, Halstead ES, Hall MW, Nguyen TC, Reeder R, Aneja R, et al. Three hypothetical inflammation pathobiology phenotypes and pediatric sepsis-induced multiple organ failure outcome. Pediatr Crit Care Med. 2017;18(6):513-23. https://doi.org/10.1097/PCC.0000000000001122
https://doi.org/10.1097/PCC.000000000000... . If this inflammation could be modulated, the microcirculation damage (especially endothelial cell damage) would stabilize, which would stop the apoptotic and pyroptotic cascade, allowing recovery of innate immunity and lung function (the lung being one of the most severely affected organs)¹⁰10. Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87. https://doi.org/10.1007/s00134-020-06022-5
https://doi.org/10.1007/s00134-020-06022... .

Accordingly, the implementation of a rapid approach has been a determining factor in many of the outcomes seen in this pandemic¹1. World Health Organization. Coronavirus disease 2019 (COVID-19): situation report. Geneva: World Health Organization; 2020. [cited on August 2, 2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
https://www.who.int/emergencies/diseases... , as proposed in the paper by Al-Hajjar and McIntosh⁵5. Al-Hajjar S, McIntosh K. Pediatric COVID-19: an update on the expanding pandemic. Int J Pediatr Adolesc Med. 2020;7(2):61-3. https://doi.org/10.1016/j.ijpam.2020.05.001
https://doi.org/10.1016/j.ijpam.2020.05.... , the disease manifestation is less serious than so in the pediatric population than in adults. Thus, a sepsis bundle is proposed for patients with COVID-19 infection, which we believe could be useful in modifying the clinical course of the disease, just as it has proven useful in sepsis from other etiologies¹¹11. Fernández-Sarmiento J, Carcillo JA, Salinas CM, Galvis EF, López PA, Jagua-Gualdrón A. Effect of a sepsis educational intervention on hospital stay. Pediatr Crit Care Med. 2018;19(6):e321-8. https://doi.org/10.1097/PCC.0000000000001536
https://doi.org/10.1097/PCC.000000000000... (Figure 2).

Figure 2
Bundle for COVID-19 sepsis

The bundle components for COVID-19 sepsis should include:

1. Early recognition: The recent sepsis guidelines for both adults and children, as well as the recommendations for management of COVID-19 sepsis, indicate that this measure is key in modifying the clinical course. It should be adhered to fulfill the case definition proposed by WHO, adapted to each center¹1. World Health Organization. Coronavirus disease 2019 (COVID-19): situation report. Geneva: World Health Organization; 2020. [cited on August 2, 2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
   https://www.who.int/emergencies/diseases... . Keep in mind that fever associated with rapidly developing respiratory symptoms and deterioration have been the most important characteristic of this pandemic.

2. Protection, handwashing, and isolation measures: These measures are what have helped lower the pandemic’s peak. Personal protection for health care personnel who care for these patients is essential. Countries like Spain have described up to 12% contagion of the health care team¹1. World Health Organization. Coronavirus disease 2019 (COVID-19): situation report. Geneva: World Health Organization; 2020. [cited on August 2, 2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
   https://www.who.int/emergencies/diseases... . Universal isolation measures will avoid nosocomial contagion and dissemination of the virus (SARS-CoV-2).

3. Oxygen therapy: Given that the lung is the main organ affected, oxygen delivery systems should be offered quickly, according to the patient’s needs. Consider using non-rebreather masks with high-efficiency face masks (N95 or FFP) over them¹1. World Health Organization. Coronavirus disease 2019 (COVID-19): situation report. Geneva: World Health Organization; 2020. [cited on August 2, 2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
   https://www.who.int/emergencies/diseases... . This technique has also been described with the use of high-flow nasal cannulas (HFNCs) to avoid aerosol dissemination²2. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81. PMID: 32105632
   https://doi.org/PMID:32105632... ,¹⁰10. Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87. https://doi.org/10.1007/s00134-020-06022-5
   https://doi.org/10.1007/s00134-020-06022... . The noninvasive ventilation (NIV) should be limited and recommended only if adequate levels of staff protective equipment is available.

4. Early invasive mechanical ventilation: In the experience of the most severely affected countries (China, Italy, and Spain, given their greater number of cases), rapid initiation of mechanical ventilation has been essential for those who have survived¹1. World Health Organization. Coronavirus disease 2019 (COVID-19): situation report. Geneva: World Health Organization; 2020. [cited on August 2, 2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
   https://www.who.int/emergencies/diseases... ,²2. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81. PMID: 32105632
   https://doi.org/PMID:32105632... . Delaying intubation and ventilatory support has been associated with greater mortality⁵5. Al-Hajjar S, McIntosh K. Pediatric COVID-19: an update on the expanding pandemic. Int J Pediatr Adolesc Med. 2020;7(2):61-3. https://doi.org/10.1016/j.ijpam.2020.05.001
   https://doi.org/10.1016/j.ijpam.2020.05.... . Adequate preparation for intubation, pre-oxygenation without positive pressure ventilation, and rapid sequence of intubation using videolaryngoscope should be considered¹1. World Health Organization. Coronavirus disease 2019 (COVID-19): situation report. Geneva: World Health Organization; 2020. [cited on August 2, 2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
   https://www.who.int/emergencies/diseases... ,²2. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81. PMID: 32105632
   https://doi.org/PMID:32105632... . The presenting pathophysiological pattern will guide the ventilatory support which will cause the least alveolar damage. It may be useful to establish an “optimal” PEEP graphically, numerically or using an esophageal balloon with monitoring with volumetric capnography¹²12. Matthay MA, Aldrich JM, Gotts JE. Treatment for severe acute respiratory distress syndrome from COVID-19. Lancet Respir Med. 2020;8(5):433-4. https://doi.org/10.1016/S2213-2600(20)30127-2
   https://doi.org/10.1016/S2213-2600(20)30... . The hypoxic pulmonary vasoconstriction phenomenon may be leading to severe pulmonary hypertension, right heart failure, and death. Therefore, reports have indicated that the early use of nitric oxide could be useful. The prone position should be considered when Pa02/Fi02 is <150¹²12. Matthay MA, Aldrich JM, Gotts JE. Treatment for severe acute respiratory distress syndrome from COVID-19. Lancet Respir Med. 2020;8(5):433-4. https://doi.org/10.1016/S2213-2600(20)30127-2
   https://doi.org/10.1016/S2213-2600(20)30... .

5. Treatment aimed at modifying the clinical course: The studies published to date have not described a specific treatment which could be universally recommended. The use of hydroxychloroquine, azithromycin, and ritonavir, among others, has been reported with inconsistent results¹³13. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949. https://doi.org/10.1016/j.ijantimicag.2020.105949
   https://doi.org/10.1016/j.ijantimicag.20... . In this respect, the presenting immunophenotype in the disease’s severe phase could help guide treatment. If we posit that the scenario meets the MAS criteria with immunoparalysis related to MOF (TNF-alpha <200pg / ml), immunoglobulins or colony stimulating factor could be useful⁸8. Lachmann G, Knaak C, Vorderwülbecke G, La Rosée P, Balzer F, Schenk T, et al. Hyperferritinemia in critically ill patients. Crit Care Med. 2020;48(4):459-65. https://doi.org/10.1097/CCM.0000000000004131
   https://doi.org/10.1097/CCM.000000000000... ,⁹9. Carcillo JA, Halstead ES, Hall MW, Nguyen TC, Reeder R, Aneja R, et al. Three hypothetical inflammation pathobiology phenotypes and pediatric sepsis-induced multiple organ failure outcome. Pediatr Crit Care Med. 2017;18(6):513-23. https://doi.org/10.1097/PCC.0000000000001122
   https://doi.org/10.1097/PCC.000000000000... . Likewise, in patients with TAMOF (<57% ADAMTS-13 activity), plasmapheresis, or eculizumab could be considered⁹9. Carcillo JA, Halstead ES, Hall MW, Nguyen TC, Reeder R, Aneja R, et al. Three hypothetical inflammation pathobiology phenotypes and pediatric sepsis-induced multiple organ failure outcome. Pediatr Crit Care Med. 2017;18(6):513-23. https://doi.org/10.1097/PCC.0000000000001122
   https://doi.org/10.1097/PCC.000000000000... .

CONCLUSION

The bundle for COVID-19 sepsis can be a useful strategy for the control of the disease, as it has been demonstrated in sepsis of another etiology. Studies are needed to confirm its utility and its potential to modify the clinical course in this disease.

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