Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case seriesBMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1996 (Published 29 May 2020) Cite this as: BMJ 2020;369:m1996
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SARS-Cov-2 particles are made not just of viral structural proteins and RNA (Chen et al., 2020), but also of a foreign component: the lipid membrane stolen from the human endoplasmic reticulum-Golgi intermediate compartment (ERGIC) (Tozzi, 2020). It is no coincidence that coronaviruses display markers for the endoplasmic reticulum and Golgi (Brian and Baric, 2005). During intracellular assembly, coronaviruses anchor their structural proteins to the physical support of the hosts’ ERGIC membranes. Subsequently, SARS-Cov-2 particles, including viral proteins, viral RNA and host ERGIC membranes, are released by exocytosis (Risco et al. 2002; Krijnse-Locker et al., 1994).
It is noteworthy that biochemical, morphological, and functional modifications of endoplasmic reticulum (REL) and Golgi membranes take place during ageing. Several clues point towards a difference in human ERGIC membranes at different ages. Liu et al (2018) found that Serum Golgi protein 73 (GP73), a promising marker for liver fibrosis in adults, decreases with age in healthy controls. Morphological studies on aging in rat brain revealed a disorganization on the normally well-laminated pattern of REL and Golgi vescicles (Brizzee et al., 1975). Janikiewicz et al. (2018) argued that mitochondria-associated membranes’ biology, composition, and action play roles in longevity, through modifications in lipid biosynthesis and trafficking, calcium homeostasis, reactive oxygen species production, and autophagy. Calvo-Rodríguez et al. (2016) suggested that neuronal aging is associated to increased ER-mitochondrial cross talking and subcellular Ca2+ remodeling. Acute murine γ-herpesvirus 68 infection, that causes apoptosis of type II lung epithelial cells in aging mice, up-regulates endoplasmic reticulum stress markers (Torres-González et al., 2012). Brown and Naidoo (2012) and Chadwick and Lajoie (2019) described the role of ER stress response pathways in aging and age-related diseases, occurring via pathways such as unfolded protein responses.
Once established that human ERGIC membranes modify with time passing, we are allowed to state that the SARS-Cov-2 particles produced in the tissues of adults (and possibly children) are phenotypically different from the SARS-Cov-2 particles produced in the tissues of elder people. Whether SARS-Cov-2 strikes children, adults or elder people, the released virions will display different arrangement and composition of ERGIC membranes. These premises might unexpectedly help to investigate one of the most bothersome questions raised during these frantic months of pandemics: why are elder people more affected by SARS-Cov-2 and display more severe COVID-19 symptoms? In turn, why are children less severely affected? The ERGIC structures discrepancy in different SARS-Cov-2 virions might contribute to variations in symptoms severity, viral load, infectivity in populations of different ages. Also, this paves the way to build artificially attenuated virions.
Furthermore, it is noteworthy that intracellular structures like the Golgi complex and endoplasmic reticulum may cause autoimmune reactions and production of specific monoclonal antibodies during distinct events of cellular apoptosis and necrosis (Ma et al., 2019; Grossmann et al, 1989; Nozawa et al., 2002; Hong et al., 2004; Borradaile et al., 2006; Weber et al., 2010). We suggest looking for Golgi and endoplasmic reticulum antibodies in the serum and bronchoalveolar liquid of patients affected by COVID-19.
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Center for Nonlinear Science, Department of Physics, University of North Texas, Denton, Texas, USA
1155 Union Circle, #311427Denton, TX 76203-5017 USA
Competing interests: No competing interests
Bimodal distribution: a real finding or possible extra blip(s) from unknown confounders in retrospective study
I thank Argenziano et al for their interesting analysis of 1000 "consecutive" COVID-19 patients admitted to their hospital (New York-Presbyterian/Columbia University Irving Medical Center or NYP/CUIMC) from 1 March 2020.
I would like to query the significance of the "bimodal distribution in time to intubation from symptom onset" as identified by the authors as one of the key conclusions from their retrospective research.
It is interesting to note that this finding is based on 136 (62%) out of 220 COVID-19 admitted patients intubated (at least once). Also, some 71.6% of admitted patients who were intubated (225?), had their intubation initiated within first 3 days after arrival at the Emergency Department (ED).
It will be even more interesting to know the number of days COVID-19 patients had symptoms before presenting to ED for medical attention and the duration of waiting for test result for COVID-19, considering that in-house coronavirus testing only started from 11 March 2020, with tests sent out to be performed externally prior to this date.
These issues are relevant as it is unclear if the criteria for intubation for COVID-19 patients (as stated in Box 1) applies equally to patients not formally diagnosed as COVID-19 positive, since, depending on the date of presentation to ED, a significant proportion of these COVID-19 patients may not be identified as COVID-19 positive at the time of intubation (keeping in mind at least one-third of COVID-19 patients who have intubation, had this intubation procedure occur within 24 hours of presentation to ED according to Supplemental figure 1). Similarly although the criteria for intubation is stated clearly in the article, there are certain other conditions (for example, chronic obstructive airway disease) that would have similar clinical findings but would not normally be considered a trigger for intubation if not for the COVID-19 positive labelling.
I am aware of the "second week crash" but the bimodal peak intubation risk findings, especially one so early in the first week would require further investigation. However, before other researchers start looking into their own data, it will be important to ensure this occurrence is not due to record keeping practice nor an administrative blip due to external test result reporting (and its effect on tolerance to intubation whenever a patient is labelled as COVID-19 positive).
Competing interests: No competing interests
Argenziano et al describe a bimodal distribution occurring at 3.5 and 9 days in regards to time from onset of symptoms to requirement for mechanical ventilation in COVID-19, with 96% requiring intubation within the first 14 days . We would suggest this is perhaps the golden period when escalation of pharmacotherapy might be helpful in ameliorating the cytokine cascade and associated hyper-inflammatory state before the onset of acute respiratory distress syndrome (ARDS)  .
Hence clinicians looking after sick patients with COVID-19 should be aware that raised circulating levels of interleukin-6 or C reactive protein on initial admission to hospital or rising levels thereafter are a harbinger of impending respiratory failure and need to intensify treatment  . Early clinical trials point to the possibility for using either anti-IL1 or anti-IL6 to improve outcomes in patients with late stage severe COVID-19 infection and hyperinflammation [4, 5] . Preliminary data also suggest that remdesivir might also help to speed up clincial recovery  .
We await with interest the results of larger randomised controlled trials to assess which cytokine inhibitors given alone or combination with antivirals might offer the best chance to obviate progression to ARDS and associated respiratory failure .
1. Argenziano MG, Bruce SL, Slater CL, et al. Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series. BMJ 2020;369:m1996. doi: 10.1136/bmj.m1996
2. Lipworth B, Chan R, Lipworth S, et al. Weathering the cytokine storm in susceptible patients with severe SARS-CoV-2 infection. J Allergy Clin Immunol Pract 2020 doi: 10.1016/j.jaip.2020.04.014 [published Online First: 2020/04/21]
3. Herold T, Jurinovic V, Arnreich C, et al. Elevated levels of interleukin-6 and CRP predict the need for mechanical ventilation in COVID-19. Journal of Allergy and Clinical Immunology doi: 10.1016/j.jaci.2020.05.008
4. Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences 2020:202005615. doi: 10.1073/pnas.2005615117
5. Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. The Lancet Rheumatology doi: 10.1016/S2665-9913(20)30127-2
6. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report. New England Journal of Medicine 2020 doi: 10.1056/NEJMoa2007764
Competing interests: No competing interests