Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1091 (Published 26 March 2020) Cite this as: BMJ 2020;368:m1091Read our latest coverage of the coronavirus outbreak
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Dear Editor
Epidemiology of covid-19 and the unexpected death rates. Could not the reason for this be the way out of the Mire.
The NHS figures have shown unexpected low numbers of those under 60 yrs been admitted to hospital when compared to previous Influenza outbreaks.
The high risk group over 60yr especially males appears higher than might have expected considering the low numbers below 60yr.
Some patients admitted to hospital suddenly deteriorate after one week in what appears to be an immune response by the body.
The papers from Wuhan Dr Fei Zhou et al had already not only indicated that the risk group was the over 60yrs and higher numbers of males but patients classed as having Hypertension having a high risk. These facts are agreed by Dr Albini et al in his comments in rapid response regarding 9000 patients in Italy where 73% had hypertension .
Surely these very facts link point to the fact that the higher illness rate and death rate over age 60yr is related to other factors than just comorbidity. Dr Albini has suggersted that ACE inhibitors and ARBs could possibly be indicated as a causal element.
These facts clearly link with the right and proper campaign you have started regarding BAME doctors and ethnic groups who are likely to be prescribed these drugs for treating hypertension particularly if they have diabetes.
Surely there is a case for a rapid proactive research project in a few areas in UK where those on these drugs are changed to others where possible . this would quickly identify or rule this out rapidly.
Competing interests: No competing interests
Dear Editor,
In their paper (1), Chen et al. reported hypertension, cardiovascular disease, and diabetes as frequent comorbidities in patients with COVID-19, consistent with other studies (2-4). Endothelial dysfunction is a common feature of all these disorders. Furthermore, all of the co-factors harnessed by SARS-CoV-2 coronavirus to access host cells, including ACE2, CD147, sialic acid receptor, and TMPRSS2, are expressed by human endothelial cells (5, 6).
Hence, our theory is that SARS-CoV-2 could directly affect endothelial cells, explaining the main systemic manifestations observed in COVID-19 patients, including thrombotic complications (4, 7). Of interest, Chen et al. are in line with our view, reporting higher D-dimer levels in deceased patients compared to survived patients (1). If our hypothesis is correct, several drugs that have been shown to improve endothelial function, such as modulators of the renin-angiotensin-aldosterone system, anti-coagulants, statins, and anti-inflammatory drugs, could be extremely helpful in the treatment of COVID-19 patients. Do the authors have any data regarding the percentage of patients in their study who were receiving these drugs and whether such treatment had any effect on the outcome or on the severity of the disease?
References
(1) Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020 Mar 26;368:m1091. doi: 10.1136/bmj.m1091.
(2) Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020 Apr 6. doi: 10.1001/jama.2020.5394.
(3) McMichael TM, Currie DW, Clark S, et al. Epidemiology of Covid-19 in a long-term care facility in King County, Washington. N Engl J Med. 2020; in press.
(4) Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020; in press.
(5) Ou X, Liu Y, Lei X, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020 Mar 27;11(1):1620. doi: 10.1038/s41467-020-15562-9.
(6) Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020; in press.
(7) Tang N, Li D, Wang X and Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844-847.
Gaetano Santulli, MD, PhD
Albert Einstein College of Medicine, Montefiore University Hospital, New York, NY, USA
Federico II University, Naples, Italy;
gaetano.santulli@einstein.yu.edu
Marco Bruno Morelli, PhD
Albert Einstein College of Medicine, New York, NY, USA
marco.morelli@einsteinmed.org
Jessica Gambardella, PhD
Albert Einstein College of Medicine, New York, NY, USA
Federico II University, Naples, Italy;
jessica.gambardella@einstein.yu.edu
Competing interests: No competing interests
Dear Editor
This is an interesting article from a Paediatric Surgeon’s perspective.
We would like to highlight the possibility of histopathology similarity between the critically ill SARS-Cov-2 patients to moribund infants with a congenital diaphragmatic hernia (CDH). Hopefully, this may lead to a possible lead upon clinical management of the acutely ill SARS-CoV-2 patients.
A) CLINICAL COURSE SIMILARITY:
The novel coronavirus disease 2019 (COVID-19) can induce acute respiratory distress syndrome (ARDS), which can progress to refractory pulmonary failure. The mortality of critically ill patients with SARS-CoV-2 pneumonia is considerable. The survival time of the non-survivors is likely to be within 1–2 weeks after ICU admission. [1] In such cases, extracorporeal membrane oxygenation (ECMO) may be considered as rescue therapy.
Similarly, in the immediate postnatal phase of some CDH moribund infants, there is a short period of better oxygenation referred to as the “honeymoon” period. [2] However, progressive deterioration in oxygenation is commonly observed due to a combination of pulmonary arterial hypertension, right ventricular hypertrophy and/or failure, and left ventricular hypoplasia with pulmonary venous hypertension results in severe Persistent pulmonary hypertension of the newborn (PPHN) unresponsive to conventional management following birth. [2]
Treatment after birth requires all the refinements of critical care including extracorporeal membrane oxygenation (ECMO) prior to surgical correction.
B) HISTOPATHOLOGIC SIMILARITY:
Animal models of CDH have demonstrated that in utero compression of developing fetal lungs by herniated abdominal viscera impairs pulmonary growth and maturation, resulting in pulmonary hypoplasia, which can be quantified by histologic, biochemical, and pulmonary morphometric techniques. Whatever its cause, pulmonary hypoplasia, which usually is a bilateral process, even in unilateral CDH, results in alveolar hypoplasia and a distinctly abnormal pulmonary vascular bed. Arterial branches are reduced, and there is a medial thickening in the small preacinar and intra-acinar arterioles. The physiologic consequence of this abnormality in pulmonary vasculature is an increase in pulmonary vascular resistance, which contributes to the development of persistent pulmonary hypertension, arguably the principal determinant of mortality in CDH. Another contributing factor appears to be a hyperreactivity to known stimuli of pulmonary vasoconstriction, including hypoxia, acidosis, hypothermia, and stress.
Similarly, the microscopic findings in SARS-CoV-2 patients included diffuse alveolar damage with exudates. The inflammation was predominantly lymphocytic, and multinucleated giant cells were seen alongside large atypical pneumocytes, although no definitive viral inclusions were noted.
POSSIBLE INFERENCES:
ECMO IN CDH moribund Infants provides a means of maintaining oxygen delivery only temporarily, and its salvage rate depends on the reversibility of the pathologic factors that led to respiratory failure within the time frame that ECMO can be used. Although the pulmonary hypoplasia associated with CDH can be “outgrown”, the time required for this adaptive process often exceeds that provided by ECMO bypass. This accounts for the significant differences in survival observed between patients who have CDH and those who have more rapidly reversible causes of respiratory failure, including PPHN, meconium aspiration syndrome, and sepsis.
However, that may not be the case in critically ill SARS-CoV-2. Hopefully, the timely use of ECMO would lead to better clinical outcomes in critically ill SARS-CoV-2 patients as compared to CDH infants. More so considering that in the study of ECMO for ARDS in patients with Middle East Respiratory Syndrome Coronavirus (MERS-CoV), a similar coronavirus disease that emerged in 2012, a significant decrease of in-hospital mortality rate and length of intensive care unit (ICU) stay was found in patients treated with ECMO compared to those managed with conventional therapy.
References:
1. Brandon Michael Henry, Giuseppe Lippi. Poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19): Pooled analysis of early reports. J. Crit Care 2020 Apr 1 doi: 10.1016/j.jcrc.2020.03.011 [Epub ahead of print]
2. Nair J, Lakshminrusimha S. Update on PPHN: mechanisms and treatment. Semin Perinatol. 2014;38(2):78–91.
Competing interests: No competing interests
Dear Editor
The main results of this paper as presented in table 4 are hard to understand.
For instance, in the colum under deaths, the complication of type 1 respiratory failure is reported as 18/35 (51). Clearly, and as stated in the legend, 18 is 51% of 35. What is not clear is what the denominator of 35 refers to. Is it a subset of the type 1 respiratory failure totals reported as: 18/67 (27)?
Without this information the result lacks meaning. Clarification is called for.
Competing interests: No competing interests
Dear Editor,
In their paper, Chen et al. [1] reported signs of systemic inflammation and cytokine storm in a subset of patients who died from coronavirus disease 2019 (COVID-19). This phenomenon has been heavily debated, and the optimal treatment strategy is currently unknown.
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), shares similarities with SARS, which was caused by SARS-CoV-1. Both SARS and COVID-19 can cause acute respiratory distress syndrome (ARDS) and multiorgan failure, which is thought to result from a combination of virus-induced cytopathic effects and a dysregulated hyperinflammatory state [2].
SARS-CoV-1 (and likely SARS-CoV-2) express proteins which attenuate the host antiviral type I interferon-response, which facilitates rapid viral replication and extensive virus-induced cytopathic effects in early stages of disease [2]. In a mice model of SARS, a delayed and persistent type I IFN-response was associated with a subsequent aberrant and dysregulated hyperinflammatory stage characterized by high levels of pro-inflammatory cytokines and chemokines and massive pulmonary infiltration of inflammatory monocytes/macrophages and neutrophils, culminating in severe lung injury [2]. Depletion of inflammatory monocytes/macrophages mitigated the lung damage [2], suggesting that dysregulated and counterproductive macrophage activation may be central to the pathophysiology of the hyperinflammatory stage.
NLRP3 inflammasomes are intracellular multiprotein complexes found in macrophages, which are assembled and activated in response to a number of cellular threats [3]. Activation of NLRP3 inflammasome triggers a series of events, in which pro-IL-1β and pro-IL-18 are cleaved into their active forms. The macrophage subsequently undergoes pyroptosis, which results in release of these newly formed pro-inflammatory cytokines [3]. SARS-CoV-1 has been shown to activate the NLRP3 inflammasome [4], and pyroptotic macrophages may contribute to the detrimental hyperinflammatory phenotype observed in a subset of critically ill COVID-19 patients [5].
Immunosuppressive strategies, including IL-1 and IL-6 inhibition, have been suggested for patients with COVID-19 and hyperinflammation [6]. In theory, this may be of benefit in carefully selected cases, after weighing the risk of impaired host antimicrobial defense and secondary bacterial infections. However, IL-1 and IL-6 inhibitors are expensive and not readily available worldwide. Hence, investigation of other potential strategies for mitigating the hyperinflammatory response is of interest. Colchicine is a cheap and readily available drug which inhibits polymerization of microtubules, thereby preventing chemotaxis and NLRP3 inflammasome assembly [7], both of which have theoretical therapeutic potential in the hyperinflammatory state. We encourage research evaluating the efficacy and safety of colchicine in mitigating the hyperinflammatory manifestation of COVID-19.
Jens Vikse, M.D.
Clinical Immunology Unit
Stavanger University Hospital
Gerd-Ragna Bloch Thorsens gate 8, 4068 Stavanger, Norway
jens.vikse@sus.no
Guiseppe Lippi, M.D.
Section of Clinical Biochemistry
University of Verona
Via S. Francesco 22, 37129, Verona VR, Italy
giuseppe.lippi@univr.it
Brandon Michael Henry, M.D.
Cardiac Intensive Care Unit
The Heart Institute, Cincinnati Children’s Hospital Medical Center
3333 Burnet Ave., Cincinnati, OH, USA 45229
brandon.henry@cchmc.org
References
1 Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020;368. doi:10.1136/bmj.m1091
2 Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe 2016;19:181–93. doi:10.1016/j.chom.2016.01.007
3 Man SM, Karki R, Kanneganti T-D. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev 2017;277:61–75. doi:10.1111/imr.12534
4 Shi C-S, Nabar NR, Huang N-N, et al. SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes. Cell Death Discov 2019;5:101. doi:10.1038/s41420-019-0181-7
5 Fung S-Y, Yuen K-S, Ye Z-W, et al. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect 2020;9:558–70. doi:10.1080/22221751.2020.1736644
6 Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet 2020;395:1033–4. doi:10.1016/S0140-6736(20)30628-0
7 Leung YY, Yao Hui LL, Kraus VB. Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum 2015;45:341–50. doi:10.1016/j.semarthrit.2015.06.013
Competing interests: No competing interests
Dear Editor,
The article by Chen et al. on their experience of managing patients, including those who have have succumbed, with COVID-19 in Wuhan City, China is of interest to those of us tackling the global pandemic[1].
One aspect of the article perplexes me.
The authors are based in the Tongji Hospital, Wuhan City, Hubei Province, China where the causative virus, SARS-CoV 2 originated. As the authors describe, this was one of the rapidly built COVID-19 hospitals established to cope with this serious epidemic.
The authors describe in detail the SARS-CoV 2 PCR test used to diagnose COVID-19. If they are only referred “confirmed COVID-19” positive patients, why were patients tested for SARS-CoV 2? Was this a confirmatory test following a PCR result at the referring hospital? Was it the initial diagnostic test? This is not clear. I could not see information on numbers of tests performed at Tongji Hospital or positivity rate in this cohort of 799 patients.
What happened if “confirmed COVID-19” patients referred by another hospital had a negative SARS-CoV 2 result at Tongji Hospital?
It would be interesting and helpful to have clarification of the testing strategy, rationale and test results in this early COVID-19 cohort in a designated COVID-19 hospital in Wuhan. This additional information would make this article even more valuable.
References:
1. Chen T et al. Clinical characteristics of 113 deceased patients with coronavirus 2019 : retrospective study. BMJ 2020;368 doi: https://doi.org/10.1136/bmj.m109 (accessed 2/4/20)
Competing interests: Any views expressed are my own and not those of my employer.
Dear Editor
This study has been extremely useful for clinicians elsewhere in the world, and we are grateful for the expedited review and publication in the BMJ.
However, there seems to be an overlap between this publication and a preprint published on MedRXiv on 20 February (https://www.medrxiv.org/content/10.1101/2020.02.18.20023242v1). While this is not unreasonable, and in fact is preferred to get the data out as fast as possible, it would be useful for readers to notify them on the preprint server that this has been published in the BMJ, and for BMJ readers to be aware that an earlier version was posted on a preprint server.
Similarly, there is a paper published in Kidney International, which also mentions the exact same number of deaths, 113 in number (https://www.kidney-international.org/article/S0085-2538(20)30255-6/fulltext). That paper gives more nuanced details about kidney involvement, however, it would again be useful for readers to be aware that these publications come from the same data set.
The conclusions above are made from the fact that the numbers seem to be very close, and the data comes from the same institution with many authors being in common. There is nothing wrong in these papers been published in this manner, in this responder's view, however, transparent notification would be useful for readers, as well as researchers who might be looking at a quantitative synthesis of the literature. For more on the utility of preprints, BMJ readers might read this blogpost by J. Brian Byrd (http://www.nephjc.com/news/2020/3/21/byrds-words-preprints-and-peer-review).
Competing interests: No competing interests
Dear Editor
The SARS -CoV-2 (COV) pandemic is currently being managed primarily through Non-Pharmaceutical Interventions (NPIs) due to the lack of any approved therapies or a vaccine against COV. This has led to the repositioning of some existing medications, many of which have limited direct relationship to the causality, pathophysiology or clinical course of COV. These medications, at most, have minimal evidence, usually from in-vitro studies or inadequately powered clinical studies [1] on the benefit-risk in COV patients and should therefore be considered as “experimental” therapies demonstrating only equipoise (neither benefit nor harm). There is therefore an urgent need to collect clinical data that will facilitate or prevent their continued use in COV patients.
The conduct of clinical trials on experimental medicines during a pandemic requires pragmatism when emotions run high and preserving public health and saving lives remain paramount. When the workload and stress levels are high amongst HCPs [2], it will be unfair to impose an additional workload through the conduct of poorly designed trials. Implementing simple and well-designed trials in real time during a pandemic allows society to rapidly access medicines of “potential value”, whilst at the same time enabling the collection of data to make appropriate scientific assessments of the “real value” of the medicine(s) for use in the current and future COV epidemics. Emotions should not be allowed to override the science. Lessons from the experience of the Ebola epidemic and the report of the WHO panel convened to look at the ethics of providing experimental medicines during epidemics [3] could be helpful.
The usual ethical considerations such as informed consent and ethical committee approvals should continue to apply even in pandemics, but these could be implemented using simple pragmatic processes. The ethical use of control arms with available standard of care (SoC) needs careful consideration. In a disease such as COV, which has significantly variable outcomes across the population, it is essential to have a control group of patients to compare the effect of the experimental medicines. However, patients , investigators and indeed ethics committees could reject participation in trials with a control arm when some healthcare systems allow the use of some of the medications perceived to be “safe” to patients with COV. The recent FDA approval of Hydroxyquinoline for hospitalized COV patients, though only for patients where access to clinical trials are unavailable, will further complicate the recruitment into control arms. Every effort should be made to educate the scientific community, ethics committees and the public at large on the need for a control arm. It will be a shame to end up in a situation where meaningful conclusions cannot be made on the benefit-risk profile or the value of these medications for future COV recurrences.
Most of the ongoing and planned trials have rightly focused on hospitalized COV patients where the need for effective therapies remains critical. However, the PRINCIPLE trial that is currently being launched to study the effect of Hydroxyquinoline in older patients with mild symptoms in a primary care setting will provide useful data that will facilitate the early use of the drug to contain the disease in future flareups.
Several clinical endpoints are being assessed in many of the trials. The use of mortality as the primary end point in the SOLIDARITY AND RECOVERY trials should be welcomed, as it is not only the most medically relevant patient centric endpoint but as a hard and robust measurement, it is easy to register in any resource restrained environment, including pandemics. The thousands of patients required to provide an acceptable power to the trials will require the participation of many sites from the non-High-Income countries which in addition will allow the data to be globally relevant. Global pandemics will need global solutions. It will also be helpful to have an internationally accepted definition of what constitutes “death directly attributed to COV”. In many instances COV acts only to “precipitate” a downward course in many patients who already have compromised organ function [4]. Perhaps restricting the mortality endpoint only to patients with the characteristic radiological and/or hypoxic features of a “COV lung” may be a possibility. A consensus view on “Covid Deaths” is overdue not only to facilitate the power calculations for the conduct of clinical trials but also to meaningfully compare case fatality rates across various countries during the pandemic and understand the overall course and prognosis of COV.
When resources are limited, the ethical principles of Justice and Societal utility should also come into play in the allocation of limited supplies of diagnostics and therapeutics to the population. Health Care
Professionals and Carers, especially those working in highly exposed environments, should have been given priority in the allocation of the limited supplies of the diagnostic test for COV in UK. It is hoped that when similar situations develop in the future, priority will be given to frontline essential workers in the distribution of any limited supplies of proven therapies and/or vaccines based on the ethical principle of reciprocity”.
REFERENCES:
1. Gautret P et al, Hydroxychloroquine and azithromycin as a treatment of COVID -19 : results of an open label non-randomized clinical trial, International J of Anti-Microbial agents 2020 online, 105949.
https://doi.org/10.1016/j.ijantimicag.2020.105949
2. Brooks SK, Webster RK, Smith LE, Woodland L, Wessely S, Greenberg N et al. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet 2020; 395: 912-920.
3. Report of the Ebola Interim Assessment Panel – July 2015. https://www.who.int/csr/resources/publications/ebola/ebola-panel-report/en/
4. Zunyou Wu & McGoogan JM, Characteristics of and important lessons from the Coronavirus Disease 2019 (Covid 19) Outbreak in China, JAMA 2020 online. doi:10.1001/jama.2020.2648
Competing interests: No competing interests
Dear Editor
COVID-19 emerged in Wuhan, China in December 2019 and despite tremendous efforts to contain, it has spread to the whole of the world (1). On 11th March 2020 WHO declared it a pandemic. (2) Strategies are continually under development to reduce coronavirus burden and consequently interrupt the transmission.
Historically, mass drug administration, of a therapeutic regimen to a whole or high-risk population at the same time, without screening or diagnostic testing prior to administration (3) has been used to contain in many public health challenges across the world such as interrupting malaria transmission in endemic areas by administering antimalarial drugs in a single or multiple rounds to vulnerable population groups such as pregnant women, infants, and non‐immune travelers, to prevent clinical disease and similarly, controlling tuberculosis where isoniazid is given to exposed and vulnerable persons in a household, reducing the risk of clinical infection. (4,5)
Some literature has shown that hydrochloroquine besides being an anti-malarial drug might also be an antiviral drug (9). Recently, the potential use of hydro-chloroquine for treating COVID-19, has been investigated as a treatment strategy for COVID-19 (7,8). In vitro studies have shown that hydroxychloroquine contributes to attenuating the inflammatory response and can efficiently inhibit SARS-COV-2 infection (6). Its safety profile is better than other antimalarials of the same category such as chloroquine, as it allows higher daily doses and fewer side effects (10).
Given the high human case fatality rate, we propose that targeted oral mass administration of the drug might be useful, starting with a loading dose of 400 mg twice followed by a maintenance dose of 200 mg twice daily for 4 days in high-risk groups such as health care providers, travelers from high-risk countries, and their immediate contacts (6). To implement this, hot spots of infection need to be identified using spatial analysis technique. Integrated drones and geographic information system which has promising outputs could be used in tracking and combating contagion. Drones can also be used for disinfection in highly contaminated areas such as the containment zone (11,12). This public health approach might be cost-effective, available and feasible to contain the pandemic of COVID-19. Identified hot spots can then be divided into:
1) Containment zone, which is a particular area, such as locality or hospital where corona positive cases and their possible contacts are present. In this zone drugs such as hydro chloroquine should be given to everyone and non-pharmaceutical intervention should be used such as hand and respiratory hygiene, social distancing measures, voluntary quarantine for 14 days, movement restrictions in and out of the containment zone.
2) Buffer zone, which is an area surrounding the containment zone where active and complete surveillance including laboratory testing, emphasis on containment communication should be done. There could be movement of some people from the containment zone to the buffer zone.
However, this drug has a few side effects in the long term; therefore, it should be used cautiously in diseases such as psoriasis, porphyria, and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, and in patients with liver disease, alcoholism, heart rhythm disorder (such as long QT syndrome).
References
1. Chinese Center for Disease Control and Prevention (CCDC). The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19)–China. 2020.
2. World Health Organization. Statement on the second meeting of the International Health Regulations Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV), Geneva, Switzerland, 30 January 2020. 2005.
3. Eisele TP. Mass drug administration can be a valuable addition to the malaria elimination toolbox. Malaria journal. 2019 Dec;18(1):1-5.
4. https://www.cdc.gov/malaria/malaria_worldwide/reduction/mda_mft.html.
5. https://clinicaltrials.gov/ct2/show/NCT04261517.
6. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases. 2020 Mar 9.
7. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Bioscience trends. 2020.
8. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020;30:269–271.
9. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P. A novel coronavirus from patients with pneumonia in China, 2019. New England Journal of Medicine. 2020 Jan 24.
10. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, Li Y, Hu Z, Zhong W, Wang M. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery. 2020 Mar 18;6(1):1-4.
11. Huber M. Drones Enlisted To Fight Corona Virus in China. AIN Online, 7 February 2020.
12. Brickwood B. XAG introduces drone disinfection operation to fight the coronavirus outbreak. Health Europa.
Competing interests: No competing interests
Re: Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study
Dear Editor
We read the article of Tao Chen and researchers [1] with great interest. Their results show that recently coronavirus disease-19 (COVID-19) outbreak, 113 COVID-19 patients with sepsis and acute respiratory distress syndrome (ARDS) did not be survived. Of them, 95.8% (23/24) patients with hypoxic encephalopathy died in hospitalized. We agree with their work, but the diagnosed criteria of hypoxic encephalopathy was not described.
As we know, new sepsis-3 is defined sepsis as a life-threatening organ dysfunction due to a dysregulated host response to infection. [2] Moreover, in COVID-19 outbreak, older patients are especially at an high risk for life‐threatening respiratory, cardiovascular, and cerebral complications. [3] These cerebral complications or central nervous system (CNS) manifestations caused by COVID-19 can range from dizziness or headache, seizure and impaired consciousness, and acute cerebrovascular disease. [4] Actually, according to the new definition of sepsis-3, all abovemetioned term can generally be called sepsis-associated acute brain dysfunction, including COVID-19-associated encephalo -pathy without virus crossing the blood-brain barrier (BBB), meningitis/encephalitis due to COVID-19 direct into CNS, and vasculopathy/stroke caused by COVID-19.
To our knowledge, COVID-19-associated encephalopathy has been reported between Mar to May. [5,6] The authors reported two patients with COVID-19 pneumonia and one was intubated for acute hypoxemic respiratory failure. Their characteristics included systemic inflammatory response, impaired consciousness (from delirium to lethargy). The brain image of case 1 has not showed any acute lesion and another case showed a small hyperintense signal lesson on Diffusion weighted images(DWI) in the left parietocoritcal region. Electroencephalographies (EEG) of two cases were confirmed having diffuse slowing. The cerebrospinal fluid (CSF) analysis of two patients did not show any evidence of CNS infection ( i.e., normal cell count, negative PCR COVID-19, and negative other microbes). These authors indicated that the cause of the encephalopathy in COVID-19 is multifactorial. Also, some authors [7] reported a first case of COVID-19-associated acute necrotizing encephalopathy (ANE) with altered mental status; her DWI image showed hemorrhagic rim enhancing lesions in the bilateral thalami, medial temporal lobes, and subinsular regions. Moreover, CSF bacterial culture showed no growth, and tests for herpes simplex virus 1 and 2, varicella zoster virus, and West Nile virus were negative. But, the COVID-19 in the CSF was not to be performed and her CSF analysis was limited due to a traumatic lumbar puncture. These authors considered that ANE is a rare encephalopathy caused by COVID-19 and other virus due to an intracranial cytokine storm.
Interestingly, Scullen,et al in May [8] reported on twenty patients with COVID-19-associated encephalopathy, 2 cases with COVID-19- associated ANE，and 5 with COVID-19-associated vasculopathy in a series of 27 COVID-19. Due to respiratory failure and hypoxiemia, all cases was intubated and transferred to the RICU. Most of COVID-19-associated encephalopathy and vasculopathy with diffuse or multifocal subcortical lesions was confirmed by EEG or CT/MRI-DWI, only 1 case with features of hypoxic injury. More recently, Benameur et al [9] reported three COVID-19 cases (including 2 encephalopathy and 1 encephalitis) with increased cytokine in CSF, supporting that cytokine is most likely to lead to BBB leakage and brain edema. [10] Futhermore, the brain edema had been demonstrated by autopsy from died COVID-19 cases. [11]
Despite the data from Chen et al showing that 100% of sepsis patients had acute respiratory failure/ARDS and hypoxiemia, their data also showed that those patients had severe systemic inflammatory response and cytokine storms (increased tumour necrosis factor in blood)；suggesting that the mechanisms of encephalopathy are not likely to be explained by a single cause. Moreover, the potential mechanisms of COVID-19-associated encephalopathy or SAE is also related to the sereve inflammation, cytokine storm, sepsis-induced coagulopathy, hypoxiemia, and neurovirulence. [9-13] Thus, we consider that the COVID-19- associated encephalopathy may not only be masquerading as hypoxic encephalopathy, but also imitating as acute stroke.
Unlike meningitis/encephalitis caused by COVID-19, the CSF analysis can be showed an increased white cell count and with positive PCR. Whereas, the encephalopathy caused by COVID-19 pneumonia, its CSF analysis would only indicate an elevated pressure, mildly elevated protein level, and normal white cell count and glucose level as well as negative PCR. Yet, the diagnosis of COVID-19-associated encephalopathy has to be on the clinical manifestations with acute brain dysfunction (from altered mental status to focal or diffuse neurological deficits), images of COVID-19 pneumonia, without a significant evidence of direct CNS infection, and ruled out other encephalopathy/effects of sedatives.
According to the report from WHO, current about 8 million cases with COVID-19 were diagnosed in global, and near half million of them died of acute organ failure. Thus, recognizing the COVID-19- associated encephalopathy as a common acute organ failure and with high risk of death is very important for surviving COVID-19. Yet, it is necessary to further exploring its pathogenesis, clinical manifestations, and treatment.
Competing interests
No competing interests.
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Competing interests: No competing interests