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Abstract
The sense of smell (olfaction) is one of the most important senses for animals including
humans. Despite significant advances in the understanding mechanism of olfaction,
currently, there are no objective non-invasive methods that can identify loss of smell.
Covid-19-related loss of smell has highlighted the need to develop methods that can
identify loss of olfaction. Voltage-gated sodium channel 1.7 (Na
V1.7) plays a critical role in olfaction by aiding the signal propagation to the olfactory
bulb. We have identified several conditions such as chronic inflammation and viral
infections such as Covid-19 that lead to loss of smell correlate with downregulation
of Na
V1.7 expression at transcript and protein levels in the olfactory epithelium. Leveraging
this knowledge, we have developed a novel fluorescent probe Tsp1a-IR800 that targets
Na
V1.7. Using fluorescence imaging we can objectively measure the loss of sense of smell
in live animals non-invasively. We also demonstrate that our non-invasive method is
semiquantitative because the loss of fluorescence intensity correlates with the level
of smell loss. Our results indicate, that our probe Tsp1a-IR800, can objectively diagnose
anosmia in animal and human subjects using infrared fluorescence. We believe this
method to non-invasively diagnose loss of smell objectively is a significant advancement
in relation to current methods that rely on highly subjective behavioral studies and
can aid in studying olfaction loss and the development of therapeutic interventions.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.
COVID-19 can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery. This systematic review and meta-analysis aims to identify studies assessing the long-term effects of COVID-19. LitCOVID and Embase were searched to identify articles with original data published before the 1st of January 2021, with a minimum of 100 patients. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. PRISMA guidelines were followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included (age 17–87 years). The included studies defined long-COVID as ranging from 14 to 110 days post-viral infection. It was estimated that 80% of the infected patients with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). Multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.
Dear editor, In this journal, we recently reported a series of 279 hospitalized patients with novel coronavirus 2019 disease (COVID-19) and their short-term outcome. 1 However, only a few studies have assessed post-discharge persistent symptoms and health-related quality of life (HRQoL) after hospitalization for COVID-19. 2 , 3 Here, we describe a single-centre study assessing post-discharge persistent symptoms and HRQoL of patients hospitalized in our COVID-19 ward unit more than 100 days after their admission. COVID-19 diagnosis was based on positive SARS-CoV-2 real-time reverse transcriptase-polymerase chain reaction on nasal swabs, and/or typical abnormalities on chest computed tomography. Patients who were directly admitted to the ICU without being hospitalized in our COVID-19 unit were excluded. Demographic and clinical data at admission were extracted from electronic medical records. We designed a short phone questionnaire to collect post-discharge clinical symptoms, modified Medical Research Council (mMRC) dyspnoea scale scores, professional and physical activities, and attention, memory and/or sleep disorders. HRQoL was assessed using the EQ-5D-5L questionnaire, a widely used, validated European questionnaire 4 . Patients are asked to rate their health state from 1 to 5 in five domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and on a scale ranging from 0 (“the worst possible health”) to 100 (“the best possible health”) on a visual analogue scale (EQ-VAS). Based on the answers, an EQ-5D- index can be calculated, ranging from states worse than dead (<0) to 1 (full health). 5 All eligible patients were contacted by phone by trained physicians and were asked to answer to the questionnaire. Deceased, unreachable, demented, bedridden and non-French speaking patients were excluded. We compared patients managed in hospital ward without needing intensive care (“ward group”) with those who were transferred in intensive care units (ICU) for artificial ventilation, including non-invasive ventilation, high flow nasal cannula and/or mechanical ventilation (ICU group), with t-tests for quantitative variables and Chi-square tests for qualitative variables. All tests were two-sided, and a P-value <0.05 was considered statistically significant. All analyses were performed with R version 3.6.1. (R Foundation for Statistical Computing, Vienna, Austria). The study was approved by the local institutional review board (IRB 00006477). Of the 279 hospitalized patients between March 15th and April 14th, 2020 in our COVID-19 unit, 48 were admitted to ICU, and 57 patients died within the three months following admission (43 in the ward group and 14 in the ICU group) (Supplementary figure 1). After having excluded demented or bedridden (n=18), unreachable (n=69), non-French speaking patients (n=12), and those declining participation (n=2), 120 patients answered the phone questionnaire after a mean (±SD) of 110.9 (±11.1) days following admission: 96 in the ward group and 24 in the ICU group for artificial ventilation (mechanical ventilation for 14, CPAP for 10 and high flow nasal cannula for 7). After a mean of 110.9 days, the most frequently reported persistent symptoms were fatigue (55%), dyspnoea (42%), loss of memory (34%), concentration and sleep disorders (28% and 30.8%, respectively) (Table 1 ). Loss of hair was reported by 24 (20%) patients, including 20 women and 4 men. Comparisons between ward- and ICU patients led to no statistically significant differences regarding those symptoms. Thirty-five (29%) patients had a mMRC grade ≥2 (“Walks slower than people of the same age because of dyspnoea or has to stop for breath when walking at own pace”). Table 1 Post-discharge persistent symptoms and health-related quality of life of 120 patients after a mean of 110.9 days after their admission for COVID-19. Table 1 Overall Ward patients ICU patients P value N=120 N=96 N=24 Age, years 63.2 (15.7) 64.1 (16.1) 59.6 (13.7) 0.208 Sex, male 75 (62.5) 56 (58.3) 19 (79.2) 0.099 Comorbidities Diabetes 26 (21.7) 22 (22.9) 4 (16.7) 0.698 Hypertension 56 (46.7) 45 (46.9) 11 (45.8) 1.000 Body mass index (kg/m²) <0.001 <25, n (%) 35 (29.2) 32 (33.3) 3 (12.5) ≥25, n (%) 57 (47.5) 37 (38.5) 20 (83.3) Missing, n (%) 28 (23.3) 27 (28.1) 1 (4.2) Clinical features at admission Confusion 7 (5.8) 6 (6.2) 1 (4.2) 1.000 Cough 87 (72.5) 69 (71.9) 18 (75.0) 0.959 Dyspnoea 88 (73.3) 68 (70.8) 20 (83.3) 0.327 Myalgia 19 (15.8) 16 (16.7) 3 (12.5) 0.851 Diarrhoea 29 (24.2) 25 (26.0) 4 (16.7) 0.488 Admission data Length of stay in hospital, days 11.2 (13.4) 7.4 (5.4) 26.5 (22.3) <0.001 Length of stay in ICU, days - - 17.1 (15.7) - Persistent symptoms Cough 20 (16.7) 14 (14.6) 6 (25.0) 0.358 Chest pain 13 (10.8) 11 (11.5) 2 (8.3) 0.941 Fatigue 66 (55.0) 52 (54.2) 14 (58.3) 0.891 Dyspnoea 50 (41.7) 38 (39.6) 12 (50.0) 0.487 Ageusia 13 (10.8) 9 (9.4) 4 (16.7) 0.509 Anosmia 16 (13.3) 14 (14.6) 2 (8.3) 0.638 Hair loss 24 (20.0) 18 (18.8) 6 (25.0) 0.690 Attention disorder 32 (26.7) 28 (29.2) 4 (16.7) 0.327 Memory loss 41 (34.2) 36 (37.5) 5 (20.8) 0.194 Sleep disorder 37 (30.8) 29 (30.2) 8 (33.3) 0.535 mMRC dyspnoea scale 0.438 Grade 0 56 (46.7) 47 (49.0) 9 (37.5) Grade 1 29 (24.2) 22 (22.9) 7 (29.2) Grade 2 or more 35 (29.2) 27 (28.1) 8 (33.3) Professional and physical activities Returned to work/worked before hospitalization 38/56 (67.9) 31/41 (75.6) 7/15 (46.7) 0.061 Resumed sport/practiced sport regularly before hospitalization 28/39 (71.8) 23/31 (74.2) 5/8 (62.5) 0.937 EQ-5D-5L EQ-VAS (%) 70.3 (21.5) 69.9 (21.4) 71.7 (22.2) 0.711 EQ-5D index 0.86 (0.20) 0.86 (0.19) 0.82 (0.21) 0.306 Results are expressed as count (%) for categorical variables and as mean (standard deviation) for quantitative variables. ICU: intensive care unit; mMRC: modified Medical Research Council; Before COVID-19 infection, 56 (46.7%) were active workers. Among them, 38 (69.1%) had gone back to work at the time of the phone interview. Among the 39 patients who had regular sports activity before their hospitalizations for COVID-19, 28 (71.8%) have been able to resume physical activity, but at a lower level for 18 (46%). There was no statistically significant difference between ward and ICU groups, but there was a non-significant trend towards a reduced proportion of patients returning to work among ICU patients (46.7% versus 77.5%, P=0.061). In both group, dimensions of the EQ-5D (mobility, self-care, pain, anxiety or depression, usual activity) were altered with a slight difference in pain in the ICU group, but no statistically significant difference in the other groups (Figure 1 ). Mean EQ-VAS was 70.3% and mean EQ-5D index 0.86, with no difference between ICU and ward patients (Table 1). Figure 1 Health-related quality of life after hospitalization for COVID-19 assessed by the EQ-5D 5L in the ward and the ICU groups. 1A: Distribution of the EQ-5D index (0: death to 1: full health). 1B: EQ-5D 5L scores in the ward and in the ICU groups on each domain. Each domain is scored on a 5-point scale: 1 no problem, 2 slight problem, 3 moderate problem, 4 severe problem, 5 unable to do. *: P=0.032. Figure 1 The present study shows that most patients requiring hospitalization for COVID-19 still have persistent symptoms, even 110 days after being discharged, especially fatigue and dyspnoea. These results highlight the need for a long-term follow-up of those patients and rehabilitation programs. Surprisingly, many patients (mainly women) spontaneously reported significant hair loss, which may correspond to a telogen effluvium, secondary to viral infection and/or a stress generated by the hospitalization and the disease. 6 Nevertheless, HRQoL was quite satisfactory, as most patients who had a professional activity before the infection went back to work. Except pain or discomfort, we found no significant difference regarding persistent symptoms and HRQoL between ward patients versus ICU patients. This clearly supports the interest of a full resuscitation for COVID patients despite heaviness of cares. However, patients from our “ICU group” were relatively non-severe, as those who were directly admitted to ICU (thus corresponding to the most severe forms) were not included in our study. Other limitations of our study include the limited number of patients, the single-centre nature of our series, and the high rate of unreachable patients, which could lead to differential bias. In conclusion, many symptoms persist several months after hospitalization for COVID-19. While there were few differences between HRQoL between ward and ICU patients, our findings must be confirmed in larger cohorts, including more severe ICU patients. AUTHOR CONTRIBUTIONS All authors have made substantial contributions to this work and have approved the final version of the manuscript. Concept and design: EG, BF, YN. Acquisition of data: all authors. Statistical analysis: YN. Interpretation of data: EG, BF, YN. Writing original draft: EG, YN. Writing review and editing: all authors. FINANCIAL SUPPORT None Declaration of Competing Interest None of the authors declared any competing interest in link with the present study.
[1
]Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
[2
]Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
[3
]Mortimer B. Zuckerman Mind, Brain and Behavior Institute, Columbia University, New
York, NY 10027, USA
[4
]Department of Genetics and Development, Columbia University Irving Medical Center,
Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032,
USA
[5
]Department of Otolaryngology- Head and Neck Surgery, Columbia University Irving Medical
Center, Vagelos College of Physicians and Surgeons, Columbia University, New York,
NY, 10032, USA
[6
]Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072,
Australia
[7
]Australian Research Council Centre of Excellence for Innovations in Peptide and Protein
Science, The University of Queensland, St Lucia, QLD 4072, Australia
[8
]Center for Infection and Inflammation Imaging Research, Johns Hopkins University School
of Medicine, Baltimore, MD, USA
[9
]Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore,
MD, USA
[10
]Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins
University School of Medicine, Baltimore, MD, USA
[11
]Department of Radiology, Weill Cornell Medical College, New York, NY, USA
[12
]Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Author notes
[#]
Contributed equally
[ǂ]
Contributed equally
Author Contributions.
D.A., J.G., T.R., S.P. and N.P. conceived the study and designed the experiments.
D.A. J.G, T.V., P.D.S.F, S.R., S.J, A.O., L.C. and T.R. carried out the experiments
and collected the data. J.G., C.Y.C., G.K. and T.R. produced Tps1a-IR800. D.A., N.P.
and T.R. analyzed the data, D.A., J.G., N.P. and T.R. conducted statistical analysis
of the data. D.A., J.G., N.P. and T.R. primarily wrote and edited the manuscript.
All the authors reviewed and approved the manuscript.
[*
]Corresponding authors: Nagavarakishore Pillarsetty, Department of Radiology, Memorial Sloan Kettering Cancer
Center, New York, NY, USA, 1275 York Avenue, New York, NY 10065, USA.
pillarsn@
123456mskcc.org
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