key: cord-0952483-qirxw9y3
authors: Okuhama, Ayako; Ishikane, Masahiro; Hotta, Masatoshi; Sato, Lubna; Akiyama, Yutaro; Morioka, Shinichiro; Suzuki, Setsuko; Tajima, Tsuyoshi; Yamamoto, Makiko; Teruya, Katsuji; Izumi, Shinyu; Ohmagari, Norio
title: Clinical and radiological findings of silent hypoxia among COVID-19 patients
date: 2021-07-08
journal: J Infect Chemother
DOI: 10.1016/j.jiac.2021.07.002
sha: 2f7bbb6a07bc73be8dfc41c8addf1890251ab253
doc_id: 952483
cord_uid: qirxw9y3

The aim of this study was to describe the clinical and radiological findings of COVID-19 patients with “silent hypoxia,” who had no dyspnea on admission even though their oximetry saturation was less than 94%. This retrospective cohort study included all COVID-19 patients (n=270) at a large tertiary care hospital between January 31 and August 31, 2020. Clinical and radiological characteristics of patients who met our criteria of “silent hypoxia”, which included those who reported no dyspnea even though oximetry saturation was < 94%, were extracted. Eight patients (3.0%) met the criteria for “silent hypoxia.” The median age was 61 years (interquartile range [IQR]: 48.8-72.3), and five (62.5%) were men. All patients had consolidation on CT and showed a moderate to high COVID-19 CT severity score (median: 13.5, IQR: 10.8-15.3). The median FIO2 of the maximum oxygen required was 55 (IQR: 28-70)%. Two patients (25.0%) were intubated, and one patient (12.5%) underwent extracorporeal membrane oxygenation. Some COVID-19 patients with “silent hypoxia” may develop severe disease. Close and accurate monitoring of patients using arterial blood gas and pulse oximetry is necessary, regardless of their symptoms.

Since its emergence in December 2019, many unique features of coronavirus disease 2019 , diseases caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been reported [1] [2] . Among them, some patients with hypoxia have been labeled with a condition called "silent hypoxia/hypoxemia" or "happy hypoxia/hypoxemia" because they do not experience dyspnea [3] . One French study reported that the prognosis of these patients was worse than those who experienced dyspnea, partially because of their delayed attention to the necessary medical care [4] . There have been several studies proposing possible mechanisms behind this phenomenon, including direct viral entry into respiratory control centers [5] and altered ventilation/perfusion (VA/Q) due to pulmonary micro-thrombosis [6] . However, detailed clinical and radiological characteristics of these patients in Asian population are still not understood well. Therefore, we aimed to describe the clinical and radiological findings of Japanese COVID-19 patients with "silent hypoxia". This study was approved by the ethics committee of National Center for Global Health and Medicine (NCGM) (NCGM-G-003665-00) and was implemented in accordance with the 1964 Declaration of Helsinki. A retrospective cohort study of all COVID-19 patients was conducted between January 31 and August 31, 2020, at the NCGM, Tokyo, Japan. All COVID-19 patients were diagnosed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) for SARS-CoV-2 using nasopharyngeal swabs, according to the protocol recommended by the National Institute of Infectious Disease in Japan [7] . Enrolled patients were those who reported no dyspnea on admission, even though their oximetry saturation was < 94% [3] . All data were extracted from the COVID-19 Registry Japan (COVIREGI-JP) of the NCGM, with permission. The study data of COVIREGI-JP were collected and managed using the Research J o u r n a l P r e -p r o o f Electronic Data Capture, a secure, web-based data capture application hosted at the Japan Clinical Research Assist Center data center of the NCGM [8] . The parameters retrieved from the database included (i) demographics and comorbidities; (ii) number of days from symptom onset to hospital admission and CT scan; (iii) clinical symptoms; (iv) laboratory findings; (v) radiological findings on CT scan, including COVID-19 severity score [9] ; and (vi) clinical outcomes.

During the study period, 270 patients were hospitalized in the NCGM. Among them, eight (3.0%) met the criteria for "silent hypoxia". The median age was 61 (interquartile range

[IQR]: 48.8 -72.3) years, and five (62.5%) were male. The median days from symptom onset to hospital admission and CT were 6 (IQR: 4.5 -6.3) and 6 (IQR: 4.5 -7.5) days, respectively. All patients had consolidation on CT, and the COVID-19 CT severity score was moderate to high (median 13.5, IQR: 10.8 -15.3) ( Table 1) . Laboratory results associated with poor prognosis were markedly elevated in our cohort; the median of C-reactive protein (CRP) was 5.5 (IQR: 4.6-7.5) mg/dL, and the median of D-dimer was 1500 ng/mL (IQR: 800 -3800). Figure 1 shows an example of the CT image of a patient with "silent hypoxia". The patient was a 86-year-oldfemale with a chief complaint of fever, denying dyspnea. Chest X-ray on admission showed bilateral grand-glass opacity (GGO) and consolidation with a predominantly peripheral distribution. Her oximetry saturation was 90% on admission, body temperature was 37.6℃, and blood pressure was 136/61 mmHg. Chest CT scan taken on day 10 showed bilateral GGO and consolidation with a predominantly peripheral distribution with CT severity score of 16.

Although her oximetry saturation was 93% on 0.5 L oxygen on that day, she did not report dyspnea. In our cohort, while oxygen was not administered to one (12.5%) patient whose J o u r n a l P r e -p r o o f oximetry saturation was 93% at the lowest, the median FIO2 of maximum oxygen required was 55 (IQR: 28-70) %. During the clinical course, two patients (25.0%) were intubated, and one patient (12.5%) underwent extracorporeal membrane oxygenation (ECMO). The median total length of hospital stay was 26.5 (IQR: 19.8 -38.8) days, and no patient died ( Table 2 ).

Our study showed that the clinical characteristics of COVID-19 patients with "silent hypoxia" varied, and their outcomes can be severe. In our cohort, two patients were intubated, and one patient required ECMO, with no in-hospital death. Interestingly, CT revealed moderate to severe pneumonia, with a median chest CT score of 13.5 (IQR: 10.8 -15.3), which is disproportionate to the absence of dyspnea. As previously suggested from a report from France [4] , Japanese patients with "silent hypoxia" might also have poor prognosis. Our study also implies that this poor prognosis might not be due to the patient delay, because all patients in our study presented themselves within seven days, suggesting pathophysiological process producing "silent hypoxia" is essentially aggravating the disease severity. Several pathophysiological hypotheses behind "silent hypoxia" have been proposed. Some reports pointed out that baseline characteristics, such as age and diabetes, may affect perception of the lack of oxygen. However, in our cohort, the youngest patient was 33 years old, and 7 out of 8 patients (87.5%) did not have diabetes. Thus, our results implicate that more complicated mechanisms beyond comorbidities are involved in this condition. One report claims that SARS-CoV-2 may cause neuronal damage in the corticolimbic network, altering the perception of dyspnea and respiration control [5] .

Histopathological examination of COVID-19 patient brain specimens revealed neuron loss in the cerebral cortex, hippocampus, and cerebellar Purkinje cell layer; SARS-CoV-2 was also detected in several brain sections [10] . Additionally, pulmonary microthrombosis in COVID-19 patients without large decrements in lung compliance disrupts the VA/Q relationship, resulting in reduced J o u r n a l P r e -p r o o f increases in breathing to achieve appropriate oxygenation [6] . Elevated D-dimer level in our study might reflect this. Our study has several limitations. First, because of the small sample size, we were not able to conduct a case-control study, which hindered us from identifying any patterns or factors related to silent hypoxia when compared with patients experiencing dyspnea.

Second, we did not clarify the mechanisms of "silent hypoxia". Lung and brain biopsies were not performed, thus, we do not know whether the patients had actual neuronal damage or microthrombosis in the lungs, as reported earlier [5] [10] . Third, we did not evaluate patients who presented "silent hypoxia" after admission, as the clinical information which we were able to extract from our database was symptoms and oximetry saturation on admission. The database does not hold information on whether the patients developed dyspnea or not during the hospital course. Because COVID-19 is known to progress during day 7 to 10 after onset, we might have been able to include some patients in this study if we were able to extract information on patients who developed "silent hypoxia" after hospitalization.

In conclusion, COVID-19 patients with "silent hypoxia" may present with or progress to severe COVID-19 pneumonia disproportionate to their symptoms. Therefore, close monitoring of arterial blood gas and pulse oximetry is necessary. Further large-scale studies are needed to clarify the characteristics and risk factors of "silent hypoxia" COVID-19 patients. Oximetry saturation of the patient was 90% on admission, and body temperature was 37.6℃.

Chest CT scan taken on day 10 showed bilateral GGO and consolidation with a predominantly peripheral distribution with CT severity score of 16. Although her oximetry saturation was 93% on 0.5 L oxygen on that day, she did not report dyspnea.

J o u r n a l P r e -p r o o f 

Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

SARS-CoV-2 infection among returnees on charter flights to Japan from Hubei, China: a report from National Center for Global Health and Medicine

The mystery of the pandemic 'happy hypoxia'

Asymptomatic hypoxia in COVID-19 is associated with poor outcome

Dyspneic and non-dyspneic (silent) hypoxemia in COVID-19: Possible neurological mechanism

Silent hypoxaemia in COVID-19 patients

Development of Genetic Diagnostic Methods for Novel Coronavirus 2019 (nCoV-2019) in Japan

Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support

Chest CT score in COVID-19 patients: correlation with disease severity and short-term prognosis

Neuropathological Features of Covid-19

We thank all the clinical staff at our hospital for their dedication to patient care, and all the technical staff at COVID-19 REGISTRY JAPAN (COVIREGI-JP).