This study retrospectively investigated the clinical characteristics of COVID-19 patients with HFNC failure and the risk factors associated with HFNC failure. We observed that patients with severe COVID-19 had a high failure rate with HFNC treatment (48.1%, 26/54), which is similar to results in a study by Wang et al. (41.2%, 7/17) [9]. Notably, HFNC failure was seen more commonly in patients aged ≥ 60 years and in men. In addition, patients experiencing HFNC failure had the following characteristics: higher percentage of fatigue and anorexia as well as cardiovascular disease; increased time from onset to diagnosis and SOFA scores; elevated body temperature, respiratory rate, and heart rate; more complications such as ARDS, septic shock, myocardial damage, and acute kidney injury; increased neutrophil counts and prothrombin time; and decreased PaO2/FiO2. However, only male gender and PaO2/FiO2 were independent risk factors significantly associated with HFNC failure.
Increasing data show that the severity of SARS-CoV-2 infection is gender-related [12]. Two studies have reported a higher rate of severe cases in adult men compared with women, with rates ranging from 58–67% [13, 14]. A retrospective cohort study in China also showed that male gender is a major risk factor for higher disease severity and mortality [15]. This association of male gender with disease severity and high mortality may be explained by high expression of type 2 angiotensin converting enzyme (ACE2) and serine-protease TMPRSS2 in male patients, which are two major host proteins involved in cell–virus entry and in triggering the viral cell cycle. Previous studies of SARS-CoV-2 showed that only serine-protease TMPRSS2 is essential for viral spread and pathogenesis [16, 17]. In addition, estrogen can enhance TMPRSS2 expression through the binding of their respective receptors to their responsive elements because the androgen-responsive element is the only known transcription promoter for TMPRSS2 [12]. Data from murine models showed that androgenic control of TMPRSS2 expression is also maintained in lung tissue [18]. Therefore, male patients with COVID-19 have a possibility of more severe lung injury resulting from SARS-CoV-2 infection. In the present study, we found that male COVID-19 patients had a higher possibility of HFNC failure, which was consistent with the tendency toward more severe disease and higher mortality in male patients with COVID-19 [4, 5, 14, 19, 20]. This higher possibility of HFNC failure may be because of the greater disease severity and poorer tolerance to HFNC treatment in male patients, especially older male patients. Thus, early monitoring with high-quality supportive care is needed for these patients, and HFNC treatment should be implemented as early as possible to avoid treatment delay for older male patients with COVID-19 at high risk.
We also found that low PaO2/FiO2 was an independent risk factor significantly associated with HFNC failure. Increasing evidence shows that patients with severe COVID-19 are characterized by classic ARDS, as indicated by the signs of dyspnea and decreased PaO2/FiO2 [4, 5, 14, 19–22]. Indeed, from a therapy perspective, positive end-expiratory pressure (PEEP) ventilation is optimally used to increase functional residual capacity and open collapsed alveoli, thereby improving ventilation–perfusion matching and reducing intrapulmonary shunting, as well as improving lung compliance and thus, reducing respiratory load. In addition, PEEP assists respiratory muscles during inspiration, reducing the work of breathing and dyspnea. From a theoretical and physiological point of view, HFNC may also be beneficial in patients with ARDS. However, HFNC is only a “partial support” therapy. This is mainly because HFNC generates only a small positive pressure spike at end-expiration that depends on the nasal airflow and the extent of mouth opening. HFNC appears to improve oxygenation primarily by flushing the nasal airspaces, reducing anatomical dead space. As such, HFNC does not sufficiently address the underlying pathology of ARDS, such as the ventilation–perfusion mismatch caused by atelectasis or consolidation in the dependent areas when patients are supported with HFNC [23]. Therefore, HFNC is more likely to be unsuccessful when used in COVID-19 patients with low PaO2/FiO2. A recent study showed that HFNC alone could be offered for mild cases (PaO2/FiO2 between 200 mmHg and 300 mmHg) [22]. Therefore, COVID-19 patients with severe ARDS are not appropriate candidates for HFNC [24], and invasive ventilation is an optimal choice. This is because invasive ventilation may result in better physiological effects on ventilation–perfusion mismatch and greater homogeneity in ARDS mechanics during positive pressure support [24].