Abbreviations: ACE2: Angiotensin Converting Enzyme 2; COVID-19: Corona Virus Disease 19; CPE: Cytopathic Effect; HCoV: Human Corona Virus; HTS: Hypertonic Solution; NaCl: Sodium Chloride; SARS-CoV-2: Severe Acute Respiratory Syndrome Corona Virus.

Given the high viral titers detected in the upper respiratory tract of asymptomatic and symptomatic individuals [1], and in agreement with the preclinical data mentioned above, use of NI as a means to bring down the viral load, reduce transmission, symptoms and duration of illness has been proposed recently in a series of publications. In human samples, Ramalingam and colleagues [7] were the first to show reduced viral shedding as a result of use of hypertonic saline nasal irrigation (HSNI; 2-3% NaCl) combined with standard treatment versus standard treatment alone in the ELVIS (Edinburgh and Lothians Viral Intervention Study) clinical study. The study participants suffered from common cold originating from several viruses including Rhinovirus, coronavirus COV-229E and other strains, Influenza A virus, and Human metapneumovirus. In a follow up study [8] conducted by the same investigators, post-hoc secondary analysis of data from the ELVIS study showed that hypertonic saline nasal irrigation and gargling (HSNIG) reduced the duration of coronavirus upper respiratory tract infection (URTI) by an average of two-and-a-half days. Overall, NI with hypertonic solution reduced illness duration by 22%, use of over-the-counter medication for symptom relief by 36%, and virus spread to the family by 35%. These conclusions suggested that saline rinses can reduce symptom burden and decrease viral shedding -including that of coronaviruses- in patients.

A series of additional publications confirmed the results mentioned above further promoting NI as an easily implementable technique to be used for preventing and/or controlling COVID-19 infection. Chatterjee et al [9] performed a clinical trial to investigate if normal saline nasal spray and gargle (NSNSG) can protect nasopharyngeal mucosa from SARS-CoV-2 infection. 129 individuals with laboratory confirmed SARS-CoV-2 were allocated to study and control groups. In the study group, 61 patients received NSNSG for 4 days whereas 68 patients in the control group received no intervention. In 91% of patients of the study group, SARS-CoV-2 severity score was either improved or did not progress compare to the control group. Tolerability with NSNSG was found acceptable in the study group. The authors concluded that NSNSG significantly washes off SARS-CoV-2 from the nasal cavity, pharynx and the lung alveoli preventing micro aspiration and pneumonia [9]. NSNSG with hypertonic solution performed several times a day also helped a 54-year-old asymptomatic SARS-CoV-2 infected physician who was quarantined. The infected physician remained asymptomatic, and serum immunoglobulin IgG for SARS-CoV-2 was tested negative two months after the infection [10].

In non-hospitalized patients with COVID-19, hypertonic saline rinses can reduce symptom burden. An open-label randomized controlled trial evaluated the effect of NI with hypertonic saline or saline with 1% surfactant on upper respiratory symptoms and viral load. Analysis of nasal swabs showed that NI relieved upper respiratory symptoms with nasal congestion and headache resolving a median of 7-9 days earlier in the intervention groups. Additionally, headache was significantly reduced. A trend toward decreased cough and fatigue between groups was also reported [11]. Another study found that when COVID-19 patients performed HSNI supplemented with steroids, the olfactory dysfunction duration was significantly reduced restoring the sense of smell [12].

Duration of viral shedding of SARS-CoV-2 after nebulization with a galenic mixture based on HTS was reduced in two different clinical studies comprising 248 patients with mild or asymptomatic COVID-19. In the first study including 76 patients with mild disease phenotype, a galenic preparation containing hypertonic saline (3%), high-molecular-weight sodium hyaluronate, xylitol and antibiotics was administered twice daily for a period of up to 10 days. At the end of the treatment, all patients were symptomless and had a negative molecular test on the 10th day [13]. In the second study, 172 asymptomatic COVID-19 subjects received the HTS-based preparation mentioned above without antibiotics for 7 days; the patients were negative at the nasal swab testing performed on the 14th or 21st post-treatment day [14]. The same hypertonic solution was additionally administered via nebulization in 42 patients with hyposmia/hypogeusia due to COVID-19. All patients in the study improved after treatment and achieved normal sensory function ten days after treatment initiation. Cacosmia completely disappeared between 10- and 30-days post-treatment [15]. In all cases, the treatment was safe and well-tolerated in all treated subjects. The results from infected patients with mild or no symptoms showed that NI with hypertonic solutions represents a simple, practically feasible, and globally implementable strategy with important therapeutic value. All research studies supporting use of hypertonic or isotonic solutions in patients with COVID-19 can be found in Table 2.

Table 2. Clinical studies and case reports supporting use of hypertonic or isotonic solutions in patients with COVID-19.