EPs7630 and AVRS

EPs7630 not only blocks the enzyme neuraminidase, which is necessary for the virus to enter the cell and multiply, but also may trigger a strong immune response that works differently from viral infections. The immunomodulatory effect of EPs7630 in viral infections has been demonstrated in three in vitro studies. In a study by Witte et al. (Ref. Reference Witte17), human peripheral blood mononuclear cells (PBMCs) previously infected with the influenza virus and cytomegalovirus (CMV) were treated with EPs7630. The results showed that EPs7630 strongly stimulated the production of the proinflammatory cytokines IL-6 and TNF-α in PBMCs (Ref. Reference Witte17) (Table 1). This stimulative effect was shown to be dose-dependent, and the first effect on the concentrations of all three cytokines was already visible at a drug concentration of 1 μg/ml. In addition, a less pronounced effect on the anti-inflammatory cytokine IL-10 was observed (Ref. Reference Witte17). The results suggested the presence of an EPs7630-induced different inflammatory mediator profile from that induced by viral infection, which causes the production of more anti-inflammatory cytokines (Ref. Reference Witte17) (Table 1). These results suggest that EPs7630 may act as an immunostimulant before viral infection. It could promote innate immune defence and the body’s ability to eliminate potentially invading viruses (Ref. Reference Witte17) (Table 1). In another in vitro study, Witte et al. (Ref. Reference Witte, Koch, Volk, Wolk and Sabat18) showed that the administration of EPs7630 to a culture of human CD4+ memory T cells and monocytes selectively stimulated the production of IL-17 and IL-22 in these cells at a drug concentration of 3 μg/ml (Table 1). In addition, IL-22 significantly increased the expression of the antimicrobial protective protein S100A9 in the respiratory epithelium. EPs7630 has a strong inhibitory effect on interferon-gamma production (IFN-γ). Thus, it may prevent local mucosal damage by this proinflammatory T1 cytokine (Ref. Reference Witte, Koch, Volk, Wolk and Sabat18). These results suggest that EPs7630 could replace antibiotics in treating a potential bacterial superinfection in viral sinusitis and bronchitis (Ref. Reference Witte, Koch, Volk, Wolk and Sabat18) (Table 1).

Table 1. Immunomodulatory effects of EPs7630 in the treatment of acute rhinosinusitis

The site of entry of SARS-CoV-2 into the human body is, in most cases, the olfactory neuroepithelium (Ref. Reference Chen, Geng, Jiang, Xiong and Lei19). Although inflammation often has the characteristics of AVRS, it also has its peculiarities, especially the more frequent impairment of the sense of smell and taste, which can affect the patient’s emotional state. Research has shown that olfactory impairment in COVID-19 is due to damage to the sustentacular supporting cells of the olfactory neuroepithelium (Ref. Reference Chen, Geng, Jiang, Xiong and Lei19). COVID-19 infection harms the speed of mucociliary transport, making the airway mucosa more susceptible to bacterial infection in the post-viral period (Ref. Reference Ozer Ozturk, Aslan and Bayındır20). A subsequent in vitro study showed that the administration of EPs7630 at a concentration of 10 μg/ml reduced the ability of SARS-CoV-2 to invade cultured lung epithelial cells by altering the protein composition of the viral spike (Ref. Reference Papies, Emanuel, Heinemann, Kulić, Schroeder, Tenner, Lehner, Seifert and Müller21) (Table 1). In addition, the concentration of IL-6 and IL-1β was increased, while the concentrations of IL-8, IL-13, TNF-α, IFN-γ-induced monokine (MIG) and interferon γ-induced protein 10 kDa (IP-10) were decreased in the epithelial cell culture fluid (Ref. Reference Papies, Emanuel, Heinemann, Kulić, Schroeder, Tenner, Lehner, Seifert and Müller21) (Table 1). The presence of similar respiratory mucosa in the nose and sinuses could imply similar results related to AVRS. Part of the results related to the production of TNF-α is in contradiction with the previous results of in vitro studies, where the stimulatory effect of this extract on the production of this cytokine was reported as strong (Refs. Reference Perić13–Reference Witte17). This underlines the fact that the results of in vitro research depend on which cell cultures are used and on the local conditions prevailing in the laboratory, implying the need for in vivo studies.

EPs7630 and APRS

The pathophysiology of APRS is not entirely clear. In this clinical entity, viral infections trigger numerous changes in the structure of the airway mucosa, including increased infiltration by neutrophils and monocytes and disturbances in host immune response and adaptive immunity (Refs. Reference Fokkens, Lund, Hopkins, Hellings, Kern, Reitsma, Toppila-Salmi, Bernal-Sprekelsen, Mullol, Alobid, Terezinha Anselmo-Lima, Bachert, Baroody, von Buchwald, Cervin, Cohen, Constantinidis, De Gabory, Desrosiers, Diamant, Douglas, Gevaert, Hafner, Harvey, Joos, Kalogjera, Knill, Kocks, Landis, Limpens, Lebeer, Lourenco, Meco, Matricardi, O’Mahony, Philpott, Ryan, Schlosser, Senior, Smith, Teeling, Tomazic, Wang, Wang, Zhang, Agius, Ahlstrom-Emanuelsson, Alabri, Albu, Alhabash, Aleksic, Aloulah, Al-Qudah, Alsaleh, Baban, Baudoin, Balvers, Battaglia, Bedoya, Beule, Bofares, Braverman, Brozek-Madry, Richard, Callejas, Carrie, Caulley, Chussi, de Corso, Coste, El Hadi, Elfarouk, Eloy, Farrokhi, Felisati, Ferrari, Fishchuk, Grayson, Goncalves, Grdinic, Grgic, Hamizan, Heinichen, Husain, Ping, Ivaska, Jakimovska, Jovancevic, Kakande, Kamel, Karpischenko, Kariyawasam, Kawauchi, Kjeldsen, Klimek, Krzeski, Kopacheva Barsova, Kim, Lal, Letort, Lopatin, Mahdjoubi, Mesbahi, Netkovski, Nyenbue Tshipukane, Obando-Valverde, Okano, Onerci, Ong, Orlandi, Otori, Ouennoughy, Ozkan, Peric, Plzak, Prokopakis, Prepageran, Psaltis, Pugin, Raftopulos, Rombaux, Riechelmann, Sahtout, Sarafoleanu, Searyoh, Rhee, Shi, Shkoukani, Shukuryan, Sicak, Smyth, Sindvongs, Soklic Kosak, Stjarne, Sutikno, Steinsvag, Tantilipikorn, Thanaviratananich, Tran, Urbancic, Valiulius, Vasquez de Aparicio, Vicheva, Virkkula, Vicente, Voegels, Wagenmann, Wardani, Welge-Lussen, Witterick, Wright, Zabolotniy, Zsolt and Zwetsloot1, Reference Arcimowicz3). Infection of the respiratory epithelium by viruses induces strong pro-inflammatory cytokine production. Those cytokines are IL-6, TNF-α, IL-1β, IFN-β and IFN-γ, and the chemokines are IP-10, IL-8 and interferon-inducible T-cell alpha chemoattractant [I-TAC]) (Refs. Reference Fokkens, Lund, Hopkins, Hellings, Kern, Reitsma, Toppila-Salmi, Bernal-Sprekelsen, Mullol, Alobid, Terezinha Anselmo-Lima, Bachert, Baroody, von Buchwald, Cervin, Cohen, Constantinidis, De Gabory, Desrosiers, Diamant, Douglas, Gevaert, Hafner, Harvey, Joos, Kalogjera, Knill, Kocks, Landis, Limpens, Lebeer, Lourenco, Meco, Matricardi, O’Mahony, Philpott, Ryan, Schlosser, Senior, Smith, Teeling, Tomazic, Wang, Wang, Zhang, Agius, Ahlstrom-Emanuelsson, Alabri, Albu, Alhabash, Aleksic, Aloulah, Al-Qudah, Alsaleh, Baban, Baudoin, Balvers, Battaglia, Bedoya, Beule, Bofares, Braverman, Brozek-Madry, Richard, Callejas, Carrie, Caulley, Chussi, de Corso, Coste, El Hadi, Elfarouk, Eloy, Farrokhi, Felisati, Ferrari, Fishchuk, Grayson, Goncalves, Grdinic, Grgic, Hamizan, Heinichen, Husain, Ping, Ivaska, Jakimovska, Jovancevic, Kakande, Kamel, Karpischenko, Kariyawasam, Kawauchi, Kjeldsen, Klimek, Krzeski, Kopacheva Barsova, Kim, Lal, Letort, Lopatin, Mahdjoubi, Mesbahi, Netkovski, Nyenbue Tshipukane, Obando-Valverde, Okano, Onerci, Ong, Orlandi, Otori, Ouennoughy, Ozkan, Peric, Plzak, Prokopakis, Prepageran, Psaltis, Pugin, Raftopulos, Rombaux, Riechelmann, Sahtout, Sarafoleanu, Searyoh, Rhee, Shi, Shkoukani, Shukuryan, Sicak, Smyth, Sindvongs, Soklic Kosak, Stjarne, Sutikno, Steinsvag, Tantilipikorn, Thanaviratananich, Tran, Urbancic, Valiulius, Vasquez de Aparicio, Vicheva, Virkkula, Vicente, Voegels, Wagenmann, Wardani, Welge-Lussen, Witterick, Wright, Zabolotniy, Zsolt and Zwetsloot1, Reference Arcimowicz3). This increased local production of inflammatory mediators, together with protective surfactant proteins and increased mucus production, is thought to prevent bacterial superinfection but leads to persistent inflammation in the nasal and paranasal sinus mucosa (Refs. Reference Fokkens, Lund, Hopkins, Hellings, Kern, Reitsma, Toppila-Salmi, Bernal-Sprekelsen, Mullol, Alobid, Terezinha Anselmo-Lima, Bachert, Baroody, von Buchwald, Cervin, Cohen, Constantinidis, De Gabory, Desrosiers, Diamant, Douglas, Gevaert, Hafner, Harvey, Joos, Kalogjera, Knill, Kocks, Landis, Limpens, Lebeer, Lourenco, Meco, Matricardi, O’Mahony, Philpott, Ryan, Schlosser, Senior, Smith, Teeling, Tomazic, Wang, Wang, Zhang, Agius, Ahlstrom-Emanuelsson, Alabri, Albu, Alhabash, Aleksic, Aloulah, Al-Qudah, Alsaleh, Baban, Baudoin, Balvers, Battaglia, Bedoya, Beule, Bofares, Braverman, Brozek-Madry, Richard, Callejas, Carrie, Caulley, Chussi, de Corso, Coste, El Hadi, Elfarouk, Eloy, Farrokhi, Felisati, Ferrari, Fishchuk, Grayson, Goncalves, Grdinic, Grgic, Hamizan, Heinichen, Husain, Ping, Ivaska, Jakimovska, Jovancevic, Kakande, Kamel, Karpischenko, Kariyawasam, Kawauchi, Kjeldsen, Klimek, Krzeski, Kopacheva Barsova, Kim, Lal, Letort, Lopatin, Mahdjoubi, Mesbahi, Netkovski, Nyenbue Tshipukane, Obando-Valverde, Okano, Onerci, Ong, Orlandi, Otori, Ouennoughy, Ozkan, Peric, Plzak, Prokopakis, Prepageran, Psaltis, Pugin, Raftopulos, Rombaux, Riechelmann, Sahtout, Sarafoleanu, Searyoh, Rhee, Shi, Shkoukani, Shukuryan, Sicak, Smyth, Sindvongs, Soklic Kosak, Stjarne, Sutikno, Steinsvag, Tantilipikorn, Thanaviratananich, Tran, Urbancic, Valiulius, Vasquez de Aparicio, Vicheva, Virkkula, Vicente, Voegels, Wagenmann, Wardani, Welge-Lussen, Witterick, Wright, Zabolotniy, Zsolt and Zwetsloot1, Reference Arcimowicz3). Bacteria do not usually play a role in the pathogenesis of APRS. The concentrations of inflammatory mediators in nasal secretions reliably reflect the condition of the nasal mucosa. A previous in vivo case–control study has shown that, the concentrations of non-selective chemokines (monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1 alpha [MIP-1α], MIP-1β, MIP-3α), which attract various inflammatory cells (monocytes, eosinophils, neutrophils) to the site of acute inflammation, are increased in patients with APRS (Ref. Reference Perić, Vezmar Kovačević, Barać, Gaćeša, Perić and Vojvodić22) (Table 1). Also, the concentrations of chemokines responsible for attracting and activating neutrophils (IL-8 and epithelial-derived neutrophil-activating peptide 78 [ENA-78]) were locally elevated compared to healthy individuals (Ref. Reference Perić, Vezmar Kovačević, Barać, Gaćeša, Perić and Vojvodić22). However, after 10 days of oral administration of EPs7630 (three times daily, 20 mg in tablet form), there was an increase in the concentrations of chemokines related to monocytes (MCP-1, IP-10 and MIP-1β) and a decrease in the concentration of chemokines related to neutrophil function (IL-8, growth-regulated oncogene alpha [GROα], ENA-78 and MIP-1α) (Ref. Reference Perić, Vezmar Kovačević, Barać, Gaćeša, Perić and Vojvodić22) (Figure 2) (Table 1). At the same time, an improvement was shown in all endoscopic findings and signs of APRS (Ref. Reference Perić, Vezmar Kovačević, Barać, Gaćeša, Perić and Vojvodić22) (Table 1). Thus, as in a viral infection, EPs7630 may stimulate monocyte activity and partially suppress neutrophil activity at the site of acute inflammation. Although this study was not placebo-controlled, these results suggest that EPs7630 could be considered one of the drugs in APRS therapy.

Figure 2. Immunomodulatory effects of EPs7630 in the treatment of APRS. Abbreviations: MCP1: monocyte chemoattractant protein 1; IP10: interferon γ-induced protein 10 kDa; MIP1β: macrophage inflammatory protein 1 beta; IL8: interleukin 8; ENA78: epithelial-derived neutrophil-activating peptide 78; GROα: growth-regulated oncogene alpha; MIP1α: macrophage inflammatory protein alpha; T Ly: T lymphocyte; MF: macrophage; Act. Endot. Cell: activated endothelial cell; Mastocyte: mast cell; NK: natural killer cell.

EPs7630 and uncomplicated ABRS

Previous studies suggest that EPs7630 may be effective in the treatment of uncomplicated ABRS (Refs. Reference Thäle, Kiderlen and Kolodziej23–Reference Bachert26). A prospective, randomised, open-label study has shown that 10-day use of EPs7630 (20 mg three times daily in tablet form) significantly reduced the incidence of patients with positive cultures of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis from the middle nasal meatus (Ref. Reference Perić, Gaćeša, Barać, Sotirović and Perić25). In contrast, amoxicillin tablets (3 × 500 mg/day) only reduced the growth of Streptococcus pneumoniae and Haemophilus influenzae cultures (Ref. Reference Perić, Gaćeša, Barać, Sotirović and Perić25). The results of the same study showed higher absolute improvement in the total score of nasal symptoms as well as separate nasal symptoms, such as nasal congestion, weakened sense of smell and sense of facial pain and pressure (Ref. Reference Perić, Gaćeša, Barać, Sotirović and Perić25). In endoscopic findings, patients using EPs7630 had less mucosal oedema and mucopurulent secretions than those treated with amoxicillin (Ref. Reference Perić, Gaćeša, Barać, Sotirović and Perić25). The explanation for such effects could be the fact that EPs7630 was shown to increase the release of antibacterial peptides (defensins, lactoferrin and bactericidal/permeability-increasing protein [BP-IP]) from neutrophils and increase the phagocytic activity of macrophages against bacteria (Ref. Reference Bachert26).

In another in vivo randomised, prospective, open-label study, the clinical and immunomodulatory effects of the macrolide antibiotic roxithromycin and EPs7630 were compared in the treatment of uncomplicated ABRS (Ref. Reference Perić, Vezmar Kovačević, Barać, Perić and Vojvodić27). After a 10-day administration of EPs7630 (three times daily, 20 mg in tablet form), an improvement in endoscopic findings and nasal symptoms was observed, although the clinical effect of roxithromycin in tablet form (2 × 150 mg/day) was better. In the control group of untreated patients with ABRS, there was no improvement after 10 days. This indicates that we cannot expect spontaneous improvement of symptoms and clinical findings in patients with uncomplicated ABRS (Ref. Reference Perić, Vezmar Kovačević, Barać, Perić and Vojvodić27) (Table 1). Therefore, medical treatment of ABRS is necessary. In the nasal secretions of patients who did not receive therapy, an increase in the concentration of almost all chemokines was observed after 10 days. Interestingly, similar to APRS, following treatment with EPs7630, the results indicated increased concentrations of MCP-1, IP-10 and MIP-β and decreased levels of MIP-1α, ENA-78, GROα and IL-8 in the nasal secretions (Ref. Reference Perić, Vezmar Kovačević, Barać, Perić and Vojvodić27) (Figure 3) (Table 1). Roxithromycin therapy significantly increased the concentration of IP-10 and decreased the concentration of IL-8, ENA-78, MCP-1 and MIP-1α in nasal fluid (Figure 3) (Table 1). The results showed that the two drugs similarly affect the production of chemokines that regulate the function of monocytes and neutrophils in the nasal and paranasal sinus mucosa (Ref. Reference Perić, Vezmar Kovačević, Barać, Perić and Vojvodić27).

Figure 3. Immunomodulatory effects of EPs7630 and roxithromycin in therapy of uncomplicated ABRS. MCP1: monocyte chemoattractant protein 1; IP10: interferon γ-induced protein 10 kDa; MIP1β: macrophage inflammatory protein 1 beta; IL8: interleukin 8; ENA78: epithelial-derived neutrophil-activating peptide 78; GROα: growth-regulated oncogene alpha; MIP1α: macrophage inflammatory protein alpha; T Ly: T lymphocyte; MF: macrophage; Mastocyte: mast cell; NK: natural killer cell.