Hyper-inflammation in Coronavirus disease 2019

The COVID-19 has a heterogeneous presentation and clinical course. The majority of cases are either asymptomatic or have mild symptoms^{(Reference Castagnoli, Votto and Licari2–Reference Ma, Liu and Chen5)}. The severe or critical diseases have been documented in 2–5 % of cases. The mortality among patients admitted to intensive care units ranges from 30 % to more than 60 %^{(Reference Wang, Lu and Li6–Reference Petrilli, Jones and Yang9)}. The severe COVID-19 is characterised by immune dysregulation, hyper-inflammation and hypercytokinaemia (cytokine storm or cytokine release syndrome). The level of cytokines (IL-1β, IL-1ra, IL-2, IL-6, IL-10, IL-17, TNF, interferon-γ, granulocyte monocyte-colony stimulating factor, interferon-induced protein-10 and monocyte chemotactic protein-3) is higher in non-survivors or severe COVID-19^{(Reference Liu, Li and Liu10–Reference Dhar and Mohanty16)}. Therefore, with the onset of a cytokine storm, the antiviral drugs alone may not be sufficient and it is suggested to add anti-inflammatory treatment^{(Reference Infusino, Marazzato and Mancone1,Reference Dhar and Mohanty16,Reference Conte and Toraldo17)} .

In late April 2020, clinicians from the United Kingdom (UK) reported eight previously healthy children who presented with cardiovascular shock, fever and hyper-inflammation^{(Reference Riphagen, Gomez and Gonzalez-Martinez18)}. Subsequently, Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), multisystem inflammatory syndrome in children (MIS-C), Kawasaki disease and Kawasaki-like syndrome have been reported from the countries with high load of COVID-19 like UK, France, Italy and the USA^{(Reference Pouletty, Borocco and Ouldali14,Reference Whittaker, Bamford and Kenny15,Reference Riphagen, Gomez and Gonzalez-Martinez18–Reference Verdoni, Mazza and Gervasoni25)} . Most of these children were treated with intravenous immunoglobulin (IVIG) and/or steroids.

Gut–lung axis and gut microbiome in Coronavirus disease 2019

In addition to alveolar epithelial cells, enterocytes also express angiotensin-converting enzyme 2 receptors and SARS-CoV-2 RNA has been demonstrated in the faeces of infected patients^{(Reference Dhar and Mohanty16,Reference Kim, Kim and Lee26–Reference Park, Lee and Park28)} . Also, SARS-CoV-2 can invade enterocytes, and therefore, the gut may act as a reservoir for the virus^{(Reference Baud, Dimopoulou Agri and Gibson29,Reference Lin, Jiang and Zhang30)} . The interaction of SARS-CoV-2 with angiotensin-converting enzyme 2 receptors in the gut may be responsible for the gastrointestinal symptoms, which are noted in 12–60 % cases of COVID-19, and is associated with increased disease severity^{(Reference Gupta, Madhavan and Sehgal31)}.

There is evidence available to indicate the crosstalk between gut microbiota and lung (gut–lung axis). This axis maintains the host homoeostasis and may be altered in diseased states. The gut–lung interaction is bidirectional, and the gut plays a vital role in influencing lung disease. In diseased states, the gut microbiome is disturbed (dysbiosis), leading to translocation of endotoxins and microbial metabolites from the gut, which can then impact the lung through the bloodstream. Similarly, when inflammation occurs in the lungs (e.g. respiratory viral infections), it causes perturbations in the gut microbiome (gut–lung axis)^{(Reference Dhar and Mohanty16,Reference Dumas, Bernard and Poquet32,Reference Keely, Talley and Hansbro33)} .

This bidirectional gut–lung interaction may be playing an important role in COVID-19, leading to increased disease severity. In extreme of ages and among those with underlying co-morbid conditions, the gut microbiota is less in diversity leading to gut dysbiosis^{(Reference Salazar, Arboleya and Valdes34–Reference Elena, Gabriela and Arnulfo37)}. This could be one of the reasons for the increased disease severity of COVID-19 among cases with the extreme of ages and in those with underlying co-morbid medical conditions^{(Reference Patel38,Reference Guan, Ni and Hu39)} . It has been demonstrated that the gut microbiome is altered in cases with COVID-19 in terms of a significant reduction in diversity and number of beneficial gut microbiota and an increase in the number of opportunistic pathogens^{(Reference Dhar and Mohanty16,Reference Gu, Chen and Wu40,Reference Zuo, Zhang and Lui41)} . This can ultimately lead to gut dysbiosis, translocation of pathogenic organisms across the gut mucosa, secondary bacterial infections, enhanced inflammatory response, multiple organ dysfunction and poor clinical outcome. Zuo et al.^{(Reference Zuo, Zhang and Lui41)} performed metagenomic sequencing analyses on the faecal samples of COVID-19 patients (n 15) from the time of admission until discharge and compared them with fifteen healthy controls. The authors demonstrated that these patients had significant depletion of beneficial commensals and enrichment of opportunistic pathogens at the time of admission as well as at all time points during the hospital stay when compared with controls. Similarly, Gu et al.^{(Reference Gu, Chen and Wu40)}, in a cross-sectional study involving COVID-19 patients (n 30), demonstrated that the gut microbiome (faecal sample collected at admission) of COVID-19 cases had significantly reduced bacterial diversity, a lower count of beneficial symbionts and a higher number of opportunistic pathogens (Streptococcus, Rothia, Veillonella and Actinomyces).

Therefore, the heightened or dysregulated inflammation and gut dysbiosis may be the major pathophysiological processes in cases with COVID-19 leading to increased severity of illness and poor clinical outcomes.

Current treatment strategies for Coronavirus disease 2019

The therapies such as antiviral drugs that inhibit the viral entry and/or replication (remdesivir, favipiravir and lopinavir–ritonavir) and drugs/strategies that modulate the cytokine storm (hydroxychloroquine, chloroquine, azithromycin, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, IVIG, tocilizumab, colchicine and plasma therapy) have been the focus of research in COVID-19 but without much clinical success^{(Reference Atal and Fatima42–Reference Antwi-Amoabeng, Kanji and Ford51)} (Fig. 1).

Fig. 1. The figure shows a cascade of the pathogenesis of COVID-19 and site of action of antiviral, anti-inflammatory drugs and probiotics. The antiviral drugs act at viral docking, entry and viral replication stage (*). Anti-inflammatory drugs act at the stage of hyper-inflammation (†). Probiotics may act at multiple stages as viral docking, entry and replication, restoration of gut microbiota and gut–lung axis, reduction in bacterial translocation and secondary bacterial infection, and modulation of hyper-inflammation (cytokine storm) (‡).SARS nCoV-2, severe acute respiratory syndrome Coronavirus-2; ACE2, angiotensin-converting enzyme 2;

Probiotics in Coronavirus disease 2019

In the absence of proven effective therapy for COVID-19, the treatment is mainly supportive. Therefore, the alternative strategies that target pathophysiological pathways in patients with COVID-19 need to be tested. One such approach is probiotics. The WHO and FAO defined probiotics as ‘live microorganisms which, when administered in adequate amounts, confer a health benefit on the host.’ Many different micro-organisms have been considered as probiotics, including Lactobacillus species (L. acidophilus, L. casei and L. rhamnosus); Bifidobacterium species (B. bifidum, B. longum and B. lactis); Enterococcus species (E. faecalis and E. faecium) and Saccharomyces (S. boulardii and S. cerevisiae). The most commonly used strains are Lactobacillus and Bifidobacterium ^{(Reference Kumar and Singhi52)}.

Safety of probiotics

Most of the probiotic strains are generally safe even in the vulnerable population and in an intensive care setting, including neonates, children and adults. Many probiotic strains have shown beneficial effects in these settings^{(Reference Kumar and Singhi52–Reference Angurana, Bansal and Singhi55,Reference Arribas, Garrido-Mesa and Peran61–Reference Timmerman, Niers and Ridwan66,Reference Goldenberg, Ma and Saxton69–Reference Dermyshi, Wang and Yan79,Reference Kazemi, Soltani and Ghorabi82–Reference Wang, Wen and Xu85,Reference Sanders, Merenstein and Ouwehand97)} . However, there are few case reports of probiotic-associated bacteraemia, infective endocarditis, liver abscesses and fungaemia. These are majorly reported in severely debilitated cases, premature babies and immunocompromised patients who were treated with preparations lacking adequate quality control^{(Reference Esaiassen, Cavanagh and Hjerde98–Reference Hennequin, Kauffmann-Lacroix and Jobert104)}.

It has been suggested to exercise caution while using probiotics in the presence of a one major risk factor (immunocompromised state and premature infants) or more than one minor risk factor (central venous catheter, cardiac valvular disease, impaired intestinal epithelial barrier, administration of probiotics by jejunostomy and probiotics with properties of high mucosal adhesion or known pathogenicity) because of the risk of probiotics-sepsis^{(Reference Singhi and Kumar80,Reference Boyle, Robins-Browne and Tang105)} .

Other safety concerns are the genetic transfer of antimicrobial resistance from probiotic strains to pathogenic organisms in the gut (particularly Staphylococcus aureus and Enterococcus)^{(Reference Egervarn, Danielsen and Roos106,Reference Egervarn, Roos and Lindmark107)} , deleterious metabolic activities and excessive immune stimulation in susceptible individuals^{(Reference Kumar and Singhi52,Reference Singhi and Kumar80)} . The use of probiotics may be limited in the presence of immunocompromised states or premature neonates because of safety concerns, as discussed above. The supplementation with probiotics may not be possible in whom enteral administration is contraindicated.

The rationale for using probiotics in Coronavirus disease 2019

Several clinical trials of antiviral and anti-inflammatory drugs are in progress to evaluate the therapeutic effects of these drugs in patients with COVID-19^{(Reference Zhu, Gao and Robert108)}. The site of action of currently used antiviral and anti-inflammatory medications is at limited steps in the pathogenesis of COVID-19 (Fig. 1). The probiotics, such as Lactobacillus and Bifidobacterium, possibly act at multiple levels in this cascade of COVID-19. They act through antiviral actions^{(Reference Ang, Too and Tan86–Reference Zelaya, Alvarez and Kitazawa96)}, restoration of the gut microbiome^{(Reference Angurana, Bansal and Singhi55,Reference Arribas, Rodriguez-Cabezas and Comalada58–Reference Timmerman, Niers and Ridwan66,Reference Singhi and Kumar80,Reference Haak, Prescott and Wiersinga81)} , modulation of inflammation/cytokine storm (anti-inflammatory)^{(Reference Angurana, Bansal and Singhi55,Reference Cui, Wang and Peng62,Reference McNaught, Woodcock and Anderson63,Reference Sanaie, Ebrahimi-Mameghani and Hamishehkar65,Reference Timmerman, Niers and Ridwan66,Reference Kazemi, Soltani and Ghorabi82–Reference Wang, Wen and Xu85)} and prevention of secondary bacterial and fungal infections^{(Reference Kumar and Singhi52–Reference Kumar, Bansal and Chakrabarti54,Reference Goldenberg, Ma and Saxton69–Reference Yang, Wu and Liu75)} (Fig. 1). Though the evidence for the rationale of using probiotics to treat COVID-19 comes from indirect evidence, these actions of probiotics may help in the prevention of and/or alleviation of COVID-19 related symptoms and complications. Moreover, probiotics are readily available, easy to administer (oral administration), relatively safe and economical compared with antiviral drugs, immunomodulators or other strategies tested in COVID-19^{(Reference Infusino, Marazzato and Mancone1)}.

Therefore, probiotics, due to their mechanisms of action, are a potential strategy that need to be tested in moderate to severe cases with COVID-19 by conducting well-designed clinical trials. Few registered trials are going on to evaluate the possible beneficial effects of probiotics supplementation in cases with COVID-19 (NCT04366180, NCT04368351 and NCT04366089).

A better understanding of the pathophysiology of COVID-19 and the results of the clinical trials will guide further on the efficacy, benefits and safety of probiotics in COVID-19. Despite these limitations, considering various mechanisms of actions of probiotics on the regulation of gut dysbiosis and anti-inflammatory activity, and clinical evidence about the beneficial effects of probiotics in critically ill adults and children, probiotics are a potential therapeutic strategy that need to be tested in moderate to severe cases with COVID-19.