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INFECTIOUS DISEASES: Edited by Michael S. Niederman and Alimuddin Zumla

Host-directed therapies for COVID-19

Maeurer, Markusa,b,∗; Ramalho, Renatac,∗; Wang, Fu-Shengd,∗; Zumla, Alimuddine,∗

Author Information
Current Opinion in Pulmonary Medicine: May 2021 - Volume 27 - Issue 3 - p 205-209
doi: 10.1097/MCP.0000000000000769
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Abstract

INTRODUCTION

Infection with the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a spectrum of clinical manifestations from asymptomatic, mild, moderate, to severe or critical multiorgan disease and death [1]. As of 11th February 2021, there have been 106,991,090 confirmed cases of COVID-19, including 2,347,000 deaths (2.2% case fatality rate), reported to the World Health Organization (WHO) from all continents [2]. Management outcomes are determined by a range of pathogen (SARS-CoV-2) and host factors including comorbidities [3], innate and adaptive cellular immune responses [4,5▪▪]. Apart from reducing the death rate, an important clinical management need for COVID-19 patients, is to prevent or alleviate long term functional disability [6]. Many patients who survive severe COVID-19 develop end-organ tissue damage because of excessive inflammation, including deleterious cytokine responses [5▪▪] with consequential fibrosis leading to long term functional disability [6]. Host-directed therapies (HDTs) targeting aberrant host immune and inflammatory responses are an area of growing interest for more holistic treatment of patients with severe COVID-19 disease [7▪]. 

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Box 1:
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HOST-DIRECTED THERAPIES FOR COVID-19

The inflammatory and immune responses to SARS-CoV-2 infection influence pathogenesis and clinical expression of COVID-19. Studies of immunological and inflammatory profiles in mild and severe cases of COVID-19 show that lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and Natural Killer cells cells, excessive T-cell activation, high expression of T-cell inhibitory molecules, excess cytokine responses are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules [4,5▪▪]. Abberant activation and dysregulation of CD8+ T cells occurs in patients with severe COVID-19 and this may indicate that immune-based targets and HDT interventions may be important in the management of severe COVID-19 patients. A range of HDTs with different mechanisms of action are being considered as adjunct treatment for COVID-19 (Fig. 1). Since disease severity and progression is related to the excessive inflammatory responses and dynamic nature of the immune response, it is likely that the maximal impact of any adjunct HDT will depend on the optimal timing of the HDT, relative to specific phase(s) of disease, and the beneficial effects are likely to be restricted to specific groups of patients. Of over 1000 COVID-19 related Phase 1, 2 and 3 treatment trials registered on clinical trials.gov website over 100 are on a range of HDTs such as biologics, repurposed drugs, traditional remedies, nutrients and cellular therapies

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FIGURE 1:
Categories of host-directed therapies. Host-directed therapy categories.

(Ref: https://clinicaltrials.gov/ct2/results?cond=covid19&term=treatment&cntry=&state=&city=&dist=&Search=Search). We review data from recent trials of mesenchymal stem cells (MSCs) and monoclonal antibody trials and discuss the importance of advancing HDTs for improving long-term management outcomes and functional recovery.

MESENCHYMAL STEM CELL THERAPY FOR COVID-19

MSCs are nonhematopoietic cells with immune-modulatory, regenerative and differentiation properties. Use of MSC therapy can inhibit cell-mediated immune-inflammatory responses induced by the influenza virus in animal models and clinical trials [8,9▪▪,10]. The safety and potential efficacy of MSCs have also been evaluated in patients with acute respiratory distress syndrome (ARDS). Several trials are evaluating their use in COVID-19 patients. Currently, the ClinicalTrials.gov and the WHO Clinical Trials Registry Platform (WHO ICTRP) report a combined 28 trials exploring the potential of MSCs or their products for the treatment of COVID-19 [7▪]. Since infusion of millions of cells into COVID-19 patients who already have a hypercoagulable state may induce thrombotic events, careful evaluation of the safety of infusions of MSCs in Phase 1 and 2 trials was required.

Recent data from Phase 1 trials demonstrated that intravenous transfusions of the human umbilical cord (UC)-MSCs in patients with moderate and severe COVID-19 were safe and well tolerated (NCT04252118) [9▪▪,10]. A Phase 2 randomized, double-blind, placebo-controlled trial performed at two medical centres in Wuhan, China, evaluated further the safety and efficacy of intravenous treatment with UC-MSCs in severe COVID-19 patients with lung damage [11▪▪]. One hundred patients were recruited to receive either UC-MSCs (n = 65) or placebo (n = 35). The patients receiving UC-MSCs exhibited a trend of numerical improvement in whole lung lesion size from baseline to day 28 compared with the placebo cases. UC-MSCs administration significantly reduced the proportions of consolidation lesion size from baseline to day 28 compared with the placebo (median difference: −15.45%, 95% CI −30.82%, −0.39%, P = 0.043). The 6-min walk test showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m, 95% CI 0.00, 57.00, P = 0.057). A total of three doses of 4 × 107 UC-MSCs were transfused and no MSC-related predefined haemodynamic or respiratory adverse events were observed. No patient died during an inpatient stay or the follow-up period and thus effects on mortality could not be concluded. These data confirmed that UC-MSC therapy was well tolerated and very safe. Phase 3 trials in severely ill patients are required to evaluate the effect of MSC infusion on mortality and long-term pulmonary damage. Several ongoing clinical trials (some with a higher dose of MSCs) are being conducted in China, Ireland and America more safety and preliminary efficacy data are expected soon [12,13▪▪]. Determining which patients will benefit from MSC therapy, several variables will need to be defined such as the timing of MSC delivery with a specific phase of COVID-19 disease, single or repeated doses, escalating dose and specific source of MSCs, and viability before infusion.

MONOCLONAL ANTIBODY THERAPIES

A systematic review and meta-analysis of COVID-19 studies [14] in which interleukin-6 (IL-6) concentrations were recorded analysed data from 1245 patients with severe disease. Comparator groups included trials in sepsis (n = 5320), cytokine release syndrome (n = 72) and ARDS unrelated to COVID-19 (n = 2767). In severe COVID-19 patients, the pooled mean serum IL-6 concentration was 36.7 pg/ml, nearly 100 times higher than patients with cytokine release syndrome, 27 times higher than sepsis patients 12 times higher than patients with acute respiratory distress syndrome unrelated to COVID-19. Many questions remain about the immune features of COVID-19 and the potential role of anti-cytokine and immune-modulating treatments in patients with the disease.

CLINICAL TRIALS OF IL-6 ANTAGONISTS

The cytokine storm that is well described in patients with severe COVID-19 has led to retrospective analyses and clinical trials of the use of anti-cytokine therapies, particularly IL-6 antagonists such as Tocilizumab and Sarilumab [15,16,17▪▪,18▪▪]. A retrospective analysis of 112 consecutive hospitalized COVID-19 patients [15] [50 treated with tocilizumab and 62 treated with the standard of care without tocilizumab (control group)] concluded that tocilizumab was effective in the treatment of medium to severe forms of COVID-19 pneumonia, reducing the risk of mortality due to multiorgan failure. Rajendrum et al.[16] performed a retrospective, observational, multicentre, cohort study using propensity score matching based on ICU admission source, C-reactive protein, Sequential Organ Failure Assessment score, vasopressor use, age, race, weight and mechanical ventilation. One hundred and two patients received tocilizumab and were compared to 342 who did not receive tocilizumab and the study concluded that tocilizumab use was associated with a significant decrease in ICU mortality in critically ill COVID-19 patients. This mortality benefit has very recently been borne out by a large trial of 4116 adults which showed that in hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the level of respiratory support and were additional to the benefits of systemic corticosteroids [19▪▪].

Salama et al.[17▪▪] evaluated the safety and efficacy of the anti-IL-6 receptor antibody tocilizumab in ethnic minority patients hospitalized with COVID-19 pneumonia randomly assigning 2:1 ratio patients who were not receiving mechanical ventilation to receive standard care and one or two doses of either tocilizumab. The primary outcome was mechanical ventilation or death by day 28. Two hundred and forty-nine patients were in the tocilizumab group and 128 patients in the placebo group (56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White and 3.7% were of other or unknown race or ethnic group). The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% in the tocilizumab group and 19.3% in the placebo group. The conclusion of the study was that hospitalized patients with COVID-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival.

Stone et al.[18▪▪] performed a randomized, double-blind, placebo-controlled trial of standard care plus a single dose of either tocilizumab (8 mg/kg of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. Enrolling 243 patients (45% of the patients were Hispanic or Latino), the study concluded that tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with COVID-19. Some benefit or harm could not be ruled out because the confidence intervals for efficacy comparisons were wide.

Veiga et al.[20] performed an open-label trial to determine whether tocilizumab improves clinical outcomes for patients with critical or severe COVID-19. The data safety monitoring committee stopped the trial early after 129 patients were recruited since an increased number of deaths occurred at 15 days in the tocilizumab group. The study concluded that patients with severe or critical COVID-19, tocilizumab and standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality.

VARIABLES TO CONSIDER IN DESIGNING HDT TRIALS

Ongoing trials of MSC therapy in COVID-19 patients are different in design, have different sources of MSCs, different dose administration schedules, selection of patients and primary outcomes highlighting the need for standardizing protocols through a global consortium network [8]. There is an urgent need for reaching global consensus on advancing HDTs for COVID-19 and other infectious diseases.

Other variables which could affect the outcome of MSC therapy for COVID-19 patients include Major Histocompatibility Complex or ethnic background [21], inherent defects in the type I interferon response patterns, and route of administration of HDTs. SARS-CoV-2 specific T cells have been identified in healthy (SARS-CoV-2-negative) individuals who exhibit a different epitope focus as compared to individuals after a COVID-19 infection. HDTs may therefore work differently in individuals with pre-existing innate immune responses and they will imprint and shape the long-term immune memory response. Access of HDTs (drugs or cells into the CNS) also needs to be considered, particularly if ‘Neuro-COVID’, a recently coined term for patients with considerable neurological symptoms is to be treated in those who show a curtailed interferon response.

Nearly all components of the immune system are affected by age, although along with other co-morbidity risk factors increased COVID-19 mortality is seen in those above 70 years old [22]. According to the Leiden Longevity Study, expression levels of the gene encoding IL-7R (Il7R) decreases with chronological age. IL-7R expression is higher in both the nonagenarians and middle-aged individuals, pointing to higher Il7R expression levels in ‘healthy’ and immune-fit individuals. A multicentre study with recombinant IL-7 that aims to increase immune fitness, replenish the lymphocyte pool, increase SARS-CoV-2 specific T-cell responses and to decrease TGF-β production is currently underway.

CONCLUSIONS

SARS-CoV-2 induced hyperinflammation is a major cause of death or end-organ dysfunction in patients with severely ill with COVID-19. A range of HDTs shows promise for reducing mortality and improving long-term disability in patients with severe COVID-19. Use of umbilical cord-derived MSCs as HDT for COVID- 19 have been shown to be safe. Trials of anti-IL-6 receptor antibodies show mortality benefit for hospitalized patients. Repurposed drugs, monoclonal antibodies targeting specific cytokines acting on different aspects of the pro- and anti-inflammatory cascades are under evaluation.

Acknowledgements

Sir Zumla is co-Principal Investigator of the Pan-African Network on Emerging and Re-Emerging Infections (PANDORA-ID-NET – https://www.pandora-id.net/) funded by the European and Developing Countries Clinical Trials Partnership the EU Horizon 2020 Framework Programme. Sir Zumla is in receipt of a National Institutes of Health Research Senior Investigator award and he is a Mahathir Science Award Laurette.

Financial support and sponsorship

None.

Conflicts of interest

All authors are members of The Global Alliance between Clinical Cancer and Infectious Disease Research with a particular focus on the COVID-19 pandemic, to better understand the nature of COVID-19 pathophysiology and to take forward host-directed therapies (Website:https://fchampalimaud.org/covid19/aci/).

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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All authors contributed equally to writing of this article.

Keywords:

COVID-19; host-directed therapies; interleukins; mesenchymal stem cells; severe acute respiratory syndrome coronavirus-2

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