If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, SC Pediatria Pneumoinfettivologia, Milan, ItalyDepartment of Pathophysiology and Transplantation, University of Milan, Milan, Italy
Omalizumab, which downregulates the immunoglobulin E (IgE) receptor site on plasmacytoid dendritic cells and thereby increases interferon-α (INF-α) production, may shorten the duration of viral infections by enhancing the antiviral immunity.
A systematic review was conducted to investigate whether previous anti-IgE treatment with omalizumab could protect against SARS-CoV-2 disease (“COVID-19”) (infection, disease duration, and severity), and whether IFN-α upregulation could be involved. The research included articles published from March 2020 to January 2022. An accurate search was performed on bibliographic biomedical database (MEDLINE – Pubmed, SCOPUS, EMBASE, BIOMED CENTRAL, Google scholar, COCHRANE LIBRARY, ClinicalTrial.gov) including cohorts, case reports and reviews. Different methods were used, based on the study design, to assess the quality of eligible studies.
Several authors link omalizumab to a possible protection against viruses, but they often refer to studies carried out before the pandemic and with viruses other than SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) (eg, rhinoviruses -RV). Few cases of COVID-19 patients treated with omalizumab have been recorded, and, in most of them, no increased susceptibility to severe disease was observed. According to these data, the current indication is to continue omalizumab therapy during the pandemic.
Moreover, although omalizumab may enhance the antiviral immune response even for SARS-CoV-2, further studies are needed to confirm this hypothesis. It would be helpful to establish a registry of omalizumab-treated (or in treatment) patients who have developed COVID-19. Finally, randomized controlled trials could be able to demonstrate the effect of omalizumab in protecting against severe SARS-CoV-2, through IFN-α upregulation or other immunological pathways.
COVID-19 spread rapidly around the world causing numerous deaths. The immune response against SARS-CoV-2 follow several stages. During the early stages of the disease, type I interferon (including IFN-α) and adaptive immunity preclude the disease progression.
When this immune response is impaired, high virus loads lead to pathological inflammation, massive organ dysfunction, and acute respiratory distress syndrome (ARDS).
In humans, the IFN type I multigene cytokine family includes 13 subtypes of IFN-α, only one IFN-β, a single (poorly defined) IFN-ε, IFN-κ, and IFN-ω subtypes.
IFN-α acts at cellular and intercellular level with autocrine and paracrine activities, hindering the spread of the virus and above all eliminating virus-infected cells.
IgEs are a very important part of hypersensitivity; they also play a role in susceptibility to respiratory infections and they can activate mast cells or inhibit inflammatory cells such as neutrophils.
Furthermore, after omalizumab treatment, interleukin 33 levels decrease. It's important to notice that IL-33 is involved in production of inflammatory cytokines (such as IL-6, IL-1 β, tumor necrosis factor and prostaglandin D2).
Anti-IgE antibody seems also able to upregulate the production of IFNs (with a complex mechanism that prevent IgE-FcεRI cross-linking on dendritic cells).
Toll-like receptor-9 expression and TLR-7 signaling usually enhance interferon production from pDCs, but they are reduced by IgE cross-linking (Fig. 1).
Fig. 1Multiple effects of omalizumab. (IgE immunoglobulin E; pDCs plasmacytoid dendritic cells; FceRs Fc epsilon receptor, type I and II; INF α interferon alpha; IL-6 interleukin 6; IL1 beta interleukin 1 beta)
Some authors noticed that omalizumab could stabilize effector cells and make innate immunity much more efficient at fighting some respiratory viral infections.
Mild COVID-19 respiratory infection associated with moderate fare of chronic spontaneous urticaria in a 43-year old female long-term care worker on omalizumab.
We can suppose a potential omalizumab-induced effect on antiviral responses also against SARS-CoV-2.
To investigate whether omalizumab treatment could protect against severe COVID-19 and whether type I IFN (especially IFN-α) upregulation could be involved a systematic review was performed. We analyzed available evidence to understand whether concurrent or previous use of omalizumab could have a protective effects on SARS-CoV-2 infection and COVID-19 severity and/or duration.
Materials and methods
An extensive literature search using validated keyword and filters to select articles related to omalizumab as a potential IFN I inducer to prevent and/or protect against SARS-CoV-2 infection was conducted.
Following the PICO process we developed a literature search strategies including patients treated (or in treatment) with omalizumab who had COVID-19 (P –population), investigating a possible positive effect of omalizumab mediated by increase virus-induced IFN-α responses (I- Intervention), comparing with COVID-19 patients without omalizumab treatment (C – Comparison), in order to clarify if a protective effects on COVID-19 could be present, or an effect on his duration or severity (O – Outcome). We wrote a protocol including review questions, research strategy, inclusion/exclusion criteria, and eventual study bias.
At first, titles and abstracts were screened to choose eligible studies, then full texts were selected for the final evaluation. Systematic reviews, research papers, letters to the editors, abstracts, case reports and series were included, considering the limited time window of pandemic.
Inclusion criteria were:
1)
full text availability
2)
English language
3)
presence of the keywords “omalizumab”AND“COVID-19″AND“interferon”. The following Mesh term were used: “omalizumab”; “COVID-19”; “interferon”.
Exclusion criteria were:
•
articles with themes or topics not related to the present review
•
duplicate articles (when one article appeared in different literature sources, we only counted it one time)
•
outcomes far away from our purposes
Primary outcome
1)
to evaluate if omalizumab is a potential IFN I inducer, thus preventing COVID-19 and/or limiting COVID-19 severity.
Secondary outcomes
1)
to analyze omalizumab adverse events in patients with previous or concomitant SARS CoV-2 infection
2)
to evaluate the continuation of biological therapy with omalizumab during the illness
3)
to dissect possible bias and assess the quality of evidence
Most authoritative documents were considered on the basis of chronological parameters, in particular date of publication, to set up a definite research path and a coherent development of the argument supporting conclusions.
Two reviewers independently agreed on the selection of studies. The characteristics of included studies were clarified and unified in a graphical way in Table 1.
Table 1Results of the literature review. (aICU: intensive care unit)
N
Study
Year
Type of study
Scale/score
Population/comparator
“Intervention"
Outcome
Founding
Omalizumab for a better antiviral response (increasing IFN-α production) (e.g. against rhinovirus, influenzavirus, etc.)
1
Farmani A.R.
2021
Review
AMSTAR low
/
/
/
no
2
Menzella F.
2021
Review
AMSTAR low
/
/
/
no
3
Costanzo G.
2021
Review
AMSTAR low
/
/
/
no
4
Greene T.T.
2021
Review
AMSTAR low
/
/
/
YES, NIH grants AI145314, AI081923, AI113923 and AI132122
5
Padayachee Y.
2021
Narrative Review
SANRA 1-0-0-2-1-1
/
/
/
no
6
Bencze D.
2021
Review
AMSTAR low
/
/
/
YES, NKFIH FK 128294 to K.P., NKFIH PD 135193;, also supported by GINOP-2.3.2-15-2016-00050 project
7
Galati D.
2021
Narrative Review
SANRA 2-2-0-2-2-2
/
/
/
no
8
Kumar K.
2020
Narrative Review
SANRA 2-2-0-2-2-2
/
/
/
YES, Novartis
9
Criado P.R.
2020
Review
SANRA 2-2-0-2-2-1
/
/
/
YES, authors are speaker of Novartis
10
Novak N.
2020
Narrative Review
SANRA 2-2-1-2-2-2
/
/
/
YES, grant number: 2019-T1/BIO-12690; PI20/00351
11
Visentin A.H.
2020
Review
AMSTAR low
/
/
/
no
12
Ding M.
2021
Narrative Review
SANRA 2-2-0-2-2-1
/
/
/
no
13
Sarioglu N.
2020
Narrative Review
SANRA 1-2-0-2-1-2
/
/
/
no
14
Assaf S.M.
2020
Narrative Review
SANRA 1-2-0-2-2-2
/
/
/
no
15
Liu S.
2020
Narrative Review
SANRA 2-2-1-2-2-2
/
/
/
no
16
Morais-Almeida M.
2020
Narrative Review
SANRA 2-2-0-2-2-2
/
/
/
no
17
Wang C.-J.
2021
Review
AMSTAR low
/
/
/
no
18
Ramakrishnan, R.K.
2021
Narrative Review
SANRA 1-0-0-1-1-2
/
/
/
no
19
Ayobami T.
2020
Narrative Review
SANRA 1-0-0-2-1-1
/
/
/
no
20
Lin Y.
2021
Narrative Review
SANRA 2-1-0-2-1-2
/
/
/
no
21
Klimek L.
2020
Position Paper
AMSTAR low
/
/
/
YES
22
Pfaar O.
2021
Position Paper
AMSTAR low
/
/
/
YES
23
Vultaggio A.
2020
Position Paper
AMSTAR low
/
/
/
YES
24
Paladini E.
2021
Pediatric case report
JBI-case report high
1 patient in Omalizumab
COVID-19
mild disease
YES, Novartis
No increased risk of COVID-19 (and severe COVID-19) in patients treated with Omalizumab
2
Menzella F.
2021
Review
AMSTAR low
/
/
/
no
3
Costanzo G.
2021
Review
AMSTAR low
/
/
/
no
9
Criado P.R.
2020
Review
SANRA 2-2-0-2-2-1
/
/
/
YES, authors are speaker of Novartis
12
Ding M.
2021
Narrative Review
SANRA 2-2-0-2-2-1
/
/
/
no
13
Sarioglu N.
2020
Narrative Review
SANRA 1-2-0-2-1-2
/
/
/
no
14
Assaf S.M.
2020
Narrative Review
SANRA 1-2-0-2-2-2
/
/
/
no
23
Vultaggio A.
2020
Position Paper
AMSTAR low
/
/
/
YES
25
Lombardi C.
2021
Narrative Review
SANRA 2-2-0-2-2-1
/
/
/
no
26
Ortega J.
2020
Observational cohort study
STROBE low
46 patients in Omalizumab
5 COVID-19
0 ICUa (intensive care unit)
no
27
Izquierdo J.L.
2021
Observational cohort study
STROBE high
641 patients in Omalizumab
9 COVID-19
0 ICUa
YES
28
Adir Y.
2021
Observational cohort study
STROBE high
8242 asthmatic COVID-19 vs 72.360 asthmatic without COVID-19
24 in Omalizumab vs 200 in Omalizumab
0 ICUa
YES
29
Rial M.J.
2020
Observational cohort study
STROBE low
263 patients in Omalizumab
14 COVID-19
1 ICUa
YES
30
Matucci A.
2021
Observational cohort study
STROBE low
145 patients in Omalizumab
2 COVID-19
1 ICUa
no
31
Hanon S.
2021
Observational cohort study
STROBE low
129 patients in Omalizumab
4 igG COVID-19
0 admitted in Hospital/0 ICUa
YES
32
Antonicelli L.
2021
Observational cohort study
STROBE low
558 asthmatic patients (NOT KNOWN how many in omalizumab)
3 COVID-19
1 admitted in Hospital/0 ICUa
no
33
Garcıa-Menaya G.M.
2020
Observational cohort study
STROBE medium
112 COVID-19 patients
1 Omalizumab treatment
good outcome
YES, Grants RETICS RD16/0006/0004 (ARADyAL), PI15/00303, and PI18/00540
34
Nassim D.
2020
Letter to the editor
SANRA 1-1-0-1-1-1
/
/
/
no
35
Licari A.
2020
Observational cohort study
STROBE medium
308 patients in biologics/286 in omalizumab
3 patient had COVID-19 in omalizumab
paucisymptomatic disease
no
Omalizumab may enhance an antiviral immune response against SARS-CoV-2 (throught interferon)
1
Farmani A.R.
2021
Review
AMSTAR low
/
/
/
no
17
Wang C.-J.
2021
Review
AMSTAR low
/
/
/
no
18
Ramakrishnan, R.K.
2021
Narrative Review
SANRA 1-0-0-1-1-2
/
/
/
no
27
Izquierdo J.L.
2021
Observational cohort study
STROBE high
641 patients in Omalizumab
9 COVID-19
0 ICUa
YES
36
Yalcin A.D.
2021
Narrative Review
SANRA 2-2-0-2-2-2
/
/
/
no
37
Wisnu Wardana V. A.
2021
Review
AMSTAR low
/
/
/
no
38
Tan C.
2021
Observational cohort study
STROBE high
/
/
/
no
39
Manti S.
2020
Narrative Review
SANRA 1-1-0-2-2-2
/
/
/
no
40
Marques J.G.
2022
Narrative Review
SANRA 1-2-2-2-1-2
/
/
/
no
41
Abdelmaksoud A.
2020
Letter to the editor
JBI-case report low
/
/
/
no
42
Wang J-Y.
2021
Letter to the editor
JBI-case report low
/
/
/
no
43
Lommatzsch M.
2020
Case report (1 pt)
JBI-case report high
1 allergic asmatic patient with COVID-19
1 patient continued Omalizumab
good outcome
no
44
Lanoue D.
2021
Case report (1 pt)
JBI-case report very low
1 chronic spontaneous urticaria (CSU) patient with COVID-19
2 patient continued Omalizumab
good outcome
no
50
Mantlo E.
2021
Experimental study
JADAD scale low
Vero cells infected by SARS-CoV-2
tested the antiviral efficacy of IFN-α and IFN-β
significant reduction of viral titer
no
No sufficient data or clinical evidence about Omalizumab and reduced risk of SARS-CoV-2 infection/duration/severity
3
Costanzo G.
2021
Review
AMSTAR low
/
/
/
no
14
Assaf S.M.
2020
Narrative Review
SANRA 1-2-0-2-2-2
/
/
/
no
15
Liu S.
2020
Narrative Review
SANRA 2-2-1-2-2-2
/
/
/
no
16
Morais-Almeida M.
2020
Narrative Review
SANRA 2-2-0-2-2-2
/
/
/
no
22
Pfaar O.
2021
Position Paper
AMSTAR low
/
/
/
YES
24
Paladini E.
2021
Pediatric case report
JBI-case report high
16 years old female in Omalizumab
COVID-19
mild disease
YES, Novartis
25
Lombardi C.
2021
Narrative Review
SANRA 2-2-0-2-2-1
/
/
/
no
28
Adir Y.
2021
Observational cohort study
STROBE high
8242 asthmatic COVID-19 vs 72.360 asthmatic without COVID-19
24 in Omalizumab vs 200 in Omalizumab
0 ICUa
YES
45
Schön M.P.
2020
Narrative Review
SANRA 2-1-0-2-1-2
/
/
/
no
46
Chhiba K. D.
2020
Observational cohort study
STROBE low
220 patients in Omalizumab
1 COVID-19
1 ICUa
no
48
Pfaar O.
2020
Review
AMSTAR low
/
/
/
no
49
Humbert M.
2021
Review
AMSTAR medium
/
/
/
no
Biologic therapy for asthma linked to a more severe course of COVID-19
47
Eger K.
2021
Retrospective cohort study: 120 in Omalizumab/2 COVID-19/2 ICU
Different methods were used, based on the study design, to assess the quality of eligible studies. The Amstar Checklist for Systematic Reviews, The SANRA scale for Narrative Reviews, The Jadad score for Randomized Clinical Trials (RCT), The Strobe Checklist for the Observational Studies, Joanna Briggs Institute Critical Appraisal Checklist for Case Reports and Joanna Briggs Institute Critical Appraisal Checklist for Case Series. Information regarding study design, date of publication, setting, characteristics of the population sample, objective of the study and outcome measure were considered.
The source of funding for each article included was reported in Table 1. The authors of the present review had no competing interests.
Results
According to inclusion and exclusion criteria 155 studies were retrieved.
The overall results of literature search were displayed in Fig. 2.
Fig. 2The studies checked according to PRISMA 2020 for systematic reviews
The studies included were 50 from different databases and other sources: PUBMED (N = 4); EMBASE (N = 9); SCOPUS (N = 19), Google Scholar (n = 3), Citation searching (n = 14), Congress Abstract (n = 1).
studies suggesting a link between omalizumab and a better antiviral response (increasing IFN-α production), but referring to other viruses besides SARS-CoV-2 (eg, rhinovirus, influenza virus);
2)
studies that do not identify an increased risk of COVID-19 and severe disease in omalizumab-treated patients;
3)
studies hypothesizing that omalizumab may potentiate antiviral responses also against SARS-CoV-2:
4)
studies highlighting the lack of sufficient data or clinical evidence that omalizumab may be an advantage in COVID-19;
5)
a single study suggesting that omalizumab therapy for asthma may be the cause of a more severe COVID-19 (course and duration).
We reported the first author, publication year, and type of study and assessed their quality, which was not as high as scoring scale shows (see Table 1).
The population treated (or in treatment) with omalizumab was recorded with precise numbers (that were relatively high), investigating possible consequences of SARS-CoV-2 infections (comparing with general population) in order to clarify outcomes. A possible protective effect against SARS-CoV-2 duration and severity were supposed by some authors because of the low rate of infection and, above all, the low rate of patients in intensive care units.
We also reported eventual funding above all by Novartis (when explicated) to clarify the eventual financial bound that could have conditionate the results (see Table 1).
Discussion
Evidence supporting the effect of omalizumab in enhancing the antiviral response to viruses other than SARS-CoV-2
Several studies link omalizumab to an enhanced antiviral response (via dendritic cells and IFN-α). However, the studies were carried out before the pandemic and with viruses other than SARS-CoV-2.
The most common causes of viral asthma exacerbations are human rhinoviruses (RV), respiratory syncytial virus (RSV), influenza viruses, parainfluenza viruses, coronaviruses, adenoviruses, and human metapneumovirus.
In fact, viral shedding and risk of virus-related disease are lower compared with guideline-driven care alone. Omalizumab decreases the expression of the pDC FcεRIα protein and in this way seems to increase IFN-α responses to RV and influenza virus.
What the physicians should know about mast cells, dendritic cells, urticaria, and omalizumab during COVID-19 or asymptomatic infections due to SARS-CoV-2?.
Type I IFNs other than IFN-α such as IFN-β1 or IFN-γ (usually low in allergic asthmatic patients) could also be upregulated and responsible for the increased viral clearance seen in patients treated with omalizumab as Cardet and Casale hypothesized.
Of note, all these studies analyzing the cellular and molecular mechanisms that link omalizumab therapy and IFN-α production refer to viruses different than SARS-CoV-2 (Table 2). Moreover, restoration of IFN-α during omalizumab treatment involved ex vivo experiments on peripheral blood and not interferon generation by airway cells. Consequently, the association between blood cell IFN-α production and clinical improvement may be only considered surrogate markers for in vivo events in the lung. Regarding the IFN production in the lung, some authors demonstrated that type III IFN (IFN-λ1-4) play a crucial role in limiting SARS-CoV-2 infection in the airways during the early phase of the disease. Overall, these data highlight the complexity of the IFN biology and the importance of assessing the IFN effect in the different anatomical sites.
Table 2The most cited studies about Omalizumab and a better antiviral response (increasing IFN- α production)
STUDY
VIRUS
OUTCOME
Busse (2011)
influenza virus, rhinovirus
“Omalizumab significantly reduced the proportion of participants who had one or more exacerbations”
Durrani SR (2012)
rhinovirus, RV-16
“Innate immune responses reduced by the high-affinity IgE receptor in allergic asthmatic children; after FcεRI cross-linking, allergic asthmatic children had significantly lower HRV-induced IFN responses”
Teach SJ (2015)
rhinovirus RV-16
“Omalizumab improved IFN-α responses to rhinovirus, and within the omalizumab group, greater IFN-α increases were associated with fewer exacerbations” (PROSE STUDY)
Saini SS (2015)
upper airway infections
“Targeting IgE with Omalizumab in asthma or chronic spontaneous urticaria patients did not increase upper airway infections”
Kantor DB (2016)
rhinovirus
“Omalizumab reduces acute severity of rhinovirus-triggered asthma exacerbation”
Esquivel A (2017)
rhinovirus
“Direct evidence that blocking IgE decreases susceptibility to RV infections and related-illness”
Edwards MR (2017)
viral infections
“Anti-T2 biologics are particularly successful in controlling asthma exacerbations”
“Pre-seasonal treatment with Omalizumab has been shown to eliminate the seasonal peaks in asthma exacerbations, most of which are associated with RV infection”
Heymann PW (2020)
rhinovirus, RV-16
“The effect of administering Omalizumab on the response to rhinovirus was most pronounced during the early/innate phase of the infection”
Altman MC (2020)
viral infection
“There are emerging therapeutic options to decrease severity of wheezing exacerbations caused by respiratory viral infections”
Is it logical to think that IgE blockade can reduce susceptibility also to COVID-19 infection? We must notice that there are remarkable (or evident or striking) differences in the cell receptor for rhinovirus and coronavirus, can the observations on rhinovirus be extended to SARS-CoV-2? Rhinovirus and influenza virus are among the most common viruses involved in the development of asthma exacerbations, but also coronavirus are involved, in a weaker way.
The cell receptors are indeed very different between three viruses: receptor of major group serotype of rhinovirus is ICAM 1 (intercellular adhesion molecule 1), sialic acid is the one for influenza virus and ACE-2 the one for SARS-CoV-2.
But as some valid observation for rhinovirus have been proven and then extended to the influenza virus, we can hypothesize that it could also happen for SARS-CoV-2. All are single-stranded RNA viruses, both influenza virus and coronaviruses have the envelope. However, the beneficial effect of omalizumab in treating virus-induced exacerbations may be due to its effect on IFN-α production (and not about the receptor involved).
In adults and children omalizumab treatment (for 6 months) increased IFN production against influenza virus A (in a statistically significant way), also a positive trend versus RV and an improvement in control of asthma symptoms were observed.
It has also been supposed for SARS-CoV-2 (even if there are not solid studies about this hypothesis).
Evidence showing no increased risk of COVID-19 (and severe COVID-19) in patients treated with omalizumab
In the first period of pandemic, one of allergists' first questions was whether patients they were treating with biologics would be at increased risk of infection. Patients with severe asthma treated with biologics don't have an increased risk of SARS-CoV-2 infection or progression to severe forms than the age- and geography-matched non-asthmatic population.
Position statement of expert panel of the Polish Allergology Society on the management of patients with bronchial asthma and allergic diseases during SARS-Cov-2 pandemics.
Alergologia Polska – Polish Journal of Allergology.2020; 7: 117-130
Discontinuation of biologics may lead to an increased risk of asthma exacerbations, oral corticosteroid use and a greater likelihood of access to the emergency room and hospitalization which represent risk factors for SARS-CoV-2 infection.
Biological treatment for asthma or dermatologic allergic disease do not seem to increase the risk of COVID-19 as several cohorts show.
In Belgian Severe Asthma Registry and Italian Severe Asthma Network biologic therapy was not associated with increased risk of infection of disease severity.
In a multivariate analyze, Adir et al demonstrated that biologic use was not associated with increased risk of COVID-19 severity or mortality (adjusted odds ratio 0.99; 95% CI 0.73–1.33).
Extrapolating data from a large Spanish database Izquierdo et al reported that COVID-19 related hospital admission and mortality was very low among asthmatic patients treated with biologics.
COVID-19 in severe asthmatic patients during ongoing treatment with biologicals targeting type 2 inflammation: results from a multicenter Italian survey.
In Ortega's cohort, 5 patients out of 46 in omalizumab treatment had COVID-19 infection, and none was admitted to the hospital: the use of biologics for severe asthma seemed not have an impact on poorer clinical outcomes due to SARS-CoV-2 respiratory infection as the authors suggested.
The same results (no increased risk of infection or disease severity or mortality) were found in another Spanish study that included 545 asthmatic patients treated with biologics.
A Turkiye study enrolled 75 asthmatic patients treated with omalizumab, comparing patient who continued biologic treatment and patients who interrupted it. Only 12 patients interrupted the treatment (because they were afraid of pandemic and refused to return to the hospital): the risk of infection and severe disease was higher in these second group (relative risk of 2.71; 95% CI, 1.21–6.06).
Between 13 Turkish patients with severe asthma (treated with omalizumab or mepolizumab) that contracted SARS-CoV-2, five (38.5%) had mild COVID-19, eight (61.5%) had moderate disease, none required mechanical ventilation or intensive care, all patients fully recovered.
Evidence supporting that omalizumab may enhance the antiviral immune response even against SARS-CoV-2
Several authors suggest that omalizumab treatment could protect against severe forms of COVID-19. Might misfortune (allergic disease and biologic treatment) be a blessing in disguise (pandemic)?
The antiviral and anti-inflammatory effects against virus-exacerbated asthma that omalizumab showed in previous studies may be relevant to the treatment of COVID-19.
A letter published in the journal Allergy details an asthma patient who developed a COVID-19 infection while receiving ongoing treatment with omalizumab.
Because the patient's COVID 19 illness did not progress into a more severe illness, the authors of this paper raised the possibility that omalizumab may have attenuated the seriousness of the infection. This interpretation extends beyond the available data and does not necessarily support the hypothesis under review, however, numerous cohorts show relevant data about the low severity of COVID-19 in omalizumab-treated patients compared to the incidence data of the general population (Table I). When acute respiratory distress syndrome (ARDS) develops in the severe phase of COVID-19 omalizumab perhaps could contribute to a better respiratory function.
Mild COVID-19 respiratory infection associated with moderate fare of chronic spontaneous urticaria in a 43-year old female long-term care worker on omalizumab.
Criado described the first favorable outcome of omalizumab in Chronic Spontaneous Urticaria in a patient with COVID-19, without deterioration of clinical status and excellent response.
The same IFN-alpha was considered as a potential therapeutic strategy to treat COVID-19 in that early phase in which the immune system produces cytokine as first line defense against viral infection.
This early activation of the innate immunity is intact in adult patients with mild disease and is enhanced in children that usually experience a benign disease course.
Among 308 Italian children and adolescents (mean age 12.8 years) treated with biologics, only 3 subjects (1%) who were treated with omalizumab experienced pauci-symptomatic COVID-19. As Licari et al showed their symptoms promptly resolved.
Mild COVID-19 respiratory infection associated with moderate fare of chronic spontaneous urticaria in a 43-year old female long-term care worker on omalizumab.
Asthma and allergic disorders are associated with a significant reduction of ACE-2 expression in nasal and bronchial cells, both in adults and children.
and, as it has been well demonstrated, to be related to patient's age. The production of pro inflammatory cytokines can be inhibited by type 2 cytokines.
Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome.
The epithelium with his mucus lining is the first physical barrier that blocks the invasion of the virus. Then activated eosinophils with their ribonucleases are another defense promoting viral clearance. Early airway inflammation caused by virus infection is attenuated also by low-dose inhaled corticosteroids (part of maintenance therapy). Allergen immunotherapy induces regulatory T cells (Tregs) with consequent suppression of inflammation. Tregs also prevent tissue damage: in fact they downregulate the induction and proliferation of other T-cell subsets.
In one of the first China-nationwide analysis of comorbidities in COVID-19 patients, 1590 patients were screened and none of them reported a diagnosis of asthma.
It seems true also in pediatric allergic patients. Only one of 52 young patient hospitalized for COVID-19 had a diagnosis of asthma in Ciprandi's study (including patients from 2 big Italian hospitals of Liguria and Lombardy).
Other worldwide studies suggest a different interpretation. Some authors suppose that there was an underreporting of chronic respiratory disease. Others suggested that there is an epidemiologically relevant difference in the prevalence of comorbidities (such asthma) between countries and that this was the reason of low prevalence of asthma in COVID-19 patients in early Asian studies.
Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study.
In children the type-2 skewed immunity drives a less pathogen associated molecular patterns (PAMPs) activation resulting in less inflammation. This mechanism decreases host's protection against viruses, but also determine a hypo-inflammatory state.
The key role of pDC in anti-viral immunity is underlined also by some interesting considerations about multisystem inflammatory syndrome in children (MIS-C). Circulating pDCs were severely decreased in MISC-C (comparing this condition to COVID-19 children). IFN- α plasma levels and expression of type I IFNs inducible genes were higher in COVID-19 children than in MIS-C patients.
Most studies emphasize the lack of sufficient data or clinical evidence that omalizumab may be an advantage in SARS-CoV-2 infection
Most studies suggest insufficient data about COVID-19 incidence of severity in omalizumab-treated patients. It is not known if omalizumab reduces (or increase) SARS-CoV2 risk.
We agree that the evidence is too few because there are not double-blind placebo-controlled, randomized controlled trials, or open controlled trials to strongly link omalizumab to protection against severe SARS-CoV-2 (through IFN alpha or other ways).
The number of omalizumab-treated patients with severe COVID-19 remains low, but the right sample size or study design to affirm causal relationships is lacking.
There are ethical and temporal reasons why we do not have controlled trials. Further investigations and studies are actually needed to prove that the protective role of anti-IgE on rhinovirus clearance can be extrapolated and generalized to SARS-CoV-2.
If omalizumab effectively reduces the risk of COVID-19 infections, the benefit may occur because interferon production generation is enhanced, but no data in the literature, either from the airway or peripheral blood cells, have indicated or assessed this possibility with SARS-CoV-2. This idea is almost like a syllogism. pDCs are involved in antiviral response in asthmatic patients treated with omalizumab, because they target the immune response with rapid and massive IFN I type production, enhanced by TLRs.
IFN- α and IFN- β inhibit virus infection in a dose-dependent way. IFN- α in a concentration as low as 5 IU/mL already has an anti-SARS-CoV-2 activity: viral titer result in a reduction of 1 log (p < 0.01). Increasing progressively IFN- α concentrations virus titers decrease in a proportional way.
However, some confounding factors are present in the study: for example higher prevalence of comorbidities such as obesity in omalizumab-treated population. COVID-19 severity can be explained by this comorbidities independently from biological therapy.
A possible “IgE mediated protection” is suggested by a lower risk of COVID-19 in allergic patients with higher IgE values. Therefore, can we suppose that reducing IgE with omalizumab may enhance the risks of infection and be a complication from the same therapy? Probably this hypothesis is not correct. In fact the apparent protective effects is not due to the higher IgE expression, but it is a marker of an higher activity of the higher humoral immune system, as Farmani showed in some asthmatic patients.
Moreover, omalizumab reduces only IgE and not also the other immunoglobulins. The allergic patient has other numerous protective pathway that does not involve “only” IgE mediated effect. Larsson in 2021 demonstrated a positive association between genetic predisposition to any allergic disease and lower risk of SARS-CoV-2 infection (with a mendelian randomization analysis of 136 uncorrelated single nucleotide polymorphisms related with a broad allergic disease phenotype). We must also notice that patients with more elevated IgE levels seems to be more prone to virus-induced asthma exacerbations: between IgE and IFN-α seems to be is a negative correlation. IL-4 and IL-13 can downregulate ACE2 expression and are not very influenced by omalizumab.
ACE2 also circle in a soluble form that is upregulated in asthma. It can limit the ability of SARS-CoV-2 to bind to airway cell membranes acting as a competitive soluble interceptor. The increase of eosinophils number in asthmatic patients could be another protective factor against excessive inflammatory responses in severe COVID-19. Omalizumab decreases their lung recruitment but not the total number, and a reduction in recruitment could also be linked with a minor risk of cytokine storm. Omalizumab has pleiotropic effects for example it not only reduces IgE, but also IL-33 and as a consequence, other inflammatory cytokines such as IL-6, TNF- α, IL-1 β and prostaglandin.
In this way it seems able to protect from severe COVID-19.
Levels of specific IgE are associated with COVID-19 progression and severity at admission in the hospital. Tan and al. in 2021 showed that anti SARS-CoV-2 spike S1-specific IgE (SP-IgE) and anti-SARS-CoV-2 nucleocapsid specific IgE (NP-IgE) were higher in worst cases. The total lung severity score (TLSS) was correlated with IgE level with a positive correlation, the PoO2/FiO2 ratio with a negative one.
Omalizumab reducing IgE response could be protective in these severe COVID-19 cases.
What are the limitations of the present review?
We performed a broad literature search and we found that there is little convincing evidence to indicate that omalizumab affects the course of a COVID-19 illness. Most of the evidence referred to is circumstantial or based on observational studies.
Some data show that a reduction of cell surface IgE enhances viral defense. Little data are presented to suggest that a reduction of cell surface bound IgE is beneficial with a COVID-19 illness. A counterregulatory mechanism was revealed between FcεRI (Fc epsilon RI - high affinity receptor of IgE) and TLR 7.
It is not very clear also the relative effect of bound IgE and free serum IgE.
In the different cohort it is not always well explained if omalizumab was administered before or concomitant COVID-19 and how many weeks before the infection in the first case. In fact, the modulation could be evanescent in time and to establish a correlation it is important to clarify temporal correlation.
Conclusions
Omalizumab is an anti-IgE biologic therapy with proven antiviral activity. It reduces incidence and severity of upper respiratory tract infections and asthma exacerbations.
This is a very interesting quality in pandemic time: the hypothesis of a possible protection against severe COVID-19 is very fascinating, although currently there are not sufficient data on a possible positive effect of anti-IgE therapy on COVID-19.
An EAACI consensus paper states that “patients with SARS-CoV-2 infection, irrespective of the severity of the infection, should withhold the application of biologicals until recovered”, while treatment of patients on biologicals should be maintained in noninfected individuals.
An international registry of omalizumab-treated COVID-19 cases could be very useful to clarify the outstanding issues in this area. Moreover, randomized controlled trials are necessary to clearly demonstrate the effect of omalizumab in protecting against severe SARS-CoV-2, through IFN-α upregulation or other immunological pathways.
The source of data and materials are mentioned in the manuscript, in support of the findings. The authors are available (upon request) to send all the articles used for the review and the complete list of excluded articles.
Authorship
Ghiglioni Daniele Giovanni has made substantial contributions to conception and interpretation of data.
Cozzi Laura has made substantial contributions to conception and design, or acquisition of data, analysis and interpretation of data.
Castagnoli Riccardo has been involved in drafting the manuscript or revising it critically for important intellectual content.
Maffeis Laura contributed with data collection.
Bruschi Gaia contributed with data collection.
Marchisio Paola Giovanna has been involved in drafting the manuscript or revising it critically for important intellectual content.
Marseglia Gian Luigi has been involved in drafting the manuscript or revising it critically for important intellectual content.
Licari Amelia has been involved in drafting the manuscript or revising it critically for important intellectual content.
All the authors gave final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Ethics approval
Not applicable.
Authors’ consent for publication
All authors’ gave their permission to publish research findings.
Potential competing interests
The authors report no competing interests.
To note
Ghiglioni Daniele Giovanni and Cozzi Laura should be considered joint first author.
References
Wang C.J.
Cheng S.L.
Kuo S.H.
Asthma and COVID-19 associations: focus on IgE-related immune pathology.
Mild COVID-19 respiratory infection associated with moderate fare of chronic spontaneous urticaria in a 43-year old female long-term care worker on omalizumab.
What the physicians should know about mast cells, dendritic cells, urticaria, and omalizumab during COVID-19 or asymptomatic infections due to SARS-CoV-2?.
Position statement of expert panel of the Polish Allergology Society on the management of patients with bronchial asthma and allergic diseases during SARS-Cov-2 pandemics.
Alergologia Polska – Polish Journal of Allergology.2020; 7: 117-130
COVID-19 in severe asthmatic patients during ongoing treatment with biologicals targeting type 2 inflammation: results from a multicenter Italian survey.
Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome.
Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study.
00001-7&id=gr1.jpg){kind=link}
00001-7&id=gr2.jpg){kind=link}