Selective IgA deficiency is an under-recognized risk factor for severe COVID-19

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Medical researchers from Auckland Hospital-New Zealand, University of Auckland-New Zealand and Wellington Hospital-New Zealand have in a new study found that selective immunoglobulin A deficiency (sIgAD) is a risk factor for severe COVID-19.

The study findings were published in the peer reviewed Journal of Allergy and Clinical Immunology.
https://www.sciencedirect.com/science/article/pii/S2213219822010431

PIDs have been termed experiments of nature.37 Previous studies of PID patients with defects of the immune response, have demonstrated specific vulnerabilities to pathogens. Patients with T cell deficiency are at risk of viral, fungal and bacterial infections.

Those with humoral immune defects are predisposed to bacterial, protozoal and selected viral infections. Patients with innate immune defects are at risk of Salmonella, Mycobacterial and viral infections. Individuals with terminal complement defects are susceptible to recurrent Neisseria infections. These vulnerabilities illustrate the role of specific immune components in normal protective responses to pathogen groups.

IgA plays a critical role in protecting mucosal surfaces, including the upper respiratory tract, which is the primary route of SARS-CoV-2 infection. Relatively few patients with sIgAD are included in recent case series of PID patients infected with SARS-CoV-2. 38-41 In one large series, only 7 of 961 sIgAD patients contracted COVID-19 and there were no fatalities.41

Given it’s higher prevalence than other PIDs, it is unclear why so few sIgAD patients contracted SARS-CoV-2 in these case series. Possibilities include these individuals sheltering in place or having higher COVID-19 vaccination rates. Most of these PID case series were however published before the widespread availability of COVID-19 vaccines.

Given most patients with sIgAD are asymptomatic, ascertainment of IgA levels of patients with severe COVID-19 may be more informative than case series of PID patients. A recent publication containing a larger number of sIgAD patients infected with SARS-CoV-2 showed a much greater risk of adverse outcomes.

Eleven of 424 patients admitted to Hospital were infected with SARS-CoV-2 had sIgAD. These individuals had a 7.7 fold increased risk of severe COVID-19 compared to patients with normal IgA levels (odds ratio [OR], 7.789; 95% confidence interval [CI], 1.665-36.690, P = 0.008).36 In this group of hospitalized patients, the prevalence of sIgAD was 1/38 compared with 1/188 in the general Turkish population. This is important evidence that patients with sIgAD are at increased risk of severe COVID-19.

In another study, there was a gradient of risk for severe COVID-19, based on levels of IgA and IgG in the serum.42 In a third study protective vaccine responses may have been less effective in patients with reduced IgG and IgA compared to healthy controls.43 sIgAD is at the extreme end of this gradient of host susceptibility, supporting a causal relationship between the severity of COVID-19 and reduced IgA levels.

These observations are also evidence that mucosal SARS-CoV-2 IgA levels following vaccination, plays an important role in protecting against COVID-19 in healthy individuals (Figure 1).

The potential vulnerability of patients with sIgAD to COVID-19 illustrates the importance of research into the role of mucosal immunity in protecting against SARS-CoV-2.44 Saliva is a readily accessible source of mucosal IgA for research. Unsurprisingly, children prefer saliva tests to venipuncture. Children in general have much milder COVID-19 than adults and one possible explanation is robust mucosal immunity. This possibility needs to be investigated.

Breast milk from lactating mothers is another source of secreted IgA for investigation.45 Anti-SARS-CoV-2 IgA in breast milk may protect infants against COVID-19.46 Orally administered breast milk has been successfully used to treat an adult immunodeficient patient with Chronic COVID-19.47

The potential immunological mechanisms underlying severe COVID-19 in sIgAD remain to be defined. During the incubation period of COVID-19, the viral load reaches very high levels in the nasal mucosa before aspiration into the lungs. Given the mucosal defect, it is currently unknown if sIgAD patients have higher viral loads compared to those with normal IgA levels.

This is an important research question as there is evidence that a higher initial viral inoculation, as judged by the Reverse Transcriptase quantitative polymerase chain reaction (RT-qPCR) cycle threshold (Ct), is associated with worse outcomes. 48, 49 Early studies from China showed that even young Health Care Workers (HCWs) were at risk of death from COVID-19.50

Prior to the use of personal protective equipment (PPE), these HCWs were exposed to high viral concentrations, presumably resulting in heavy inoculation. A high mucosal viral load might thus be an explanation for severe COVID-19 in sIgAD patients.

A second possibility for severe COVID-19 in sIgAD patients is systemic autoimmunity triggered by SARS- CoV-2.51

Patients with sIgAD are predisposed to autoimmunity, which could contribute to adverse outcomes.52 Patients with sIgAD have altered T cell subsets, which may predispose to autoimmunity following COVID-19.53 The potential role of neutralizing anti-interferon antibodies in exacerbating autoimmunity in sIgAD is not currently known.

A third non-mutually exclusive possibility is increased intestinal viral entry in the absence of gut SARS- CoV-2 neutralising IgA or alternations in the gut microbiome caused by sIgAD.54

The gut is a secondary route of entry for SARS-CoV-2 and may contribute to a higher systemic viral load in sIgAD patients.55

It is interesting to compare the COVID-19 risk profiles of patients with XLA and those with sIgAD. Both groups of patients are unable to produce mucosal IgA, yet the risk profiles seem to differ. As noted, there is conflicting data about the protective role of the systemic humoral immune response.7 Some studies indicate ADE in severe COVID-19.56 Perhaps the absence of ADE in patients with XLA compensates for the lack of mucosal IgA, mitigating their risk. As noted above, XLA patients may be predisposed to Chronic COVID-19. It is currently unknown if patients with sIgAD are at increased risk of Chronic COVID-19.

Potentially severe outcomes in sIgAD patients suggest targeting the nasal phase may reduce the risk of severe pulmonary and systemic disease in other vulnerable patients.57 New vaccines and therapeutics impeding SARS-CoV-2 nasal mucosal entry may improve the prognosis of high-risk patients.58

Nasal vaccines are being studied in animals as well as in human phase1-3 trials. 59, 60 Systemic primary vaccination with nasal boost strategies may prove to be very effective in the future.61 The efficacy of nasal vaccines in sIgAD patients would need to be determined separately.

Some current COVID-19 vaccines induce mucosal IgA antibodies, which may provide protection against SARS-CoV-2. There are important differences between vaccines. The Janssen (Ad26.COV2.S) and Coronavac (inactivated SARS-CoV-2 virus) vaccines seem to stimulate less salivary SARS-CoV-2 IgA than the Astra Zeneca (ChAdOx1) vaccine and much less than the mRNA vaccines (Pfizer BNT162b2 and Moderna mRNA-1273).44, 62

How mRNA vaccines administered intramuscularly, induce mucosal IgA responses is unclear, but this mechanism may at least partly underlie their efficacy.63

Current data indicate heterologous booster doses are more effective in countering new SARS-CoV-2 VOCs.64, 65 Future studies will indicate if the superiority of heterologous vaccination with mRNA and subunit or adenovirus-based vaccines is due higher protective mucosal SARS-CoV-2 IgA levels. Saliva (and breast milk) neutralizing IgA antibody studies can similarly be undertaken for VOCs.

Future vaccine- efficacy studies should measure both systemic and mucosal immunity to SARS-CoV-2. Most studies have focused on the systemic adaptive immune response to SARS-CoV-2. This is understandable, as a dysregulated cellular immune response is associated with severe outcomes. 9

The NZACE2-Pātari project seeks to intercept and block SARS-CoV-2 in the nasal mucosa. 66 Pātari is the Māori verb for decoy, leading to interception. This project utilizes modified ACE2 molecules to intercept SARS-CoV-2 in the nasal phase of COVID-19 to mitigate the severity of the pulmonary and systemic phases.

Because the project uses modified ACE2 molecules, viral evolution to evade these molecules will result in the loss of virulence. 67 NZACE2-Pātari is likely to be effective against current and future VOCs.

These drugs may compensate for the mucosal defect in sIgAD. They may also be of value for the elderly and those with comorbidities, who are at high risk of adverse outcomes. NZACE2-Pātari may have synergistic therapeutic benefits with other treatments such as protease inhibitors and monoclonal antibodies.

Future research will indicate if patients with sIgAD should undergo robust immunological evaluation. Vaccine challenge responses are not typically undertaken in patients with selective IgAD unless there is concern the disease is evolving into another more severe disorder such as CVID.68, 69

In the absence of IgA, other secreted immunoglobulin isotypes such as IgG or IgM may compensate for mucosal protection.70 This redundancy in mucosal immune protection is presumably why the majority of patients with sIgAD are asymptomatic. Future studies may indicate if measuring salivary SARS-CoV-2 specific IgG or IgM following COVID-19 vaccination, is of prognostic value in sIgAD patients.70

Prospective studies may also indicate if in vitro T cell responses to SARS-CoV-2 are a surrogate marker for protection against COVID-19 in patients with PIDs, including sIgAD.71, 72 The outcomes of such studies will allow personalized medicine for COVID-19 in patients with PIDs, including sIgAD. 73

At the time of writing, SARS-CoV-2 omicron and its sub-variants are dominating global COVID-19 infections. Previously ineffective treatments such as convalescent plasma infusions may be more effective for omicron and its sub-variants. Omicron appears to provoke less severe perturbations of cellular immunity and protection could be more reliant on antibodies.74

If this hypothesis is accurate, therapeutic plasma infusions from sIgAD omicron survivors may reduce the risk of severe COVID-19 in sIgAD patients.74 Younger sIgAD convalescent plasma donors are preferred as they are less likely to have anti-interferon antibodies, which could aggravate disease. The immunopathology of COVID-19 (and therapeutics) will need to be reviewed for each successive SARS-CoV-2 VOC.

Patients with sIgAD may be in good health until they contract SARS-CoV-2 and suffer severe COVID-19. Future studies will confirm if patients with sIgAD have a specific pathogen vulnerability to SARS-CoV-2. There are many other examples of critical pathogen vulnerabilities in patients with PIDs, including X-linked lymphoproliferative Disease (XLP).75 XLP patients are mostly in good health until they contract EBV, which can lead to fulminant EBV, lymphoma or bone marrow failure.75

The preliminary data presented here indicates patients with sIgAD may need to be considered severely immune compromised in the context of COVID-19, similar to patients with innate or cellular immune defects (Figure 1). Patients with sIgAD should be encouraged to receive three or four primary vaccine doses and heterologous boosters. sIgAD patients should also be offered other prophylactic therapeutics such as sotrovimab or evulsheld (tixagevimab and cilgavumab), depending on the sensitivity of VOCs circulating in the community.

These observations may also have important clinical implications for the treatment of SARS-CoV-2 infected patients with sIgAD. Because most sIgAD patients are asymptomatic, they may not be aware of their potential vulnerability to COVID-19. Immunoglobulin levels should be routinely measured in patients admitted to Hospital with COVID-19.

SARS-CoV-2 infected sIgAD patients should receive priority for early treatment with monoclonal antibodies and antiviral drugs such as paxlovid, molnupiravir or remdesivir. 76

On the precautionary principle, pending further data, previously diagnosed sIgAD patients should be pre- emptively recalled from case notes and other databases (including PID registries and Blood bank data) to receive the relevant clinical advice. Further research into the vulnerability of sIgAD patients to COVID-19 is a high priority.44 Enhancing mucosal protection against SARS-CoV-2 with vaccines and therapeutics may be the key to ending the pandemic.

Figure 1. The stages of COVID-19, specific vulnerabilities of patients with PIDs and possible treatments. Patients with humoral, cellular and combined defects may not be optimally protected by COVID-19 vaccines. Patients with sIgAD may have a poor mucosal response to vaccines. The systemic phase is caused by an unbalanced immune response and vaccines reduce the risk of a dysfunctional immune response including ADE. Because of immune dysregulation in the pulmonary and systemic phases, deficiency of the complement cascade, neutrophils and humoral immunity may mitigate disease severity. The role of specific treatments for Chronic COVID-19 remain to be defined. Convalescent plasma has not been successful in previous variants of SARS-CoV-2 but may prove more effective for Omicron and its sub- variants. Immunosuppressive drugs include steroids, tocilizumab and baricitinib. * Innate immune defects include patients with PIDs and those with neutralizing anti-interferon antibodies. ** The NZACE2-Pātari project has not reached clinical trials. Mabs- monoclonal antibodies

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