Question: I care for many immunology patients, all of whom have questions related to COVID-19 spike antibody levels and immunity to COVID-19 infection. Are there any data supporting an antibody level that confers protection from infection?

Answer: I have not seen any data that has been published on what an IgG protective level IgG may be for COVID-19.


Question: I have a 33-year-old male who was sick with COVID-19 in March this year and is considered a long hauler. His prior immuno work up came back IL28B genotype homozygous and was referred to me to discuss its implications. What do we know about any connections?

Answer: Regarding COVID-19 long haulers, we understand very little about the mechanisms of that process but as far as we know, it is not increased among people with immune deficiencies. It does seem to have an immunologic component but what the process is that leads to long haul status and importantly, the interventions that could be helpful remain frustratingly enigmatic.

Regarding IL28 deficiency, I would need to see what the variants are that were found but there is no known human disease associated with IL28 deficiency. The gene, IFNL3, is believed to be important in the incubation period of COVID-19 so there is a reason to consider whether this might be relevant for your patient but since we have not found any other IL28 deficient people I would not want to make too much of it.


Question: The CDC is recommending booster COVID-19 vaccinations for patients who are immunosuppressed. This includes active treatment with high-dose corticosteroids (i.e., ≥20mg prednisone or equivalent per day), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor-necrosis (TNF) blockers, and other biologic agents that are immunosuppressive or immunomodulatory.

I can’t find a list anywhere that lists the biologics that that the CDC considers immunosuppressive or immunomodulatory. Does this include Anti-IL 5 agents that we as allergists use such as Nucala or Fasenra? What about dupilumab, which is anti- IL-4 and IL-13? Do we consider low dose cyclosporine, sometimes used for urticaria, to be immunosuppressive enough to qualify?

Answer: As you state, the CDC has not delineated which biologics are considered immunosuppressive, other than TNF-alpha blockers. Some are obvious, such as Rituximab. Regarding those commonly used by A/I, I do not feel there is significant risk of immunosuppression. Early studies reported that asthmatics controlled on biologics where not at increased risk for COVID, nor a more severe course.

Along with other DMRD therapy, I would consider cyclosporin immunosuppressive, warranting a 3rd mRNA vaccine. Cyclosporine is a potent immunomodulatory agent with an increasing number of clinical applications. Its major mode of action is inhibition of the production of cytokines involved in the regulation of T-cell activation, primarily by inhibiting transcription of interleukin 2.


Question: I have many patients calling the office who are NOT immunecompromised and want to get the COVID-19 booster. Are there age guidelines? Are patients whose functional antibody deficiency was corrected with a pneumovax to be considered immune deficient?

Answer: These are certainly stressfully times, and some deal with stress differently than others. The guidance from the CDC is clear, without being rigid. I interpret your example of correcting functional antibody following Pneumovax as a normal response, rather than evidence of immunodeficiency.

Simply put, if the patient that desires a third vaccine at this time is not immunocompromised, then they are not a candidate for a third dose currently. It is anticipated that in September, we will be giving booster doses to those 6 to 8 months following their second mRNA vaccine. Once your patients meet that criterium they will be eligible for the vaccine. In addition to providing reassurance, I suggest you recommend they continue to follow masking and distancing guidance.

Here is the link to considerations for use of an additional mRNA COVID-19 vaccine dose after an initial two-dose COVID-19 mRNA vaccine series for immunocompromised people:
https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html#considerations-additional-vaccine-dose


Question: I work at a private allergy office and we are trying to figure out what to recommend for our specific antibody deficient patients and whether or not they should be getting a booster vaccine based off of the CDC's new guidelines for immunocompromised people. I'm not sure if there's any research regarding this specific population or if there's consensus in regards to this.

Answer: The purpose of the third vaccine is to address those that had sub-optimal response to the initial series. The CDC has stated those with moderate to severe primary immunodeficiency (PIDD) should receive the booster. In my opinion, other than IgA deficiency, all patients with PIDD should be considered eligible for a third vaccine.

To my knowledge, there are no data regarding criteria for third dose in primary immunodeficiency. In fact, there are limited data specifically addressing COVID-19 vaccine response in patients with primary immunodeficiency. The NIH is conducting a large study of 400 patients with primary immunodeficiency addressing response to COVID-19 vaccine, the results of which are pending and may address your question best. Though outside the scope of your question, I have summarized the limited data that are available at this time.

Three small studies addressing the effectiveness of the mRNA COVID-19 vaccine, focusing on CVID, have been published (1, 2, 3). Most recently, Romano et. al (1), was released pre-publication in Annals of Allergy, Asthma, and Immunology (link below). This study looked at 5 CVID patients, one had had a natural infection and the remaining 4 had no detectable anti–SARS-CoV-2 antibodies before vaccination. Each patient was vaccinated with the Pfizer-BioNTech mRNA vaccine.

Postvaccination, all patients but 1 developed neutralizing antibodies against SARS-CoV-2. The patient who failed to have a substantial rise in postvaccination titers of anti–SARS-CoV-2 antibodies also had a marked decrease in the frequency of circulating B cells. They concluded that SARS-CoV-2 vaccination is safe and effective even in patients with primary antibody deficiencies. Two additional studies (2,3), reported on 6 patients and 13 patients respectively, likewise demonstrated that patients were able to mount specific antibody responses after vaccination. However, patients with absence of B cells (ie, patients with X-linked agammaglobulinemia) failed to have production of neutralizing antibodies against SARS-CoV-2. These patients did produce robust antiviral cellular responses, which still may justify vaccination.

Although the data are limited, these small studies support mRNA COVID-19 vaccination in primary immunodeficiency, with regards to safety and production of neutralizing antibodies.

References

  1. Romano C, Esposito S, Donnarumma G, Marrone A. Detection of neutralizing anti-severe acute respiratory syndrome coronavirus 2 antibodies in patients with common variable immunodeficiency after immunization with messenger RNA vaccines. Ann Allergy Asthma Immunol. 2021 Aug 2:S1081-1206(21)00523-8. doi: 10.1016/j.anai.2021.07.026. Epub ahead of print. PMID: 34352358; PMCID: PMC8327608. In Press
  2. Squire J, Joshi A. Seroconversion after coronavirus disease 2019 vaccination in patients with immune deficiency [e-pub ahead of print]. Ann Allergy Asthma Immunol. doi:10.1016/j.anai.2021.05.015, accessed June 12, 2021.
  3. Hagin D, Freund T, Navon M, et al. Immunogenicity of Pfizer-BioNTech COVID-19 vaccine in patients with inborn errors of immunity [e-pub ahead of print]. J Allergy Clin Immunol. doi:10.1016/j.jaci.2021.05.029, accessed June 12, 2021.

Question: Does anyone know how long it might take for COVID-19 anti-spike antibodies to get into the immunoglobulin supply for patients being treated for hypogammaglobulinemia? I realize that it might take quite a while, but I'm not really sure how long, and I haven't gotten a return call from the couple of companies I've called. I really don't check antibody levels but I decided to go ahead with it in one of my SIgG deficiency patients who'd been vaccinated and her #'s were great. As I know that her T-cells generally work I'd like to be able to tell whether what she has was actually made by her.

Answer: The time from acquisition of donor serum to final product takes approximately nine months. Administration of SARS-CoV-2 vaccines began mid-December 2020, eight months ago. We saw our first case of COVID-19 in the U.S. in January 2020, twenty months ago. It is almost certain there would be measurable SARS-CoV-2 antibody in current immunoglobulin product, the majority of which from natural infection rather than vaccine.


Question: My patient 60 yr old female has CVID, and is stable on four years of IVIG therapy. She did have mild bronchiectasis which has mostly resolved on Chest CT, and had a history of recurrent sinus and lung infections prior to IVIG but these have been rare since being on IVIG. She had COVID-19 infection recently with diarrhea, reduced appetite and fatigue, and has been working from home. Her employer has asked her to return to in person as they are assuming she has immunity. My question is how reliable is a COVID-19 IgG antibody level in a patient with CVID? Do we have evidence of normal immune response? What about response to vaccine? I assume there will be recommendation to vaccinate those with CVID? Also, as an aside, are patients with selective IgA deficiency at more risk for COVID-19?

Answer: Regarding patients with CVID, those on regular immunoglobulin replacement appear to have a milder clinical course. In April 2020, Quinti et al, postulated complete B cell depletion (such as in XLA) may actually be a protective factor (1). This hypothesis was further strengthened by another report of two XLA patients with mild COVID-19 courses (2). There are reports of COVID -19 related fatalities in patients with CVID, but a review of literature suggests that this is likely the exception rather than the rule. The majority of patients with CVID who have therapeutic IgG levels will likely have a benign clinical course.

Antibody testing will not be reliable in patients with CVID. Some reports indicate patients with CVID did not have detectable SARS-COV2 IgG antibody responses despite having PCR positivity. Further, a positive SARS-COV2 IgG could be reflective of the IVIG donor rather than the patient herself (as infection rates climb precipitously in the United States). A recent study published that the seroprevalence in the general population in the US is <10%, so at best there would be limited IVIG donors that have anti-SARS-COV2 antibodies (5)

It appears that both RNA and adenovirus vaccines are safe for patients with CVID, although their efficacy in this population is unknown. Dr. Kate Sullivan has been providing fantastic COVID-19 related updates on the Immune Deficiency Foundation website. See here for her most recent video regarding vaccination.

In terms of selective IgA deficiency, there has been a case report of a patient developing complications of COVID-19 (6) and a Japanese report suggesting a strong positive correlation between frequency of selective IgA deficiency and the rate of COVID-19 infection in the community. These authors suggested the extremely low frequency of selective IgA deficiency in Japan versus the US (40 times more in the US) may explain higher mortality in the United States (7). However, these are very preliminary data and should be viewed cautiously.

Patients with humoral immunodeficiency appear to mostly have mild disease. Additional risk factors such as obesity, other medical co-morbidities as well as subtherapeutic IgG levels seem contribute towards a more complicated clinical course. There is continued need to gather additional data regarding this vulnerable patient population, but at present, we can continue to provide reassurance and encourage social distancing, wearing masks and frequent hand washing.

References:
1. Quinti I, Lougaris V, Milito C, et al. A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia. J Allergy Clin Immunol. 2020;146(1):211-213.e4. doi:10.1016/j.jaci.2020.04.013

2. Soresina A, Moratto D, Chiarini M, Paolillo C, Baresi G, Focà E, Bezzi M, Baronio B, Giacomelli M, Badolato R. Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover. Pediatr Allergy Immunol. 2020 Jul;31(5):565-569. doi: 10.1111/pai.13263. Epub 2020 May 19. PMID: 32319118; PMCID: PMC7264678.

3. Fill L, Hadney L, Graven K, Persaud R, Hostoffer R. The clinical observation of a patient with common variable immunodeficiency diagnosed as having coronavirus disease 2019. Ann Allergy Asthma Immunol. 2020;125(1):112-114. doi:10.1016/j.anai.2020.04.033

4. Mullur J, Wang A, Feldweg A. A fatal case of coronavirus disease 2019 in a patient with common variable immunodeficiency [published online ahead of print, 2020 Aug 18]. Ann Allergy Asthma Immunol. 2020;S1081-1206(20)30573-1. doi:10.1016/j.anai.2020.08.017

5. Bajema KL, Wiegand RE, Cuffe K, et al. Estimated SARS-CoV-2 Seroprevalence in the US as of September 2020. JAMA Intern Med. Published online November 24, 2020. doi:10.1001/jamainternmed.2020.7976

6. Pfeuffer S, Pawlowski M, Joos GS, et al. Autoimmunity complicating SARS-CoV-2 infection in selective IgA-deficiency. Neurol Neuroimmunol Neuroinflamm. 2020;7(6):e881. Published 2020 Aug 12. doi:10.1212/NXI.0000000000000881

7. Naito Y, Takagi T, Yamamoto T, Watanabe S. Association between selective IgA deficiency and COVID-19. J Clin Biochem Nutr. 2020;67(2):122-125. doi:10.3164/jcbn.20-102


Question: A 47 year-old white female with a past medical history of recurrent infections years ago has had an immune evaluation reveal normal QIA with inadequate response to pneumococcal titres. She was treated with IgRTx until December when she decided it was inconvenient and it was discontinued. She has done well without recurrent infections. She is employed as a teacher and is concerned she may become infected with COVID-19 and requested she resume IgRTx. Repeat immune work up revealed persistently normal QIA and only 3/23 pneumococcal titres protective. In addition to resuming IgRTx she requests a letter for short term and possibly long-term disability. In the absence of recurrent infections, I will not resume the IgRTx, however how likely is she to become infected with COVID-19 and have a poor outcome? Does she need to remain out of school for the duration of the pandemic?

Answer: There is no data to support the assertion that a patient with inadequate pneumococcal titers would be at increased risk for contracting COVID-19. We are not aware of any data that would support the off-label use of replacement IgG therapy to lower one's risk of contracting COVID-19. In addition, COVID-19 antibodies are not likely to be present in current immunoglobulin products, so resumption of IgRTx would not be helpful in reducing her risk of infection and isn’t otherwise indicated based on the absence of recurrent infections.


Question: Any thoughts on a 37y/o pediatric nurse, recently diagnosed with CVID and on SCIG for 3 months, returning to work? She has had a very good response to treatment with normalization of IgG and significant reduction in Chronic Sinusitis and respiratory symptoms. At work she has been restricted from patient care and is essentially doing telephone duties. She and her employer are anxiously wanting her to return to working “well child visits”. I have been asked for guidance in clearing her to return to direct patient care. Are there any recommendations for health care workers with CVID working with patients? I am in an area that is currently considered a hot spot.

Answer: We don’t have a lot of data on CVID patients and the risk for COVID-19 infection or the severity of infection, but what we do have is reassuring.  CVID patients have generally fared well during this pandemic.  Studies reported on infections from various hot spots (China, Italy, US) have not included very many patients with CVID, suggesting that they are not at increased risk of severe disease, and patients with CVID generally do well with viral infections, unless they have a significant problem with T cell immunity.  Whether this patient is able to return to work or not is dependent on factors that would relate to any individual who would like to return to work during the pandemic.  What is the current transmission rate in the community in which they are going to work? What is the capability of the practice to protect the person, and what will their role be in the work?  General pediatric practices in areas in which there is high community transmission of the virus should be considering performing virtual well child visits.  Does the practice screen patients before they are allowed into the office?  Does the office have the capability to provide physical distancing?  Does the office have adequate amounts of PPE to protect their staff?  What is the “culture of safety” within the office, meaning what sort of precautions do staff members take outside of the office?  If the answers to these questions are reassuring, then your patient can most likely return to work.


Question: A 23 y/o patient with CVID diagnosed solely on poor response to childhood vaccines (while in nursing school) and poor studies of functional antibody response has not had any serious infection problems, and is on IG replacement therapy. She currently works as a nurse in a small hospital. Two questions – with COVID-19 what are hazards of her working in hospital with CVID and no history of recurrent or severe infections? She is not going to respond to COVID-19 vaccine when it is available. She will get passive COVID-19 immunity as more are vaccinated (when available).

Answer: Viral disease is generally not as much of a problem as bacterial infection with humoral immunodeficiency including CVID, IgG subclass deficiency and functional antibody deficiency. There are exceptions, such as enteroviral infections, and disseminated viral disease in CVID with significant T cell abnormalities, but in general viral disease is not the clinical problem. 

I would not consider your patient at significant increased risk working in a hospital since she is receiving gamma globulin and has no history of infections. The experience with immune suppressants, as used in rheumatologic and other autoimmune conditions, is treated subjects are not experiencing much greater disease severity. Generally, the problems with immunosuppressants/immunomodulators is atypical infections or systemic viral disease and not viral respiratory viral illness. Whether this applies to COVID-19 is not clear but there is no compelling evidence of increased risk.

I disagree she will not respond to a COVID-19 vaccine based upon her clinical status (unclear diagnosis of CVID, especially given the lack of any infection history). Giving gamma globulin would mitigate responses to vaccines for which there is significant antibody specific for the immunogen in the gamma globulin, but this is not the case for SARS-CoV-2. Furthermore, there is not sufficient information to assess how she may respond to a possible COVID-19 vaccine and there is no totally agreement on what characterizes an immune response. Therefore, she may or may not respond but I would posit she will benefit similarly to other adults.

References
Perez, Elena, et al. "Specific antibody deficiency: controversies in diagnosis and management." Frontiers in immunology 8 (2017): 586.

Bonilla, Francisco A. "Update: vaccines in primary immunodeficiency." Journal of Allergy and Clinical Immunology 141.2 (2018): 474-481.

Ameratunga, Rohan, et al. "Diagnosing common variable immunodeficiency disorder in the era of genome sequencing." Clinical reviews in allergy & immunology 54.2 (2018): 261-268.

Marsh, Rebecca A., and Jordan S. Orange. "Antibody deficiency testing for primary immunodeficiency: A practical review for the clinician." Annals of Allergy, Asthma & Immunology 123.5 (2019): 444-453.

Lebwohl, Mark, Ryan Rivera-Oyola, and Dedee F. Murrell. "Should biologics for psoriasis be interrupted in the era of COVID-19?" Journal of the American Academy of Dermatology 82.5 (2020): 1217-1218.

Blaszczak, Alecia, John CL Trinidad, and Alexander M. Cartron. "Adalimumab for treatment of hidradenitis suppurativa during the COVID-19 pandemic: Safety considerations." Journal of the American Academy of Dermatology (2020).

Patruno, Cataldo, et al. "Dupilumab and COVID‐19: what should we expect?" Dermatologic Therapy (2020).


Question: Have a 10 y/o female patient with selective IgA deficiency - no recurrent infections, no autoimmune disease - mild asthma. Mother very concerned about COVID-19 exposure and potential for severe course if exposed. When schools open in fall, mother asks about home school until vaccine available. Would this be a reasonable consideration or could she safely (as much as other children) return to school exposure with safety precautions in place?

Answer: Since the COVID-19 pandemic is a dynamic situation and information is constantly evolving, it is near impossible to make definitive recommendations regarding events in the Fall. Also, we are still gathering data regarding patients with primary immunodeficiency and their risk factors for contracting SARS-CoV2 or having a more severe disease course. A few organizations have put out guidelines for patients with PID. They include: Working Group for Pediatric Immunology (API) from Europe and International Patient Organization for Primary Immunodeficiencies (IPOPI).

It is important to note that not all immunodeficiencies are equally susceptible to the infection/complications related to SARS-CoV2. In the case of your patient, she has a history of selective IgA deficiency, which in general has a milder phenotype. Given the absence of infections, autoimmunity and only mild asthma, per API guidelines, this patient would likely follow a similar course as that of a patient WITHOUT immunodeficiency. In addition, IPOPI provides the following recommendations:

  • "If a country has started lifting the confinement measures it is because their authorities have made a thorough risk assessment, concluding that it is safe to return to school and work if appropriate hygiene measures are put in place. If nothing else is mentioned this also includes PID patients, but we encourage PID patients to seek advice from their PID expert if they are in doubt. Please ensure to follow appropriate hygiene measures carefully and to monitor and follow your countries national guidelines."
  • The decision regarding return to school would depend on local disease prevalence in the Fall and adherence to medical recommendations by the general public as well as the local schools. In addition, new information may emerge specifically regarding PID patients over the next few months that could alter recommendations.
  • At this juncture, the expert consensus would be to allow a patient with selective IgA deficiency to attend school if proper measures are in place. Though the risk for severe complications exists, it is not yet clear what the risk factors are for a more severe disease course in pediatric patients. So far, selective IgA deficiency has not been identified as a risk factor, though it is the most common PID. Given the marked anxiety surrounding the COVID-19 pandemic, we recommend shared decision making which would involve providing the families with the available information/recommendations, but also taking the individual family's fears and concerns into account.

Here are links to the guidelines mentioned:
IPOPI: https://ipopi.org/pids/covid-19-and-pids-faqs/#toggle-id-35 

Additionally, these websites may also provide helpful information about PID and COVID-19.
For patients: Immune Deficiency Foundation COVID-19 Resource Page https://primaryimmune.org/coronavirus
For providers: Clinical Immunology Society COVID-19 Resources https://clinimmsoc.org/CIS/News/Latest-News/COVID-19-Resources.htm


Question: Is there anything we should know in regards to immunocompromised patients since they are in a high-risk category when it comes to COVID-19?

Answer: The published data from China has very few immunodeficient patients included in their cohorts, for example, out of 1,066 hospitalized there were two, and they had non-severe disease (NEJM 2020. DOI: 10.1056/NEJMoa2002032). Nonetheless, it makes sense that patients who have compromised immune systems will be at risk of a more severe infection, if they get COVID-19. The importance here is to prevent infection in the first place. As has been said numerous times, the best approach at this time is for these patients to: (1) practice social distancing (avoid crowds and travel, keep at least six feet away from anyone who appears ill), (2) frequently wash their hands with soap and water for 20 seconds, and don’t touch your face, (3) continue any medications for their underlying health conditions, and (4) call before going to any healthcare provider (including emergency department and urgent care). The last issue is important because providers need to make sure that when an immunocompromised patient comes to their office they are not exposed to potential COVID-19 patients. Providers should keep a close eye on their own health and take appropriate precautions to not become infected with SARS-CoV-2, and to stay at home should they exhibit signs of COVID-19.


Question: I have a patient recently diagnosed with CVID. She has no ability to make antibodies at all, and is now receiving IVIG. For COVID-19, even if a vaccine becomes available in the fall, are there any antiviral medication regimens you would recommend at this juncture to utilize prophylactically or maintain on standby if required?

Answer: At this point there is no proven effective therapy for COVID-19. There are a number of clinical trials ongoing. Social isolation is key in this setting. Anti-COVID 19 IgG will eventually make its way into IVIg materials, but this will take several years at a minimum. This is a very difficult problem. You will also find information on this topic in the Special Article: COVID-19: Pandemic Contingency Planning for the Allergy and Immunology Clinic

 

Some answers have been updated to reflect changing circumstances and information since the individuals submitting the questions were originally provided with a response. While we’re working on keeping answers updated as best we can, information continues to evolve rapidly. Please email us at practicematters@aaaai.org with concerns or additional questions.