Infectious Disease

COVID-19 and the immunocompromised patient

October 19, 2021

13 min read


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  • Cajamarca-Baron J, et al. Reumatol Clin. 2021;doi:10.1016/j.reuma.2020.08.004.
  • Connolly CM, et al. Ann Rheum Dis. 2021;doi:10.1136/annrheumdis-2021-221252.
  • Corey L, et al. N Engl J Med. 2021;doi:10.1056/NEJMsb2104756.
  • Earle KA, et al. Vaccine. 2021;doi:10.1016/j.vaccine.2021.05.063 0264-410X/ 2021.
  • Strangfeld A. Ann Rheum Dis. 2021;doi:10.1136/annrheumdis-2020-219498.
  • Disclosures:
    Cassandra Calabrese reports speaking and consulting fees from Sanofi-Genzyme. Leonard Calabrese reports serving as an investigator and a consultant to Horizon Pharmaceuticals. Laster reports speaking fees from Amgen, Eli Lilly & Co., Exagen, Genentech, Myriad/Crescendo, Novartis and Pfizer, as well as consulting fees from Amgen and Eli Lilly & Co. Sparks reports consulting for AbbVie, Bristol Myers Squibb, Gilead Sciences, Inova Diagnostics, Janssen, Optum and Pfizer. Wallace reports receiving research support from Bristol Myers Squibb and Principia and consulting fees from Medpace and Viela Bio.


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    Nothing is easy in the management of COVID-19. Similarly, nothing is easy in managing immunocompromised patients. Marry the two and the challenges more than double.

    There are a number of factors to consider. One is whether immunocompromised patients are at increased risk for acquiring COVID-19 and another is whether they are at risk for severe complications if they do acquire the virus.

    Source: Adobe Stock.

    Source: Adobe Stock.

    “Similar to risk for COVID infection, the risk for severe complications is going to vary based on the patient’s demographics and disease-specific features,” Zachary S. Wallace, MD, MSc, of the Clinical Epidemiology Program in the Division of Rheumatology, Allergy, and Immunology at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, told Healio Rheumatology. “Patients on certain medications, like B-cell depletion, glucocorticoids, JAK inhibitors and others, may be at higher risk for worse outcomes.”

    Zachary S. Wallace, MD, MSc
    Zachary S. Wallace

    Disease-related factors are also at play, according to Wallace. “Patients with underlying comorbidities, including cardiovascular disease and interstitial lung disease, and poorly controlled rheumatic disease activity may also be at higher risk for poor outcomes,” he said. “As in the general population, older patients also do less well.”

    Other clinical challenges faced by immunocompromised individuals surround COVID-19 vaccine efficacy and antibody production. These questions open to others regarding the necessity or utility of additional vaccine doses or booster shots.

    “Like with the risks associated with infection itself, vaccine response also depends on the patient’s risk factors,” Cassandra Calabrese, DO, of the department of rheumatologic and immunologic disease at the Cleveland Clinic, said in an interview.

    Many of the same drugs mentioned by Wallace can also impact vaccine response. Rituximab (Rituxan, Genentech), in particular, has a long history of disruptive impact on any vaccine response, and the same pattern holds true for the COVID-19 shots. What this means for rheumatologists is that, given patient factors and poor vaccine response, the threat of breakthrough infection is considerably higher in immunocompromised individuals than in the general population.

    If vaccines are not working, then effective treatments should be the next priority. Many experts have hope for monoclonal antibody therapies and antivirals. But sorting out which drugs are appropriate for which immunocompromised patients and at what point in the infection cycle is a multifaceted equation with no perfect solutions yet.

    If there is a reason for encouragement, it is that rheumatologists are well-versed in managing complicated patient cases, according to Andrew J. Laster, MD, FACR, a practicing community-based rheumatologist in Charlotte, NC, and president of Arthritis & Osteoporosis Consultants of the Carolinas. “COVID is so much of our practice now,” he said. “But it is hard to have blanket answers about anything from treatments to booster/additional doses. Like with so many of our patients, everything has to be individualized.”

    Tailoring those individual responses starts with understanding the risk in any given patient.

    Elevated Risk

    While logic might dictate that being immunocompromised would lead to higher risk of acquiring the infection, Calabrese stressed that it is not so simple. “This is still a gray area,” she said. “Early on, it was not apparent that having an immune-mediated disease increased acquisition risk, but we are starting to see some evidence of elevated infections, particularly in patients with RA and lupus.”

    She went on to explain how this was like most other data in COVID-19. “It is not consistent, but it’s there,” she said. “There may be something to it.”

    Jeffrey Sparks, MD, MMSc, associate physician at Brigham and Women’s Hospital and Harvard Medical School, dug deeper. “The risk for rheumatology patients acquiring COVID varies by many factors that include type, severity and activity of the underlying condition, immunosuppressive treatment regimen, age and comorbidities, among many others,” he said, noting the broad range of cardiovascular and pulmonary complications seen in these patients. “Overall, rheumatology patients likely have slightly higher risk of acquiring COVID than the general population.”

    Sparks then repeated a refrain voiced by all of the experts who spoke to Healio Rheumatology, in one form or another. “Risk mitigation strategies such as vaccination, masking and social distancing can all lower the risk for acquiring COVID,” he said.

    Compared with the general population, rheumatology patients are likely at higher risk for acquiring COVID-19, Jeffrey Sparks, MD, MMSc, told Healio Rheumatology.
    Compared with the general population, rheumatology patients are likely at higher risk for acquiring COVID-19, Jeffrey Sparks, MD, MMSc, told Healio Rheumatology. However, that risk varies by factors like type of rheumatic disease, treatment regimen, age and comorbidities. “Risk mitigation strategies such as vaccination, masking and social distancing can lower the risk for acquiring COVID,” he said.

    Source: Brigham and Women’s Hospital.

    Risk for Severe Disease

    While there is still some debate about acquisition, there is less debate about disease severity in immunocompromised individuals. “Unarguably, they do more poorly,” Calabrese said, detailing a laundry list of medications linked to adverse outcomes ranging from hospitalization to poor vaccine response. “It is clear that higher-dose steroids and B-cell depleting agents are associated with adverse COVID outcomes.”

    In addition, sulfasalazine may be on that list, but she said that it is still not understood why.

    Cassandra Calabrese, DO
    Cassandra Calabrese

    Calabrese cited the Global Rheumatology Alliance as a useful source of rheumatology-specific information for all things COVID-19. For example, using data from the Alliance, Strangfeld and colleagues published a study in the Annals of Rheumatic Diseases demonstrating that factors ranging from poorly controlled disease to use of immunosuppressive drugs yielded increased rates of mortality and hospitalization.

    But like so many aspects of rheumatology, there are two sides to every story. In their 2020 study in Reumatología Clínica, Cajamarca-Baron and colleagues examined COVID-19 outcomes in immunosuppressed populations, notably transplant recipients and patients with cancer, neurological diseases, primary and secondary immunodeficiencies. Their findings showed that only cancer patients exhibited a higher risk for poor COVID-19 outcomes.

    “Additional studies have shown that among patients with rheumatic diseases and other inflammatory/autoimmune conditions, those on certain biologics, like TNF inhibitors, may actually do better than patients on other treatments,” Wallace added. “So, the risk really varies quite a bit based on the individual patient’s profile.”

    Leonard H. Calabrese, DO, director of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic, believes that comorbidities are essential to understanding the risk profile of any individual immunocompromised rheumatology patient. “Renal and cardiovascular disease and pulmonary complications are all elevated in immunocompromised populations,” he said.

    While most experts would hope for clinical trials to elucidate these potential associations, Leonard Calabrese explained why it would be “almost impossible” to conduct these studies. “It would require ongoing surveillance,” he said, and noted that the current milieu makes it particularly difficult to undertake this task.

    Given the potential risks to rheumatology patients, pre-emptive vaccination against COVID-19 would be the next logical decision. However, it does not take a practicing rheumatologist to understand that COVID-19 vaccination comes with a whole different set of obstacles.

    Boosters and ‘Third’ Doses

    The center of the discussion, at the moment, pertains to supplemental vaccine doses in immunocompromised patients. For Laster, it is important to define the terms. “Booster is for those individuals who had a good initial response to the vaccine but it has waned over time,” he said. “The booster dose is currently approved for the Pfizer vaccine only at this time and is given 6 months or more from the initial vaccine series.”

    Andrew J. Laster, MD, FACR
    Andrew J. Laster

    A third dose is for immunocompromised individuals who did not respond to the initial mRNA vaccine, Laster added. “This would include solid organ transplant patients, patients with heritable and acquired immunodeficiency and some of our patients on biologic therapies, such as rituximab, mycophenolate mofetil, abatacept [Orencia, Bristol Myers Squibb], as well as high-dose steroids,” he said. “The third dose can be either Pfizer or Moderna and can be administered 28 days or more following the initial series.”

    Regarding immunocompromised individuals who received the Johnson & Johnson vaccine, Laster said that an additional dose — preferably one of the mRNA products — may be suggested. “It is not technically a third dose but it is not a booster, either,” he said. “We need a name for this.”

    Leonard H. Calabrese, DO
    Leonard H. Calabrese

    Leonard Calabrese described another unmet need. “We do not have a reliable assay to quantify risks at the individual patient level to tell them anything of actionable counsel based on boosting,” he said.

    It is for this reason that Cassandra Calabrese brought the topic back to basics. “It is likely that a third dose or booster shot is only going to help, and not hurt,” she said.

    However, understanding that the extra dose will help and understanding exactly how it will help are two different concepts. The starting point is in determining thresholds of antibody response.

    Antibody Response

    While Sparks highlighted the “good news” that the vast majority of rheumatology patients make antibodies to the COVID-19 vaccines, further study is required. “The level of antibodies in rheumatology patients after COVID vaccination seems to be a bit lower than the general population,” he said.

    In their paper published in Vaccine, Earle and colleagues detailed issues surrounding antibody titers. “A correlate of protection (CoP) is urgently needed to expedite development of additional COVID-19 vaccines to meet unprecedented global demand,” they wrote, suggesting that a CoP is, essentially, a measure of vaccine response.

    Laster discussed the difficulties in defining the terms of CoP. “Clearly, a strong antibody response to the spike protein is good and an absent antibody response is not good, but, for many patients, the level will fall somewhere in the middle,” he said.

    “Although T-cell mediated immune responses are not typically measured in commercial labs, antibody responses to spike protein do in fact correlate with neutralizing antibodies and clinical protection from severe breakthrough COVID. But, threshold levels are uncertain and test results are not yet standardized across the many assays available.”

    In an effort to evaluate the extent to which antibody titers may predict vaccine efficacy and serve as the basis of a CoP, Earle and colleagues assessed the association between efficacy and in vitro neutralizing and binding antibodies of seven vaccines that have sufficient data available. “Once calibrated to titers of human convalescent sera reported in each study, a robust correlation was seen between neutralizing titer and efficacy (q = 0.79) and binding antibody titer and efficacy (q = 0.93).”

    These findings were observed in a geographically diverse study population, according to Earle and colleagues. They added that this meant that “different forces of infection and circulating variants,” were in play, along with a variety of study endpoints and vaccine products. From all of this they concluded that post-vaccine antibodies could ultimately serve as a basis for correlates of protection for the COVID-19 vaccines.

    What this could potentially mean for rheumatologists is that an equation involving neutralizing titer, antibody titer and efficacy could be a useful tool for assessing whether a vaccine is working in an immunocompromised patient.

    But there is work to be done in this regard, according to Sparks. “Researchers are still trying to understand what antibody level threshold offers sufficient protection against COVID,” he said.

    “One challenge is that we don’t necessarily have a ‘cut-off’ for saying this antibody level is insufficient or this T cell response is sufficient to protect you,” Wallace added. “We still have a lot to learn about how to interpret the results of some these studies.”

    If there is another question raised by the Earle data set, it is the extent to which clinicians of any kind are actively measuring antibody response — many are not. This could be leaving patients open to the risk of breakthrough infections even after they have been vaccinated.

    “It is important to remind everyone that for immunocompromised patients, vaccination is not a protective shield against COVID,” Cassandra Calabrese said.

    Break on Through

    In a paper published in MedRxIv, Cook and colleagues evaluated 16 breakthrough infections from 340 confirmed COVID-19 cases. Results showed that 93% of these infections were symptomatic, with six hospitalizations and two fatalities. One patient required mechanical ventilation. “Symptomatic, including severe, breakthrough infections were observed in systemic autoimmune rheumatic disease (SARD) patients; many were on treatments associated with attenuated antibody responses to vaccination,” they wrote. “Further studies are needed to determine the rate of breakthrough infection associated with SARD treatments and other features.”

    A data set like this raises the question of if or when to withhold these drugs to optimize response.

    Connolly and colleagues examined this problem in a paper published in the Annals of Rheumatic Disease. Specifically, they studied withholding mycophenolate in a cohort of 24 patients who received one of the three available COVID-19 vaccines. Of this group, 13 participants withheld their dose or doses prior to vaccination, while nine withheld both before and after vaccination and two withheld after vaccination only. Results showed that a positive antibody response was more likely in patients who withheld than in those who continued treatment (OR = 5.8; P = .02). This trend persisted through logistic regression analysis (OR = 7.24; P = .01).

    “We know only 15% to 20% of patients on rituximab and ocrelizumab [Ocrevus, Genentech] — drugs that specifically bind to B cells that carry the CD20 antigen — can mount a sufficient antibody response to COVID vaccination,” Laster said. “This is a profound effect.”

    Laster noted that, in addition to the aforementioned medications, methotrexate may be implicated in a reduced antibody response in some, but, reassuringly, biologics that inhibit cytokines such as TNF, IL-6, IL-17, IL-12/23 and IL-23 as well as JAK inhibitors and conventional DMARDS hydroxychloroquine, leflunomide, azathioprine and sulfasalazine are not usually associated with a reduced antibody response. “Emerging data are helping us think about who is truly immunocompromised and who should be eligible for third doses or additional doses of the vaccine,” he said. “Patients on rituximab and mycophenylate appear to be at higher risk for severe breakthrough infections.”

    Regardless of how the virus is being transmitted, it is being transmitted. Given the vulnerability of immunocompromised patients and the slow global rollout and uptake of COVID vaccines eroding herd immunity, there is a pressing need for additional COVID-19 therapeutic options.

    Monoclonal Antibodies

    Corey and colleagues looked at monoclonal antibodies head on in a paper published in the New England Journal of Medicine. “The recent demonstration of the use of combination monoclonal antibodies for preventing SARS-CoV-2 acquisition in nursing homes and home settings suggests that passive antibody prophylaxis may be another approach for immunosuppressed patients who do not have an adequate immune response to vaccination or for patients and their family members with high-risk exposure,” they wrote.

    In particular, the researchers noted that certain monoclonal antibody mutations that extend its effective half-life or boost immune clearance of the virus may provide “an alternative form of COVID-19 prevention for immunocompromised patients who do not have a response to a vaccine.”

    “Monoclonal antibody treatments are effective in preventing hospitalization in patients recently infected with COVID,” Sparks said. “They seem to be particularly important for patients with risk factors for a severe COVID course and rheumatology patients certainly qualify.”

    Wallace stressed that patients with rheumatic diseases, especially those on medications associated with a blunted vaccine response, should be prioritized to receive these antibody treatments either as prophylaxis with high-risk exposure or soon after a positive test. “Additional studies are needed to further evaluate the role of these treatments for patients on B cell depleting treatments who may not be able to mount an appropriate response to the COVID vaccine,” he said.

    As with so many therapies that have been used throughout the pandemic, there are logistical hurdles that need to be overcome prior to use of monoclonal therapies, according to Cassandra Calabrese. “Some declarative and procedural knowledge is necessary, and many rheumatologists do not yet have this information,” she said.

    In short, patients with risk factors for progression are prime candidates for these drugs. “This is all of our patients,” Cassandra said. “But you have to understand that they are authorized to be given within 10 days of symptom onset. The earlier the better.”

    She encouraged clinicians to familiarize themselves with the approval process and workflow so that patients can indeed be administered the drugs earlier. “This process will be different from health system to health system,” she said. “Find out how to do this, how to get access, in your system. It can make a huge difference in a patient’s outcome.”

    There are a similar set of obstacles and solutions for the various antiviral therapies that have been used or are making their way to market.

    Future of COVID-19 Treatment

    Additional commentary from Corey and colleagues suggested that COVID-19 mutations may be more likely in immunocompromised individuals. “These highly mutated variants are indicative of a form of rapid, multistage evolutionary jumps, which could preferentially occur in the milieu of partial immune control,” they wrote. “The presence of a large number of mutations is also a hallmark of the variants of concern — including B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta) — which suggests that viral evolution in immunocompromised patients may be an important factor in the emergence of such variants.”

    In the same paper, Corey and colleagues noted that molnupiravir (Merck) suppressed replication of SARS-CoV-2 in 203 patients with early infection. Further studies are underway. “Stopping the replication of SARS-CoV-2 in a compromised host by means of an effective monoclonal antibody or small molecule offers an opportunity to halt the development of mutations and the spread of SARS-CoV-2 to close contacts,” they wrote. “Strategies to ensure that appropriate selection and monitoring for rapid detection of resistance to these therapies will become a key part of medical and public health management.”

    Leonard Calabrese underscored this point. “At the present time, the greatest single need is outpatient therapy that is oral and lessens the risks for disease progression,” he said. “We have high hopes that antivirals in advanced trials may show some promising data. However, we have not seen that yet. We are not close to that iconic goal.”

    A drug to stop or slow serious infection would “put us well on our way to controlling this pandemic,” Leonard Calabrese added. But he stressed an important point for the current discussion. “They have to work in healthy people before they have a good chance of working in immunocompromised people.”

    Remdesivir (Gilead Sciences) has been used with some efficacy in severe COVID patients and may be a promising option for immunocompromised patients, Sparks added.

    Laster highlighted the recent FDA emergency use authorization for casirivimab and imdevimab (REGEN-COV, Regeneron) and emerging data on oral antivirals such as molnupiravir, as another reason for immunocompromised patients to have some hope. “Having these drugs available is huge,” he said. “Hopefully, it will prevent more serious breakthrough infections in our at-risk patients.”

    Sparks offered a final comment on all of these drugs as they move from clinical trials and into the clinic. “We certainly need more therapies for COVID,” he said. “However, we also need to make sure there is enough supply of these drugs for rheumatology patients that also need these medications to treat these diseases.”


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