Vaccinated yet vulnerable: COVID-19 and the immunocompromised patient
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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 increase.
There are numerous factors to consider. One is whether immunocompromised patients are at an increased risk for SARS-CoV-2 infection, and another is whether they are at risk for severe COVID-19.
Source: Cleveland Clinic
“Similar to risk for 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, a physician in the rheumatology unit at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, told Infectious Disease News. “Patients on certain medications — like B-cell depletion, glucocorticoids, [Janus kinase (JAK)] inhibitors and others — may be at higher risk for worse outcomes.”
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.”
We spoke with experts about these and other clinical challenges surrounding vaccinating immunocompromised people against COVID-19.
“Like with the risks associated with infection itself, vaccine response also depends on the patient’s risk factors,” Cassandra Calabrese, DO, a rheumatologist and infectious diseases physician at the Cleveland Clinic, said in an interview.
Many of the same drugs mentioned by Wallace can also impact vaccine response. Rituximab, in particular, has a long history of disruptive impact on any vaccine response, and the same pattern holds true for COVID-19 shots. What this means is that, given patient factors and poor vaccine response, the threat of breakthrough infection is considerably higher among immunocompromised patients than in the general population.
If vaccines are not working, then effective treatments should be the next priority, although sorting out which drugs are appropriate and at what point in the infection cycle they should be given is an equation with no perfect solution yet, experts said.
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, a community-based rheumatologist in Charlotte, North Carolina, and president of the 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 or additional doses. Like with so many of our patients, everything has to be individualized.”
Tailoring those individual responses starts with understanding the risk for any given patient.
Elevated risk
While logic might dictate that being immunocompromised would lead to a higher risk for 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 rheumatoid arthritis 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 A. Sparks, MD, MMSc, associate physician at Brigham and Women’s Hospital and Harvard Medical School, said the risk “varies by many factors that include type, severity and activity of the underlying condition, immunosuppressive treatment regimen, age and comorbidities, among many others, and noted 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.”
Although 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 it is still not understood why.
A study published in the Annals of Rheumatic Diseases demonstrated 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 a 2020 study in Reumatología Clínica, researchers examined COVID-19 outcomes in immunosuppressed populations, notably transplant recipients and patients with cancer, neurological diseases and primary and secondary immunodeficiencies. The 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 [tumor necrosis factor (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, a professor of medicine at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University and R.J. Fasenmyer Chair of 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.
Although 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 these patients, pre-emptive vaccination against COVID-19 would be the next logical decision. However, vaccination comes with a whole different set of obstacles.
Additional doses
The center of the discussion, at the moment, pertains to supplemental COVID-19 vaccine doses in immunocompromised patients.
In August, the FDA authorized a third dose of COVID-19 messenger RNA vaccine for certain immunocompromised patients. The CDC recommends they receive the dose at least 28 days after their second shot as part of a primary series and now also recommends they get a booster shot 6 months after the third dose.
The FDA authorization of an additional primary dose applies to only the mRNA vaccines made by Pfizer-BioNTech and Moderna. Immunocompromised patients who received a Johnson & Johnson vaccine are not recommended to receive a second shot as part of their primary series but are recommended to get a booster shot of COVID-19 vaccine at least 2 months after their initial dose.
“It is likely that a third dose or booster shot is only going to help, and not hurt,” Cassandra Calabrese 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
Although Sparks highlighted the “good news” that the vast majority of rheumatology patients make antibodies to COVID-19 vaccines, he said further study is required.
“The level of antibodies in rheumatology patients after COVID-19 vaccination seems to be a bit lower than the general population,” he said.
In a paper published in Vaccine, researchers 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.”
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 (rho = 0.79) and binding antibody titer and efficacy (rho = 0.93).”
These findings were observed in a geographically diverse study population, according to Earle and colleagues. This meant that “different forces of infection and circulating variants” were in play, along with a variety of study endpoints and vaccine products, they said. They concluded that post-vaccine antibodies could ultimately serve as a basis for CoP for the COVID-19 vaccines.
What this could potentially mean 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.
However, 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-19,” 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 dataset, experts said, it is the extent to which clinicians of any kind are actively measuring antibody response — many are not. This could leave patients open to 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.
Breakthrough infections
In a paper published on the preprint server medRxiv, researchers evaluated 16 breakthrough infections among 340 confirmed COVID-19 cases in a cohort of patients with systemic autoimmune rheumatic disease (SARD). They found that 93% of the infections were symptomatic, with six hospitalizations and two fatalities. One patient required mechanical ventilation.
“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.”
Researchers examined the question of if or when to withhold these drugs to optimize response in a paper published in the Annals of Rheumatic Disease. Specifically, they studied the withholding of 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 before vaccination, whereas 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 — drugs that specifically bind to B cells that carry the CD20 antigen — can mount a sufficient antibody response to COVID-19 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 patients, but reassuringly, biologics that inhibit cytokines such as TNF, interleukin-6, IL-17, IL-12/23 and IL-23, as well as JAK inhibitors and conventional disease-modifying antirheumatic drugs, such as 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 mycophenolate appear to be at higher risk for severe breakthrough infections.”
Given the vulnerability of immunocompromised patients, there is a pressing need for additional COVID-19 therapeutic options as well, experts said.
Monoclonal antibodies
Researchers assessed monoclonal antibodies 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 their 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 before using 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 treatments
In a commentary published in The New England Journal of Medicine, researchers suggested that SARS-CoV-2 variants can emerge in patients who are immunocompromised.
“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 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. We have high hopes that antivirals in advanced trials may show some promising data. However, we have not seen that yet.”
A drug to stop or slow serious infection would “put us well on our way to controlling this pandemic,” he added, although he stressed an important point: “They have to work in healthy people before they have a good chance of working in immunocompromised people.”
Laster highlighted the FDA emergency use authorization for Regeneron’s antibody cocktail, a combination of casirivimab and imdevimab, and emerging data on oral antivirals like molnupiravir, as another reason for immunocompromised patients to have hope.
“Having that drug available is huge,” he said. “Hopefully, it will prevent more serious breakthrough infections in this population.”
Sparks offered a final comment on all of these drugs as they move from clinical trials into the clinic.
“We certainly need more therapies for COVID-19,” 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.” – by Rob Volansky
- References:
- 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.
- Cook C, et al. medRxiv. 2021;doi:10.1101/2021.08.04.21261618.
- 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.
- For more information:
- Cassandra Calabrese, DO, can be reached at calabrc@ccf.org.
- Leonard H. Calabrese, DO, can be reached at calabrl@ccf.org.
- Andrew J. Laster, MD, can be reached at alaster@aocc.md.
- Jeffrey A. Sparks, MD, MMSc, can be reached at jsparks@bwh.harvard.edu.
- Zachary S. Wallace, MD, MSc, can be reached at zswallace@mgh.harvard.edu.
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