• Of those with CD, 81% of patients report mild to no symptoms from SARS-CoV-2 infection.

  • Patients with CD mount a humoral response to SARS-CoV-2 vaccination.

Abstract

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in increased morbidity and mortality in patients with impaired immunity, hematologic malignancies, and on immunosuppressive regimens. COVID-19 can cause a cytokine storm with some patients benefiting from blockade of the proinflammatory cytokine, interleukin 6 (IL-6). Because Castleman disease (CD) is an atypical lymphoproliferative disorder that can involve a cytokine storm and often requires immunosuppressive therapies, including IL-6 inhibition, we sought to evaluate outcomes after COVID-19 and SARS-CoV-2 vaccination in patients with CD. We administered a survey in April 2021 to characterize experiences with COVID-19 and SARS-CoV-2 vaccination among 300 patients enrolled in ACCELERATE, a CD natural history registry. Among 128 respondents, the prevalence of SARS-CoV-2 infection (16/95, 17%), severe disease (1/16, 6%), vaccination rates (112/128, 88%), and vaccine adverse effects after dose 1 (62/112, 55%) were comparable with that of the general US population. Although there were 2 cases of CD flares occurring shortly after SARS-CoV-2 infection (n = 1) and vaccination (n = 1), >100 patients that were infected and/or vaccinated did not experience CD flares. Among patients with CD, the median antispike titer 6 months after the second vaccine dose was comparable to that of individuals with other immune-related diseases and healthy populations. Despite being on immunosuppressive therapies, patients with CD do not appear to be at increased risk of poor COVID-19 outcomes and can mount a humoral response to SARS-CoV-2 vaccination. This study was registered at www.ClinicalTrials.gov as #NCT02817997.

Castleman disease (CD) is a rare hematologic disorder involving enlarged lymph nodes with characteristic histopathology.1 Approximately 30% to 40% of all CD cases are unicentric (UCD), involving 1 lymph node station, and the remaining have multicentric lymphadenopathy with a systemic inflammatory syndrome (MCD).2 MCD can be driven by human herpesvirus 8 (HHV-8); cooccur with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; or occur for an unknown or idiopathic cause (iMCD).2-4 Treatment of MCD is challenging and is dependent on the MCD subtype. Patients with CD can be immunosuppressed from immunomodulatory therapies, and limited data suggest that there may be underlying immunologic dysfunction attributable to the disease.5-7 

Given that there is an inflammatory syndrome without explicit autoimmune or neoplastic mechanisms, iMCD is best described as a cytokine storm disorder in which immune system hyperactivation causes laboratory abnormalities, constitutional symptoms (fatigue, night sweats, fever, and weight loss), and organ dysfunction.8 Similarly, infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in a heterogeneous presentation, which can progress to a severe cytokine storm disorder in the most severe cases of coronavirus disease 2019 (COVID-19).8-10 Interleukin 6 (IL-6) is a proinflammatory cytokine that has been implicated in the pathogenesis of both iMCD and severe COVID-19.8,11-13 Secreted, soluble IL-6 can signal through a membrane-bound receptor to provoke JAK-STAT signaling, which upregulates a distinct profile of proinflammatory gene expression (supplemental Figure 1).8,14-17 High levels of IL-6 have been associated with a poorer prognosis, respiratory symptoms, and other clinical manifestations in COVID-19.11-13 Now, anti–IL-6 antibodies, which were initially developed and already approved for the treatment of iMCD, have well-demonstrated efficacy against severe COVID-19.17-21 Particularly, the anti–IL-6-receptor monoclonal antibody, tocilizumab, which is used off-label in the treatment of iMCD, has been shown to decrease mortality in severe COVID-19.14,22,23 

Evidence has emerged that patients with impaired immunity, hematologic malignancies, and on immunosuppressive treatments are at increased risk of death from COVID-19 and have an impaired antibody response to vaccination.24-26 Given that patients with CD often receive additional immunosuppressive therapies, such as rituximab,27 and the overlap between both diseases, concerns exist about whether natural SARS-CoV-2 infection or vaccination against SARS-CoV-2 could lead to CD or cause a disease relapse. We used ACCELERATE, an international CD natural history registry, to better understand the impact of SARS-CoV-2 infection and vaccination on patients with CD.

Survey data collection and extraction

The international ACCELERATE natural history registry of CD (ClinicalTrials.gov identifier: NCT02817997) has been described previously.28 In brief, the eligibility criteria to enroll into ACCELERATE requires a pathology report suggestive of CD. Once enrolled, clinical and laboratory data from medical records are extracted. Patients are then evaluated by the ACCELERATE certification and access subcommittee, a panel comprised of experienced CD clinicians and hematopathologists who review and adjudicate each case to determine the likelihood of a CD diagnosis based on extensive clinical and radiologic data, and diagnostic lymph node pathology slides.

In this study, all patients who were enrolled in the registry (N = 300) were invited to participate in a qualitative survey intended to characterize their experience with COVID-19 and SARS-CoV-2 vaccination, with 128 of 300 (43%) responding to the survey (supplemental Material 1). The survey was sent in April 2021. The survey was designed to assess COVID-19 testing history, diagnosis, disease severity, treatments, and vaccine experience, as well as how each related to CD. All data reported from the survey are based on subjective patient experiences and outcomes regarding their experiences with COVID-19 in relation to their CD. We provided additional definitions within the survey such as definitions for disease severity (ie, what we defined as asymptomatic, mild, moderate, and severe) for patients to self-characterize their COVID-19 experience (supplemental Material 1). Pertinent medical data were also extracted from the ACCELERATE database and paired with survey respondent data. Additional demographic breakdown of survey participants and survey respondents in the ACCELERATE registry can be found in supplemental Table 1. Study CONSORT diagram is depicted in Figure 1. All patients provided informed consent and the ACCELERATE natural history registry has received ethical approval from the University of Pennsylvania institutional review board, with most recent approval on 9 March 2023 (Protocol: 824758).

Figure 1.

Study selection CONSORT diagram. CAS, certification and access subcommittee.

Figure 1.

Study selection CONSORT diagram. CAS, certification and access subcommittee.

Close modal

Investigating antibody response to SARS-CoV-2 vaccination using serological assays

In May 2021, the Castleman Disease Collaborative Network sent out targeted social media posts inviting patients with CD on social media forums to participate in an external study by Johns Hopkins University (JHU) aimed at better understanding immunogenic responses to SARS-CoV-2 vaccinations in patients with CD, and 35 patients chose to participate (supplemental Figure 2). Given that ACCELERATE is a Castleman Disease Collaborative Network–sponsored registry, overlap may exist between patients who participated in the JHU study and patients enrolled into ACCELERATE. However, given concerns about sharing protected health information, we could not confirm whether participants in the JHU study were also enrolled in ACCELERATE. The JHU study was designed to assess antibody response to sequential SARS-CoV-2 vaccine doses. For the study, enrolled patients self-reported their CD diagnosis and subtype. Given that low levels of antispike antibodies have been shown to be associated with poor outcomes in individuals who are immunocompromised,29 participants were asked to undergo SARS-CoV-2 antispike antibody testing on the semiquantitative Roche Elecsys anti–SARS-CoV-2 S enzyme immunoassay after each vaccine dose. A value of ≥0.8 U/mL was considered positive, with the upper limit of quantification set at >2500 U/mL.30 Additional demographic and relevant medical data were compiled for further analysis. Immunogenicity and reactogenicity profiles were also analyzed in these patients.

Statistical analyses

Descriptive statistics were performed on survey data compiled and analyzed for all survey respondents. Continuous data are reported as mean (standard deviation) or median (interquartile range [IQR]), as stated. Categorical variables are reported as frequencies and percentages. Additional data visualization was performed using R version 4.2.2 using “tidyverse” packages.

Prevalence of SARS-CoV-2 infection

Of 300 patients who were invited to participate, 128 (43%) responded and completed the survey (additional information on these patients and the 172 patients who did not participate in the survey can be found in Figure 1; supplemental Table 2). Of those tested for SARS-CoV-2 (95/128, 74%), 16 of 95 (17%) patients reported ever having a positive diagnosis from a nasal or saliva sample. Within this cohort, 6 of 16 (38%) patients self-identified as males and 10 of 16 (63%) self-identified as females, with the median age at CD diagnosis of 38.4 years (IQR, 34.8-48.9; Table 1; supplemental Table 3). Six (38%) patients self-reported iMCD, 8 (50%) UCD, 1 (6%) HHV-8–associated MCD, and 1 (6%) CD subtype unknown. Of 6 patients who reported having iMCD, 4 patients had clinical and laboratory markers consistent with a subtype of iMCD, iMCD-NOS (not otherwise specified), which means that the patient does not have TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly) syndrome4,31 or idiopathic plasmacytic lymphadenopathy.32 The available records were insufficient to adjudicate the iMCD subtype for the remaining 2 patients. Of 16 patients reporting a positive COVID-19 diagnosis, 11 (69%) self-reported having received a SARS-CoV-2 vaccination. Of patients vaccinated against SARS-CoV-2, 9 of 11 (82%) patients received the vaccine after COVID-19 diagnosis, whereas 2 of 11 (18%) patients received the vaccine before COVID-19 diagnosis. Given that patients in ACCELERATE needed to have a pathology report suggestive of CD to enroll and that we surveyed patients early in the pandemic, all patients in this cohort reported a SARS-CoV-2 infection after their CD diagnosis, with mean (standard deviation) of 7.7 years (6.9) after their CD diagnosis.

Table 1.

Study cohort selection from ACCELERATE natural history registry of surveyed patients with CD tested for SARS-CoV-2

SARS-CoV-2 positive (N = 16)SARS-CoV-2 negative (N = 79)
Gender n/N (%) n/N (%) 
Male 6/16 (37.5) 33/68 (48.5) 
Female 10/16 (62.5) 35/68 (51.5) 
Not assessed 11 
Age at CD diagnosis Median (IQR; range), y Median (IQR; range), y 
 38.4 (34.8-48.9; 12.8-58.5) 44.8 (33.3-53.1;14.1-76.5) 
Race n/N (%) n/N (%) 
White 16/16 (100.0) 66/79 (83.5) 
Black or African American 0/0 (0.0) 3/79 (3.8) 
Chinese 0/0 (0.0) 3/79 (3.8) 
Asian Indian 0/0 (0.0) 1/79 (1.3) 
Other Asian 0/0 (0.0) 1/79 (1.3) 
American Indian or Alaska Native 0/0 (0.0) 2/79 (2.5) 
Other 0/0 (0.0) 1/79 (1.3) 
Refuse to answer 0/0 (0.0) 2/79 (2.5) 
Ethnicity n/N (%) n/N (%) 
Other   
Non-Hispanic   
Non-Latino 12/16 (75.0) 60/79 (75.9) 
Non-Ashkenazi Jewish   
Hispanic/Latino 2/16 (12.5) 5/79 (6.3) 
Ashkenazi Jewish 0/0 (0.0) 3/79 (3.8) 
Unknown 0/0 (0.0) 3/79 (3.8) 
No answer 2/16 (12.5) 8/79 (10.1) 
Self-reported CD diagnosis n/N (%) n/N (%) 
iMCD 6/16 (37.5) 43/79 (54.4) 
UCD 8/16 (50.0) 15/79 (19.0) 
CD subtype unknown 1/16 (6.3) 12/79 (15.2) 
HHV-8–associated MCD 1/16 (6.3) 4/79 (5.1) 
HHV-8–unknown MCD 0/16 (0.0) 5/79 (6.3) 
SARS-CoV-2 vaccination status n/N (%) n/N (%) 
Yes, received 11/16 (68.8) 72/79 (91.1) 
No, not received 5/16 (31.3) 7/79 (8.9) 
Breakdown for SARS-CoV-2 testing by CD subtype n/N (%) n/N (%) 
iMCD 6/49 (12.2) 43/49 (87.8) 
UCD 8/23 (34.8) 15/23 (65.2) 
CD subtype unknown 1/13 (7.7) 12/13 (92.3) 
HHV-8–associated MCD 1/5 (20.0) 4/5 (80.0) 
HHV-8–unknown MCD 0/5 (0.0) 5/5 (100.0) 
SARS-CoV-2 vaccine temporality with COVID-19 diagnosis (n = 11) n/N (%)  
SARS-CoV-2 vaccine before COVID-19 diagnosis 2/11 (18.2)  
SARS-CoV-2 vaccine after COVID-19 diagnosis 9/11 (81.8)  
Time between COVID-19 onset and vaccine administration (n = 9) Mean (SD; range), d  
 125.4 (81.0; 33-238)  
Time between vaccine administration and COVID-19 onset (n = 2) Mean (SD; range), d  
 130.5 (167.6; 12-249)  
Time between CD diagnosis and self-reported COVID-19 onset (n = 16) Mean (SD; range), y  
 7.7 (6.9; 0.9-25.8)  
CD treatments at time of COVID-19 diagnosis, by subtype n/N (%)  
iMCD   
Corticosteroid monotherapy 1/6 (16.7)  
Siltuximab 2/6 (33.3)  
IVIGs + other (unspecified) 1/6 (16.7)  
UCD   
Corticosteroids + IVIGs 1/8 (12.5)  
Other (unspecified) 1/8 (12.5)  
Not on medications for CD   
iMCD 2/6 (33.3)  
UCD 6/8 (75.0)  
CD subtype unknown 1/1 (100.0)  
HHV-8–associated MCD 1/1 (100.0)  
CD treatments stopped because of COVID-19 diagnosis n/N (%)  
Yes 3/15 (20.0)  
No 11/15 (73.3)  
Unsure 1/15 (6.7)  
Not assessed  
CD treatments stopped because of COVID-19 diagnosis, by subtype n/N (%)  
iMCD   
Siltuximab 2/3 (66.7)  
UCD   
IVIGs 1/3 (33.3)  
CD treatments changed because of COVID-19 diagnosis n/N (%)  
Yes 1/15 (6.7)  
No 13/15 (86.7)  
Unsure 1/15 (6.7)  
Not assessed  
CD treatments changed because of COVID-19 diagnosis, by subtype n/N (%)  
UCD   
Corticosteroid monotherapy 1/1 (100.0)  
SARS-CoV-2 positive (N = 16)SARS-CoV-2 negative (N = 79)
Gender n/N (%) n/N (%) 
Male 6/16 (37.5) 33/68 (48.5) 
Female 10/16 (62.5) 35/68 (51.5) 
Not assessed 11 
Age at CD diagnosis Median (IQR; range), y Median (IQR; range), y 
 38.4 (34.8-48.9; 12.8-58.5) 44.8 (33.3-53.1;14.1-76.5) 
Race n/N (%) n/N (%) 
White 16/16 (100.0) 66/79 (83.5) 
Black or African American 0/0 (0.0) 3/79 (3.8) 
Chinese 0/0 (0.0) 3/79 (3.8) 
Asian Indian 0/0 (0.0) 1/79 (1.3) 
Other Asian 0/0 (0.0) 1/79 (1.3) 
American Indian or Alaska Native 0/0 (0.0) 2/79 (2.5) 
Other 0/0 (0.0) 1/79 (1.3) 
Refuse to answer 0/0 (0.0) 2/79 (2.5) 
Ethnicity n/N (%) n/N (%) 
Other   
Non-Hispanic   
Non-Latino 12/16 (75.0) 60/79 (75.9) 
Non-Ashkenazi Jewish   
Hispanic/Latino 2/16 (12.5) 5/79 (6.3) 
Ashkenazi Jewish 0/0 (0.0) 3/79 (3.8) 
Unknown 0/0 (0.0) 3/79 (3.8) 
No answer 2/16 (12.5) 8/79 (10.1) 
Self-reported CD diagnosis n/N (%) n/N (%) 
iMCD 6/16 (37.5) 43/79 (54.4) 
UCD 8/16 (50.0) 15/79 (19.0) 
CD subtype unknown 1/16 (6.3) 12/79 (15.2) 
HHV-8–associated MCD 1/16 (6.3) 4/79 (5.1) 
HHV-8–unknown MCD 0/16 (0.0) 5/79 (6.3) 
SARS-CoV-2 vaccination status n/N (%) n/N (%) 
Yes, received 11/16 (68.8) 72/79 (91.1) 
No, not received 5/16 (31.3) 7/79 (8.9) 
Breakdown for SARS-CoV-2 testing by CD subtype n/N (%) n/N (%) 
iMCD 6/49 (12.2) 43/49 (87.8) 
UCD 8/23 (34.8) 15/23 (65.2) 
CD subtype unknown 1/13 (7.7) 12/13 (92.3) 
HHV-8–associated MCD 1/5 (20.0) 4/5 (80.0) 
HHV-8–unknown MCD 0/5 (0.0) 5/5 (100.0) 
SARS-CoV-2 vaccine temporality with COVID-19 diagnosis (n = 11) n/N (%)  
SARS-CoV-2 vaccine before COVID-19 diagnosis 2/11 (18.2)  
SARS-CoV-2 vaccine after COVID-19 diagnosis 9/11 (81.8)  
Time between COVID-19 onset and vaccine administration (n = 9) Mean (SD; range), d  
 125.4 (81.0; 33-238)  
Time between vaccine administration and COVID-19 onset (n = 2) Mean (SD; range), d  
 130.5 (167.6; 12-249)  
Time between CD diagnosis and self-reported COVID-19 onset (n = 16) Mean (SD; range), y  
 7.7 (6.9; 0.9-25.8)  
CD treatments at time of COVID-19 diagnosis, by subtype n/N (%)  
iMCD   
Corticosteroid monotherapy 1/6 (16.7)  
Siltuximab 2/6 (33.3)  
IVIGs + other (unspecified) 1/6 (16.7)  
UCD   
Corticosteroids + IVIGs 1/8 (12.5)  
Other (unspecified) 1/8 (12.5)  
Not on medications for CD   
iMCD 2/6 (33.3)  
UCD 6/8 (75.0)  
CD subtype unknown 1/1 (100.0)  
HHV-8–associated MCD 1/1 (100.0)  
CD treatments stopped because of COVID-19 diagnosis n/N (%)  
Yes 3/15 (20.0)  
No 11/15 (73.3)  
Unsure 1/15 (6.7)  
Not assessed  
CD treatments stopped because of COVID-19 diagnosis, by subtype n/N (%)  
iMCD   
Siltuximab 2/3 (66.7)  
UCD   
IVIGs 1/3 (33.3)  
CD treatments changed because of COVID-19 diagnosis n/N (%)  
Yes 1/15 (6.7)  
No 13/15 (86.7)  
Unsure 1/15 (6.7)  
Not assessed  
CD treatments changed because of COVID-19 diagnosis, by subtype n/N (%)  
UCD   
Corticosteroid monotherapy 1/1 (100.0)  

Data are presented for 95 patients.

SD, standard deviation.

Next, we hypothesized that clinicians might change their CD treatment after SARS-CoV-2 diagnosis to reduce or eliminate immunosuppressive therapies. Of 6 patients with iMCD who reported a positive SARS-CoV-2 test, 1 (17%) patient was receiving corticosteroids, 2 (33%) patients were receiving siltuximab, 1 (17%) patient was receiving intravenous immunoglobulins (IVIGs) and another unspecified treatment, and 2 (33%) patients were not on any CD treatments at the time of their COVID-19 diagnosis. Of 8 patients with UCD, 1 (13%) patient was receiving corticosteroids and IVIGs, 1 (13%) patient was receiving an unspecified medication, and the rest were not on any CD treatments. CD treatments were altered in a subset of patients after COVID-19 diagnosis. Siltuximab was stopped in 2 patients with iMCD whereas IVIG was stopped in 1 patient with UCD. Additionally, 1 patient with UCD reported a change in dosage of corticosteroids and reported that they did not return to the normal dosage of this medication after COVID-19 diagnosis. No patients reported the addition of any new CD treatments during their COVID-19 course.

Clinical symptoms and severity of COVID-19 in patients with CD

We hypothesized that patients with MCD would be more likely to experience a severe course of COVID-19 disease. Of 16 patients with CD with SARS-CoV-2 infection, 2 (13%) patients reported being asymptomatic, 11 (69%) patients reported a mild disease, 2 (13%) patients reported a moderate disease, and 1 (6%) reported severe disease that lasted >2 weeks (Table 2). Breakdown of COVID-19 disease severity according to CD subtype can be further visualized in supplemental Figure 3. Additional medical history of the 3 patients who experienced moderate or severe COVID-19 disease can be found in supplemental Table 4.

Table 2.

Disease severity and treatment after SARS-CoV-2 infection among study cohort

Disease severity (all CD subtypes) n/N (%) 
Asymptomatic 2/16 (12.5) 
Mild 11/16 (68.8) 
Moderate 2/16 (12.5) 
Severe 1/16 (6.3) 
Breakdown of disease severity by CD subtype  
CD subtype unknown n/N (%) 
Asymptomatic 0/1 (0.0) 
Mild 1/1 (100.0) 
Moderate 0/1 (0.0) 
Severe 0/1 (0.0) 
HHV-8–associated MCD n/N (%) 
Asymptomatic 0/1 (0.0) 
Mild 1/1 (100.0) 
Moderate 0/1 (0.0) 
Severe 0/1 (0.0) 
iMCD n/N (%) 
Asymptomatic 0/6 (0.0) 
Mild 4/6 (66.7) 
Moderate 2/6 (33.3) 
Severe 0/6 (0.0) 
UCD n/N (%) 
Asymptomatic 2/8 (25.0) 
Mild 5/8 (62.5) 
Moderate 0/8 (0.0) 
Severe 1/8 (12.5) 
Severe disease duration n/N (%) 
1-3 d 0/1 (0.0) 
3-7 d 0/1 (0.0) 
1-2 wk 0/1 (0.0) 
>2 wk 1/1 (100.0) 
Not assessed 15 
Number of hospitalized patients who report being prescribed medications to treat moderate and severe COVID-19 n/N (%) 
Yes 2/3 (66.7) 
No 1/3 (33.3) 
Medications received to treat moderate and severe COVID-19 n/N (%) 
Antibiotic (unspecified) 1/2 (50.0) 
Other, dexamethasone; bamlanivimab; tocilizumab; linezolid/meropenem/micafungin 1/2 (50.0) 
Number of patients who report taking over-the-counter medications to treat SARS-CoV-2 infection n/N (%) 
Yes 8/16 (50.0) 
No 7/16 (43.7) 
Unsure 1/16 (6.3) 
Over-the-counter medications received to treat SARS-CoV-2 infection n/N (%) 
Acetaminophen 2/8 (25.0) 
Acetaminophen + ibuprofen 3/8 (37.5) 
Acetaminophen + vitamin supplement 1/8 (12.5) 
Acetaminophen + ibuprofen + vitamin supplement 1/8 (12.5) 
Nonsteroidal anti-inflammatory drug (not listed) + vitamin supplement 1/8 (12.5) 
Recovery from SARS-CoV-2 infection (n = 16) n/N (%) 
Recovered 12/16 (75.0) 
Not recovered 3/16 (18.8) 
Unsure 1/16 (6.3) 
Duration of COVID-19 among recovered patients (n = 12) Median (IQR; range), d 
 11.5 (8.5, 19.5; 5-48) 
Relapse of CD after SARS-CoV-2 infection, per patient self-report n/N (%) 
Relapse 2/16 (12.5) 
No relapse 13/16 (81.3) 
Unsure 1/16 (6.3) 
Disease severity (all CD subtypes) n/N (%) 
Asymptomatic 2/16 (12.5) 
Mild 11/16 (68.8) 
Moderate 2/16 (12.5) 
Severe 1/16 (6.3) 
Breakdown of disease severity by CD subtype  
CD subtype unknown n/N (%) 
Asymptomatic 0/1 (0.0) 
Mild 1/1 (100.0) 
Moderate 0/1 (0.0) 
Severe 0/1 (0.0) 
HHV-8–associated MCD n/N (%) 
Asymptomatic 0/1 (0.0) 
Mild 1/1 (100.0) 
Moderate 0/1 (0.0) 
Severe 0/1 (0.0) 
iMCD n/N (%) 
Asymptomatic 0/6 (0.0) 
Mild 4/6 (66.7) 
Moderate 2/6 (33.3) 
Severe 0/6 (0.0) 
UCD n/N (%) 
Asymptomatic 2/8 (25.0) 
Mild 5/8 (62.5) 
Moderate 0/8 (0.0) 
Severe 1/8 (12.5) 
Severe disease duration n/N (%) 
1-3 d 0/1 (0.0) 
3-7 d 0/1 (0.0) 
1-2 wk 0/1 (0.0) 
>2 wk 1/1 (100.0) 
Not assessed 15 
Number of hospitalized patients who report being prescribed medications to treat moderate and severe COVID-19 n/N (%) 
Yes 2/3 (66.7) 
No 1/3 (33.3) 
Medications received to treat moderate and severe COVID-19 n/N (%) 
Antibiotic (unspecified) 1/2 (50.0) 
Other, dexamethasone; bamlanivimab; tocilizumab; linezolid/meropenem/micafungin 1/2 (50.0) 
Number of patients who report taking over-the-counter medications to treat SARS-CoV-2 infection n/N (%) 
Yes 8/16 (50.0) 
No 7/16 (43.7) 
Unsure 1/16 (6.3) 
Over-the-counter medications received to treat SARS-CoV-2 infection n/N (%) 
Acetaminophen 2/8 (25.0) 
Acetaminophen + ibuprofen 3/8 (37.5) 
Acetaminophen + vitamin supplement 1/8 (12.5) 
Acetaminophen + ibuprofen + vitamin supplement 1/8 (12.5) 
Nonsteroidal anti-inflammatory drug (not listed) + vitamin supplement 1/8 (12.5) 
Recovery from SARS-CoV-2 infection (n = 16) n/N (%) 
Recovered 12/16 (75.0) 
Not recovered 3/16 (18.8) 
Unsure 1/16 (6.3) 
Duration of COVID-19 among recovered patients (n = 12) Median (IQR; range), d 
 11.5 (8.5, 19.5; 5-48) 
Relapse of CD after SARS-CoV-2 infection, per patient self-report n/N (%) 
Relapse 2/16 (12.5) 
No relapse 13/16 (81.3) 
Unsure 1/16 (6.3) 

Data are presented for 16 patients.

Commonly reported symptoms among symptomatic patients (n = 14) included fatigue (12, 86%), fever (12, 86%), and anosmia (11, 79%; supplemental Table 5). The most common respiratory symptoms were cough (9 patients, 64%), shortness of breath (8 patients, 57%), and congestion/runny nose (7 patients, 50%). Four (29%) patients reported persistent pain or pressure in the chest. Nausea/vomiting and diarrhea were reported in 7 (50%) and 6 (43%) patients, respectively. The most common neurologic symptom was headache, which occurred in 11 (79%) patients. Lastly, 10 (71%) patients reported muscle or body aches. Breakdown of symptoms experienced by CD subtype is shown in supplemental Table 5 and supplemental Figure 4, respectively.

The median duration of COVID-19 disease reported among patients was 11.5 days (IQR, 8.5-19.5). Of 3 patients who reported moderate or severe COVID-19 resulting in hospitalization, 1 patient reported being prescribed an antibiotic (unspecified), 1 patient reported being treated with other medications (dexamethasone, bamlanivimab, tocilizumab, and linezolid/meropenem/micafungin), and 1 reported no treatment. Of 16 patients with SARS-CoV-2 infection, 8 (50%) reported taking over-the-counter medications to treat their COVID-19 symptoms; 2 (25%) reported acetaminophen; 3 (38%) reported acetaminophen and ibuprofen; 1 (13%) acetaminophen and vitamin supplement; 1 (13%) acetaminophen, ibuprofen, and vitamin supplement; and 1 (13%) a nonsteroidal anti-inflammatory medication (unspecified) and vitamin supplement.

Next, we wanted to evaluate the theoretical concern that COVID could trigger a CD flare or long COVID-19 in patients with CD. Two (13%) patients self-reported a relapse of their CD symptoms after their COVID-19 diagnosis. To further investigate these reports of CD relapse after COVID-19 infection, we interrogated medical records of these patients. Based on medical records review of clinician comments about COVID-19 diagnosis, physicians for 1 patient reported constitutional symptoms, respiratory symptoms, and “occasional flares of MCD” after COVID-19 documented in their records. For the other patient, we could not find sufficient evidence from medical records or from clinician notes confirming a relapse of CD symptomatology.

We also identified 1 patient in ACCELERATE (who did not overlap with our survey cohort) who had a CD flare after COVID-19, which was confirmed by the patient’s treating physician (A.N.). The patient was a 47-year-old man who had been diagnosed with iMCD–TAFRO syndrome ∼3.5 years before his COVID-19 diagnosis. He had been in complete clinical remission from CD since starting siltuximab, with partial resolution of lymphadenopathy around 1 year after CD diagnosis. The patient was twice vaccinated and boosted against SARS-CoV-2 (Pfizer/BioNTech 162b2) before COVID-19 diagnosis. He experienced constitutional symptoms and respiratory symptoms with COVID-19. Although on siltuximab maintenance since CD diagnosis, he complained of ongoing malaise after COVID-19. Fifty-one days after the COVID-19 diagnosis, he had evidence of iMCD progression with worsening fluid retention, low-grade fevers despite antibiotics, elevated C-reactive protein, and lymphadenopathy, resulting in hospitalization. A core lymph node biopsy showed fragments of reactive lymphoid tissue with focal polytypic plasmacytosis, suspicious for CD. See Figure 2 for a timeline of the patient’s disease course, COVID-19 diagnosis, regimens received, as well as clinical and laboratory abnormalities before and after COVID-19 diagnosis. Siltuximab was discontinued and the patient clinically improved on a thalidomide, cyclophosphamide, and prednisone regimen. In subsequent months, thalidomide was discontinued because of drug intolerance, and lenalidomide was added to the existing cyclophosphamide and prednisone regimen (as per available medical records). The patient has continued this regimen without flare for 16 months.

Figure 2.

Possible temporal association observed between COVID-19 diagnosis and CD progression. (A) Timeline of events from natural history of CD, COVID-19 diagnosis, and subsequent CD flare. Upon initial presentation of CD symptoms, the patient was on corticosteroids and underwent an excisional biopsy diagnostic of CD (regimen 1). For the next regimen, corticosteroids were tapered, and the patient received siltuximab (regimen 2). As a result of the CD flare and subsequent hospitalization, siltuximab was discontinued and the patient went on to receive cyclophosphamide, thalidomide, lenalidomide, and corticosteroids. Figure created using BioRender.com. (B) Any CD-specific symptoms assessed and positive up to 1 year before and after COVID-19 diagnosis. (C) CD-specific laboratory markers measured up to 1 year before and after COVID-19 diagnosis. Time (t) = 0 days is denoted by the vertical dotted line and represents the date of COVID-19 diagnosis. Data points preceding t = 0 highlights laboratory markers before COVID-19 diagnosis (gray shaded region) whereas data points after t = 0 highlights laboratory markers after COVID-19 diagnosis (blue shaded region). For comparison, at TAFRO syndrome diagnosis, creatinine peaked at 3.4 mg/dL and C-reactive protein (CRP) at 8 mg/dL, both normalized with siltuximab. CS, corticosteroids; eGFR, estimated glomerular filtration rate; LN, lymph node.

Figure 2.

Possible temporal association observed between COVID-19 diagnosis and CD progression. (A) Timeline of events from natural history of CD, COVID-19 diagnosis, and subsequent CD flare. Upon initial presentation of CD symptoms, the patient was on corticosteroids and underwent an excisional biopsy diagnostic of CD (regimen 1). For the next regimen, corticosteroids were tapered, and the patient received siltuximab (regimen 2). As a result of the CD flare and subsequent hospitalization, siltuximab was discontinued and the patient went on to receive cyclophosphamide, thalidomide, lenalidomide, and corticosteroids. Figure created using BioRender.com. (B) Any CD-specific symptoms assessed and positive up to 1 year before and after COVID-19 diagnosis. (C) CD-specific laboratory markers measured up to 1 year before and after COVID-19 diagnosis. Time (t) = 0 days is denoted by the vertical dotted line and represents the date of COVID-19 diagnosis. Data points preceding t = 0 highlights laboratory markers before COVID-19 diagnosis (gray shaded region) whereas data points after t = 0 highlights laboratory markers after COVID-19 diagnosis (blue shaded region). For comparison, at TAFRO syndrome diagnosis, creatinine peaked at 3.4 mg/dL and C-reactive protein (CRP) at 8 mg/dL, both normalized with siltuximab. CS, corticosteroids; eGFR, estimated glomerular filtration rate; LN, lymph node.

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Safety and tolerability of SARS-CoV-2 vaccination among patients with CD

Next, we investigated the safety and tolerability of the SARS-CoV-2 vaccines among patients with CD. Among 128 survey respondents, 112 (88%) reported having received at least 1 dose of the COVID-19 vaccine at the time of survey completion whereas 16 (12%) did not receive the vaccine (Table 3). Among 112 patients who reported SARS-CoV-2 vaccination, 73 (65%) received the monovalent Pfizer/BioNTech 162b2 vaccine, 35 (31%) the Moderna mRNA-1273 vaccine, 2 (2%) the Oxford/AstraZeneca ChAdOx-1 vaccine, and 2 (2%) the Johnson & Johnson Ad26.COV2 vaccine. Among patients who had not received any vaccine dose at the time of the survey (n = 16), 2 (13%) reported that they intend to receive the vaccine, 8 (50%) reported they did not intend to receive the vaccine, and 6 (38%) reported being unsure of their vaccine decision. Primary concerns among vaccine-hesitant nonrecipients (n = 15) included a potential interaction between the vaccine and CD (10, 67%) and the limited data on the safety and effectiveness of the vaccine (9, 60%; supplemental Table 6).

Table 3.

SARS-CoV-2 vaccine experience by all survey respondents

SARS-CoV-2 vaccine status n/N (%) 
Vaccinated 112/128 (87.5) 
Not vaccinated 16/128 (12.5) 
Number of doses of vaccine received n/N (%) 
23/112 (20.5) 
89/112 (79.5) 
Vaccine manufacturer n/N (%) 
Pfizer/BioNTech (162b2) 73/112 (65.2) 
Moderna (mRNA-1273) 35/112 (31.3) 
Oxford/AstraZeneca (ChAdOx1) 2/112 (1.8) 
Johnson & Johnson (Ad26.COV2) 2/112 (1.8) 
Relapse of CD after SARS-CoV-2 vaccine, per patient self-report n/N (%) 
Relapse 10/112 (8.9) 
No relapse 88/112 (78.6) 
Unsure 14/112 (12.5) 
Plans for future vaccine n/N (%) 
Yes 2/16 (12.5) 
No 8/16 (50.0) 
Unsure 6/16 (37.5) 
Side effects, dose 1 n/N (%) 
Yes 62/112 (55.4) 
No 49/112 (43.8) 
Unsure 1/112 (0.9) 
Dose 1, side effects experienced n/N (%) 
Arm pain 52/62 (83.9) 
Arm swelling 7/62 (11.3) 
Fever 7/62 (11.3) 
Chills 11/62 (17.7) 
Tiredness 41/62 (66.1) 
Headache 32/62 (51.6) 
Anaphylaxis 0/62 (0.0) 
Other, myalgias 3/62 (4.8) 
Other, nausea/vomiting/diarrhea 2/62 (3.2) 
Other, hives/rash 2/62 (3.2) 
Other, dizziness/lightheadedness 1/62 (1.6) 
Other, sweating 1/62 (1.6) 
Other, influenza-like symptoms 1/62 (1.6) 
Duration of side effects, dose 1 n/N (%) 
1-3 d 52/62 (83.9) 
3-7 d 9/62 (14.5) 
>1 wk 1/62 (1.6) 
Hospitalization, dose 1 n/N (%) 
Hospitalized 1/62 (1.6) 
Not hospitalized 61/62 (98.4) 
Hospitalization duration, dose 1 n/N (%) 
1-3 d 0/1 (0.0) 
3-7 d 0/1 (0.0) 
>1 wk 1/1 (100.0) 
Side effects, dose 2 n/N (%) 
Yes 59/89 (66.3) 
No 29/89 (32.6) 
Unsure 1/89 (1.1) 
Dose 2, side effects experienced n/N (%) 
Arm pain 45/59 (76.3) 
Arm swelling 9/59 (15.3) 
Fever 18/59 (30.5) 
Chills 21/59 (35.6) 
Tiredness 42/59 (71.2) 
Headache 37/59 (62.7) 
Anaphylaxis 0/59 (0.0) 
Other, myalgias 6/59 (10.2) 
Other, nausea/vomiting/diarrhea/abdominal pain 4/59 (6.8) 
Other, hives/rash 5/59 (8.5) 
Other, sweating 1/59 (1.7) 
Other, influenza-like symptoms 1/59 (1.7) 
Other, joint pain 1/59 (1.7) 
Other, axillary lymphadenopathy 2/59 (3.4) 
Duration of side effects, dose 2 n/N (%) 
1-3 d 45/59 (76.3) 
3-7 d 11/59 (18.6) 
>1 wk 3/59 (5.1) 
Hospitalization, dose 2 n/N (%) 
Hospitalized 0/59 (0.0) 
Not hospitalized 59/59 (100.0) 
Hospitalization duration, dose 2 n/N (%) 
1-3 d 0/0 (0.0) 
3-7 d 0/0 (0.0) 
>1 wk 0/0 (0.0) 
SARS-CoV-2 vaccine status n/N (%) 
Vaccinated 112/128 (87.5) 
Not vaccinated 16/128 (12.5) 
Number of doses of vaccine received n/N (%) 
23/112 (20.5) 
89/112 (79.5) 
Vaccine manufacturer n/N (%) 
Pfizer/BioNTech (162b2) 73/112 (65.2) 
Moderna (mRNA-1273) 35/112 (31.3) 
Oxford/AstraZeneca (ChAdOx1) 2/112 (1.8) 
Johnson & Johnson (Ad26.COV2) 2/112 (1.8) 
Relapse of CD after SARS-CoV-2 vaccine, per patient self-report n/N (%) 
Relapse 10/112 (8.9) 
No relapse 88/112 (78.6) 
Unsure 14/112 (12.5) 
Plans for future vaccine n/N (%) 
Yes 2/16 (12.5) 
No 8/16 (50.0) 
Unsure 6/16 (37.5) 
Side effects, dose 1 n/N (%) 
Yes 62/112 (55.4) 
No 49/112 (43.8) 
Unsure 1/112 (0.9) 
Dose 1, side effects experienced n/N (%) 
Arm pain 52/62 (83.9) 
Arm swelling 7/62 (11.3) 
Fever 7/62 (11.3) 
Chills 11/62 (17.7) 
Tiredness 41/62 (66.1) 
Headache 32/62 (51.6) 
Anaphylaxis 0/62 (0.0) 
Other, myalgias 3/62 (4.8) 
Other, nausea/vomiting/diarrhea 2/62 (3.2) 
Other, hives/rash 2/62 (3.2) 
Other, dizziness/lightheadedness 1/62 (1.6) 
Other, sweating 1/62 (1.6) 
Other, influenza-like symptoms 1/62 (1.6) 
Duration of side effects, dose 1 n/N (%) 
1-3 d 52/62 (83.9) 
3-7 d 9/62 (14.5) 
>1 wk 1/62 (1.6) 
Hospitalization, dose 1 n/N (%) 
Hospitalized 1/62 (1.6) 
Not hospitalized 61/62 (98.4) 
Hospitalization duration, dose 1 n/N (%) 
1-3 d 0/1 (0.0) 
3-7 d 0/1 (0.0) 
>1 wk 1/1 (100.0) 
Side effects, dose 2 n/N (%) 
Yes 59/89 (66.3) 
No 29/89 (32.6) 
Unsure 1/89 (1.1) 
Dose 2, side effects experienced n/N (%) 
Arm pain 45/59 (76.3) 
Arm swelling 9/59 (15.3) 
Fever 18/59 (30.5) 
Chills 21/59 (35.6) 
Tiredness 42/59 (71.2) 
Headache 37/59 (62.7) 
Anaphylaxis 0/59 (0.0) 
Other, myalgias 6/59 (10.2) 
Other, nausea/vomiting/diarrhea/abdominal pain 4/59 (6.8) 
Other, hives/rash 5/59 (8.5) 
Other, sweating 1/59 (1.7) 
Other, influenza-like symptoms 1/59 (1.7) 
Other, joint pain 1/59 (1.7) 
Other, axillary lymphadenopathy 2/59 (3.4) 
Duration of side effects, dose 2 n/N (%) 
1-3 d 45/59 (76.3) 
3-7 d 11/59 (18.6) 
>1 wk 3/59 (5.1) 
Hospitalization, dose 2 n/N (%) 
Hospitalized 0/59 (0.0) 
Not hospitalized 59/59 (100.0) 
Hospitalization duration, dose 2 n/N (%) 
1-3 d 0/0 (0.0) 
3-7 d 0/0 (0.0) 
>1 wk 0/0 (0.0) 

Data are presented for 128 patients.

Of 112 vaccine recipients, 62 (55%) patients reported experiencing side effects after the first dose. The most common side effects reported after patients’ first dose were arm pain (52, 84%), tiredness (41, 66%), and headache (32, 52%). Fifty-two (84%) patients reported that their side effects after the first dose lasted for 1 to 3 days, and 9 (15%) patients reported that their side effects lasted for 3 to 7 days. Side effects reported after the second dose were similar to the first dose (see Table 3 for additional information on vaccine-attributed adverse effects).

Next, we wanted to evaluate the theoretical concern that SARS-CoV-2 vaccination could trigger a CD flare. Among 112 vaccine recipients, 10 (9%) patients subjectively reported that they felt they had a relapse of CD symptoms after vaccination. We further investigated medical records of these 10 patients to identify and categorize the symptoms present before and after vaccination. Based on medical records review, we found documentation by clinicians noting worsening of CD symptoms, days after vaccination in 1 (10%) patient self-reporting a CD flare. In 8 (80%) patients, we did not find evidence or documentation supporting a relapse of CD symptoms from medical records or noted by clinicians. For 1 (10%) patient, we did not have sufficient data to be able to assess whether the patient appeared to have a CD flare after vaccination.

Follow-up of a single report of worsening CD in a SARS-CoV-2 vaccine recipient

To further characterize the report of a CD relapse after vaccination, we investigated the patient’s medical records. The 32-year-old man had been diagnosed with iMCD–TAFRO syndrome and had initial improvement in clinical and laboratory markers on tocilizumab and siltuximab. Ten days after siltuximab initiation, he received the Pfizer/BioNTech 162b2 SARS-CoV-2 vaccine. Three days after SARS-CoV-2 vaccine administration, the patient developed a low-grade fever, chills, diarrhea, and fatigue. Shortly afterward, clinicians noted worsening ascites and thrombocytopenia. As seen in the patient’s timeline (Figure 3A), the time course is consistent with a relapse of CD and appears to be temporally associated with the SARS-CoV-2 vaccine administration, although causality is unknown in this single patient (Figure 3B-C).

Figure 3.

Possible temporal association observed between SARS-CoV-2 vaccination and CD progression. (A) Timeline of events from start of CD symptoms, administration of SARS-CoV-2 vaccination (first dose), and subsequent hospitalization from CD progression. Upon initial presentation of CD symptoms, the patient was on corticosteroids (regimen 1) and had 2 excisional biopsies of the enlarged LN with the latter biopsy being diagnostic of CD. The patient continued to receive corticosteroids and was also placed on tocilizumab (regimen 2). The patient was then switched to siltuximab and dexamethasone (regimen 3) for the next regimen preceding the SARS-CoV-2 vaccine. Figure created using BioRender.com. (B) Any CD-specific symptoms identified before and after SARS-CoV-2 vaccination. (C) CD-specific laboratory markers measured before and after SARS-CoV-2 vaccine. Time (t) = 0 days is denoted by the vertical dotted line and represents the date of the first SARS-CoV-2 vaccine. Data points preceding t = 0 highlights laboratory markers measured before SARS-CoV-2 vaccine (gray shaded region) whereas data points after t = 0 highlights laboratory markers measured after SARS-CoV-2 vaccine (blue shaded region). CS, corticosteroids; eGFR, estimated glomerular filtration rate; LN, lymph node.

Figure 3.

Possible temporal association observed between SARS-CoV-2 vaccination and CD progression. (A) Timeline of events from start of CD symptoms, administration of SARS-CoV-2 vaccination (first dose), and subsequent hospitalization from CD progression. Upon initial presentation of CD symptoms, the patient was on corticosteroids (regimen 1) and had 2 excisional biopsies of the enlarged LN with the latter biopsy being diagnostic of CD. The patient continued to receive corticosteroids and was also placed on tocilizumab (regimen 2). The patient was then switched to siltuximab and dexamethasone (regimen 3) for the next regimen preceding the SARS-CoV-2 vaccine. Figure created using BioRender.com. (B) Any CD-specific symptoms identified before and after SARS-CoV-2 vaccination. (C) CD-specific laboratory markers measured before and after SARS-CoV-2 vaccine. Time (t) = 0 days is denoted by the vertical dotted line and represents the date of the first SARS-CoV-2 vaccine. Data points preceding t = 0 highlights laboratory markers measured before SARS-CoV-2 vaccine (gray shaded region) whereas data points after t = 0 highlights laboratory markers measured after SARS-CoV-2 vaccine (blue shaded region). CS, corticosteroids; eGFR, estimated glomerular filtration rate; LN, lymph node.

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Incipient CD in patients with recent diagnosis of COVID-19

Considering that both COVID-19 and CD can cause cytokine storms, we investigated the temporal association between COVID-19 and CD diagnoses. Considering that the current cohort of 128 patients with CD was surveyed early in the pandemic and are unlikely to have developed COVID-19 before their CD diagnosis, we used medical records from the ACCELERATE registry to find additional patients with a documented COVID-19 comorbidity, and identified 15 patients (supplemental Tables 3 and 7). Of 15 patients identified within ACCELERATE, only 1 patient overlapped with the 16 patients in the survey cohort self-reporting a COVID-19 diagnosis. We identified 9 of 15 (60%) patients with a CD diagnosis preceding their COVID-19 diagnosis and 6 of 15 (40%) patients with a CD diagnosis after their COVID-19 diagnosis (supplemental Table 7). From 6 patients, the median time between COVID-19 onset and CD diagnosis was 148.5 days (IQR, 27.8-262.5; range, 16-382). Notably, we found 1 patient with a COVID-19 diagnosis that preceded their CD diagnosis by 16 days. We further interrogated the medical records of this patient to piece together a timeline between COVID-19 and CD. The patient was a 14-year-old girl who was unvaccinated against SARS-CoV-2, reporting 12 to 13 days of fatigue, sore throat, diarrhea, decreased appetite, and fever with a positive COVID-19 polymerase chain reaction test. In the days after COVID-19 diagnosis, the patient was found to have multicentric lymphadenopathy above and below the diaphragm, hepatomegaly, and fluid retention. The patient also had worsening inflammatory markers, anemia, thrombocytopenia, hypoalbuminemia, and elevated creatinine levels, suggesting acute renal failure. Bone marrow biopsy showed moderate reticulin fibrosis. An excisional biopsy of an enlarged lymph node, 16 days after COVID-19 diagnosis showed features consistent with the plasmacytic variant of CD. The patient was hospitalized for 31 consecutive days requiring hemodialysis and received multiple therapies (IVIGs, corticosteroids, plasmapheresis, tocilizumab, eculizumab, and sirolimus). The patient was reviewed and adjudicated by the certification and access subcommittee to more likely have multisystem inflammatory syndrome in children than iMCD–TAFRO syndrome. Although the CD diagnosis occurred after COVID-19 onset in a subset of the cases presented here, the time lag makes it difficult to determine causality.

Assessing immunogenicity in patients with CD after SARS-CoV-2 vaccination series

Next, we assessed antibody response to SARS-CoV-2 vaccination in a third cohort of patients with CD (n = 35; supplemental Table 3). Median age of participants was 44.3 years (IQR, 36.0-52.0), with 69% of the cohort being female and 31% male (Table 4). Most patients reported an MCD diagnosis (25, 71%) with 24 (69%) patients reporting iMCD and 1 (3%) patient reporting HHV-8–associated MCD. Ten (29%) patients reported having UCD. Of 35 patients, 3 (9%) reported COVID-19 diagnosis before vaccination. Thirty-one (89%) patients received the 2-dose vaccination series whereas 4 (11%) patients lacked data at the time of the second dose. Eight (23%) patients received 3 vaccine doses whereas 27 (77%) lacked data at the time of the third dose.

Table 4.

Study cohort characteristics for patients with CD enrolled in study evaluating antibody response to vaccination

Gender n/N (%) 
Male 11/35 (31.4) 
Female 24/35 (68.6) 
Age of study participants, median (IQR), y 44.3 (36.0-52.0) 
Race n/N (%) 
White 26/35 (74.3) 
Asian 4/35 (11.4) 
African American/Black 1/35 (2.9) 
Pacific Islander 1/35 (2.9) 
Multiracial 2/35 (5.7) 
Prefer not to answer 1/35 (2.9) 
CD subtype n/N (%) 
iMCD 24/35 (68.6) 
UCD 10/35 (28.6) 
HHV-8–associated MCD 1/35 (2.9) 
Treatment history at enrollment n/N (%) 
Siltuximab 12/35 (34.3) 
Prednisone/equivalents 5/35 (14.3) 
Rituximab 3/35 (8.6) 
Tocilizumab 2/35 (5.7) 
Sirolimus 2/35 (5.7) 
Hydroxychloroquine 1/35 (2.9) 
Cyclosporine 1/35 (2.9) 
IVIGs 1/35 (2.9) 
Not on immunosuppressive therapy 13/35 (37.1) 
Other clinical history before vaccination n/N (%) 
Common variable immunodeficiency diagnosis/low antibody status 7/35 (20.0) 
Epinephrine use for allergies 2/35 (5.7) 
Vaccine-related allergies 0/35 (0.0) 
COVID-19 infection before vaccination 3/35 (8.6) 
Hospital/intensive care unit admissions 0/35 (0.0) 
Vaccination status n/N (%) 
Dose 1/dose 2 31/35 (88.6) 
Dose 3 8/35 (22.9) 
Vaccination type n/N (%) 
Dose 1/dose 2: BNT162b2 (Pfizer/BioNTech) 18/31 (58.1) 
Dose 1/dose 2: mRNA-1273 (Moderna) 13/31 (41.9) 
Dose 3: BNT162b2 (Pfizer/BioNTech) 2/8 (25.0) 
Dose 3: mRNA-1273 (Moderna) 5/8 (62.5) 
Dose 3: NA (missing) 1/8 (12.5) 
Vaccination outcomes after dose 1 and 2 n/N (%) 
Local reaction, not severe 25/31 (80.6) 
Local reaction, severe 0/31 (0.0) 
Systemic reaction, not severe 10/31 (32.2) 
Systemic reaction, severe 0/31 (0.0) 
Postvaccination neuropathy 1/31 (3.2) 
CD flare requiring treatment 0/31 (0.0) 
Allergic reaction requiring epinephrine use 0/31 (0.0) 
Breakthrough COVID-19 diagnosis after dose 1 3/31 (9.7) 
Vaccination outcomes after dose 3 n/N (%) 
Local reaction, severe 0/3 (0.0) 
Systemic reaction, severe 0/3 (0.0) 
Breakthrough COVID-19 diagnosis after dose 3 1/3 (33.3) 
Hospital/intensive care unit admissions during vaccine period 0/3 (0.0) 
Humoral response after dose 2 n/N (%) 
Number of patients with anti-RBD titers quantified 10/31 (32.3) 
After dose 2 anti-RBD titers, quantified Median (IQR) U/mL 
 576.2 (414.0-1015.0) 
After dose 2 anti-RBD titers, timing Median (IQR), d 
 177 (150.0-204.5) 
Humoral response after dose 3 n/N (%) 
Number of patients with anti-RBD titers quantified 5/8 (62.5) 
After dose 3 anti-RBD titers, quantified Median (IQR) U/mL 
 >2500 
After dose 3 anti-RBD titers, timing Median (IQR), d 
 NA 
Treatment history (after dose 2) n/N (%) 
Rituximab monotherapy 2/10 (20.0) 
Sirolimus monotherapy 1/10 (10.0) 
Siltuximab monotherapy 1/10 (10.0) 
Cyclosporine + tocilizumab 1/10 (10.0) 
Not on immunosuppressants 5/10 (50.0) 
Treatment history (after dose 3) n/N (%) 
Siltuximab monotherapy 1/5 (20.0) 
Hydroxychloroquine monotherapy 1/5 (20.0) 
Prednisone monotherapy 1/5 (20.0) 
Siltuximab + prednisone 1/5 (20.0) 
Sirolimus + prednisone 1/5 (20.0) 
Gender n/N (%) 
Male 11/35 (31.4) 
Female 24/35 (68.6) 
Age of study participants, median (IQR), y 44.3 (36.0-52.0) 
Race n/N (%) 
White 26/35 (74.3) 
Asian 4/35 (11.4) 
African American/Black 1/35 (2.9) 
Pacific Islander 1/35 (2.9) 
Multiracial 2/35 (5.7) 
Prefer not to answer 1/35 (2.9) 
CD subtype n/N (%) 
iMCD 24/35 (68.6) 
UCD 10/35 (28.6) 
HHV-8–associated MCD 1/35 (2.9) 
Treatment history at enrollment n/N (%) 
Siltuximab 12/35 (34.3) 
Prednisone/equivalents 5/35 (14.3) 
Rituximab 3/35 (8.6) 
Tocilizumab 2/35 (5.7) 
Sirolimus 2/35 (5.7) 
Hydroxychloroquine 1/35 (2.9) 
Cyclosporine 1/35 (2.9) 
IVIGs 1/35 (2.9) 
Not on immunosuppressive therapy 13/35 (37.1) 
Other clinical history before vaccination n/N (%) 
Common variable immunodeficiency diagnosis/low antibody status 7/35 (20.0) 
Epinephrine use for allergies 2/35 (5.7) 
Vaccine-related allergies 0/35 (0.0) 
COVID-19 infection before vaccination 3/35 (8.6) 
Hospital/intensive care unit admissions 0/35 (0.0) 
Vaccination status n/N (%) 
Dose 1/dose 2 31/35 (88.6) 
Dose 3 8/35 (22.9) 
Vaccination type n/N (%) 
Dose 1/dose 2: BNT162b2 (Pfizer/BioNTech) 18/31 (58.1) 
Dose 1/dose 2: mRNA-1273 (Moderna) 13/31 (41.9) 
Dose 3: BNT162b2 (Pfizer/BioNTech) 2/8 (25.0) 
Dose 3: mRNA-1273 (Moderna) 5/8 (62.5) 
Dose 3: NA (missing) 1/8 (12.5) 
Vaccination outcomes after dose 1 and 2 n/N (%) 
Local reaction, not severe 25/31 (80.6) 
Local reaction, severe 0/31 (0.0) 
Systemic reaction, not severe 10/31 (32.2) 
Systemic reaction, severe 0/31 (0.0) 
Postvaccination neuropathy 1/31 (3.2) 
CD flare requiring treatment 0/31 (0.0) 
Allergic reaction requiring epinephrine use 0/31 (0.0) 
Breakthrough COVID-19 diagnosis after dose 1 3/31 (9.7) 
Vaccination outcomes after dose 3 n/N (%) 
Local reaction, severe 0/3 (0.0) 
Systemic reaction, severe 0/3 (0.0) 
Breakthrough COVID-19 diagnosis after dose 3 1/3 (33.3) 
Hospital/intensive care unit admissions during vaccine period 0/3 (0.0) 
Humoral response after dose 2 n/N (%) 
Number of patients with anti-RBD titers quantified 10/31 (32.3) 
After dose 2 anti-RBD titers, quantified Median (IQR) U/mL 
 576.2 (414.0-1015.0) 
After dose 2 anti-RBD titers, timing Median (IQR), d 
 177 (150.0-204.5) 
Humoral response after dose 3 n/N (%) 
Number of patients with anti-RBD titers quantified 5/8 (62.5) 
After dose 3 anti-RBD titers, quantified Median (IQR) U/mL 
 >2500 
After dose 3 anti-RBD titers, timing Median (IQR), d 
 NA 
Treatment history (after dose 2) n/N (%) 
Rituximab monotherapy 2/10 (20.0) 
Sirolimus monotherapy 1/10 (10.0) 
Siltuximab monotherapy 1/10 (10.0) 
Cyclosporine + tocilizumab 1/10 (10.0) 
Not on immunosuppressants 5/10 (50.0) 
Treatment history (after dose 3) n/N (%) 
Siltuximab monotherapy 1/5 (20.0) 
Hydroxychloroquine monotherapy 1/5 (20.0) 
Prednisone monotherapy 1/5 (20.0) 
Siltuximab + prednisone 1/5 (20.0) 
Sirolimus + prednisone 1/5 (20.0) 

Data are presented for 35 patients.

Anti–receptor-binding domain (RBD) titers after the second dose were evaluated in 10 of 31 (32%) patients who received their second vaccine dose. The median antispike titer was 576.2 U/mL (IQR, 414.0-1015.0) after a median of 177 days (IQR, 150.0-204.5) from the second dose. Only 1 patient from this cohort did not achieve the threshold for seroconversion after the second dose, but that patient was receiving a B-cell depleting agent, rituximab, known to reduce the likelihood of mounting a robust immune response.33 Another patient treated with rituximab did seroconvert. Five (50%) patients were not on any immunosuppressive therapy, and the remaining 3 patients seroconverted while they were on regimens of cyclosporine and tocilizumab, sirolimus monotherapy, and siltuximab monotherapy, respectively. Overall, 9 of 10 (90%) patients mounted an immune response to SARS-CoV-2 vaccination.

Anti-RBD titer after the third dose was also evaluated in 5 of 8 (63%) patients who received their third vaccine dose. All 5 patients had an anti-RBD level that exceeded the ceiling of the assay (>2500 U/mL) at ∼1 month after the third vaccination dose. Importantly, all 5 patients were on at least 1 immunosuppressive agent at this time; siltuximab monotherapy (n = 1), hydroxychloroquine (n = 1), prednisone monotherapy (n = 1), siltuximab and prednisone (n = 1), and sirolimus and prednisone (n = 1).

Of the 31 patients assessed, 3 (10%) developed COVID-19 after the first vaccine dose. Of 3 patients assessed, 1 (33%) patient developed COVID-19 after the third vaccine dose. No patients in the JHU cohort reported hospitalization for COVID-19.

We leveraged a natural history registry of CD, targeted surveys, and serological assays to characterize the experience of patients with CD with SARS-CoV-2 infection and vaccination. Despite concerns that patients with CD might have an increased susceptibility to SARS-CoV-2 infection and worse outcomes, the prevalence of SARS-CoV-2 in our cohort (16/95, 17%) was comparable with the prevalence of SARS-CoV-2 (20%) in the United States around March 2021.34 Although patients with MCD are on immunosuppressive medications and are thought to have greater immune dysregulation than patients with UCD, a comparable proportion of SARS-CoV-2 infection was observed among iMCD (6/49, 12%) and UCD (8/23, 35%) among the patients tested. The comparable prevalence between patients with MCD and UCD could be because of susceptibilities to infection in both populations. The perceived vulnerability of the MCD population might have made these patients more cautious and likely to strictly follow infection control practices recommended by the Centers for Disease Control and Prevention.35 The proportion of patients with COVID-19 who experienced more severe illness was also similar to that of the general population.36 Most patients reported mild COVID-19 symptoms and patients with MCD did not appear to have had worse outcomes. In fact, the only patient with CD who reported severe COVID-19 disease lasting >2 weeks had UCD.

We also found limited information to suggest that SARS-CoV-2 infection could trigger a CD flare. We found 1 patient with iMCD–TAFRO syndrome on siltuximab maintenance for ∼3.5 years that developed a CD flare, 51 days after COVID diagnosis. For this patient, laboratory markers and clinical manifestations progressively worsened after the COVID-19 diagnosis and a core lymph node biopsy continued to show features suggestive of CD, suggesting a relationship between COVID-19 and his CD flare. Interestingly, there is a documented case report of a patient experiencing an systemic inflammatory syndrome shortly after COVID-19 onset that is very similar to iMCD–TAFRO syndrome.37 However, it still remains difficult to draw any definitive conclusions about whether the SARS-CoV-2 infection triggered TAFRO or a TAFRO-like syndrome. For the remaining cohort, COVID-19 symptoms largely corresponded with common symptoms reported in the general US population during the 2021 strains (ie, alpha, beta, gamma, and delta) of COVID-19.38-40 Taken together, the risk of infection, severity of symptoms, and constellation of symptoms did not appear to be notably different from those of the general population, and this 1 case of iMCD–TAFRO syndrome exacerbation was unique in our data set.

Likewise, we found limited information to suggest that SARS-CoV-2 vaccination could trigger a CD flare. Notably, a high proportion of survey respondents had received the vaccine (88%) and the proportion of mild side effects was consistent with that of other populations.41 Among survey respondents reporting COVID-19 recovery (n = 12), the median duration of COVID-19 disease was 11.5 days, which was comparable with the median of 13.5 days reported in the literature.42 Although laboratory markers and clinical manifestations fluctuated over time after vaccination in the 1 patient with CD who had severe vaccine side effects, it is challenging to determine whether the vaccine caused this patient’s CD. Nevertheless, there have been a few previously reported cases of patients developing an MCD clinical picture days after COVID-19 diagnosis or SARS-CoV-2 vaccination.43-46 

We also found that most patients with CD in the JHU cohort (90%) mounted detectable antibody responses to SARS-CoV-2 vaccination despite being on a variety of immunosuppressive medications. The median (IQR) anti-RBD titer levels observed among the CD cohort after the second vaccination dose was 576.2 U/mL (IQR, 414.0-1015.0). Furthermore, titers in the CD cohort were comparable with median titer levels in patients with autoimmune disorders (419 U/mL [IQR, 91.9-861.0]) and a healthy cohort (1709 U/mL [IQR, 937.0-2438.0]) reported in the literature in the same 6-month period.47,48 Additionally, titer levels in this cohort were also comparable with those of other studies in literature that evaluated titer levels of age-matched healthy controls at similar time points and using the same serological assay.49-51 The only patient from this cohort who did not achieve the threshold for seroconversion after the second dose, received the CD20 monoclonal antibody, rituximab. Rituximab, and the CD38 monoclonal antibody, daratumumab, are 2 examples of monoclonal antibodies already reported to reduce the humoral response to vaccination.33,52 

There are several limitations to this study. First, natural history registries, such as ACCELERATE, are susceptible to selection bias. Patients with a poorer prognosis or who are significantly debilitated are less likely to complete surveys than healthier populations. Additionally, CD is a rare disease, and the sample size is limited for providing an epidemiological estimate to compare with the population as a whole. As such, statistical comparisons were not performed. Furthermore, survey respondents who are seeking care and who have a greater degree of disease burden have more of an incentive to participate in these surveys and could thus skew our data set to more unhealthy outcomes.53 The cohort recruited for serology studies was also subject to bias, particularly because of the high attrition rate from the start of the study to data extracted at subsequent dose intervals. The low number of patients tested for seroconversion (10/31) precludes broader insights into the robustness and durability of the humoral immune response to vaccination. Additional limitations are attributable to the inherent survey design that involves selection bias among a heterogenous patient cohort (with varying diagnosis and treatment), response bias, nonresponse bias, and recall bias with patients self-reporting their medical history. Furthermore, these data only reflect experience with COVID-19 through 2021, when surveys were completed. Since completion of the survey, the delta and omicron variants were more prevalent, and this study does not present data relevant to those variants.54 

Altogether, we found that patients with CD in our cohort had proportions of COVID-19 diagnoses and vaccine use comparable with those of the general US population.34,55 Similar clinical courses, vaccine adverse effect profiles, and humoral response after vaccination were observed between both populations.41,56-58 We identified 2 isolated cases within ACCELERATE that suggest a possible temporal relationship between SARS-CoV-2 infection or vaccination resulting in CD symptomatology. This study revealed that despite possible risks associated with SARS-CoV-2 vaccine administration in patients with CD, these risks do not appear to outweigh the benefits of the vaccine. Future studies aimed at investigating the temporal relationship between COVID-19 and/or SARS-CoV-2 vaccination with CD, using bioinformatics and multiomics studies to investigate other possible pathogenic causes of CD, and exploring drug repurposing efforts for both diseases are needed.

The authors thank all patients and their families for their participation in the ACCELERATE registry. The authors thank the Castleman Disease Collaborative Network and the ACCELERATE Registry team for their support. The authors thank the volunteers for the Castleman Disease Collaborative Network who have supported this research, including Mary Zuccato and Mileva Repasky. The authors thank Shawnee Bernstein, Nathan Hersh, Gerard Hoeltzel, and Jeremy Zuckerberg for their contributions to this study; and the authors thank Faizaan Ahkter, Erin Napier, Eric Haljasmaa, Katherine Floess, Mark-Avery Tamakloe, Victoria Powers, Alexander Gorzewski, Johnson Khor, Reece Williams, Freda Coren, Jasira Ziglar, Amy Liu, Natalie Mango, Mateo Sarmiento Bustamante, Criswell Lavery, and Bridget Austin. Figure 2A, Figure 3A, and supplemental Figure 1, and the visual abstract were created with BioRender.com.

The ACCELERATE natural history registry has received funding from Janssen Pharmaceuticals (2016-2018), EUSA Pharma LLC (United States), which has merged with Recordati Rare Diseases Inc (2018-2022) and is now supported by the US Food and Drug Administration (grant R01FD007632) (2022-present). D.C.F. has also received research funding relevant to this project from the National Institutes of Health-National Heart, Lung, and Blood Institute (grant R01HL141408).

Contribution: S.S. was responsible for investigation, formal analysis, visualization, writing the original draft, and for reviewing and editing the manuscript; S.K.P. was responsible for conceptualization, supervision, investigation, and for reviewing and editing the manuscript; C.M.C., M.T., D.L.S., and W.A.W. were responsible for investigation, and for reviewing and editing the manuscript; F.v.R. and C.C. were responsible for reviewing and editing the manuscript; J.D.B. was responsible for supervision, and reviewing and editing the manuscript; A.N. was responsible for reviewing and editing the manuscript; D.C.F. was responsible for conceptualization, supervision, funding acquisition, and for reviewing and editing the manuscript; and all authors reviewed and approved the manuscript.

Conflict-of-interest disclosure: D.C.F. has received research funding for the ACCELERATE registry from EUSA Pharma; has received consulting fees from EUSA Pharma; reports that Pfizer provides a study drug with no associated research funding for the clinical trial of sirolimus (ClinicalTrials.gov identifier: NCT03933904); and has 2 provisional patents pending related to the diagnosis and treatment of iMCD. W.A.W has received consulting and/or speaking fees from AstraZeneca, GlobalData, China Medical Tribune, Medical Learning Institute (CME), CDC/ISDA COVID-19 Real-Time Learning Network, advisory board fees from AstraZeneca and Novavax, and grant support from the National Institutes of Health (K23AI157893). F.v.R has received consulting fees from EUSA Pharma, GlaxoSmithKline, Karyopharm, and Takeda; and has received research funding from Janssen Pharmaceuticals and Bristol Myers Squibb. J.D.B. has received consulting fees from EUSA Pharma. The remaining authors declare no competing financial interests.

Correspondence: David C. Fajgenbaum, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Translational Medicine & Human Genetics, 3535 Market St, Suite 700, Philadelphia, PA 19104; email: davidfa@pennmedicine.upenn.edu.

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Author notes

These data are available upon request via email to accelerate@pennmedicine.upenn.edu.

The full-text version of this article contains a data supplement.

Supplemental data