COVID-19 infection in hypereosinophilic syndrome: A survey-based analysis.

This survey-based study of participants with hypereosinophilic syndrome suggests that neither eosinophilia nor depletion of eosinophils impact the severity of coronavirus disease infection and that there is no increased risk of vaccination against coronavirus disease 2019 in this patient population.

The role of eosinophils in coronavirus disease 2019 (COVID-19) infection remains controversial. As in other febrile illnesses, including sepsis and influenza, decreased blood eosinophil levels are frequent in COVID-19 infection and have been associated with increased disease severity. Moreover, retrospective studies of patients with asthma and eosinophilic gastrointestinal disorders suggest that eosinophilia and/or type 2 inflammatory responses may be protective against severe manifestations of COVID-19 infection. , Although these data led some to suggest early in the pandemic that eosinophil-depleting biologics may be detrimental in COVID-19 infection, published studies examining the association between biologic therapy and the incidence and severity of COVID-19 infections in patients with asthma do not support this hypothesis. Moreover, increased eosinophilic pulmonary inflammation has been reported in patients with fatal COVID-19 infection, consistent with a possible pathogenic role of eosinophils in the most severe cases.

Hypereosinophilic syndromes (HESs) are a heterogeneous group of rare disorders defined by hypereosinophilia and eosinophil-related disease manifestations. Although any organ system can be involved in HESs, the skin, respiratory, and gastrointestinal tracts are most commonly affected. HESs can be divided into clinical subtypes, including myeloid, lymphoid, and idiopathic variants, which have implications with respect to etiology, clinical manifestations, response to therapy, and prognosis. To explore the effects of HES treatment and COVID-19 in patients with HESs, 238 participants with HESs actively enrolled on a natural history study of eosinophilic disorders (NCT00001406), who had previously consented to email correspondence, were invited to participate in serial REDCap surveys (see Figure E1 in this article’s Online Repository at www.jaci-inpractice.org). The first surveys were distributed in November 2020 and included questions about demographic characteristics, HES status, and COVID testing. Follow-up surveys, which included vaccination and Centers for Disease Control and Prevention (CDC) guideline adherence questions, were emailed in July 2021 to all 238 participants. Because of the study time frame (November 1, 2020, to October 1, 2021), none of the COVID-19 cases were likely due to the Omicron variant, first reported in the United States by the CDC on November 22, 2021.

Figure E1

RedCap survey questionnaires.

A total of 160 unique participants responded to at least 1 survey between November 18, 2020, and October 1, 2021, of which 98 responded to follow-up surveys between July 1, 2021, and October 1, 2021. Of the 160 unique responders, 51.3% were males; 82.5% identified as White, 6.3% as Black, and 4.4% as Asian (Table I ). A total of 105 (65.6%) participants had been tested for COVID-19 at least once, of which 23 (21.9%) tested positive between March 2020 and September 2021 (HESCOVID+). There were no demographic differences between the HESCOVID+ participants and those who reported no history of COVID-19 (HESWELL). The geographic distribution of the reported cases of COVID-19 infection closely mirrors that of the total participants (see Figure E2 in this article’s Online Repository at www.jaci-inpractice.org).

Table I

Demographic and clinical characteristics of the study participants

Characteristic	HESWELL cohort∗ (n = 137)	HES COVID+ cohort (n = 23)
Sex: female, n (%)	65 (47.4)	12 (52.2)
US resident, n (%)	130 (94.9)	21 (91.3)
White, n (%)	110 (80.3)	22 (95.7)
Age (y), median (range)	53 (6-88)	50 (21-73)
Additional risk factors
Current smoker, n (%)†	9 (6.6)	3 (13.0)
Asthma, n (%)	56 (40.9)	11 (47.8)
Diabetes, n (%)	14 (10.2)	0 (0)
Cardiovascular disease, n (%)	28 (20.4)	4 (17.4)
Geo mean BMI (range)	25.4 (14.1-38.5)	27.8 (16.6-56.3)
HES subtype, n (%)‡
MHES	19 (13.9)	1 (4.3)
LHES	15 (10.9)	8 (34.8)
Overlap	63 (46.0)	14 (60.9)
IHES	36 (26.3)	0
HEUS	4 (2.9)	0
Symptoms in month before filling out survey (patient report), n (%)	55 (40.1)	9 (39.1)
Change in therapy in 3 mo before filling out survey (patient report), n (%)	19 (13.9)	5 (21.7)
Vaccinated, n (%)§	86 of 95 (90.5)	15 of 21 (71.4)
Moderna (mRNA-1273) vaccine	37 of 86 (43.0)	1 of 15 (6.7)
Pfizer (BNT162b2) vaccine	48 of 86 (55.8)	12 of 15 (80.0)
J&J (JNJ-78436735) or AstraZeneca (ChAdOx1-S)	1 of 86 (1.2)	2 of 15 (13.3)
Vaccinated before infection, n (%)	NA	3 of 15 (20.0)
Hospitalized for treatment of COVID, n	NA	4
Died from COVID-related complications, n	NA	1

NA, Not available/applicable.

Cohort that had no history of COVID or positive COVID test result (does not include the COVID+ cohort).

Includes tobacco or other inhaled substances.

HES subtypes: MHES, myeloid HES defined by clinical or molecular evidence of an eosinophilic myeloid neoplasm; LHES, lymphoid variant HES defined by the presence of an aberrant and/or clonal T-cell population; overlap HES, single-organ HES or defined eosinophilic syndrome that overlaps in clinical presentation with idiopathic HES (eg, eosinophilic gastrointestinal disorders or eosinophilic granulomatosis with polyangiitis), HEUS, hypereosinophilia of undetermined significance defined as hypereosinophilia without symptoms or clinical manifestations; and IHES, idiopathic HES defined as HES that does not fit in any of the other categories.

P < .03, Fisher exact test; data provided are restricted to the 116 participants who answered vaccination questions (added after July 1, 2021, after vaccines became available in the United States).

Figure E2

Geographic distribution of survey responders living in the United States. The number of participants by state is shown for all US survey responders (n = 151) in blue and for only the HESCOVID+ participants (n = 21) in red. Nine additional participants resided outside of the continental United States.

The distribution of HES subtypes was significantly different between the HESWELL and HESCOVID+ groups (P < .005, Freeman-Halton test), with a significantly decreased proportion of idiopathic HES and nearly significantly increased proportion of lymphoid variant HES in the HESCOVID+ group compared with the entire cohort (0% vs 18.5%, P = .017, and 34.8% vs 10.9%, P = .052, respectively, central Fisher exact test corrected for multiple comparisons) (Table I). The prevalence rates of asthma and diabetes were similar in the HESCOVID+ and HESWELL groups (47.8% vs 40.9% and 0% vs 10.2%, respectively; P = nonsignificant), as was the proportion of participants taking medication for HES (82.6% vs 83.9%; P = nonsignificant). Most participants (83.8%) were taking HES medications, including 62 who were receiving an eosinophil-lowering biologic (mepolizumab or benralizumab) (Table II ). Although the numbers are small, no significant differences in prevalence were detected for any of the medications or medication categories between the HESWELL and HESCOVID+ groups.

Table II

HES medications

Medication	HESWELL cohort∗ (n = 137)	HES COVID+ cohort (n = 23)
Any HES medication	115 (83.9)	19 (82.6)
Glucocorticoids	58 (42.3)	9 (39.1)
Oral	45 (32.8)	8 (34.8)
Swallowed	13 (9.5)	1 (4.3)
Inhaled therapy†	53 (38.7)	9 (39.1)
Biologic therapy	55 (40.1)	11 (47.8)
Mepolizumab	37 (27.0)	8 (34.8)
Benralizumab	16 (11.7)	1 (4.3)
Other‡	2 (1.5)	2 (8.7)
Tyrosine kinase inhibitors	19 (13.9)	2 (8.7)
Imatinib or nilotinib (PDGFR)	11 (8.0)	1 (4.3)
Ruxolitinib or tofacitinib (JAK)	8 (5.8)	1 (4.3)
Cytotoxic therapy	11 (8.0)	1 (4.3)
Hydroxyurea	6 (4.4)	0
Methotrexate	5 (3.6)	1 (4.3)
Immunomodulatory therapy	13 (9.5)	0
IFN-α	4 (2.9)	0
Mycophenolate mofetil	4 (2.9)	0
Cyclosporine	3 (2.2)	0
Other immunomodulatory§	2 (1.5)	0
Other||	3 (2.2)	0

JAK, Janus kinase; PDGFR, platelet derived growth factor receptor.

Values are n (%).

Cohort that had no history of COVID or positive COVID test (does not include the COVID+ cohort).

Inhaled steroids and/or β-agonists.

Dupilumab (n = 2), omalizumab (n = 1), and lirentelimab (n = 1).

Intravenous immunoglobulin (n = 1) and lenalidomide (n = 1).

Dexpramipexole (n = 1), montelukast (n = 1), romidepsin (n = 1).

Four (17.4%) of the HESCOVID+ participants were hospitalized, all of whom had significant risk factors for severe COVID (body mass index > 35 [n = 3], severe asthma [n = 3] and cardiovascular disease [n = 3) in 3 patients, and a history of vaping tobacco in the fourth). One patient died of bacterial sepsis after COVID-19 infection. All 4 hospitalized patients had lymphoid variant HES and were receiving 1 or more treatment for HES (prednisone [n = 3], ruxolitinib [n = 1], mepolizumab [n = 1]) at the time of COVID-19 infection, although eosinophilia was uncontrolled in 2 of the 4 (>1500/mm3 at the visit before infection). The hospitalization rate in the HESCOVID+ group (17.4%) was similar to that reported by the CDC for all individuals who tested positive for SARS-CoV-2 between February 12, 2020, and March 28, 2020 (21%; P = nonsignificant), but higher than the 9% hospitalization rate reported for individuals with no underlying health condition. Although there was a trend toward a lower rate in the HESCOVID+ group compared with that in patients with chronic lung disease in the same CDC report (37.5%; P = .051), rates of COVID-19 infection in a large cohort of patients with asthma that included a significant proportion of patients on biologic therapy reported hospitalization rates (26.1%) similar to those in the current study.

A total of 116 (72.5%) participants responded to the vaccination questions. The vaccination rate in the HESCOVID+ group was lower than that in the HESWELL group (71.4% vs 90.5%; P = .029). Three of the 15 HESCOVID+ vaccinated participants were immunized before their reported COVID-19 infection. Five of the 101 vaccinated participants reported an increase in eosinophil count or eosinophil-related symptoms after immunization. In only 1 case did this lead to a change in HES therapy (a transient increase in prednisone dose 2 weeks after the second dose of the Pfizer vaccine).

Consistent with published data in patients with other eosinophil-associated disorders, the data from this survey suggest that patients with HESs are no more likely to have severe COVID-19 infection than the general population and that treatment does not represent a major risk factor for severe disease. Equally important, despite isolated reports of the development of eosinophilic disorders temporally related to COVID-19 vaccination, clinically significant exacerbation of HESs (ie, requiring alteration of therapy) was reported in less than 1% of vaccinated participants.

Although encouraging, this study has limitations. As in any survey-based study, the reliability of the data is limited by the accuracy of patient reporting and bias can be introduced if one of the study outcomes (eg, COVID-19 infection) results in reduced response rates. Although the number of participants was small due to the rarity of HESs, the response rate was high (67.2%), and the demographic and clinical characteristics of the participants are comparable to those in the 604 participants currently or previously enrolled on the same natural history protocol. Moreover, chart review of the 78 survey nonresponders revealed 44 participants for whom data were available regarding COVID-19 infection over the entire study period identified only 2 additional cases of COVID-19 infection in 44 participants, neither of whom had a severe presentation. Finally, the variability in COVID-19 infection rates and the introduction of immunization during the study time frame complicated selection of an appropriate database for comparison of infection and hospitalization rates, and, perhaps more important, the application of the findings to Omicron (and future variants) is uncertain. Despite these limitations, the findings from this study suggest that patients with HESs are at no greater risk of COVID-19 infection, complications from COVID, or adverse events following immunization with currently available COVID-19 vaccines.