Assessing the risk and costs of COVID-19 in immunocompromised populations in a large United States commercial insurance health plan: the EPOCH-US Study

Abstract

Objective

To estimate the prevalence of patients with an immunocompromising condition at risk for COVID-19, estimate COVID-19 prevalence rate (PR) and incidence rate (IR) by immunocompromising condition, and describe COVID-19-related healthcare resource utilization (HCRU) and costs.

Methods

Using the Healthcare Integrated Research Database (HIRD), patients with ≥1 claim for an immunocompromising condition of interest or ≥2 claims for an immunosuppressive (IS) treatment and COVID-19 diagnosis during the infection period (1 April 2020–31 March 2022) and had ≥12 months baseline data were included. Cohorts (other than the composite cohort) were not mutually exclusive and were defined by each immunocompromising condition. Analyses were descriptive in nature.

Results

Of the 16,873,161 patients in the source population, 2.7% (n = 458,049) were immunocompromised (IC). The COVID-19 IR for the composite IC cohort during the study period was 101.3 per 1000 person-years and the PR was 13.5%. The highest IR (195.0 per 1000 person-years) and PR (20.1%) were seen in the end-stage renal disease (ESRD) cohort; the lowest IR (68.3 per 1000 person-years) and PR (9.4%) were seen in the hematologic or solid tumor malignancy cohort. Mean costs for hospitalizations associated with the first COVID-19 diagnosis were estimated at nearly $1 billion (2021 United States dollars [USD]) for 14,516 IC patients, with a mean cost of $64,029 per patient.

Conclusions

Immunocompromised populations appear to be at substantial risk of severe COVID-19 outcomes, leading to increased costs and HCRU. Effective prophylactic options are still needed for these high-risk populations as the COVID-19 landscape evolves.

PLAIN LANGUAGE SUMMARY

People who have a medical condition or take a medicine that can suppress their immune system (immunocompromised) have a high risk of getting COVID-19. Our study looked at how many immunocompromised people got COVID-19. We also looked at the costs and lengths of hospital stays for people with COVID-19. We found that 2.7% of the people in this large US population with health insurance were immunocompromised. People who were immunocompromised were more likely to get COVID-19 than people who were not immunocompromised. About 14% of the immunocompromised people in this study got COVID-19 and, of those, 24% were hospitalized. Immunocompromised patients in this study had long hospital stays and high costs associated with COVID-19. The risk of getting COVID-19 and having a severe case seemed to be highest for people with advanced kidney disease. The study results showed that COVID-19 can cause severe health issues in immunocompromised people and the use of vaccinations, medications, and other measures to prevent COVID-19 are especially important for immunocompromised people.

Keywords:

• COVID-19
• immunocompromised
• healthcare resource utilization
• epidemiology

Introduction

The global coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 757 million confirmed infections and over 6.8 million deaths globally since the start of the pandemic in 2019¹. In the United States (US), more than 103 million cases and 1.1 million deaths have been attributed to COVID-19². Certain populations, such as those with hematologic malignancies and recipients of hematopoietic stem cell or solid organ transplants, have significantly impaired immune systems; these immunocompromised (IC) patients have an increased vulnerability to SARS-CoV-2 and are at higher risk for severe COVID-19 outcomes, including prolonged hospitalization, greater healthcare resource utilization (HCRU), and death^3–9. A representative sample of 22,345 hospitalized adults from 10 states in the COVID-19 Associated Hospital Surveillance Network (COVID-NET; 1 March 2020–28 February 2022) showed that 12.2% of all hospitalized patients were immunocompromised¹⁰. Further, the IC patients had a higher risk of intensive care unit (ICU) admission and death compared to immunocompetent patients.

In December 2020, approval to begin vaccination against COVID-19 caused by SARS-CoV-2 was granted by the US Food and Drug Administration (FDA)¹¹. Despite appropriate COVID-19 vaccination uptake, some populations may not mount an adequate immune response to the COVID-19 vaccines due to underlying immunocompromising conditions and/or use of immunosuppressive (IS) treatment, which may place them at increased risk for more severe COVID-related outcomes^12–20. Underlying conditions that have been shown to decrease COVID-19 vaccine effectiveness and place individuals at risk for more severe outcomes related to COVID-19 include hematologic malignancies^12,13,21,22 and a history of solid organ transplant^{12–15,23–26}. Immunosuppressive medications such as those used to prevent allograft rejection among solid organ transplant recipients can impact immune response to vaccination in general^27,28, with documented poor antibody response to COVID-19 vaccination^{12–15,23–26}. Chronic kidney disease (CKD; particularly end-stage renal disease or dialysis)^29,30, primary immunodeficiencies^12,31–33, and use of IS or immunomodulatory medications (e.g. chemotherapy in patients with cancer; sphingosine-1-phosphate receptor modulators in patients with multiple sclerosis) may also cause immune system impairment leading to a higher risk of severe COVID-19-related outcomes^8,9. Age-related decline in immune function has also been observed, which may lead to a greater risk of SARS-CoV-2 infection and severe outcomes^15,34. However, post-immunization measurement to assess levels of immunity to SARS-CoV-2 is not recommended based on current guidelines³⁵.

The prevalence of immune suppression/compromise due to conditions or medications has been estimated to be between 2% and 3% in the US population^36,37. Although several studies have examined immunocompromising risk factors associated with breakthrough COVID-19^12,15,34, the incidence and severity of COVID-19 in these IC populations are not well understood. This is in part because patients with immunocompromising conditions were largely excluded from SARS-CoV-2 vaccine clinical trials^38–40. Furthermore, there is limited information on the impact of COVID-19 on HCRU and healthcare costs in IC populations in the US. This study aimed to estimate the prevalence of IC populations who are potentially at risk for a suboptimal COVID-19 vaccine immune response and subsequent SARS-CoV-2 infection; estimate the incidence of COVID-19 stratified by immunocompromising condition; and describe the HCRU and healthcare costs associated with COVID-19 in these populations. Results from this study will further the general understanding of the impact of COVID-19 on IC populations and inform the management of these patients and their prevention and treatment options, particularly among a commercially insured population.

Methods

Study design

This retrospective, observational cohort study was conducted among US patients identified in the Healthcare Integrated Research Database (HIRD)^® (formerly the HealthCore Integrated Research Database) between 1 April 2018, and 31 March 2022 (study period). The HIRD is a large healthcare database curated by Carelon Research (formerly HealthCore) that is built on a broad, clinically rich, and geographically diverse spectrum of longitudinal medical and pharmacy claims from health plan members across the US. Member enrollment, medical care (professional and facility claims), outpatient prescription drug use (pharmacy claims), and healthcare utilization is tracked for health plan members in the database dating back to January 2006. The HIRD contains neighborhood-level characteristics at the census block group level relevant to social determinants of health (SDOH) obtained from the 2017 American Community Survey⁴¹.

All data were accessed as a limited data set for which a business associate and data use agreement was in place with the covered entities in compliance with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule. Data was anonymized and thus exempt from Institutional Review Board review.

Study population

To be included in the study, patients with commercial or Medicare (Medicare Advantage, Supplemental, or Part D) health insurance coverage were required to have ≥1 claim for an immunocompromising condition of interest (hematologic or solid tumor malignancy [HSTM]; hematopoietic stem cell transplant [HSCT] or solid organ transplant [SOT]; primary immunodeficiency [PID]; or end-stage renal disease [ESRD; defined as patients with CKD stage 5, ESRD, or history of dialysis]) within the study period, or ≥2 fills or claims for an IS treatment from 1 October 2019 to the end of the study period (Figure 1). The index date was defined as the date of diagnosis of an immunocompromising condition or use of an IS treatment in the study period, or 1 April 2020 (the first day of the infection period), whichever came last. Only actively treated patients with HSTM were included. Active treatment was identified as patients with ≥1 claim for an antineoplastic medication from 6 months before the index date to the date of the COVID-19 diagnosis, member’s health plan disenrollment, death, or end of the study period, whichever came first. Individual IC cohorts were not mutually exclusive and were defined by each immunocompromising condition; however, a mutually exclusive composite cohort of the overall IC population was also created. The HIRD source population was defined as patients with ≥12 months of continuous pharmacy and medical benefit enrollment between 1 April 2019 and 31 March 2022. The index date for the HIRD source population was set to day 365 after the first day of continuous enrollment. The infection period was defined as 1 April 2020 to 31 March 2022 (as 1 April 2020 was the date when the specific ICD-10 diagnosis code for COVID-19 [U07.1] was released in the US); the baseline period was defined as 1 April 2018 to the index date. All patients in the IC cohorts and the HIRD source population were required to have ≥12 months of continuous medical and pharmacy health plan enrollment prior to the index date.

Figure 1. Study timeline.

^aUse of IS treatment was assessed starting on 1 October 2019. For all other cohorts, risk was assessed beginning on 1 April 2018.

Key: IS: immunosuppressive.

Outcomes

Outcomes were assessed for each individual IC cohort and the overall IC population (composite IC cohort). Evaluated measures included the prevalence of immunocompromising conditions and use of IS treatments; baseline demographic and clinical characteristics; prevalence and incidence of COVID-19; and length of stay (LOS) and costs (health plan paid + patient paid) associated with COVID-19 hospitalization. All-cause HCRU and paid costs were also captured in the 30-day pre-COVID-19 period and the 30-day post-COVID-19 period among patients who had at least 30 days of post-infection continuous enrollment. Costs were adjusted to 2021 US dollars (USD) according to medical care price index information provided by the US Bureau of Labor Statistics⁴². The baseline period was defined as the study start date to the index date (inclusive). Baseline demographic characteristics included sex, age on index date, age group, and payor type. Baseline clinical characteristics included the Quan-Charlson Comorbidity Index (QCI) score (range: 0–24; higher scores are associated with a higher likelihood of death within 1 year of hospital admission)⁴³ and comorbidities of interest, as well as the categorical number of immunocompromising conditions and IS treatments of interest. Prevalence of COVID-19 and available baseline demographic and clinical characteristics were also reported for the overall HIRD cohort. Antiviral medication use was identified using medical and pharmacy claims for remdesivir, and pharmacy claims for nirmatrelvir/ritonavir, baricitinib, or molnupiravir in the 30-day pre- and post-COVID-19 periods.

A SARS-CoV-2 infection was identified based on a positive SARS-CoV-2 polymerase chain reaction (PCR) or antigen test analyzed by accredited laboratories, or a medical encounter (inpatient, emergency room [ER], office visit, urgent care, or telehealth visit) for treatment/evaluation and management/consultation with a COVID-19 diagnosis code at any position on the medical claim. Severity of COVID-19 was classified into the following mutually exclusive categories: severe/critical, moderate, or mild/asymptomatic. Severe/critical COVID-19 was defined as an inpatient admission for COVID-19 with an ICU admission and one of the following: evidence of extracorporeal membrane oxygenation (ECMO), mechanical ventilation use, administration of high-flow oxygen via nasal cannula, or discharge status of expired. Moderate COVID-19 was defined as an inpatient admission for COVID-19 that did not meet any of the criteria for severe/critical COVID-19. Mild COVID-19 was defined as an outpatient claim for COVID-19 (e.g. office, telehealth, or stand-alone ER visit) without any inpatient claims, while asymptomatic COVID-19 was defined as a positive SARS-CoV-2 lab result with no inpatient or outpatient COVID-19 claims. These two categories (mild and asymptomatic) were combined as it was not possible to fully ascertain whether the patient had symptoms but did not seek medical care.

Statistical analysis

This study was descriptive with no statistical comparisons between cohorts. Descriptive statistics were reported as mean and standard deviation (SD) or median and interquartile range (IQR) for continuous data, and absolute and relative frequencies for categorical data. The prevalence of immune compromise was calculated as the number of patients with an immunocompromising condition or using an IS treatment in the infection period divided by the total number of patients with ≥12 months of continuous pharmacy and medical benefit enrollment prior to the index date. The prevalence of COVID-19 was calculated as the number of patients who developed COVID-19 in the infection period divided by the total number of patients within each cohort of interest with ≥12 months of continuous pharmacy and medical benefit enrollment prior to the index date. Incidence rates (IRs) of COVID-19 during the infection period were reported with 95% confidence intervals (CIs). Incidence rates were calculated as the number of new cases of COVID-19 during the infection period divided by the total person-years in each individual IC cohort and the composite IC cohort during the infection period. Both overall and monthly IRs were calculated. In addition, overall IRs by severity of COVID-19 were assessed. The frequency, LOS, and total all-cause costs of hospitalizations associated with the first COVID-19 diagnosis were stratified by severity and reported for all IC cohorts. Total aggregate costs for COVID-19-related hospitalizations were calculated by multiplying the total number of ICU and non-ICU hospitalized patients by the mean total all-cause costs for ICU and non-ICU hospitalizations, respectively.

Sample selection, creation of analytic variables, and analyses were performed using the Instant Health Data (IHD) platform (Panalgo, Boston, MA, US) and Statistical Analysis System (SAS), version 9.3 (SAS Institute Inc, Cary, NC, US).

Results

Study population

A total of 22,858,635 patients with commercial or Medicare Advantage/Supplemental/Part D health insurance were identified within the HIRD during the infection period. Of these, there were 1,518,358 (6.6%) unique members with ≥1 claim for an immunocompromising condition or ≥2 claims for an IS treatment during the study period (Figure 2). After applying the study's continuous enrollment criteria, a total of 16,873,161 patients remained in the overall HIRD cohort. Once the active treatment criteria for patients with HSTM were applied, there were 458,049 (2.7%) unique members identified as IC patients in the composite IC cohort. The individual IC cohorts were not mutually exclusive, and they included 259,914 (1.5%) patients in the IS treatment cohort; 165,081 (1.0%) patients in the HSTM cohort; 84,610 (0.5%) patients in the PID cohort; 48,131 (0.3%) patients in the ESRD cohort; and 28,698 (0.2%) patients in the HSCT/SOT cohort.

Figure 2. Patient selection and attrition.

Study period: 1 April 2018 through 31 March 2022.

Use of IS treatment was assessed starting on 1 October 2019. For all other cohorts, risk was assessed beginning on 1April 2018.

Key: ESRD: end-stage renal disease; HIRD: healthcare integrated research database; HSCT: hematopoietic stem cell transplant; HSTM: hematologic or solid tumor malignancy; IS: immunosuppressive; PID: primary immunodeficiency; SOT: solid organ transplant.

Baseline patient characteristics

Baseline and clinical characteristics varied among the cohorts. The median age for the composite IC cohort was 58 years (Table 1). Depending on the cohort, 42.1% to 64.8% of IC patients were females, and 64.3% to 85.8% of IC patients had commercial insurance coverage. Among all IC cohorts, the mean proportions of distribution of ethno-racial groups at the census level were: 4.6% to 5.4% Asian; 9.5% to 14.2% non-Hispanic Black; 63.9% to 70.7% non-Hispanic White; and 11.6% to 14.2% Hispanic/Latino of any race. Approximately twice as many patients across all IC cohorts were in the highest socioeconomic status (SES) quartile compared to the lowest SES quartile, with the exception of the ESRD cohort (which had a similar number of patients in the highest and lowest SES quartiles). The overall HIRD population was substantially younger than the IC population (median age: 38 years), 50.5% were females, and 93.4% were commercially insured.

Table 1. Demographics on index date.

Demographics	HIRD Source Population^a	HSTM	HSCT/SOT	PID	ESRD	IS Treatment	Composite IC Cohort
Number of patients	16,873,161	165,081	28,698	84,610	48,131	259,914	458,049
		(1.0%)	(0.2%)	(0.5%)	(0.3%)	(1.5%)	(2.7%)
Age (years), median (IQR)	38	63	56	54	63	55	58
	(21–54)	(55–73)	(44–64)	(37–64)	(54–74)	(43–63)	(46–67)
Sex
Female	8,524,066	106,921	12,073	49,674	20,592	152,275	274,079
	(50.5%)	(64.8%)	(42.1%)	(58.7%)	(42.8%)	(58.6%)	(59.8%)
Male	8,349,095	58,160	16,625	34,936	27,539	107,639	183,970
	(49.5%)	(35.2%)	(57.9%)	(41.3%)	(57.2%)	(41.4%)	(40.2%)
Payor
Commercial	15,765,497	121,720	24,387	71,376	30,972	223,058	368,310
	(93.4%)	(73.7%)	(85.0%)	(84.4%)	(64.3%)	(85.8%)	(80.4%)
Medicare (Advantage/Supplemental/Part D)	1,106,882	43,350	4,311	13,234	17,159	36,845	89,728
	(6.6%)	(26.3%)	(15.0%)	(15.6%)	(35.7%)	(14.2%)	(19.6%)
Race/ethnicity^b
Asian	–	5.2%	5.1%	5.4%	4.7%	4.6%	4.9%
Non-Hispanic Black	–	10.0%	11.5%	9.5%	14.2%	10.3%	10.4%
Non-Hispanic White	–	69.8%	67.1%	69.4%	63.9%	70.7%	69.6%
Hispanic/Latino	–	12.0%	13.3%	12.7%	14.2%	11.6%	12.1%
Quartiles of socioeconomic status^c
1 (Low SES)	–	26,213	4925	12,533	10,871	44,102	76,950
		(15.9%)	(17.2%)	(14.8%)	(22.6%)	(17.0%)	(16.8%)
2	–	37,290	6656	17,397	12,328	61,071	104,821
		(22.6%)	(23.2%)	(20.6%)	(25.6%)	(23.5%)	(22.9%)
3	–	44,086	7798	22,038	12,452	70,744	122,812
		(26.7%)	(27.2%)	(26.1%)	(25.9%)	(27.2%)	(26.8%)
4 (High SES)	–	54,937	8813	31,324	11,635	79,886	146,018
		(33.3%)	(30.7%)	(37.0%)	(24.2%)	(30.7%)	(31.9%)
Missing/unknown	–	2,555	506	1,318	845	4,111	7,448
		(1.6%)	(1.8%)	(1.6%)	(1.8%)	(1.6%)	(1.6%)

All values are presented as n (%) unless otherwise stated.

Key: HIRD: healthcare integrated research database; HSCT: hematopoietic stem cell transplant; HSTM: hematologic or solid tumor malignancy; IC: immunocompromised; IQR: interquartile range; IS: immunosuppressive; PID: primary immunodeficiency; SD: standard deviation; SDOH: social determinants of health; SES: socioeconomic status; SOT: solid organ transplant.

^aMeasured from the start of the study period (1 April 2018) to day 365 after the first 12 months of continuous enrollment between 1 April 2019 and 31 March 2022.

^bFrom the 2017 American Community Survey census block groups (based on zip code)⁴¹. The race/ethnicity percentages displayed represent the mean distribution of race/ethnicity in the communities in which individuals resided, as individual-level data were not available.

^cThe SES index is a composite measure based on seven SDOH variables proposed by the Agency for Healthcare Research and Quality. A score of 4 indicates the patient is in the top 25% of SES and a score of 1 indicates the patient is in the bottom 25% of SES using all Census block groups and 2017 as the reference basis for calculation. Patients unable to be linked to SDOH data or have at least one of the seven variables missing were categorized as unknown.

Patients in the overall HIRD population appeared healthier, with fewer comorbidities than patients in the IC population; the HIRD population had a median QCI score of 0, while the median QCI scores ranged from 1 to 4 across the IC cohorts (Table 2). The ESRD cohort had the highest QCI median score (4), and the IS treatment cohort had the lowest median score (1). The five comorbidities with the highest prevalence in the composite IC cohort included hypertension (55.1%), cancer (44.2%), obesity (31.0%), atherosclerotic cardiovascular disease (ASCVD; 27.8%), and chronic pulmonary disease (27.2%; including asthma and chronic obstructive pulmonary disease [COPD]). In contrast, the five comorbidities with the highest prevalence in the HIRD population were hypertension (21.7%), obesity (15.2%), anxiety (14.5%), depression (11.6%), and chronic pulmonary disease (10.7%). Comorbidities for the individual cohorts are shown in Table 2.

Table 2. Baseline (variable) clinical characteristics assessed from study start to index date.

Clinical Characteristics	HIRD Source Population^a	HSTM	HSCT/SOT	PID	ESRD	IS Treatment	Composite IC Cohort
Number of patients	16,873,161	165,081	28,698	84,610	48,131	259,914	458,049
		(1.0%)	(0.2%)	(0.5%)	(0.3%)	(1.5%)	(2.7%)
QCI score
Mean (SD)	0.4	4.0	3.4	2.4	3.9	2.3	2.5
	(1.1)	(2.6)	(2.5)	(2.6)	(2.6)	(2.6)	(2.5)
Median (IQR)	0	3	3	2	4	1	2
	(0–0)	(2–6)	(2–5)	(0–4)	(2–5)	(0–3)	(1–4)
Target comorbidities of interest
Anxiety	2,445,496	41,555	7,183	27,529	12,007	72,378	121,641
	(14.5%)	(25.2%)	(25.0%)	(32.5%)	(24.9%)	(27.8%)	(26.6%)
ASCVD	1,251,806	52,188	11,681	25,812	29,343	62,681	127,490
	(7.4%)	(31.6%)	(40.7%)	(30.5%)	(61.0%)	(24.1%)	(27.8%)
Asthma	1,181,668	18,617	3374	19,318	6367	37,702	66,862
	(7.0%)	(11.3%)	(11.8%)	(22.8%)	(13.2%)	(14.5%)	(14.6%)
CKD	283,686	14,803	13,007	14,789	42,013	24,440	68,014
	(1.7%)	(9.0%)	(45.3%)	(17.5%)	(87.3%)	(9.4%)	(14.8%)
COPD	425,474	22,126	3228	11,200	11,122	29,195	55,724
	(2.5%)	(13.4%)	(11.2%)	(13.2%)	(23.1%)	(11.2%)	(12.2%)
Depression	1,956,683	36,053	6841	23,825	12,890	62,531	108,060
	(11.6%)	(21.8%)	(23.8%)	(28.2%)	(26.8%)	(24.1%)	(23.6%)
Diabetes	1,379,068	37,146	10,260	19,315	28,605	49,352	105,969
	(8.2%)	(22.5%)	(35.8%)	(22.8%)	(59.4%)	(19.0%)	(23.1%)
Heart failure	338,382	17,309	6268	10,541	21,497	20,770	52,329
	(2.0%)	(10.5%)	(21.8%)	(12.5%)	(44.7%)	(8.0%)	(11.4%)
Hypertension	3,654,551	99,685	21,094	43,618	44,397	131,348	252,312
	(21.7%)	(60.4%)	(73.5%)	(51.6%)	(92.2%)	(50.5%)	(55.1%)
Liver disease	558,125	29,531	7,488	15,785	11,308	43,263	70,311
	(3.3%)	(17.9%)	(26.1%)	(18.7%)	(23.5%)	(16.6%)	(15.4%)
Myocardial infarction	180,822	8339	2,602	4678	9,820	10,398	24,700
	(1.1%)	(5.1%)	(9.1%)	(5.5%)	(20.4%)	(4.0%)	(5.4%)
Obesity	2,572,309	48,224	8971	25,058	21,489	82,580	142,185
	(15.2%)	(29.2%)	(31.3%)	(29.6%)	(44.6%)	(31.8%)	(31.0%)
PAD	468,400	27,188	6,633	13,995	18,636	30,327	65,565
	(2.8%)	(16.5%)	(23.1%)	(16.5%)	(38.7%)	(11.7%)	(14.3%)
RA	163,472	5,805	762	11,810	1,875	58,944	66,042
	(1.0%)	(3.5%)	(2.7%)	(14.0%)	(3.9%)	(22.7%)	(14.4%)
Smoking^b	1,651,507	49,730	7,699	20,390	16,804	71,462	120,283
	(9.8%)	(30.1%)	(26.8%)	(24.1%)	(34.9%)	(27.5%)	(26.3%)

All values are presented as n (%) unless otherwise stated.

Key: ASCVD: atherosclerotic cardiovascular disease; CHF: congestive heart failure; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; HIRD: healthcare integrated research database; HSCT: hematopoietic stem cell transplant; HSTM: hematologic or solid tumor malignancy; IC: immunocompromised; IQR: interquartile range; IS: immunosuppressive; PAD: peripheral arterial disease; PID: primary immunodeficiency; PVD: peripheral vascular disease; QCI: Quan-Charlson comorbidity index; RA: rheumatoid arthritis; SD: standard deviation; SOT: solid organ transplant.

^aMeasured from the start of the study period (1 April 2018) to day 365 after the first 12 months of continuous enrollment between 1 April 2019 and 31 March 2022.

^bBased on a combination of diagnosis and procedure codes as well as any pharmacy claims for smoking cessation products.

While the median number of immunocompromising conditions for patients in most of the individual IC cohorts was 1 (except for PID and HSCT/SOT, where the median was 2), 19.8% of the composite IC cohort had ≥2 immunocompromising conditions (Figure 3). The majority of patients in the HSTM cohort (90.8%) had solid tumor malignancies (Table 2). Among the HSCT/SOT cohort, the majority (73.3%) received a solid organ transplant (with kidney transplants being the most common [42.8%]). Among the ESRD cohort, the majority of patients (84.1%) were on dialysis. Immunocompromising conditions at baseline for the individual cohorts are shown in Table 3.

Figure 3. Categorical number of immunocompromising conditions per IC cohort.

Key: ESRD: end-stage renal disease; HSCT: hematopoietic stem cell transplant; HSTM: hematologic or solid tumor malignancy; IC: immunocompromised; IS: immunosuppressive; PID: primary immunodeficiency; SOT: solid organ transplant.

Note: Due to rounding, percentages may not add up to 100%.

Table 3. Baseline immunocompromising conditions and is therapies.

Clinical Characteristics^a	HSTM	HSCT/SOT	PID	ESRD	IS Treatment	Composite IC Cohort
Number of patients	165,081	28,698	84,610	48,131	259,914	458,049
	(1.0%)	(0.2%)	(0.5%)	(0.3%)	(1.5%)	(2.7%)
Number of immunocompromising conditions
Mean (SD)	1.3	2.4	2.0	1.7	1.4	1.2
	(0.54)	(0.94)	(0.99)	(0.96)	(0.64)	(0.54)
Median (IQR)	1	2	2	1	1	1
	(1–2)	(2–3)	(1–3)	(1–2)	(1–2)	(1–1)
Immunocompromising conditions of interest
Hematologic or STM	165,081	11,826	24,051	12,031	76,988	202,592
	(100%)	(41.2%)	(28.4%)	(25.0%)	(29.6%)	(44.2%)
STM	149,952	7540	17,943	10,745	68,608	181,391
	(90.8%)	(26.3%)	(21.2%)	(22.3%)	(26.4%)	(39.6%)
Hematologic cancers	23,537	6906	10,387	2335	15,352	32,148
	(14.3%)	(24.1%)	(12.3%)	(4.9%)	(5.9%)	(7.0%)
HSCT or SOT	3316	28,698	12,247	7768	14,973	25,383
	(2.0%)	(100%)	(14.5%)	(16.1%)	(5.8%)	(5.5%)
SOT	1069	21,025	9836	7472	13,392	19,484
	(0.6%)	(73.3%)	(11.6%)	(15.5%)	(5.2%)	(4.3%)
Heart	93	1936	1173	367	1361	1922
	(0.1%)	(6.7%)	(1.4%)	(0.8%)	(0.5%)	(0.4%)
Heart/lung	≤10	149	112	39	103	149
		(0.5%)	(0.1%)	(0.1%)	(0.0%)	(0.0%)
Kidney	510	12,282	6,251	6,598	8,900	11,367
	(0.3%)	(42.8%)	(7.4%)	(13.7%)	(3.4%)	(2.5%)
Liver	252	4610	2,538	929	3300	4463
	(0.2%)	(16.1%)	(3.0%)	(1.9%)	(1.3%)	(1.0%)
Lung	95	1230	740	205	763	1108
	(0.1%)	(4.3%)	(0.9%)	(0.4%)	(0.3%)	(0.2%)
Other/unspecified	327	3989	1818	1136	1963	3816
	(0.2%)	(13.9%)	(2.1%)	(2.4%)	(0.8%)	(0.8%)
HSCT	2442	8151	2779	394	1855	6380
	(1.5%)	(28.4%)	(3.3%)	(0.8%)	(0.7%)	(1.4%)
PID	4298	4983	84,610	2,724	10,994	56,360
	(2.6%)	(17.4%)	(100%)	(5.7%)	(4.2%)	(12.3%)
ESRD or history of dialysis^b	1,884	8015	5879	48,131	7463	41,906
	(1.1%)	(27.9%)	(6.9%)	(100%)	(2.9%)	(9.1%)
With dialysis	1,689	7601	5618	40,497	6965	35,728
	(1.0%)	(26.5%)	(6.6%)	(84.1%)	(2.7%)	(7.8%)
Without dialysis	195	414	261	7,634	498	6,178
	(0.1%)	(1.4%)	(0.3%)	(15.9%)	(0.2%)	(1.3%)
Use of IS treatment or similar products	37,983	16,601	39,556	10,594	259,914	243,012
	(23.0%)	(57.8%)	(46.8%)	(22.0%)	(100%)	(53.1%)
Alkylating agents	21,250	1,600	4,849	1,128	38,821	24,183
	(12.9%)	(5.6%)	(5.7%)	(2.3%)	(14.9%)	(5.3%)
Antimetabolites	13,715	1268	10,212	1004	78,028	69,999
	(8.3%)	(4.4%)	(12.1%)	(2.1%)	(30.0%)	(15.3%)
Azathioprine	460	944	2,854	638	12,027	12,456
	(0.3%)	(3.3%)	(3.4%)	(1.3%)	(4.6%)	(2.7%)
Basiliximab	≤10	59	51	39	64	58
		(0.2%)	(0.1%)	(0.1%)	(0.0%)	(0.0%)
Belimumab	43	14	292	28	1206	1254
	(0.0%)	(0.0%)	(0.3%)	(0.1%)	(0.5%)	(0.3%)
Calcineurin inhibitors	973	11,717	8704	5543	14,317	14,279
	(0.6%)	(40.8%)	(10.3%)	(11.5%)	(5.5%)	(3.1%)
CAR T-cell therapy	71	123	147	19	80	121
	(0.0%)	(0.4%)	(0.2%)	(0.0%)	(0.0%)	(0.0%)
High-dose corticosteroids^c	13,520	4543	15,020	3888	86,159	85,238
	(8.2%)	(15.8%)	(17.8%)	(8.1%)	(33.1%)	(18.6%)
IL-17A inhibitors	192	30	846	51	9659	9592
	(0.1%)	(0.1%)	(1.0%)	(0.1%)	(3.7%)	(2.1%)
IL-23 inhibitors	265	49	1361	93	13,598	13,602
	(0.2%)	(0.2%)	(1.6%)	(0.2%)	(5.2%)	(3.0%)
Integrin receptor antagonists	164	64	1092	55	6607	6699
	(0.1%)	(0.2%)	(1.3%)	(0.1%)	(2.5%)	(1.5%)
JAK inhibitors	221	33	1214	55	5837	5968
	(0.1%)	(0.1%)	(1.4%)	(0.1%)	(2.2%)	(1.3%)
MMF	739	7159	7018	3873	14,143	13,996
	(0.4%)	(24.9%)	(8.3%)	(8.0%)	(5.4%)	(3.1%)
mTOR inhibitors	723	1599	1391	614	2563	2562
	(0.4%)	(5.6%)	(1.6%)	(1.3%)	(1.0%)	(0.6%)
Ocrelizumab	55	18	767	29	4238	4325
	(0.0%)	(0.1%)	(0.9%)	(0.1%)	(1.6%)	(0.9%)
Rituximab and other B-cell targeted therapies	3865	888	3407	600	10,173	8480
	(2.3%)	(3.1%)	(4.0%)	(1.2%)	(3.9%)	(1.9%)
Selective T-cell costimulation blockers	234	397	1202	373	4599	4707
	(0.1%)	(1.4%)	(1.4%)	(0.8%)	(1.8%)	(1.0%)
S1PR modulators	39	≤10	205	≤10	1984	2005
	(0.0%)		(0.2%)		(0.8%)	(0.4%)
TNF inhibitors	1292	207	8510	395	58,774	59,676
	(0.8%)	(0.7%)	(10.1%)	(0.8%)	(22.6%)	(13.0)

All values are presented as n (%) unless otherwise stated.

Key: CAR: chimeric antigen receptor; ESRD: end-stage renal disease; HSCT: hematopoietic stem cell transplant; HSTM: hematologic or solid tumor malignancy; IC: immunocompromised; IL: interleukin; IQR: interquartile range; IS: immunosuppressive; JAK: Janus kinase; MMF: mycophenolate mofetil; mTOR: mammalian target of rapamycin; PID: primary immunodeficiency; S1PR: sphingosine-1-phosphate receptor; SD: standard deviation; SOT: solid organ transplant; TNF: tumor necrosis factor.

^aAssessed from the study period start date (1 April 2018) to the index date.

^bBased on the presence of diagnosis and procedure codes. Categories are mutually exclusive. If patients had a diagnosis or procedure code for dialysis at any point prior to index, they were captured as with dialysis.

^cDefined as ≥20 mg of prednisone or equivalent daily for ≥2 weeks.

Within the IS treatment cohort, the most commonly used treatments were high-dose corticosteroids (33.1%; defined as ≥20 mg of prednisone or equivalent daily for ≥2 weeks), antimetabolites (30.0%), tumor necrosis factor (TNF) inhibitors (22.6%), and alkylating agents (14.9%). A majority (57.8%) of patients in the HSCT/SOT cohort used IS treatments at baseline; of the remaining IC cohorts, 53.1% in the composite IC cohort, 46.8% in the PID cohort, 23.0% in the HSTM cohort, and 22.0% in the ESRD cohort used IS treatments at baseline. Specific IS treatments used by patients across all IC cohorts are shown in Table 3.

COVID-19 prevalence and incidence

Overall, 13.5% (n = 61,865) of IC patients developed COVID-19 during the follow-up period. Within the individual IC cohorts, ESRD had the highest proportion of patients who developed COVID-19 (20.1%), followed by PID (15.8%), HSCT/SOT (15.7%), IS treatment (13.8%), and HSTM (9.4%). In the HIRD source population, 9.7% of members developed COVID-19 during the follow-up period.

Monthly IRs of COVID-19 per 1000 person-years for all IC cohorts are shown in Figure 4(A). Figure 4(B) displays the weekly COVID-19 case rates per 100,000 population published by the Centers for Disease Control and Prevention (CDC)⁴⁴, which shows a similar pattern of COVID-19 rate surges and troughs. The overall IR of COVID-19 was 101.3 per 1000 person-years in the composite IC cohort. Within the individual IC cohorts, ESRD had the highest overall IR of COVID-19 (195.0 per 1000 person-years) and the highest IR of severe/critical COVID-19 (79.4 per 1000 person-years), while HSTM had the lowest overall IR of COVID-19 (68.3 per 1000 person-years) and the lowest IR of severe/critical COVID-19 (8.4 per 1000 person-years). Incidence rates of COVID-19 by severity are shown for each IC cohort in Figure 5. Overall and monthly IRs of COVID-19 in the HIRD source population were not available at the time of submission.

Figure 4. A. Post-index incidence rate of COVID-19 per 1000 person-years. B. US weekly case rate of COVID-19 per 100,000 population as reported by the CDC.

Key: CDC: Centers for Disease Control and Prevention; US: United States.

The dotted lines in Figures 4(A,B) represent the transition from different variants throughout the COVID-19 pandemic. Data on variants were obtained from GISAID and CDC Nowcast. [62,63]

The shaded portion in Figure 4(B) represents the weekly case rate per 100,000 population as reported by the CDC from 1 April 2020 to 31 March 2022⁴⁴.

Figure 5. Post-index incidence rate of COVID-19 by severity per 1000 person-years.

Key: ESRD: end-stage renal disease; HSCT: hematopoietic stem cell transplant; HSTM: hematologic or solid tumor malignancy; IC: immunocompromised; IS: immunosuppressive; PID: primary immunodeficiency; SOT: solid organ transplant.

HCRU and healthcare costs associated with COVID-19 hospitalization

Within the composite IC cohort, 23.5% of patients (n = 14,516) had hospitalizations associated with their first COVID-19 diagnosis, with a fairly even split between moderate/non-ICU (n = 7446) and severe/critical/ICU (n = 7070) hospitalizations. Rates of COVID-19-related hospitalizations varied across the individual IC cohorts, from 15.8% (n = 5646) in the IS treatment cohort to 65.1% (n = 6294) in the ESRD cohort (Table 4). The mean LOS associated with the first COVID-19 hospitalization was 15 days in the composite IC cohort, with a mean LOS of 11 days for moderate disease (non-ICU hospitalization) and 20 days for severe/critical disease (ICU hospitalization). Within the individual IC cohorts, LOS ranged from 10 days in the HSTM cohort to 23 days in the ESRD cohort.

Table 4. HCRU and costs associated with hospitalization for first COVID-19 diagnosis.

	HSTM	HSCT/SOT	PID	ESRD	IS Treatment	Composite IC Cohort
Number of patients	15,573	4517	13,364	9673	35,800	61,865
Patients with hospitalization associated with first COVID-19 diagnosis, n (%)
Overall (ICU + non-ICU)	3820	1467	3741	6294	5646	14,516
	(24.5%)	(32.5%)	(28.0%)	(65.1%)	(15.8%)	(23.5%)
Severe/Critical (ICU)	1626	680	1673	3812	2370	7070
	(42.6%)	(46.4%)	(44.7%)	(60.6%)	(42.0%)	(48.7%)
Moderate (non-ICU)	2194	787	2068	2482	3276	7446
	(57.4%)	(53.6%)	(55.3%)	(39.4%)	(58.0%)	(51.3%)
Length of stay, days
Overall (ICU + non-ICU)
Mean (SD)	9.8	15.4	13.1	22.7	10.7	15.4
	(13.03)	(27.08)	(20.34)	(30.71)	(16.76)	(23.96)
Median (IQR)	6	7	6	13	6	8
	(3–11)	(4–16)	(4–14)	(6–27)	(3–12)	(4–17)
Severe/Critical (ICU)
Mean (SD)	12.1	20.3	17.5	25.9	13.9	19.9
	(14.99)	(29.08)	(23.88)	(29.27)	(18.70)	(25.67)
Median (IQR)	7	10	10	17	8	12
	(4–14)	(5–22)	(5–20)	(8–31)	(4–16)	(5–23)
Moderate (non-ICU)
Mean (SD)	8.1	11.1	9.5	17.8	8.5	11.2
	(11.07)	(24.45)	(16.08)	(32.20)	(14.79)	(21.37)
Median (IQR)	5	5	5	8	5	5
	(3–9)	(3–9)	(3–9)	(4–19)	(3–8)	(3–11)
All-cause total costs (health plan paid + patient paid), 2021 USD^b
Overall (ICU + non-ICU)
Mean (SD)	$30,671	$74,722	$53,945	$102,224	$40,886	$64,029
	($68,253)	($243,935)	($161,443)	($219,330)	($103,368)	($166,814)
Median (IQR)	$16,311	$20,157	$21,428	$29,555	$19,202	$20,674
	($2193–$30,180)	($3,027–$44,679)	($6393–$40,903)	($6027–$94,935)	($3969–$37,137)	($3624–$49,553)
Severe/Critical (ICU)
Mean (SD)	$41,851	$121,609 ($340,172)	$85,398	$136,999	$56,704	$96,829
	($88,750)		($229,309)	($252,302)	($113,894)	($213,884)
Median (IQR)	$20,414	$31,332	$30,287	$54,567	$25,386	$32,264
	($4,020–$39,847)	($12,724–$71,911)	($16,056–$64,124)	($19,325–$148,744)	($12,910–$52,673)	($15,201–$84,708)
Moderate (non-ICU)
Mean (SD)	$22,386	$34,210	$28,501	$48,814	$29,443	$32,885
	($45,985)	($86,454)	($56,363)	($139,738)	($93,391)	($93,937)
Median (IQR)	$13,416	$15,085	$16,972	$14,637	$16,217	$15,263
	($1836–$24,277)	($2014–$29,572)	($2591–$29,661)	($1957–$33,261)	($2539–$29,271)	($2060–$28,649)

Key: ECMO: extracorporeal membrane oxygenation; ESRD: end-stage renal disease; HCRU: healthcare resource utilization; HSCT: hematopoietic stem cell transplant; HSTM: hematologic or solid tumor malignancy; IC: immunocompromised; ICU: intensive care unit; IQR: interquartile range; IS: immunosuppressive; PID: primary immunodeficiency; SOT: solid organ transplant.

Severity is defined as follows:.

- Severe/Critical: ≥1 inpatient admission for COVID-19 with intensive care unit admission, evidence of ECMO, mechanical ventilation use, high-flow oxygen via nasal cannula, or discharge status of expired.

- Moderate: ≥1 inpatient admission for COVID-19 and does not meet severe/critical definition as defined above.

^aApproximately 90% of patients classified as severe/critical had an ICU stay.

^bCosts were adjusted to 2021 USD according to medical care price index information provided by the US Bureau of Labor Statistics.[42].

Mean total costs (health plan paid + patient paid) associated with the first COVID-19 hospitalization were $64,029 in the composite IC cohort, with costs for severe/critical disease ($96,829) noted to be roughly 3 times higher than those for moderate disease ($32,885). Within the individual IC cohorts, overall hospitalization costs ranged from $30,671 in the HSTM cohort to $102,224 in the ESRD cohort (Table 4). Median costs were generally lower, regardless of COVID-19 severity or IC cohort. Mean aggregate costs totaled $929,442,740 for the 14,516 IC patients with hospitalizations associated with their first COVID-19 diagnosis.

All-cause HCRU and costs paid by health plans and patients were captured in the 30-day pre-COVID-19 period (as a pre-COVID-19 “baseline”) and the 30-day post-COVID-19 period for IC patients who had at least 30 days of post-infection continuous enrollment (N = 30,437). The number and percentage of patients who had at least one hospitalization was almost 4 times higher (8173 [26.9%] vs 2143 [7.0%]) post-COVID-19 compared to pre-COVID-19 in the composite IC cohort. For ER visits, the number of patients who had at least one visit was more than 3 times greater (5997 [19.7%] vs 1806 [5.9%]) between the two periods, respectively. Total all-cause paid costs were approximately 2.5 times higher ($18,673 vs $7613) in the post-COVID-19 period than the pre-COVID-19 period, primarily driven by inpatient costs. Healthcare resource utilization and costs in the 30-day pre-COVID-19 and 30-day post-COVID-19 periods for all IC cohorts may be found in Table 5. Antiviral medications were used in the 30-day pre- and post-COVID-19 periods for less than 1% population among all cohorts.

Table 5. All-cause HCRU and costs in the 30-day pre-COVID-19 (“baseline”) period and the 30-day post-COVID-19 period^a.

	HSTM (n = 8116)		HSCT/SOT (n = 2058)		PID (n = 6475)		ESRD (n = 4463)		IS Treatment (n = 17,332)		Composite IC Cohort (N = 30,437)
	Pre-COVID	Post-COVID	Pre-COVID	Post-COVID	Pre-COVID	Post-COVID	Pre-COVID	Post-COVID	Pre-COVID	Post-COVID	Pre-COVID	Post-COVID
All-cause inpatient hospitalizations
≥1 visit	554	2319	188	819	506	2067	859	2713	892	3620	2143	8173
	(6.8%)	(28.6%)	(9.1%)	(39.8%)	(7.8%)	(31.9%)	(19.3%)	(60.8%)	(5.2%)	(20.9%)	(7.0%)	(26.9%)
LOS, days, mean (SD)	8.4	8.9	10.2	12.2	8.4	11.5	15.5	20.4	8.2	9.5	11.1	12.9
	(13.3)	(11.7)	(18.7)	(20.3)	(15.2)	(17.7)	(23.8)	(28.7)	(13.9)	(14.5)	(18.1)	(20.8)
All-cause emergency room visits
≥1 visit	410	1715	113	455	484	1243	464	856	869	3534	1806	5997
	(5.1%)	(21.1%)	(5.5%)	(22.1%)	(7.5%)	(19.2%)	(10.4%)	(19.2%)	(5.0%)	(20.4%)	(5.9%)	(19.7%)
All-cause total costs (health plan paid + patient paid), 2021 USD^b
Mean (SD)	$8303	$15,066	$9144	$30,181	$7268	$20,970	$16,240	$57,053	$7013	$13,316	$7613	$18,673
	($20,740)	($42,539)	($37,324)	($117,565)	($20,063)	($80,552)	($81,492)	($146,555)	($44,199)	($43,270)	($46,535)	($70,923)
Median	$1247	$2779	$1478	$4639	$1365	$3865	$2503	$15,297	$1575	$3437	$1206	$3205

All values are presented as n (%) unless otherwise stated.

Key: ESRD: end-stage renal disease; HCRU: healthcare resource utilization; HSCT: hematopoietic stem cell transplant; HSTM: hematologic or solid tumor malignancy; IC: immunocompromised; IS: immunosuppressive; LOS: length of stay; PID: primary immunodeficiency; SOT: solid organ transplant; USD: United States dollars.

^a Among patients who had at least 30 days of post-infection continuous enrollment.

^b Costs were adjusted to 2021 USD according to medical care price index information provided by the US Bureau of Labor Statistics.[42].

Discussion

This analysis provides robust real-world data on COVID-19 risks and outcomes in IC populations in the US. Within the overall population, 2.7% of patients in this study were identified as IC (either due to an immunocompromising condition or the use of an IS treatment). This result aligns with the most recently available evidence showing an estimated prevalence of immune suppression/compromise of 2% to 3% in US adults^36,37.

The prevalence of COVID-19 among the IC cohorts in this study varied, ranging from 9.4% in the HSTM cohort to 20.1% in the ESRD cohort. In a US healthcare claims analysis of Medicare patients (median age: 66 years) undergoing chronic dialysis in 2020, the prevalence rate of COVID-19 was 12.1%⁴⁵. We surmise that the higher prevalence of COVID-19 seen in our ESRD cohort is likely due to the longer study period (1 April 2020–31 March 2022) and the different predominant variants, as well as evolving transmissibility and virulence seen with each variant over time. Patients receiving hemodialysis may also have a greater susceptibility to COVID-19 due to the procedure typically being performed in an outpatient setting three times per week^46,47. Interestingly, the prevalence of COVID-19 in the HIRD source population (9.7%) was slightly higher than that of the HSTM cohort (9.4%); this could be due to enhanced and consistent education from healthcare professionals, self-recognition of immune compromise, and continued lifestyle modifications to prevent SARS-CoV-2 infection (e.g. staying current with COVID-19 vaccinations/boosters, wearing a mask, washing hands frequently, physical distancing, and even self-isolation) in patients being actively treated for hematologic or solid tumor malignancies. While we did not examine patients with hematologic malignancies and solid tumor malignancies separately in this analysis, it is an area of interest for additional research.

Direct HCRU and costs paid by health plans and patients associated with COVID-19 hospitalizations were high across the IC cohorts, with the highest HCRU and costs seen in the ESRD cohort. Healthcare utilization and paid costs for IC patients in the 30 days prior to COVID-19 diagnosis provided a “baseline” and allowed us to observe the incremental impact of HCRU and costs due to COVID-19. In our study, the mean all-cause paid costs for the composite IC cohort in the 30-day pre-COVID-19 period were $7613 and increased to $18,673 in the 30-day post-COVID-19 period. In DeMartino 2022⁴⁸, a separate analysis of a US commercial healthcare plan, mean total incurred costs in patients without a COVID-19 diagnosis were $660 (2020 USD), and incurred costs in patients with a COVID-19 diagnosis were $4366 in the first month after the diagnosis. While the results from these studies are not directly comparable, we observed that the mean “baseline” paid costs for our composite IC population were 11.5 times higher than the mean total costs for the general population without COVID-19 in DeMartino 2022. Further, the mean paid costs for our composite IC population in the 30-day post-COVID-19 period were more than 4 times higher than the mean total costs for the general population with COVID-19 diagnosis in DeMartino 2022. Although our study and the DeMartino 2022 study differed in design and patient characteristics, both utilized administrative claims data sourced from large, nationally representative and commercially insured populations. Our results would indicate that total all-cause costs related to COVID-19 for IC populations appear to be substantially greater than those seen for the general population, even when taking the pre-COVID-19 “baseline” costs into account. This difference is likely due to the increased complexity of the IC population due to their underlying health condition(s), which may also complicate the SARS-CoV-2 infection.

In the composite IC cohort in the current study, the total aggregate paid costs associated with the first COVID-19 hospitalization for 14,516 IC patients were nearly $1 billion based on the mean cost per hospitalization; this suggests that these relatively few IC patients not only incur significant cost burden to the healthcare system but also that there are outliers with risks for much more severe COVID-19 outcomes within both the composite IC cohort and the individual IC cohorts who require additional protection. Another potential cost driver that was not analyzed in the current study was the impact of delayed or missed treatment for existing conditions due to COVID-19. In a 2020 survey of 11,114 Medicare beneficiaries, 36% reported missing treatment for an ongoing condition⁴⁹. Missing or delaying treatment for IC conditions could potentially lead to worse outcomes and greater overall costs.

Based on the clinical characteristics observed within the IC population in this study, it is possible that an increased risk of severe COVID-19 outcomes is not solely due to immune compromise; it could also be related to the older median age and the increased number of comorbidities and other concomitant diseases seen in the IC cohorts compared to the overall HIRD source population. While we chose to investigate these specific IC populations for COVID-19-related risks and outcomes, it is important to note that these are not the only patients who can be classified as IC or may be at greater risk for severe COVID-19 and hospitalization. In addition, there are likely specific subgroups of patients within these individual IC cohorts, such as those with specific tumor types, longer duration of immunocompromising conditions, and longer duration/higher intensity of IS treatment, who are at even greater risk of severe COVID-19 outcomes than what was observed in the composite IC cohort. As the total aggregated costs in this population were quite significant, the identification of these patients warrants further study to ensure appropriate protection from COVID-19 (particularly with the emergence of new variants) and could result in the avoidance of some of these costs.

As the COVID-19 landscape has evolved, vaccinations and treatments have become available to help prevent and treat COVID-19. While patients with immunocompromising conditions tend to be highly vaccinated, they may not be able to mount a complete immune response, even when considered fully vaccinated and boosted^50–53. Immunocompromised patients have been shown to have lower concentrations of antibodies, and the antibodies that are present have less neutralization activity against SARS-CoV-2⁵⁴. In addition, the protection that vaccinations provide declines more quickly in comparison with immunocompetent patients⁵⁵. Monoclonal antibodies that were previously available under an emergency use authorization are no longer authorized for use as they are not effective against the currently circulating predominant variants of SARS-CoV-2⁵⁶. Antiviral medications such as nirmatrelvir/ritonavir and molnupiravir that can decrease the risk of progression to severe COVID-19 remain available and can decrease the risk of progression to severe COVID-19 although each drug comes with related challenges^57,58. Additionally, as much of the US population now has some form of immunity to SARS-CoV-2 (either through vaccination or exposure)⁵⁹, the use of other preventive measures such as masking and physical distancing has decreased in the general population. Staying current with COVID-19 vaccinations, masking, hand washing, and avoiding poorly ventilated areas are still recommended for IC patients, but an existing unmet need for additional pre-exposure prophylaxis for COVID-19 in patients with immunocompromising conditions remains. Several monoclonal antibodies are being studied in response to the emerging variants; one such long-acting monoclonal antibody is AZD3152, which is being evaluated for the pre-exposure prophylaxis of COVID-19 in patients aged ≥12 years with immunocompromising conditions⁶⁰.

Additional interventions to prevent COVID-19-related hospitalizations in the IC population are not only important from an individual perspective but also from a broader healthcare system perspective. The US healthcare system was under immense strain at the onset of the pandemic, with limited resources and increased healthcare worker shortages. Hospitalizations in the IC population likely caused additional strain on the system. Though the COVID-19 public health emergency has ended, implementation of effective pre-exposure prophylactic options that can decrease the risk of COVID-19-related hospitalizations in the IC population is still needed and may have a positive impact on the healthcare system as the COVID-19 landscape continues to evolve.

While claims data are extremely valuable for the efficient and effective examination of healthcare outcomes, treatment patterns, HCRU, and healthcare costs, they are ultimately collected for the purpose of payment (and not for research). Therefore, limitations associated with the use of claims data exist. Any COVID-19 vaccination or testing data that did not initiate a health insurance claim (e.g. federal COVID-19 testing sites, at-home antigen tests, federal vaccination sites, etc.) would not be captured in the claims data. Some patients who are asymptomatic or have mild cases of COVID-19 may never seek testing or treatment and would not be captured in the claims data. In addition, individuals with immunocompromising conditions may be more likely to be tested for COVID-19 due to the risks associated with their underlying condition or overall increased interactions within the healthcare system. The sensitivity and specificity of PCR and antigen tests for diagnosis of COVID-19 are different and individuals may be incorrectly identified as COVID-19 cases due to the inclusion of results from these types of tests, although no home testing results were utilized. The presence of a diagnosis code on a medical claim does not guarantee the positive presence of a disease, as the diagnosis code may be incorrectly coded or included as a rule-out criterion. Certain important patient clinical characteristics (e.g. individual-level SDOH, family history, etc.) are not available in claims data, and their effect cannot be measured in the analyses. Further, it is not possible to fully assess the impact of COVID-19 on the severity of underlying conditions from claims data alone; however, the worsening of underlying conditions by COVID-19 has been observed in patients with some neurological disorders by other researchers⁶¹. While this concept was not directly explored in this analysis, it could have an impact on multiple conditions that were studied. The observed utilization of antiviral medication may vary throughout the study period due to the evolving regulatory and clinical guidance associated with their use. As with all claims-based analyses, the study results may not be fully generalizable to the overall population because patients who have commercial or Medicare health insurance may have different characteristics from those with public or no health insurance. Patients who are uninsured, underinsured, or have limited access to general healthcare may have higher rates and related costs of COVID-19 than what was observed in the IC population in this study. Finally, this initial analysis only captures data through 31 March 2022 (through the early Omicron [BA.1/BA.2] wave) and does not include new variants. Additional data and ongoing analyses will be needed to understand the impact of new variants on the IC population.

Conclusion

The IC population tends to be highly vaccinated against COVID-19, yet they may remain inadequately protected due to an inability to produce a robust protective response to the vaccine. Results from this large US healthcare claims analysis show that patients with an immunocompromising condition or using IS treatment are at greater risk for COVID-19 and have a high prevalence of severe outcomes such as hospitalizations, as well as high HCRU and healthcare costs. While only 2.7% of the overall study population was IC, 13.5% of all IC patients in our study developed COVID-19 and 23.5% of those patients required hospitalization related to their initial COVID-19 diagnosis. Mean paid costs associated with these 14,516 COVID-19-related hospitalizations totaled nearly $1 billion, but median hospitalization costs suggest that there are outliers who are at even greater risk of very severe COVID-19 outcomes within both the overall IC population and individual IC cohorts. Given the general risks observed within the IC population and the known incomplete protection from vaccination, these patients require additional protective measures in order to resume social interactions and activities. Identification of these patients is an area of interest for further research, particularly as emerging variants may present new, unforeseen risks within the IC population. As the COVID-19 landscape continues to evolve, effective prophylactic options against COVID-19 are still needed to provide additional protection to IC patients.

Transparency

Declaration of financial/other relationships

C. Dube, L. Glasser, and M. Pollack are employees of AstraZeneca. M. Verduzco-Gutierrez has received honoraria and travel to give lectures related to long COVID-19. Unrelated to this work, she has been a consultant with AbbVie (consultant/advisor, speakers bureau), Merz (consultant/advisor, speakers bureau), Ipsen (grant/research, consultant/advisor, speakers bureau), Medtronic (consultant/advisor), and Piramal (speakers bureau). D. Cunningham has been a consultant/advisor for AstraZeneca. Carelon Research received funding from AstraZeneca to conduct this study. A. Ketkar, V. Willey, C. Wenziger, and C-C Teng are employees of Carelon Research (formerly HealthCore). A. Ketkar and V. Willey are shareholders of Elevance Health (formerly Anthem), which is a parent company of Carelon Research (formerly HealthCore). C. Dobie is an employee of Xcenda LLC and a consultant for AstraZeneca.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Conception/design of the study: AK, VW, MP, LG, MVG, DC; Acquisition/analysis of the data: AK, VW, CW, CCT; Interpretation of the data: All authors; Drafting of the paper or revising it critically for intellectual content: All authors; Final approval of the version to be published: All authors. All authors agree to be accountable for all aspects of the work.

Acknowledgements

Authors would like to acknowledge Andi Gundlach, PharmD, CMPP of Xcenda LLC (Carrollton, TX) for her writing and editorial assistance, which was funded by AstraZeneca.

Data availability statement

Due to contractual obligations to the data sources, these data are not permitted to be available for use by outside parties.

Additional information

Funding

This work was supported by AstraZeneca.