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. 2026 May 18;13(6):ofag295. doi: 10.1093/ofid/ofag295

Long-term Sequelae Associated With Severe West Nile Virus Disease in Maricopa County, Arizona, 2021

Anna C Fagre 1,2,#, Kathryn G Burr 3,4,5,#, Cedar L Mitchell 6,7,8, Mark J Delorey 9, Melissa Kretschmer 10, Karen Zabel 11, O’Zandra Floyd 12, Renate Schlaht 13, Austin Earley 14, Olivia Studebaker 15, Jennifer Lehman 16, Julie M Thompson 17, Madison Meyer 18, Olivia Hunziker 19, Meghan Schindler 20, Zoha Ahmed 21, Bernny E Apodaca 22, Joshua Sager 23, Rechelle Harrion 24, Sydney N Adams 25, Nicole Foley 26, Johanna Gleason-Vergados 27, Shelby Lyons 28, Brian F Borah 29, R Nicholas Staab 30, Irene Ruberto 31, Rebecca Sunenshine 32, J Erin Staples 33, Carolyn V Gould 34, Ariella P Dale 35,✉,3
PMCID: PMC13234615  PMID: 42253282

Abstract

Background

West Nile virus (WNV)–specific long-term sequelae (LTS) are not well-defined. We assessed LTS in patients hospitalized with WNV disease and compared their outcomes to an age- and sex-matched cohort of patients hospitalized with other infectious diseases.

Methods

A total of 159 patients with WNV disease and 75 patients with predominantly COVID-19 and coccidioidomycosis completed standardized assessment tools (modified Rankin Scale, modified Control and Prevention Symptom Inventory Checklist, and 36-Item Short Form Survey) 17–24 months after hospitalization.

Results

Among patients with WNV, 40% were transferred to long-term care facilities, and 83% experienced ongoing symptoms, including fatigue, myalgia, arthralgia, pain, and problems with sleep, memory, and concentration. Overall, 33% reported disabilities and 55% reported worse health than before illness. The hospitalized infectious disease comparators reported similar LTS but had worse adjusted physical composite scores and a higher proportion reporting poor or fair health.

Conclusions

Long-term sequelae in patients hospitalized with WNV were common up to 2 years after hospitalization, but similar findings to comparators suggest there might be common inflammatory or other physiologic pathways leading to post infectious sequelae or outcomes related to hospitalization. Providers caring for patients hospitalized with WNV should make patients and caregivers aware of the prolonged and possible incomplete recovery process.

Keywords: long-term sequelae, neuroinvasive disease, West Nile virus

West Nile virus (WNV) disease is the most common domestic arboviral illness in the United States, with more than 60 000 human disease cases and 3100 deaths reported over the past 25 years [1]. Approximately 20%–30% of infections result in febrile illness, and <1% develop neuroinvasive disease including meningitis, encephalitis, and acute flaccid myelitis. Patients with neuroinvasive disease have an overall mortality of 10%. There are no specific treatments for or human vaccines to prevent WNV disease [2].

Although the epidemiology and clinical characteristics of acute WNV disease are well-documented [3–5], less is known about long-term sequelae (LTS) in those who survive [4, 6]. A systematic review of LTS including patients from 29 studies found that more than half of patients with WNV disease experienced sequelae such as ongoing muscle weakness, fatigue, myalgia, memory loss, depression, and difficulty doing activities of daily living [7]. However, many of the studies were limited by short follow-up periods, small cohort sizes, lack of comparator or control groups, and varied, subjective methodologies for clinical assessments.

To address limitations of prior studies, we used standardized tools to assess for long-term symptoms and evaluate physical, cognitive, and functional outcomes of patients 17‒25 months after hospitalization with WNV disease during a large outbreak in Maricopa County, Arizona, in 2021 [8]. We compared outcomes in patients with WNV disease to those of a contemporary cohort of patients hospitalized with other reportable communicable diseases during the same time period to assess for WNV-specific LTS.

METHODS

We conducted a retrospective cohort study to evaluate LTS among patients hospitalized with WNV and compared their outcomes to patients hospitalized with other reportable communicable diseases. Eligible participants were Maricopa County residents ≥18 years of age hospitalized in Maricopa County during 1–31 June October 2021, with an International Classification of Diseases, Tenth Revision diagnosis code for WNV or other reportable communicable diseases selected for their potential to cause severe disease (Figure 1). Patients who met confirmed or probable case definitions under the National Notifiable Diseases Surveillance System (NNDSS) for these conditions were included. Diagnoses of disseminated coccidioidomycosis were excluded because of the potential chronicity of the infection and need for long-term therapy [9]. This research was reviewed and approved by the Centers for Disease Control and Prevention (CDC) Institutional Review Board (Protocol #7424, approved 2/27/23; see 45 C.F.R part 46; 21 C.F.R. part 56).

Figure 1.

For image description, please refer to the figure legend and surrounding text.

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Flowchart detailing the recruitment of study participants for the study of long-term sequelae associated with severe West Nile virus (WNV) disease in Maricopa County, Arizona, 2021. *Patients with selected diseases were identified in the Medical Electronic Disease Surveillance Intelligence System with verified hospitalization. Reported communicable diseases (provider or laboratory-reportable) selected for inclusion in the study on the basis of potential to cause severe disease included brucellosis; coccidioidomycosis (Valley Fever); dengue; streptococcal group A infection, invasive disease; influenza, Haemophilus influenzae, invasive disease; legionellosis; malaria; Q fever; respiratory syncytial virus; COVID-19; Streptococcus pneumoniae infection (pneumococcal invasive disease); typhoid fever; viral encephalitis; WNV infection. †We aimed to include all patients identified in the WNV group. Assuming a nonparticipation rate of 40% for the WNV group and a 67% nonparticipation rate for the comparator group, the number of comparators needed for a 1:1 ratio was calculated as the expected number of WNV patients in each age–sex stratum multiplied by 3. Adjustments were made to the final sampling when there were insufficient matched comparators in a given stratum. To increase the diversity of diseases represented in the comparator group, all patients with the selected reportable diseases other than COVID-19 or coccidioidomycosis were included. The remaining comparators needed were selected at random from a pool of patients with COVID-19 and coccidioidomycosis. ‡Infectious diseases in the final comparator group included COVID-19 (44, 58.7%), coccidioidomycosis (Valley Fever) (16, 21.3%), streptococcal group A infection, invasive disease (4, 5.3%), legionellosis (4, 5.3%), respiratory syncytial virus (3, 4.0%), brucellosis (2, 2.6%), H influenzae, invasive disease (1, 1.3%), and influenza (1, 1.3%). §Eligible participants were contacted by phone or email during February to June 2023.

Patients were identified using 3 data sources: Medical Electronic Disease Surveillance Intelligence System (MEDSIS), Arizona's reportable conditions surveillance system; hospital discharge data, which includes all Arizona hospitals except federal facilities; and the state death registry (Supplementary Methods). Patients in both groups—the WNV group and the hospitalized infectious disease comparator group (“comparator group”)—were matched on 5-year age blocks and sex. Group sizes in the matched cohort design were powered to detect a 2-point difference in physical composite summary (PCS) and mental composite summary (MCS) scores between the WNV and comparator groups as measured by the 36-Item Short Form Survey (version 2)® (SF-36v2, PRO CoRE 2.1 software, QualityMetric Inc., Johnston, RI, USA) [10]. We aimed to enroll all living patients hospitalized with WNV disease in Maricopa County during 2021, assuming a nonparticipation rate of 40% for sample size calculation. For the comparator group, we used a 67% nonparticipation rate based on county experience and previous studies during the COVID pandemic [11]. Therefore, to achieve a minimum 1:1 ratio (WNV to comparators) for the analysis, the number of comparators needed was calculated as the expected number of WNV patients in each age Johnston, RI–sex stratum multiplied by 3. Adjustments were made to the final sampling when there were insufficient matched comparators in certain strata. To increase the diversity of diseases represented in the comparator group, all patients with the selected reportable diseases other than COVID-19 or coccidioidomycosis were included. The remaining comparators needed were selected at random from a pool of patients with COVID-19 and coccidioidomycosis.

Eligible participants were contacted by phone or email during February to June 2023 (17–25 months after initial hospital admission). After confirming eligibility and obtaining informed consent, participants completed the survey either through a phone interview administered by a trained investigator or online via an e-mailed link. All correspondence and survey materials were made available in English and Spanish; for other languages, phone-based interpretation services were employed.

Surveys included demographic characteristics, details of the hospital say (eg, intensive care unit [ICU] stay, discharge status), outpatient follow-up, and underlying medical conditions. In addition, standardized health-related quality of life assessments were used, including (1) modified Rankin Scale (mRS) [12, 13]; (2) modified CDC Symptom Inventory Checklist [14], and (3) SF-36v2 [15, 16].

Study data were collected and managed using Research Electronic Data Capture [17]. Only completed surveys were analyzed, defined as those with a response to the mRS or at least one completed question in each SF-36v2 health domain. Statistical differences for patient characteristics, mRS, and CDC Symptom Inventory Checklist between the WNV and comparator groups were calculated using R software (R version 4.4.1, R Core Team, 2021). Fisher's exact test was used for categories having fewer than 5 individuals in a subcategory; otherwise, the χ2 or Cochran–Mantel–Haenszel tests were used. Wilcoxon Rank-sum test was used for continuous variables. Results were considered statistically significant if the P value was < .05. A linear mixed-effects model was used to analyze differences in SF-36v2 PCS and MCS scores between the WNV and comparator groups using the “lme4” package [18]. Predictor variables were selected using least absolute square selection operator (LASSO) for each outcome (PCS and MCS) to improve statistical precision [19, 20]. A random intercept was specified for each stratum. Median PCS and MCS scores were compared with median scores for the 2009 general population adjusted for differences in age distribution [10, 16].

RESULTS

Study Population

Of 12 393 total patients identified, 9985 patients were eligible for inclusion, and 1985 were selected to be contacted, including all 687 patients in the WNV group and 1298 patients in the comparator group (Figure 1). After excluding patients who could not be reached, declined to participate, or had died since identification, 163 (23.7%) in the WNV group and 95 (7.9%) in the comparator group were administered the survey; 159 (23.1%) in the WNV group and 75 (5.8%) in the comparator group completed the survey in full.

Surveillance case classification of participants in the WNV group, as reported in MEDSIS using the NNDSS definitions, included nonneuroinvasive disease (n = 18, 11%), meningitis (n = 66, 42%), encephalitis/meningoencephalitis (n = 70, 44%), and other neurologic disease (eg, Bell's palsy, optic neuritis; n = 5, 3.1%). Diseases in the comparator group included COVID-19 (n = 44, 59%), coccidioidomycosis (n = 16, 21%), streptococcal group A infection, invasive disease (4, 5%), legionellosis (4, 5%), respiratory syncytial virus (3, 4%), brucellosis (2, 3%), Haemophilus influenzae, invasive disease (1, 1%), and influenza (1, 1%) (Table 1).

Table 1.

Characteristics of Study Participants at Time of Survey Completion by Group Status (February to June 2023)—Maricopa County, Arizona

WNV Group Comparator Group P Valuea
(n = 159) (n = 75)
Age (years)
 Median (IQR) 70 (17.5) 69 (15.5) …
 Mean ± SD 66.8 ± 13.1 67.8 ± 13.1 …
Age groups (y)b
 <50 19 (11.9%) 5 (6.7%) …
 50–59 21 (13.2%) 11 (14.7%) …
 60–69 36 (22.6%) 22 (29.3%) …
 70–79 60 (37.7%) 24 (32.0%) …
 80+ 23 (14.5%) 13 (17.3%) …
Sexb
 Male 89 (56.0%) 47 (62.7%)
 Female 70 (44.0%) 28 (37.3%)
Race and Ethnicity <.01
 White, non-Hispanic/Latino 142 (89.3%) 51 (68.0%)
 Hispanic/Latino 7 (4.4%) 13 (17.3%)
 Other racesc 8 (5.0%) 10 (13.3%)
 Missing 2 (1.3%) 1 (1.3%)
Survey administration <.01
 Online 99 (62.3%) 32 (42.7%)
 Phone interview 60 (37.7%) 43 (57.3%)
Median time between hospital admission and date of survey (m; [range]) 19.8 (16.8, 23.2) 19.4 (17.1, 24.0) .91
Comorbidity categoriesd WNV group Comparator group P Valuea
(n = 106) (n = 55)
 Cardiovascular 60 (56.6%) 34 (61.8%) .93
 Endocrine 40 (37.7%) 30 (54.5%) .06
 Behavioral health 27 (26.0%) 12 (22.0%) .93
 Respiratory 22 (20.8%) 19 (34.5%) .09
 Autoimmune 22 (20.8%) 10 (18.2%) .95
 Immunosuppression 14 (13.2%) 14 (25.5%) .10
 Neurologic 13 (12.3%) 11 (20.0%) .32
 Renal 12 (11.3%) 17 (30.9%) <.01
 Hematologic 9 (8.5%) 11 (20.0%) .07
 Hepatic 4 (3.8%) 4 (7.3%) .60
 Other chronic disease 41 (38.7%) 22 (40.0%) .96
Diseases associated with hospitalization … (n = 75) …
 COVID-19 … 44 (58.7%) …
 Coccidioidomycosis, not disseminated … 16 (21.3%) …
 Invasive group A streptococcal infection … 4 (5.3%) …
 Legionellosis … 4 (5.3%) …
 Respiratory syncytial virus … 3 (4.0%) …
 Brucellosis … 2 (2.6%) …
 Invasive Haemophilus influenzae infection … 1 (1.3%) …
 Influenza … 1 (1.3%) …
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Abbreviations: IQR, interquartile range; WNV, West Nile virus.

aUsed Fisher's exact test for categories having fewer than 5 individuals in a subcategory; otherwise used the χ2 test or Cochran–Mantel–Haenszel test. Wilcoxon rank-sum test was used for continuous variables. Bolded values are less than 0.05.

bParticipants in each study group matched by age stratum and sex.

cOther races included Black, American Indian or Alaska Native, multiracial, and self-described responses. These were grouped together to censor small numbers.

dAs reported on survey. No comorbidities were reported by 53 of 159 WNV group and 20 of 75 comparator group.

Characteristics of Participants

The median age of participants in the WNV group was 70 years (interquartile range [IQR]: 17.5 years), and most (56%) were male (Table 1). Most participants in the WNV group (89%) identified as white, non-Hispanic/Latino. Patients with WNV were contacted a median of 19.8 months (range: 16.8–23.2) after initial hospital admission, and 62% completed the surveys online. Over two-thirds of patients in the WNV group reported the presence of comorbidities at time of hospitalization, most commonly cardiovascular (57%) and endocrine (38%) conditions. A smaller proportion of patients in the comparator group were white non-Hispanic/Latino (68%, P < .01) and completed the survey online (43%, P < .01). A higher proportion of comparators had renal disease (31% vs 11%; P < .01) and diabetes (36% vs 16%; P = .02). Patients in the comparator group were contacted a median of 19.4 months (range: 17.1–24.0) after initial hospital admission.

Outcomes and Sequelae

Patients with WNV reported a median hospital stay of 7 days (range: 2–124 days), and 31% reported being admitted to the ICU with a median stay of 4 days (range: 1–65 days) (Table 2). Sixty-three (40%) patients with WNV reported being transferred to a postacute care facility, 42 of whom (67%) specified inpatient rehabilitation facilities. Outpatient care referral was reported by 98 (62%) patients with WNV, of whom 22 (22%) reported home health, 20 (20%) rehabilitation, and 30 (31%) multiple types of care. Patients in the comparator group reported longer ICU lengths of stay (median: 7 days; range: 2–60 days) (P = .05) and were less likely to be transferred to postacute care facilities (16%, P < .01) or referred for outpatient care (55%, P = .04).

Table 2.

Hospitalization Characteristics Reported by Participants in the WNV Group and the Comparator Group a  During June to October 2021, Maricopa County, Arizona

WNV Group Comparator Group P Valueb
(n = 159) (n = 75)
Hospital length of stayc (median days; [range]) 7.0 (2, 124) 9.5 (1, 42) .41
ICU admissione 50 (31.4%) 31 (41.3%) …
ICU length of stayd (median days; [range]) 4.0 (1, 65) 7.0 (2, 60) .05
Hospital readmission 19 (11.9%) 15 (20.0%) .15
Inpatient postacute care transfer 63 (39.6%) 12 (16.0%) <.01
 Inpatient rehabilitation 42 (26.4%) 6 (8.0%)
 Skilled nursing facility or LTACH 7 (4.4%) 3 (4.0%)
 Unknownf 6 (8.8%) 0 (4.0%)
Outpatient care referral 98 (61.6%) 41 (54.7%) .04
 Home health 22 (13.8%) 16 (21.3%)
 Clinic visits 15 (9.4%) 11 (14.7%)
 Outpatient rehabilitation 20 (12.6%) 4 (5.3%)
 Multiple typesg 30 (18.9%) 5 (6.7%)
 Unknownf 11 (6.9%) 5 (6.7%)
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Abbreviations: ICU, intensive care unit; LTACH, long-term acute care hospital; WNV, West Nile Virus.

aReportable communicable diseases associated with hospitalization in the final comparator group: COVID-19 (44, 58.6%), coccidioidomycosis (Valley Fever) (16, 21.3%), streptococcal group A infection, invasive disease (4, 5.3%), legionellosis (4, 5.3%), respiratory syncytial virus (3, 4.0%), brucellosis (2, 2.6%), Haemophilus influenzae, invasive disease (1, 1.3%), and influenza (1, 1.3%).

bUsed Fisher's exact test for categories having fewer than 5 individuals in a subcategory; otherwise used the χ2test. Wilcoxon rank-sum test was used for continuous variables. Bolded values are less than 0.05.

cData available for 153 participants in the WNV group and 72 in the comparator group.

dData available for 139 participants in the WNV group and 25 in the comparator group.

e20 (12.6%) patients in the WNV group and 10 (13.3%) in the comparator group reported “unknown/unsure” responses.

fRespondent indicated that they did receive a transfer or referral but was unsure of the facility type for inpatient postacute transfer or where they were referred for outpatient care.

gRespondent reported multiple outpatient referral types from the listed options: outpatient rehabilitation, home health visits, clinic visits, or other.

On the mRS, 132 (83%) participants in the WNV group reported having ongoing symptoms (score ≥1) at the time of the survey, leading to slight-moderate disability in 45/132 (34%) and moderately severe-severe disability in 8/132 (6%) (Table 3). Of the 132 WNV participants with symptoms, the most common (occurring all or most of the time on the modified CDC Symptom Inventory Checklist) were fatigue (34%), myalgia (26%), sleep problems (25%), arthralgia (24%), memory problems (20%), concentration problems (19%), and headaches (13%) (Table 4). The comparator group had similar mRS responses (P = .17) and symptom frequencies as the WNV group, except for a higher proportion with shortness of breath (P = .04).

Table 3.

Responses to the Modified Rankin Scale for Participants in the WNV and Comparator Groupsa, February to June 2023, Maricopa County, Arizona

WNV Group Comparator Group P Valueb
(n = 159) (n = 75)
Scalec .17
 0 26 (16.4%) 22 (29.3%)
 1 79 (49.7%) 26 (34.7%)
 2 26 (16.4%) 13 (17.3%)
 3 19 (11.9%) 10 (13.3%)
 4 7 (4.4%) 4 (5.4%)
 5 1 (0.6%) 0 (0%)
 Missingd 1 (0.6%) 0 (0%)
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Abbreviation: WNV, West Nile Virus.

aReportable communicable diseases associated with hospitalization in the final comparator group: COVID-19 (44, 58.7%), coccidioidomycosis (Valley Fever) (16, 21.3%), streptococcal group A infection, invasive disease (4, 5.3%), legionellosis (4, 5.3%), respiratory syncytial virus (3, 4.0%), brucellosis (2, 2.6%), Haemophilus influenzae, invasive disease (1, 1.3%), and influenza (1, 1.3%).

bFisher's exact test.

cScale: 0 = no symptoms; 1 = no significant disability, can perform all usual activities; 2 = slight disability, cannot perform all previous activities but can look after own affairs; 3 = moderate disability, needs some help but can walk without assistance; 4 = moderately severe disability, cannot walk without assistance or attend to own bodily needs; 5 = severe disability, bedridden, incontinent, and requires constant care.

dRespondents were not required to answer this question.

Table 4.

Responses to the Modified CDC Symptom Inventory Checklista by Participants in the WNV and Comparator Groupsb, February to June 2023, Maricopa County, Arizona

WNV Group Comparator Group P Valuec
mRS score ≥1 n = 132 n = 53
Fatigue (%)—any reported 109 (82.6%) 48 (90.6%) .43
 All of the time 23 (17.4%) 11 (20.8%)
 Most of the time 22 (16.7%) 15 (28.3%)
 Some of the time 40 (30.3%) 12 (22.6%)
 A little of the time 24 (18.2%) 10 (18.9%)
 None of the time 19 (14.4%) 5 (9.4%)
 Missing 4 (3.0%) 0 (0%)
Muscle aches (%)—any reported 96 (72.7%) 39 (73.6%) .52
 All of the time 15 (11.4%) 10 (19.0%)
 Most of the time 19 (14.4%) 8 (15.1%)
 Some of the time 33 (25.0%) 14 (26.4%)
 A little of the time 29 (22.0%) 7 (13.2%)
 None of the time 30 (22.7%) 12 (22.6%) …
 Missing 6 (4.5%) 2 (3.7%) …
Sleeping problems (%)—any reported 88 (66.7%) 36 (67.9%) .43
 All of the time 18 (13.6%) 13 (24.5%)
 Most of the time 15 (11.4%) 6 (11.3%)
 Some of the time 32 (24.2%) 11 (20.8%)
 A little of the time 23 (17.4%) 6 (11.3%)
 None of the time 42 (31.8%) 17 (32.1%)
 Missing 2 (1.5%) 0 (0%)
Joint pain (%)—any reported 90 (68.2%) 38 (71.7%) .61
 All of the time 17 (12.9%) 12 (22.6%)
 Most of the time 15 (11.4%) 7 (13.2%)
 Some of the time 35 (26.5%) 11 (20.8%)
 A little of the time 23 (17.4%) 8 (15.1%)
 None of the time 36 (27.3%) 15 (28.3%)
 Missing 6 (4.5%) 0 (0%)
Memory problems (%)—any reported 92 (69.7%) 35 (66.0%) .62
 All of the time 14 (10.6%) 9 (17.0%)
 Most of the time 12 (9.1%) 5 (9.4%)
 Some of the time 35 (26.5%) 9 (17.0%)
 A little of the time 31 (23.5%) 12 (22.6%)
 None of the time 35 (26.5%) 18 (34.0%)
 Missing 5 (3.8%) 0 (0%)
Concentration problems (%)—any reported 80 (60.6%) 27 (50.9%) .14
 All of the time 14 (10.6%) 9 (17.0%)
 Most of the time 10 (7.6%) 3 (5.7%)
 Some of the time 33 (25.0%) 5 (9.4%)
 A little of the time 23 (17.4%) 10 (18.9%)
 None of the time 47 (35.6%) 26 (49.1%)
 Missing 5 (3.8%) 0 (%)
Headaches (%)—any reported 60 (45.5%) 25 (47.1%) .81
 All of the time 8 (6.1%) 6 (11.3%)
 Most of the time 9 (6.8%) 4 (7.5%)
 Some of the time 21 (15.9%) 8 (15.1%)
 A little of the time 22 (16.7%) 7 (13.2%)
 None of the time 66 (50.0%) 26 (49.1%)
 Missing 6 (4.5%) 2 (3.8%)
Shortness of breath (%)—any reported 61 (46.2%) 33 (62.3%) .04
 All of the time 4 (3.0%) 7 (13.2%)
 Most of the time 12 (9.2%) 9 (17.0%)
 Some of the time 20 (15.3%) 7 (13.2%)
 A little of the time 25 (18.9%) 10 (18.9%)
 None of the time 65 (49.3%) 20 (37.8%)
 Missing 6 (4.5%) 0 (0%)
Depression (%)—any reported 60 (45.5%) 26 (49.1%) .10
 All of the time 6 (4.6%) 7 (13.2%)
 Most of the time 4 (3.0%) 4 (7.5%)
 Some of the time 23 (17.5%) 5 (9.4%)
 A little of the time 27 (20.5%) 10 (18.9%)
 None of the time 66 (50.0%) 27 (50.9%)
 Missing 6 (4.5%) 0 (0%)
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Abbreviation: WNV, West Nile virus.

aModified as in Sejvar et al (2008) [14].

bReportable communicable diseases associated with hospitalization in the final comparator group: COVID-19 (44, 58.7%), coccidioidomycosis (Valley Fever) (16, 21.3%), streptococcal group A infection, invasive disease (4, 5.3%), legionellosis (4, 5.3%), respiratory syncytial virus (3, 4.0%), brucellosis (2, 2.6%), Haemophilus influenzae, invasive disease (1, 1.3%), and influenza (1, 1.3%).

cCochran–Mantel–Haenszel test. Bolded values are less than 0.05.

As assessed by the SF-36v2, 21% of the WNV group reported their current general health as fair or poor; however, 55% indicated that their health was somewhat or much worse than before their hospitalization (Supplementary Table 1). More than half of patients in the WNV group reported limitations with vigorous physical activity (77%), bending or kneeling (57%), climbing several flights of stairs (55%), and walking more than a mile (53%). In addition, more than a third of patients with WNV reported their ability to work was limited by their health some, most, or all of the time (Supplementary Table 1). Overall, patients with WNV reported favorable emotional health, with 65% of patients reporting no impact of emotional distress on their ability to work and 64% feeling calm and peaceful all or most of the time. Most (81%) patients in the WNV group reported some degree of bodily pain, but the majority also reported feeling as healthy as anybody they knew (56%) and that their health was excellent (59%). Compared to the 2009 general population norms, the median age-adjusted PCS score for the WNV group was 47.7 versus 53.1, and MCS score was 52.7 versus 52.9.

Overall, the perception of general health after hospitalization and bodily pain was not significantly different in the comparator group from the WNV group. However, patients in the comparator group were more likely to report their current health as fair or poor (36%, P = .02) and less likely to report feeling as healthy as anybody they knew (44%, P < .01) or report their health as excellent (36%, P < .01). Comparators also reported more restrictions with several physical activities, pain interfering with normal work, and limitations and difficulty performing work or other activities (Supplementary Table 1).

The average PCS score of patients with WNV was significantly higher (3.7 points [95% CI: .5–6.9)]) than that of the comparator group when adjusting for length of hospital stay, ICU admission, and presence of renal or neurologic comorbidity (Table 5). There was no difference in average MCS score between the cohorts (2.0 points; 95% CI: −.7 to 4.6) adjusting for referral to outpatient care, hospital readmission, and mental health comorbidity.

Table 5.

Linear Mixed-effects Regression Results Assessing PCS and MCS Scores of Patients in the WNV and Comparator Groupsa

Crude Adjusted
Predictors Estimates Confidence Interval P Value Estimates Confidence Interval P Valuef
PCSb
 (Intercept) 39.8 36.5–43.0 <.01 46.9 43.1–50.7 <.01
 WNV disease 4.88 1.41–8.35 <.01 3.66 .45–6.87 .03
 Length of hospital stay (per 10 d)c … … −2.27 −3.16—−1.38 <.01
 Presence of renal comorbidity … … −7.35 −12.34—−2.35 <.01
 Presence of neurologic comorbidity … … −10.1 −15.0—−5.11 <.01
 ICU admissiond
  Yes … … −2.03 −5.4–1.34 .24
  Unknown/unsuree … … −5.59 −9.78—−1.4 <.01
MCSb
 (Intercept) 48.5 45.2–51.9 <.01 52.7 49.5–55.9 <.01
 WNV disease 2.17 −.96–5.30 .17 1.96 −.68–4.6 .15
 Referral to outpatient cared
  Yes … … −.34 −2.94–2.25 .79
  Unknown/unsuree … … −19.2 −28.7—−9.8 <.01
 Hospital readmissiond … … … … …
  Yes … … −5.37 −8.87—−1.87 <.01
  Unknown/unsuree … … −11.5 −22.2—−.72 .04
 Presence of mental health comorbidity … … −14.6 −18.1—−11.1 <.01
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Abbreviations: ICU, intensive care unit; MCS, mental component summary; PCS, physical component summary; WNV, West Nile virus.

aReportable communicable diseases associated with hospitalization in the final comparator group: COVID-19 (44, 58.7%), coccidioidomycosis (Valley Fever) (16, 21.3%), streptococcal group A infection, invasive disease (4, 5.3%), legionellosis (4, 5.3%), respiratory syncytial virus (3, 4.0%), brucellosis (2, 2.6%), Haemophilus influenzae, invasive disease (1, 1.3%), and influenza (1, 1.3%).

bWhen comparing PCS and MCS scores between groups, a >3-point difference in score was considered meaningful (Maruish [10]).

cLength of hospital stay estimate shows decrease of score for every 10 d in hospital.

dReference values for categorical variables are “no” or absence of the reported condition: Presence of renal comorbidity = absence of renal comorbidity; ICU admission = no; outpatient referral = no; hospital readmission = no.

e“Unknown/unsure” represents participant responses who were unclear if they had experienced ICU admission, hospital readmission, or an outpatient referral.

fBolded values are less than 0.05.

DISCUSSION

In this cohort of patients hospitalized with WNV disease, a significant proportion required postacute care and experienced ongoing symptoms, disabilities, and a perception of worse health up to 2 years after hospitalization. Compared with the age-adjusted general population, patients with WNV had lower physical outcome scores but similar mental scores. However, 55% of patients with WNV disease felt their health was worse than before their illness. Compared with the hospitalized infectious disease comparators, who primarily had COVID-19 and coccidioidomycosis, long-term symptoms were similar, and health perceptions, adjusted physical scores, and functional status were somewhat better in the patients with WNV.

The hospital course for patients in the WNV group was similar to that of other published WNV cohorts with respect to length of stay (median 7 vs 4–10 days) [5, 14, 21–27], proportion admitted to ICU (31% vs 27%) [14, 26–33], and proportion transferred to postacute care facilities (40% vs 23%–37% [range: 13%–73%]) [21, 24–26, 28, 31, 34–37]. The variability in postacute care across studies could reflect differences in initial disease presentation or changes in medical care over the last 25 years.

Use of standardized assessment tools allows for some comparisons of outcomes across studies. In our study, the mRS indicated moderate-to-severe disability (score of 3–5) in 17% of patients in the WNV group at 17–25 months after hospitalization. In other studies that used the mRS to assess patients with WNV at 1–2 year follow-up, only 30%–60% of whom were hospitalized, moderate-severe disability was lower (5%–8%) [6] (CDC unpublished data), likely because of less severe acute disease in those studies.

Using the modified CDC Symptom Inventory Checklist to assess outcomes 18 months after acute WNV disease, Sejvar et al [14] found that the most common LTS were fatigue, arthralgia, myalgia, depression, difficulties with balance, and problems with sleep, memory, and concentration. These findings were consistent with our study. Other studies using different survey tools noted similar symptoms at 12–18 months, with prominence of fatigue, weakness, myalgia, difficulty walking, and memory problems [6, 22, 36, 38–40].

In studies that used SF-36 survey tools, the MCS and PCS scores at 1-year follow-up were similar to those in our cohort [6, 41]. Recovery, as reported on the SF-36v2 survey that current health was better or the same compared to before hospitalization, was 44% in our study. Similarly, in studies involving patients with primarily WNV neuroinvasive disease, 32%–45% of patients were deemed fully recovered after 12–16 months [22, 36, 38]. In a study of 156 patients with WNV disease, of whom only 24 were hospitalized, 87% achieved at least one normal PCS or MCS score by 1 year, although patients with neuroinvasive disease and underlying comorbidities took longer to recover [42]. Another study found that half of patients with WNV fever and 75% with meningitis and encephalitis reported ongoing symptoms, functional impairment, and reduced quality of life at 18 months [14]. In general, improvement in functional ability seems to plateau at 12–18 months [36, 38].

The pathophysiology of functional impairments and symptoms following WNV disease is not well understood. Studies using both self-reported and objective neurocognitive assessments did not find consistent correlations; 1 study found no measured objective deficits compared to the general population despite a high proportion of self-assessed functional impairment and decreased quality of life [14]. Other studies have reported long-term neurologic impairments such as motor speed and executive function deficits in patients with WNV disease [6]. Patients with acute flaccid myelitis often have long-term weakness and other neurologic deficits because of direct viral invasion and damage to motor neurons [43].

We compared the outcomes of patients hospitalized with WNV to those of a matched cohort of patients hospitalized with other infectious diseases, several of which are known to cause postacute infectious syndromes in some patients, such as COVID-19. These syndromes are often characterized by exertion intolerance, debilitating fatigue, neurocognitive disturbances, headaches, and myalgia, which were common LTS in both groups in our study [44]. Patients in the WNV group were more likely to be transferred to inpatient postacute care or receive outpatient care referrals. This could have been driven by differences in functional outcomes between the groups and/or by differences in healthcare access [45]. Our comparator group reported similar LTS as the WNV group but reported significantly higher rates of shortness of breath, likely related to the large proportion of patients with coccidioidomycosis and COVID-19 [46, 47]. We observed significant differences in baseline characteristics between the groups including race/ethnicity (higher proportion of white/non-Hispanic in the WNV group) and comorbidities (more renal disease and diabetes in the comparator group). In the multivariable analyses of summary component scores, the comparator group had worse adjusted PCS scores than the WNV group but similar adjusted MCS scores. In addition, despite similar recovery rates after hospitalization (47% in the WNV group vs 44% in the comparators), a smaller proportion of comparators (26% vs 40%) reported their health was excellent or very good, suggesting a lower level of baseline function, consistent with having more comorbidities.

This study had several limitations. First, small sample sizes and low participation limited our analyses and could have led to potential response bias for patients with less severe outcomes. The low response rate we experienced is comparable to findings from other surveys conducted during the COVID pandemic [11]. Small sample size prevented us from stratifying outcomes by severity of WNV disease (ie, neuroinvasive vs nonneuroinvasive). However, because all patients had severe enough illness to require hospitalization, and almost 90% of the patients had neuroinvasive disease, the impact of patients with milder disease on the results was likely low. Second, our comparator group had limited generalizability, with the majority having coccidioidomycosis and COVID-19, both known to cause LTS in some patients. Because of differing diseases, underlying conditions, and demographics, comparisons between the groups were limited. Although we controlled for multiple variables in comparing summary scores, factors such as health perception, symptom reporting, and access to healthcare might have impacted the findings. Third, details about hospital stay, outpatient follow-up, and comorbidities were obtained from the survey, which likely led to inaccuracies related to recall, illness, and other factors. Finally, outcomes might have been biased by the method of survey administration (online vs interview). When we included this variable in the LASSO model, there was no significant difference in scores on the SF-36v2 survey tool between the groups when adjusting for other covariates. In a previous study, online completion of the SF-36 survey resulted in lower scores than phone interviews, suggesting that the better outcomes among patients with WNV versus the comparators are likely accurate [48].

Despite these limitations, we addressed several challenges of previous studies by assessing a longer follow-up period, using standardized assessment tools, and including a comparator group in the analysis. Our findings of similar symptoms and functional disabilities among patients in the WNV and comparator groups suggest that there might be common inflammatory or other physiologic pathways leading to postinfectious sequelae or factors related to prolonged hospitalization. Although the majority of the patients in this study had neuroinvasive disease, even patients with West Nile fever can have prolonged symptoms, particularly fatigue and myalgia, commonly up to a month after onset [5].

The significant and long-lasting sequelae experienced by patients hospitalized with WNV disease have important implications for public health agencies for prevention messaging and resource planning following WNV outbreaks and for healthcare providers in caring for and counseling their patients. Additional evaluation of the WNV cohort at later time points could allow for further assessment of chronicity of morbidity. Clinicians should be aware that patients hospitalized for WNV might experience LTS impacting their physical and mental well-being for months or even years following hospital discharge and provide education and counseling to patients and their families about posthospital care needs.

Supplementary Material

ofag295_Supplementary_Data
ofag295_supplementary_data.docx (42.8KB, docx)

Notes

Acknowledgments. We would like to thank the patients and their families for their participation. We would also like to thank James Matthews, Brenna Garrett, and Hovi Nguyen, Maricopa County Department of Public Health, for their assistance with the data systems during case finding and Ken Komatsu, Arizona Department of Health Services, for his support of the study.

Disclaimer. The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, the U.S. Department of Energy, or the Oak Ridge Institute for Science or Education.

Financial support. This research was supported in part by an appointment to the Research Participation Program at the Centers for Disease Control and Prevention (CDC) administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and CDC.

Contributor Information

Anna C Fagre, Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Kathryn G Burr, Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; Maricopa County Department of Public Health, Phoenix, Arizona, USA; Arizona Department of Health Services, Phoenix, Arizona, USA.

Cedar L Mitchell, Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; Arizona Department of Health Services, Phoenix, Arizona, USA; Pima County Health Department, Tucson, Arizona, USA.

Mark J Delorey, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Melissa Kretschmer, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

Karen Zabel, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

O’Zandra Floyd, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

Renate Schlaht, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Austin Earley, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Olivia Studebaker, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Jennifer Lehman, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Julie M Thompson, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Madison Meyer, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

Olivia Hunziker, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

Meghan Schindler, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

Zoha Ahmed, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

Bernny E Apodaca, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

Joshua Sager, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

Rechelle Harrion, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

Sydney N Adams, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Nicole Foley, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Johanna Gleason-Vergados, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Shelby Lyons, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Brian F Borah, Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

R Nicholas Staab, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

Irene Ruberto, Arizona Department of Health Services, Phoenix, Arizona, USA.

Rebecca Sunenshine, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

J Erin Staples, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Carolyn V Gould, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.

Ariella P Dale, Maricopa County Department of Public Health, Phoenix, Arizona, USA.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

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Supplementary Materials

ofag295_Supplementary_Data
ofag295_supplementary_data.docx (42.8KB, docx)

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