Active population- and laboratory-based surveillance for invasive Hi disease was conducted as a part of Active Bacterial Core surveillance (ABCs). ABCs is supported by the Centers for Disease Control and Prevention (CDC) as a part of the Emerging Infections Program Network [9]. The surveillance area includes California (3 San Francisco Bay-area counties), Colorado (5 Denver-area counties), Connecticut (statewide), Georgia (20 Atlanta-area counties, 2008–⁠2009; statewide, 2010–⁠2019), Maryland (statewide), Minnesota (statewide), New Mexico (statewide), New York (15 Rochester- and Albany-area counties), Oregon (statewide), and Tennessee (11 counties, 2008–⁠2009, 20 counties, 2010–⁠2019). The population under surveillance ranged from 36,322,812 in 2008 to 45,041,453 in 2019, representing 11.9% of the U.S. population in 2008 and 13.7% in 2019 [10].

A case was defined as isolation of NTHi from a normally sterile site (e.g., blood or cerebrospinal fluid [CSF]) in an ABCs surveillance-area resident. Epidemiologic and clinical information, including HIV status, was abstracted from medical records. Outcome was based on patient status at hospital discharge. Infants with gestational age <22 weeks were excluded from ABCs because that is below the age of fetal viability. Hi isolates were serotyped at state public health laboratories and sent to CDC for species confirmation and serotyping. Whole genome sequencing of select isolates was performed at CDC using methods previously described [1, 11–13].

Data from 1 January 2008 through 31 December 2019 were included in this analysis. Cases of invasive NTHi disease were classified into mutually exclusive syndrome categories. Cases were classified as meningitis if a clinical diagnosis of meningitis was recorded in the medical record or NTHi was isolated from CSF; bacteremic pneumonia if pneumonia was recorded in the medical record and NTHi was isolated from blood or pleural fluid; and bacteremia if NTHi was isolated from blood and the medical record did not note meningitis or bacteremic pneumonia. Race was categorized as White, Black, American Indian and Alaska Native (AI/AN), or Asian/Pacific Islander (Asian/PI). Ethnicity was categorized as Hispanic/Latino or Non- Hispanic/Latino. A neonate was defined as an infant aged ≤30 days, and preterm was defined as birth at <37 weeks gestation. Women of childbearing age were defined as women aged 15–44 years; pregnancy status at the time of NTHi isolate collection was ascertained through medical record review. Women with a NTHi isolate collected ≤30 days following a delivery or miscarriage were classified as postpartum. Adults aged ≥18 years with documented HIV infection were classified as PWH and compared to adults without documented HIV infection.

Incidence rates were reported as cases per 100,000 population and calculated using National Center for Health Statistics’(NCHS) bridged-race postcensal population estimates [10] for ABCs sites; nationwide estimates were calculated by directly standardizing to the age and race distribution of the U.S. population. For race-stratified nationwide incidence estimates, missing race was multiply imputed using sequential regression multiple imputation [14] via IVEware software (Institute for Social Research, University of Michigan, Ann Arbor). Variance estimates were calculated using standard combining rules for multiply imputed data. Incidence rates were compared using incidence rate ratios (IRR). The 95% confidence intervals (CIs) around the directly standardized rates were calculated using a method derived from the relationship between the Poisson distribution and the gamma distribution, whereas estimated age and race-specific 95% CIs were calculated using exact CI for a Poisson random variable [15]. A negative binomial model with 95% CIs was used to estimate average annual percentage change in incidence from 2008–⁠2019.

We were unable to estimate national incidence for neonates and pregnant women due to unavailability of national counts for these populations. To assess incidence in the ABCs surveillance area in infants aged <1 year by month of life, monthly population denominators were calculated by dividing the ABCs catchment population aged <1 year by 12. Denominators for pregnant women were calculated using live birth estimates. We used state vital records and national vital statistics reports to obtain ABCs site-specific live birth data. The population of preterm infants was calculated using the proportion of births in the United States that were preterm in 2019 [16].

Incidence rates for PWH were calculated using the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention AtlasPlus database [17]. HIV prevalence data from AtlasPlus was used to determine the PWH population size for each ABCs site. The non-PWH population denominator was calculated by subtracting the PWH population denominator from the NCHS population estimates. Denominator data was available for individuals aged ≥13 years in AtlasPlus, so incidence calculations for PWH were restricted to individuals aged ≥13 years.

Case-fatality ratios were calculated using the proportion of cases with known outcomes as the denominator. Wilcoxon rank-sum tests were used to compare continuous variables and Pearson’s χ² test was used for categorical variables. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.^§ At each ABCs site, it was deemed either a public health assessment or human subjects research, for which approval was granted by local institutional review boards.

A total of 5,991 cases of invasive NTHi disease were reported to ABCs sites from 2008–2019, representing 72% of all invasive Hi cases with known serotyping results. Overall, 47.3% of patients were male; 70.7% were White, 16.4% were Black, 1.1% were AI/AN, 3.2% were Asian/PI, and 8.6% had unknown race (Supplemental Table 1). Case fatality was 15.5% overall and was highest among those aged ≥80 years (25.2%; Table 1). Nearly all patients were hospitalized (93.3%); children aged <1 year had the longest median duration of hospitalization (14 days) and the highest proportion admitted to an intensive care unit (61.4%). Most patients aged ≥15 years (84.3%) had at least one underlying condition. Among all patients, 24.9% of individuals had an immunocompromising condition, with the highest proportion among those aged 45–64 years (31.1%). The most common immunocompromising conditions were receiving immunosuppressive therapy and solid organ malignancy.

Overall, the estimated national average annual incidence of invasive NTHi disease was 1.3/100,000 (Table 2), representing an average annual increase of 3.9%, from 1.1/100,000 in 2008 to 1.6/100,000 in 2019 (Figure 1). The estimated national annual number of cases ranged from 3,264 in 2008 to 5,113 in 2019 (estimated average annual cases, 4244). Incidence rose more sharply after 2014, with an average annual increase of 4.8% (95% CI: 4.1–5.5) from 2014–2019, compared to 2.6% (95% CI: 1.8–3.4) in 2008–⁠2013. Average annual incidence differed by age and was highest among children aged <1 year (5.8/100,000) and adults aged ≥80 years (10.2/100,000). By age group, the largest average annual percent increase in incidence was noted among people aged 15–44 years (6.7%; Table 2). Incidence was significantly lower in Asian/PI persons compared to all other racial groups (Figure 3). Among women of childbearing age, invasive NTHi disease incidence among Black women (0.7/100,000) was over twice that of White or AI/AN women (0.3/100,000).

Among 400 women of childbearing age with invasive NTHi, 105 (27.0%) were either pregnant (n=59) or postpartum (n=46) at the time of infection (Table 3). Pregnant/postpartum women with invasive NTHi disease were younger and healthier than their non-pregnant counterparts; nearly all had bacteremia, and none died (Table 3). Pregnancy outcome was known for 95 (90.4%) of the 105 pregnant/postpartum women with NTHi. Of those, 33 (34.7%) delivered a live, illness-free neonate, 52 (54.7%) had either spontaneous abortion or stillbirth, 2 (2.1%) had an induced abortion, 1 (1.1%) had a live birth but neonatal death, and 7 (7.4%) had a neonate with clinical infection around the time of birth. A significantly higher proportion of women who were postpartum at the time of infection had a pregnancy outcome of a live, illness-free infant compared to women who were pregnant at the time of infection (54.8% vs. 18.9%, p=.0003). Among the seven neonates with clinical infection who were born to women with pregnant/postpartum infections, 5 (71%) had confirmed NTHi infection within the first day of life and cause of infection was not provided for the remaining 2 neonates. Three of the five with confirmed NTHi were born extremely premature (23–25 weeks gestation). Four had bacteremia, one had bacteremic pneumonia, and all survived. Isolates from all five mother/infant pairs were sequenced. Each infant had an identical ST to the paired maternal isolate; however, the five paired isolates had different STs (46, 84, 139, 266, and 2317). Invasive NTHi incidence among pregnant/postpartum women within ABCs jurisdictions was 5.6 times higher (95% CI: 4.4–7.0) compared to non-pregnant women of childbearing age (1.7/100,000 vs. 0.3/100,000).

A total of 225 neonates and 122 infants aged 1–11 months with invasive NTHi infection were reported. Compared to older infants with NTHi, more neonates had bacteremia (85% vs. 52%, p<0.0001) and required ICU care (70% vs. 46%, p<0.0001). Most neonates (n=163, 72.4%) were born premature. Among those born premature, 61 (37.4%) were born at 22–28 weeks gestation, 52 (31.9%) at 29–32 weeks, 48 (29.4%) at 33–36 weeks, and 2 (1.2%) were missing gestational age. Case fatality among neonates was 12.0% overall and varied by gestational age. The highest case fatality was among neonates born 22–28 weeks (36.1%); no term neonates died. Nearly all neonates (207, 92.0%) had a positive culture within the first 7 days of life, with 183 (81.3%) positive cultures from the day of birth. Neonatal invasive NTHi incidence in the ABCs sites was 43.0/100,000 overall, and higher among AI/AN and Black compared to White neonates (76.7 and 49.9/100,000 respectively, vs 37.5/100,000). NTHi incidence was 20 times higher in neonates compared to older infants aged 1–11 months (43.0/100,000 vs. 2.1/100,000). Among neonates, NTHi incidence was 23 times higher (95% CI: 17.1–31.4) among preterm compared to term neonates (304.3/100,000 vs. 13.2/100,000).

Of the 5,297 cases of invasive NTHi infection among adults aged ≥18 years in the ABCs sites, 167 (3.2%) were among PWH. When compared to those without HIV, PWH were more likely to be male (79.6% vs. 45.0%, p<0.0001), younger (median age 42.0 vs. 71.0 years, p<0.0001), and Black (77.8% vs. 13.4%, p<0.0001) (Supplemental Table 2). While PWH were more likely to have septic arthritis (7.2% vs. 0.9%, p<0.0001) than HIV-uninfected persons, 83% (10 of 12) of patients with NTHi septic arthritis were residents of the metropolitan Atlanta area described previously [8]. In addition, the proportion of NTHi cases among PWH did not increase in any ABCs sites other than Atlanta. Incidence among PWH aged ≥13 years was 9.5 cases per 100,000, compared to 1.1 cases per 100,000 for non-PWH aged ≥13 years (RR=8.3; 95% CI=7.1–9.7; p<0.0001). No additional cases among PWH were reported in people aged 13-<18 years in the ABCs sites.