Risk for Asymptomatic Household Transmission of Clostridioides Difficile Infection Associated With Recently Hospitalized Family Members

Aaron C. Miller; Alan T. Arakkal; Daniel K. Sewell; Alberto M. Segre; Sriram V. Pemmaraju; Philip M. Polgreen

Emerging Infectious Diseases. 2022;28(5):932-939.

Abstract and Introduction

Abstract

We evaluated whether hospitalized patients without diagnosed Clostridioides difficile infection (CDI) increased the risk for CDI among their family members after discharge. We used 2001–2017 US insurance claims data to compare monthly CDI incidence between persons in households with and without a family member hospitalized in the previous 60 days. CDI incidence among insurance enrollees exposed to a recently hospitalized family member was 73% greater than enrollees not exposed, and incidence increased with length of hospitalization among family members. We identified a dose-response relationship between total days of within-household hospitalization and CDI incidence rate ratio. Compared with persons whose family members were hospitalized <1 day, the incidence rate ratio increased from 1.30 (95% CI 1.19–1.41) for 1–3 days of hospitalization to 2.45 (95% CI 1.66–3.60) for >30 days of hospitalization. Asymptomatic C. difficile carriers discharged from hospitals could be a major source of community-associated CDI cases.

Introduction

Clostridioides difficile infection (CDI) is one of the most commonly occurring types of healthcare-associated infection and is predominately associated with hospitals.^[1,2] Thus, CDI-related investigations and interventions primarily have focused on hospital settings. More recently, reports of community-associated CDI cases, in which patients without a history of recent hospitalization are infected, have become more common.^[3,4] Although healthcare-associated CDI remains a considerable problem, more emphasis on community-associated CDI cases also is needed.

Risk factors for community-associated CDI are similar to risk factors for hospital-associated cases. For example, antimicrobial drug and proton-pump inhibitor (PPI) use increase the risk for community-associated CDI.^[4,5] For some community-associated CDI cases, exposure to healthcare settings beyond hospitalization, including clinics and emergency departments,^[6,7] are associated with an increased risk for CDI. However, for some CDI cases, no clear exposure to healthcare facilities can be identified. To find a source of C. difficile in community settings, other potential exposures have been proposed. Food is one such potential exposure, and C. difficile has been recovered from several different edible substances, including meat and vegetables.^[8,9] Pets have also been implicated.^[10] In addition, the possibility of household transmission of CDI between family members has been proposed, and having a symptomatic family member is a risk factor for CDI.^[10,11]

In addition to symptomatic CDI cases, patients with asymptomatic C. difficile colonization might contribute to transmission.^[12,13] In whole-genome sequencing studies, identifying epidemiologic links between symptomatic CDI among hospitalized patients has often been difficult,^[14,15] suggesting a potential role for asymptomatic C. difficile colonization. Asymptomatic colonized patients might contribute less to environmental contamination than symptomatic cases, but in sufficient numbers they could still play a role in C. difficile transmission in healthcare settings.^[16] Furthermore, if asymptomatically colonized patients contribute to C. difficile transmission within the hospital, then they could contribute to transmission in the community after they are discharged and especially could play a role in transmission among other household members. Finally, because hospitalized patients can remain asymptomatically colonized with C. difficile after discharge,^[17–20] this patient population could represent a large reservoir of CDI outside healthcare settings.

We investigated whether recently hospitalized patients increased the risk for CDI among household members in the period after discharge. Specifically, we were interested in the risk posed to household members by patients who are discharged without a CDI diagnosis and who are not diagnosed with CDI after discharge. If the risk for asymptomatic C. difficile colonization increases with length of stay, we hypothesized that the risk for CDI among household members should increase as a function of their recently hospitalized family members' lengths of stay.

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Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Baseline enrollment characteristics of families with multiple infected members using a 60-day exposure window in study of asymptomatic *Clostridioides difficile* transmission among household members, United States*
Characteristics	All enrollees. no. (%)	No. (%) episodes of index CDI diagnosis†	No. (%) cases of possible transmission after family member hospitalization
No. CDI cases	NA	224,818	6,575
No. enrollees	142,125,247 (100)	194,424 (100)	6,453 (100)
Age group at enrollment or CDI diagnosis, y
0–17	47,733,847 (33.6)	19,719 (8.8)	547 (8.3)
18–40	46,634,859 (32.8)	37,259 (16.6)	1,156 (17.6)
41–65	44,039,682 (31.0)	103,430 (46.0)	1,822 (27.7)
>65	3,716,859 (2.6)	64,410 (28.6)	3,050 (46.4)
Sex
M	70,485,475 (49.6)	99,133 (44.1)	2,798 (42.6)
F	71,639,772 (50.4)	125,685 (55.9)	3,777 (57.4)
Family size
2	36,598,138 (25.8)	134,644 (59.9)	4,166 (63.4)
3	29,857,746 (21.0)	36,236 (16.1)	905 (13.8)
4	40,705,784 (28.6)	34,559 (15.4)	839 (12.8)
5	21,536,725 (15.2)	13,517 (6.0)	409 (6.2)
>5	13,426,854 (9.4)	5,862 (2.6)	256 (3.9)

*CDI, Clostridioides difficile infection; NA, not applicable.
†Events occurring ≥60 days before another episode.

Table 2. Bivariate comparisons of unadjusted incidence rates and incidence rate ratios for infection incidence across various patient strata using a 60-day exposure window in study of asymptomatic *Clostridioides difficile* transmission among household members, United States*
Variable	Exposed to previously hospitalized family member ≤60 days			Not exposed to previously hospitalized family member ≤60 days			Unadjusted IRR
Variable	CDI cases	Total enrollee months	CDI incidence†	CDI cases	Total enrollee months	CDI incidence†	Unadjusted IRR
Overall	3,871	69,675,026	5.56	160,779	4,998,101,178	3.22	1.73
Age group, y
0–17	317	24,432,280	1.30	15,615	1,445,786,086	1.08	1.20
18–40	567	19,978,891	2.84	29,718	1,427,785,479	2.08	1.37
41–65	1,193	19,281,059	6.19	74,803	1,868,106,655	4.00	1.55
>65	1,794	5,982,798	29.99	40,643	256,422,958	15.85	1.89
Sex
M	1,698	37,945,564	4.47	67,378	2,488,714,427	2.71	1.65
F	2,173	31,729,463	6.85	93,401	2,509,386,752	3.72	1.84
Outpatient antimicrobial drug use within 60 days
None	2,419	63,230,032	3.83	100,792	4,575,861,567	2.20	1.74
Low-risk drugs	292	2,979,748	9.80	11,944	201,200,918	5.94	1.65
High-risk drugs	1,160	3,465,248	33.48	48,043	221,038,693	21.74	1.54
PPI use within 30 days
N	3,477	68,273,806	5.09	146,185	4,913,346,960	2.98	1.71
Y	394	1,401,221	28.12	14,594	84,754,218	17.22	1.63
Infant age <2 y in family
N	3,489	48,618,765	7.18	151,291	4,597,497,625	3.29	2.18
Y	382	21,056,262	1.81	9,488	400,603,553	2.37	0.76

*IRRs compare CDI incidence among persons exposed to a family member previously hospitalized for ≥1 d relative incidence for to those not exposed to a previously hospitalized family member. The overall incidence rate ratio among those exposed to a previously hospitalized family member relative to those unexposed was 1.73 and was >1 across all strata. CDI, Clostridioides difficile infection; IRR, incidence rate ratio; PPI, proton-pump inhibitor.
†Cases per 100,000 enrollee months.

Table 3. Number of cases and enrollee-months in each exposure bin for total days of household-hospitalization using a 60-day exposure window in study of asymptomatic *Clostridioides difficile* transmission among household members, United States*
No. days family members spent hospitalized	60-day exposure window
No. days family members spent hospitalized	No. CDI cases	Total enrollment months	Incidence†
0	160,267	4,980,648,694	3.22
1–3	2,336	52,798,719	4.42
4–10	1,519	27,457,461	5.53
11–20	315	4,338,929	7.26
21–30	107	1,317,610	8.12
>30	106	1,214,792	8.73

*CDI, Clostridioides difficile infection.
†Cases per 100,000 enrollment months.

Table 4. Results of regression analysis of incidence rate ratio for *Clostridioides difficile* infection using quasi-Poisson model and 60-day exposure window in study of asymptomatic *C. difficile* transmission among household members, United States*
Variable	IRR (95% CI)
No. days member was hospitalized within 60 d
0	Referent
1–3	1.30 (1.19–1.41)
4–10	1.46 (1.32–1.62)
11–20	1.79 (1.43–2.23)
21–30	2.17 (1.48–3.18)
>30	2.45 (1.66–3.60)
Age group, y
0–17	Referent
18–40	1.71 (1.65–1.78)
41–65	2.97 (2.86–3.08)
>65	9.32 (8.92–9.73)
Sex
M	Referent
F	1.30 (1.28–1.33)
Outpatient antimicrobial drug use within 60 d
None	Referent
Low-risk drugs	2.69 (2.59–2.79)
High-risk drugs	8.83 (8.63–9.03)
PPI use within 30 d	2.23 (2.15–2.30)
Infant <2 y in family	1.51 (1.44–1.58)

*Models were adjusted for year, month, and family size. Regression models included an offset for number of enrollment months. Because family hospitalization exposure group was followed for 60 days to identify secondary Clostridioides difficile infection, the length of their enrollment period is 60 days. For the unexposed group, the length of enrollment was the length of a given month. IRR, incident rate ratio; PPI, proton-pump inhibitor.