Aircraft contact investigations for TB on domestic and inbound flights to the United States

SUMMARY

BACKGROUND:

U.S. Centers for Disease Control and Prevention (CDC) coordinates contact investigations (CIs) for TB exposures on commercial flights when criteria are met. Aircraft CIs are resource-intensive and require collaboration with health departments (HDs). Post-exposure TB assessments are challenging as multiple follow-up visits are needed. Evidence supporting TB transmission on aircraft is limited.

METHODS:

TB aircraft CI outcomes data submitted to CDC by HDs from 24 June 2011 to 31 December 2022 were analysed using descriptive statistics to summarise outcomes, risk factors for prior exposure, timing of diagnosis, and data completeness.

RESULTS:

Of 15,043 contacts identified, final determination of TB status was available for 2,282/15,043 (15%). Of these, 3/2,282 (0.1%) had TB disease and 366/22,282 (16%) had TB infection (TBI). Most (78%) contacts with TB had other exposure risk factors. Ten exhibited conversion on serial testing within 4 months after the flight, indicating recent infection. All contacts with TB disease and 44 with TBI (14% of those with test dates available) were tested before HDs were notified of aircraft exposure.

CONCLUSION:

TB aircraft CIs identified persons with TB disease or TBI; however, most had TB risk factors other than aircraft exposure. The low return of outcomes was a limitation for formulating robust recommendations.

U.S. Centers for Disease Control and Prevention (CDC) coordinates contact investigations (CIs) for TB exposures on domestic or inbound international flights that meet predetermined criteria.¹ CDC assesses potential exposure events based on modified World Health Organization (WHO) risk assessment criteria, including index case infectiousness, duration of exposure, context (exposure characteristics and consequences of transmission), and time elapsed between the exposure and the notification.^1,2 Clinical criteria include a positive culture or nucleic acid amplification test and either a positive sputum smear with cavitation on imaging or a diagnosis of multidrug-resistant TB. If a CDC medical officer determines that criteria to initiate an aircraft CI are met, CDC obtains flight manifests from the airline(s) and identifies passengers seated in the same row as the index case or within two rows in front or behind. All travelling companions of the index case are also considered contacts, regardless of seating arrangement. U.S. health departments (HDs) are then notified of contacts in their jurisdiction via a secure, web-based public health communications network (the Epidemic Information Exchange, or Epi-X).³ HDs are asked to notify and evaluate each contact in their jurisdiction and return an outcome reporting form, but both the investigation and the reporting are voluntary for HDs. HDs follow their own protocols for TB post-exposure evaluation, but the outcome reporting form requests results of tuberculin skin testing (TST), interferon-gamma release assay (IGRA), and/or chest radiographs if they are available. In the United States, this testing is typically performed free of charge if conducted through the HD and contacts may decline evaluation. If a contact is determined to be in another country when the investigation is initiated, CDC notifies the National Focal Point for that country, in accordance with the International Health Regulations.⁴ Although TB aircraft CIs are recommended by the WHO and are standard practice in many high-income, low-TB-burden countries, most sources consider the risk of in-flight transmission to be quite low because of efficient ventilation systems in modern aircraft.^2,5,6 A number of studies have attempted to quantify this risk, but delays in exposure notification, poor adherence to multi-step testing recommendations for TB, and high background prevalence of TB infection (TBI) in international travellers present unique challenges when interpreting outcomes of aircraft CIs.^5–10 To date, there have been only four investigations that documented TB test conversion in aircraft contacts with no other known TB exposure risk factors.^8,11–14 None identified any contacts with TB disease. There have been three systematic reviews of TB transmission on aircraft in the past 15 years^5,9,10; all concluded that the risk of transmission was low, and two explicitly stated that conducting CIs after aircraft exposures likely had limited public health value.^5,9

TB aircraft CIs are a resource-intensive activity, both for CDC and for HDs. An economic analysis published in 2014¹⁵ that considered both the cost of conducting the CI and the cost of treatment predicted a negative return on investment for TB aircraft CIs if TBI rates among contacts were low (1.1%–1.4%), but a positive return if TBI rates were high (19%–24%). Any decision to change CDC’s approach to TB aircraft CIs must be founded on strong evidence, and many of the studies currently available in the literature are relatively small or do not include sufficient information to assess the likelihood that contacts with TB were infected on the plane. This manuscript reviews the outcomes of TB aircraft CIs coordinated by CDC over a 10.5-year period to understand how many persons with TB were identified and the likelihood that their disease or infection resulted from aircraft exposure.

METHODS

CDC’s Port Health Activity Reporting System (previously called the Quarantine Activity Reporting System), a secure internal database, was queried for all reports of domestic or inbound international air travellers with infectious TB disease for which a CI was initiated during 24 June 2011–31 December 2022. 24 June 2011 was selected as the start date because CDC’s updated criteria for initiating aircraft CIs for TB were released on that date.¹ For each CI, we recorded the number of contacts identified and the number of contacts lost at each step of the CI process. For contacts who had outcomes available, we report demographic and risk factor information, stratified by TB status. Unless otherwise indicated, we used the final TB status that the HD reported on the outcome reporting form, regardless of whether diagnostic information was provided to support this assessment. We performed statistical comparisons of categorical variables (sex, TB history, and exposure risk factors) using χ² tests and continuous variables (age) using two-sample t tests.

For the subset of contacts whose outcome reporting forms indicated they had TB disease (reported as ‘Active TB’ on the reporting form), we contacted state/local jurisdictions to confirm their TB status and request any additional information available from their records to better characterise the contact’s likelihood of having been infected on the plane (e.g., clinical and social history, and whole genome sequencing results). For contacts with TBI, we performed closer analysis of the timing of their test results to determine 1) whether they had evidence of conversion within several months of the flight and 2) whether the timing of their testing suggested that they were tested because of the Epi-X notification or if they were identified through a different mechanism. When characterising test conversion status, we excluded tests conducted more than 4 months after the flight. A positive IGRA result collected within 1–2 weeks of an indeterminate IGRA was not considered conversion.

Ethical statement

This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy. See, for example, 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq.

RESULTS

During the analysis period, 504 air passengers with infectious pulmonary TB disease met the criteria¹ to initiate an aircraft CI (https://doi.org/10.6084/m9.figshare.29424971). The majority (313/504, 62%) were male, and male index cases had a higher median age (53 years, range: 14–91 years) than female index cases (36 years, range: 8–87 years). Most (417/504, 83%) had a positive sputum smear and pulmonary cavitation on imaging, and most were also positive on culture (447/504, 88%) and/or nucleic acid amplification testing (415/504, 82%). Sixty of 504 (12%) had isolates that were classified as multidrug-resistant or extensively drug-resistant.

Contact investigations

The median time from the flight to the issuance of an Epi-X notification to jurisdictions was 62 days (interquartile range: 42–84 days). During the analysis period, 15,043 TB aircraft contacts were identified (Figure 1), of whom 2,238/15,043 (15%) were referred to foreign public health authorities and 1,850/15,043 (12%) did not have adequate contact information to assign them to a U.S. jurisdiction. Of the contacts assigned to U.S. jurisdictions, outcome reporting forms were returned for 4,644/10,955 (42%). Of these, 2,362/4,644 (51%) did not have a final TB status listed. The greatest number and proportion of contacts (6,311/10,955, 58%) were lost at the outcome reporting step because their forms were never returned. It is unknown whether evaluations were not completed in these instances or if they were completed but outcome reports were not returned to CDC (Figure 1). There was no statistical difference in age (P = 0.53) or sex (P = 1.0) between contacts with and without outcomes.

Figure 1.

Contact cascade showing outcomes for 15,043 contacts identified during TB aircraft contact investigations coordinated by U.S. Centers for Disease Control and Prevention from 24 June 2011 to 31 December 2022. Dark blue boxes indicate contacts with a final determination of TB status who received at least one TB screening test (tuberculin skin test [TST] or interferon gamma release test [IGRA]). Light blue boxes indicate contacts who had a final TB status reported by states, despite not having TST or IGRA results listed on outcome reporting forms. Grey boxes indicate contacts for whom there was insufficient follow-up information to determine their TB status.

Contacts

Of the 4,644 contacts with outcomes (Table 1), 3/4,644 (<1%) were diagnosed with TB disease (not shown in Table 1), 369/4,644 (8%) were diagnosed with TBI, 1,910/4,644 (41%) were reported not to have TB, and the TB status of the remaining 2,362/4,644 (51%) was unknown. A similar percentage of contacts with TBI were male (134/369, 36%, vs. 118/369, 32% female, P = 0.43), and contacts with TBI had a higher mean age (45.6 years vs. 41.0 years for contacts without TBI, P < 0.001). Contacts ranged widely in age, from a few months to 94 years (Table 1). Ethnicity data were not available. Among contacts with outcomes available, prior TB history was unknown for many (2,712/4,644, 58%). Contacts with TBI were significantly more likely to have reported a prior history of TB disease or TBI (24% of contacts with TBI vs. 1% of contacts without TB, P < 0.0001). Very few contacts in any group had a history of TB disease. TB history was unknown for most contacts without a final TB status (2,004/2,362, 85%). The outcome reporting form did not collect information about whether contacts with a prior history of TB disease or TBI had received treatment. Contacts with TBI were significantly more likely to report at least one risk factor for prior exposure to TB than contacts without TB (P < 0.0001); 78% (288/369) of contacts with TBI reported at least one risk factor (Table 1). A history of living in a high-TB-burden country (incidence >20/100,000/year) was the most common risk factor (275/369, 75%) among contacts with TBI (Table 1). Living in a high-burden country was also the most common risk factor among contacts without TB but was less common (684/1,910, 36%) than in those with TBI. Most contacts without TBI either had no risk factors (467/1,910, 24%) or their risk factor history was unknown (712/1,910, 37%). Among contacts with unknown TB status, 1,945/2,362 (82%) also had unknown exposure history.

Table 1.

Demographics, TB history, and TB exposure risk factors among contacts with outcomes of TB aircraft contact investigations returned to U.S. Centers for Disease Control and Prevention during 24 June 2011–31 December 2022, stratified by TB status (as reported by health departments on outcome reporting forms).

	TB infection (n = 369)	No TB (n = 1,910)	Unknown TB status (n = 2,362)
Demographics
Male	134 (36%)	693 (36%)	483 (20%)
Female	118 (32%)	686 (36%)	465 (20%)
Sex unknown	117 (31%)	531 (28%)	1,414 (60%)
Age, mean (range)	46 years (2 months–88 years)	42 years (3 months–92 years)	40 years (2 months–92 years)
TB history
TB disease	1 (<1%)	3 (<1%)	4 (<1%)
TB infection	88 (24%)	28 (1%)	30 (1%)
No history of TB	179 (49%)	1,102 (58%)	324 (14%)
Unknown/not reported	101 (27%)	777 (41%)	2,004 (85%)
TB risk factors
At least one risk factor	288 (78%)	731 (38%)	310 (13%)
Close contact of index case	35 (12%)	30 (2%)	26 (1%)
Close contact of someone else with TB disease	15 (5%)	23 (1%)	15 (1%)
Lived in a high-TB-burden countryA	275 (75%)	684 (36%)	279 (12%)
Other unspecified risk factors	36 (13%)	59 (3%)	16 (1%)
No known risk factors	26 (7%)	467 (24%)	107 (5%)
Risk factors unknown/unreported	55 (15%)	712 (37%)	1,945 (82%)

^AIncidence >20/100,000/year.

Among outcome reporting forms returned, 2,539/4,644 (55%) reported results of at least one TB screening test (TST or IGRA) and 2,411/2,539 (95%) included test date(s). The median time from flight to first reported screening test was 81 days (interquartile range: 61–109). Overall, 139/2,411 screened contacts (6%) received their first test before the Epi-X notification was sent (Figure 2A), but the proportion was higher (44/316, 14%) among persons with TBI (Figure 2B). Among contacts with test dates available, 243/2,411 (10%) received at least two sequential screening tests (two TSTs, two IGRAs, or TST followed by IGRA) and 2,168/2,411 (90%) only received one. Among persons who only received one test, the median time between the flight and their only test was 86 days (interquartile range: 65–113). Among contacts who received two or more tests, 12/243 (7%) converted from negative to positive, of whom 10/243 (5%) converted in a timeframe consistent with infection around the time of the flight; the remaining two contacts had their initial negative test date almost a year after the flight and were excluded. Additionally, 4/243 (2%) converted from indeterminate to positive; in all cases, the second test was performed within a few weeks of the first. A small proportion of contacts with TB status reported (77/2,282, 3%; 38 with TBI and 39 with no infection) had no TB screening test results reported, and it is unclear how jurisdictions determined their final TB status.

Figure 2.

Time in days to first TB screening test (TB skin test or interferon gamma release assay) after health department notification of aircraft exposure (represented by red line) for A: all contacts (excluding six extreme outliers); and B: persons diagnosed with TB infection (excluding two extreme outliers).

Health departments reported six contacts with TB disease on outcome reporting forms, but further investigation determined that three had TBI. Of the remaining three (Table 2), all were diagnosed with pulmonary TB. Two (Cases 1 and 3) had documented abnormal test results potentially consistent with TB disease or infection before their aircraft exposures. Two (Cases 2 and 3) were family members of their respective aircraft index cases and had had extended contact with other people with TB in their countries of origin. All three were diagnosed with TB disease and had begun treatment before the state was notified of their aircraft exposure.

Table 2.

Assessment of travellers who were diagnosed with pulmonary TB disease after exposure to a person with infectious TB disease on an international flight, USA 24 June 2011–31 December 2022.

Case	Lived in high-TB-burden countryA	Known exposure outside the flight?	Evidence of possible TB before arrival?	Evaluation timingB	In-flight transmission suspected?
1	Yes	No	Yes (abnormal chest radiograph)	63 days after exposure/6 days before notification	No; evidence of possible TB disease before flight
2	Yes	Yes (family member of aircraft index case + exposure to another person with TB disease)	No	33 days after exposure/53 days before notification	No; prolonged exposure outside the flight
3	Yes	Yes (family member of aircraft index case + multiple family members with TB disease)	Yes (positive skin test)	3 days after exposure/66 days before notification	No; prolonged exposure outside the flight, positive TB screening test before flight

^AIncidence >20/100,000/year.

^BTiming of evaluation with respect to exposure on aircraft and notification of health department.

DISCUSSION

As in previous studies, this analysis did not identify any contacts with TB disease who were likely to have been infected on the plane; all three contacts with TB disease had strong evidence that they were infected in their countries of origin before boarding the plane. Evaluating the source of potential exposure for contacts with TBI is more challenging. Most flights that meet criteria for TB aircraft CIs are international flights, which are likely to have a higher proportion of people who have spent time in a high-TB-burden country than U.S. domestic flights. To be confident that a person with TBI was infected on the flight, it would be necessary to have documentation that 1) the person was infected around the time of the flight and 2) the person did not have other, more likely risk factors for exposure. The first condition is difficult to meet because many contacts do not receive two TB screening tests to document test conversion, either because they are lost to follow-up or because their HDs are not notified in time to perform the first test before conversion (within 8–10 weeks post-exposure). Only 1.6% of the contacts identified during the analysis period had two TB screening tests performed, which limited the ability to evaluate exposure timelines. Information on exposure risk factors is also limited, but 78% of contacts with TBI had at least one other risk factor for TBI. Most (8/10) contacts who converted within 4 months of flight reported other risk factors for exposure.

Every identification of a person with TB is valuable because it represents an opportunity to rapidly evaluate and treat if indicated, thereby preventing transmission to others in the community. However, screening people for TBI based on their flight history (which is likely a proxy for other exposure risk factors, such as residence in a high-TB-burden country) may not be the most effective approach, especially if other mechanisms exist to identify people at higher risk for infection. In this analysis, all contacts who had TB disease were identified through other mechanisms before their exposure on the plane was known. The timing of testing reported in this analysis suggests that at least 14% of contacts with TBI received screening tests for reasons unrelated to their aircraft exposure.

A major limitation of this evaluation lies in the high proportion of missing data. Contacts were lost at every stage of the CI process for a variety of reasons; in some cases, contacts could not be located, while in others, states may have been unable to conduct full evaluations or conducted the evaluations without returning outcomes to CDC. For the purposes of this analysis, we classified contact outcomes based on the final determination of TB status provided by HDs on the outcome reporting form, and there may have been variability in how HDs interpreted this question. A determination of final TB status was only made for 15% of contacts, and even for contacts that had a final TB status listed, there often was not sufficient information about their history and/or clinical evaluation to determine their likely source of exposure. Such high proportion of missing data increases the risk of bias, making it difficult to extrapolate the total number of people with TB that could have been identified if aircraft CIs were performed consistently and outcomes returned to CDC. It is difficult to predict the direction of the bias that these limitations introduce without information about the reasons that outcomes were not returned. It is possible that people with TB might be under-represented because they come from populations that are more difficult for HDs to reach. However, it is also possible that people with TB are over-represented because HDs might be more likely to return outcome reporting forms for people who were already diagnosed through another mechanism and did not require additional follow-up.

The available evidence does not support exposure on aircraft as an important source of TB transmission. However, if governments are considering modifying their response to these events, such policy decisions need to be based upon robust data. Future evaluations should focus on 1) at least temporarily achieving higher data quality to better characterise the number of people with TB who are identified through the aircraft CI process, 2) better understanding the reasons for low response rates and the ways in which these might bias the data, and 3) characterising the redundancies that exist to assure that passengers with TBI from non-aircraft exposures will still be identified through other mechanisms.