Characteristics of TB disease among contacts in Shanghai
This retrospective study revealed a high incidence of TB disease (848/100,000) among contacts of TB patients over an average of 2.6 years of follow-up. This rate is approximately 30 times higher than that in the general population (29.6/100,000) of Shanghai (from the Shanghai TB Report System, not published). This result (69/8137) is consistent with data reported by some researchers from Shandong, China and in California and Kenya [
11‐
13]. However, many researchers from other countries have reported a higher incidence of TB disease among contacts: researchers from the US reported a rate ranging from 1.1–2.2% [
14‐
17]; the UK reported a rate ranging from 2.9–5.9% [
18‐
21]; and data from middle- and low-income countries (i.e., Turkey, Gambia, Iran and Thailand) revealed a rate ranging from 1.4–14.5% [
22‐
25]. These higher rates reported in most studies were likely because most of the index cases included in their studies were smear-positive TB patients, and some studies even restricted contacts to close contacts or contacts within family. In contrast, we included contacts of both smear-positive and smear-negative TB patients and did not restrict contacts into specific groups.
The TB disease surveillance data revealed an increasing trend of TB disease among different age groups in Shanghai. We failed to identify such an association in the present study. This result is consistent with previous studies showing no significant difference among different age groups [
26‐
29]. Nevertheless, a higher TB disease incidence density was found among individuals with ages of 20–29 years, who exhibited a disease incidence approximately 40 times that of the general population, which indicates the importance of implementing active contact investigation among this age group. In addition, this study showed that male contacts exhibited twice the risk of acquiring TB disease as female contacts. This result is consistent with data reported from the general population in Shanghai.
Limitations of the current contact investigation strategy
Although current guidelines require contact investigation of all contacts experiencing direct contact with the index case, including family members, colleagues, classmates and roommates, the average number of contacts for each index case was only 2.3 in this study. This result is consistent with some other studies from this country [
30,
31] and primarily results from a fear of being stigmatized or shunned by others, as many index cases do not want others to know they have TB and omit the names of colleagues, friends, classmates or even relatives from the contact list. Thus, the contacts who underwent contact investigation were mainly family members who lived under the same roof and were mostly the index cases’ biological family members. Future contact investigations may require community doctors to educate TB patients on the importance of contact investigation and simultaneously educate the general public with accurate information about TB to reduce the stigmatization toward TB patients. In addition, a lack of detailed contact information (i.e., the grade of the contact) is one of the limitations of the current contact investigation strategy. We were unable to collect accurate contact information years after the original contact investigation because of the retrospective nature of this study. Future studies must include the grade of the contact and ways to reach out to the contact to further quantify the disease risk under each circumstance and guide the contact investigation with better evidence. The detection rate through contact investigation in this study was only 22% (15/69), with the remaining TB disease cases being diagnosed through other means, including individual physical check-ups. This low detection rate revealed that the current strategy of contact investigation may lack effectiveness in identifying TB cases among the contacts of TB patients. This is mainly because the current contact investigation strategy restricts the screening of contacts to within 1 month from the index case’s diagnosis, which leaves out patients with disease onset after 1 month. Among all 69 TB cases diagnosed within contacts, 46% were diagnosed within 3 years of their index case’s diagnosis. Researchers from other countries have also indicated a high detection rate of TB among contacts within 3 years of diagnosing the index case [
32]. A meta-analysis using data from 77 studies revealed that in middle- and low-income countries, contacts exposed to index cases exhibit the highest incidence of TB disease in the first year, with a rate of 1500/100,000, followed by a rate of 1000/100,000 in the 3rd year. This rate starts to decline in the 4th year, falling to approximately 500/100,000 [
32]. Indeed, the follow-up period of a TB contact investigation is usually 2 years in the UK, the US, Japan, Taiwan, and China [
33‐
35]. All these data suggest that annual follow-up may be necessary until the end of the 3rd year if healthcare resources allow.
The contact investigation strategy of performing chest radiography or fluoroscopy only on contacts with suspected TB symptoms detected 9.5% (2/21) of the TB cases. The detection rate was lower than that reported in other studies. For example, a study from Turkey indicated that a combined strategy of symptom assessment, chest X-ray evaluation and TB skin PPD testing detected 41.4% of TB cases among contacts [
26]. This finding suggests that a combined screening strategy may increase the TB detection rate among contacts. Another study on family contacts of smear-positive TB cases from China found that only 50% of TB cases among contacts had suspected TB symptoms [
36]. The results from this study indicate that performing chest radiography or fluoroscopy only on contacts with TB symptoms is not adequate since a large proportion of contacts who actually have TB may be asymptomatic. The contact investigation strategy applied from 2013 to 2014, in which chest radiography was added, increased the detection rate from the initial rate of 9.5 to 27%. Hence, performing chest radiography or the equivalent on every contact, instead of only symptomatic contacts, can increase the detection rate of TB cases among this population. Studies involving TB contact investigations from many countries have defined index cases as only smear-positive TB patients; however, the results from this study indicated that smear-negative TB patients also have a high risk of developing TB disease (not significantly different from the contacts of smear-positive TB patients). In addition, distinguishing between index cases and contact TB cases is sometimes difficult since it is quite possible that a smear-negative index case diagnosed earlier was actually infected through contact with a non-symptomatic case. As a result, contact investigation of only smear-positive index cases may not be adequate to detect non-symptomatic TB cases among contacts. The same conclusion was drawn by researchers from Arkansas, US [
37]. Therefore, we believe that performing contact investigation among the contacts of all TB patients is beneficial for TB tracing among this population.
According to the contact investigation strategy recommended by the WHO for middle- and low-income countries, clinical evaluation of household and close contacts for active TB is a priority for TB disease control [
4]. The Chinese strategy for TB contact investigation is aimed at identifying active cases of TB, which complies with the strategy recommended by the WHO. Nevertheless, the current screening methods adopted in China only identify a small percentage of disease patients, partly because chest radiography (or the equivalent) is administered only to contacts with suspected symptoms. Identifying active TB patients is a crucial step in TB control; however, identifying and treating latent TB are also an important strategy for decreasing TB incidence among the general population. With limited funding from the government, it is difficult to test and treat the large population with latent TB infection. Future endeavors may focus on finding a cost-effective way to test for latent infection in a contact investigation and may possibly treat LTBI among high risk groups such as child contact and PLHIV. We suggest a contact investigation strategy fully based on the WHO recommendations when resources are permitted.
Based on the results from this study, index case for contact investigation should be defined as both smear-positive and smear-negative active cases since index case may not necessarily be the source case. In terms of follow up period, longer period of follow up (at least 2 years) is suggested in order to identify possible incident cases. This is also consistent with the statement made by WHO that the risk of developing TB is increased for 1–2 years if infected through contact investigation. In addition, combine symptom examination with radiography will increase the case detection rate among the remaining 50% active cases without TB symptoms. Nevertheless, there is still a large gap between China and other developed countries. In the United States or other European countries, more expensive screening methods, such as IGRAs, are used in contact investigations, and latent TB infections found through the screening process also receive treatment. For a developing country, our current focus is still on identifying and treating active TB patients. We believe that testing and treating latent TB infection will be the next step.
IGRA or TST might be better alternatives in developed countries with low incidence, but can be very difficult to achieve under current circumstance in China because IGRA test is provided by TB designated hospitals as out-of-pocket service at a high price that cannot be reimbursed through government health insurance or other specific reimbursement plans. As regard to TST, it wasn’t proposed for two reasons. First, TST requires two hospital visits for each contact, and the timing of the second visit is restricted to within 48–72 h, which is difficult to achieve in reality. Second, because of the high percentage of BCG vaccinations among the Chinese population, the interpretation of TST results can be difficult since a considerable percentage of false positive will emerge. This situation is rather different from country low incidence country (i.e. the United States) where majority did not receive BCG vaccination.