Tuberculosis prevalence among university freshmen in Zhengzhou, China, during 2004–2013

Background Tuberculosis (TB) is a major public health concern worldwide, and spreads more easily in densely populated areas such as school campuses. Objectives The aim of this study was to determine the prevalence of positive TB skin tests among freshmen, i.e. newly-enrolled college students, in Zhengzhou City, China. Methods We reviewed the data of purified protein derivative (PPD) skin tests in 656,212 freshmen in 2004–2013. Results A positive test showed a diameter of swelling ≥ 5 mm. The PPD positive rate was 40.69 %, with a prevalence of 146.29 per 100,000. During the 10-year study period, the rate of students with positive PPD test increased from 34.19 % in 2004 to 40.69 % in 2013. The positive PPD rate was significantly higher in males than in females (41.68 % vs 39.61 %, P<0.0001), and in rural compared with urban areas (42.04 % vs 38.03 %, P<0.0001). Conclusion These findings indicated a high prevalence of PPD positivity among participants during the study period, with an increasing trend. Therefore, this population needs to be targeted by TB prevention and control programs.


Introduction
Where there are humans, Mycobacterium tuberculosis (MTB) seems to be present as well. Tuberculosis (TB) has been a powerful deterrent to worldwide health since ancient times, and the main cause of death due to bacterial infection 1 . Currently, TB is the seventh most common disease worldwide, a trend projected to continue until 2020 2 . According to yearly WHO global TB reports since 1997 2-8 , statistical results from 1990 to 2015 showed that TB related deaths declined from 2 to 1.

African
Health Sciences countries such as Vietnam, Philippines, Ethiopia, Korea, Japan, China, India, et al. [9][10][11][12][13][14][15][16][17][18][19][20] However, not enough precise data are available to determine whether the back-and-forth trend will re-emerge. Worldwide, TB incidence has declined by only 1.5 % from 2014 to 2015. 21 This needs to increase to a 4-5 % annual decline by 2020 to reach the first milestone of the End TB Strategy 8 . TB was a leading cause of adult mortality in low-and middle-income countries, ranking third after HIV and ischemic heart disease among individuals aged 15-59 years in 2001 22 . Besides the suffering caused by TB in humans, the monetary burden was estimated to have exceeded US$ 56 billion, up from US$ 3.5 billion in 2006 to US$ 6.7 billion in 2015. This is in part due to the WHO Millennium Development Goals (MDG) and Stop TB Partnership targets for 2015, which aim to halt and reverse TB incidence, halve prevalence and mortality rates compared to 1990 levels, detect at least 70% of infectious cases, and successfully treat 85% of the infectious cases detected 23 . The more important long-term elimination target set for 2050 will not be met with current strategies and tools. Global actions and investments fall far short of those needed to end the global TB epidemic 8 . Several key challenges persist, including unaffordable sufficient quality services to vulnerable people, multidrug-resistant M. tuberculosis strains, underlying social determinants in the community, and obsolete and inadequate technologies for diagnosis, treatment, and prevention 24 . China had the second largest number of new TB cases after India in 2004-2013 7,25 . The Fifth National Tuberculosis Epidemiological Survey (FNTES) in 2010 showed declined TB prevalence in China 26 . However, specific groups appear to be at higher risks, including freshmen from TB epidemic backgrounds, underdeveloped regions, and even some unexpected places such as college and university campuses. This high incidence could lead to widespread outbreaks if ignored. The objective of the present study was to appraise the TB epidemic in colleges and universities, exploring effective measures for disease prevention and treatment. Our findings suggest that more focus of public health is needed to prevent the outbreak of infectious diseases in colleges.

Materials and methods Study participants
There were 656,212 freshmen attending 30 colleges and universities in Zhengzhou, China, in 2004China, in -2013. This study was conducted in accordance with the ethical standards of the Helsinki Declaration, and approved by the Medical Ethics Committee of the Sixth People's Hospital of Zhengzhou (document number 2011HNIN003). In accordance with China's national conditions, the main auxiliary method of tuberculosis diagnosis for freshmen was PPD screening. All participants provided verbal consent, and permission was obtained from local authorities.

Tuberculosis testing
Study participants received 0.1 ml (5 IU) PPD (1:2000) subcutaneously in the inner forearm. Forty-eight to 72 hours after injection, the site was evaluated by a physician. The reaction was considered to be negative, weakly positive, moderately positive, and strongly positive with greatest swelling diameters of < 5 mm, 5-9 mm, 10-19 mm and ≥ 20 mm (or < 20 mm with blisters, necrosis or lymphatitis), respectively 27 .

TB treatment
Students with a strongly positive PPD test result underwent chest X-ray examination. In case of lung shadow discovery upon imaging, the students were referred to the TB Control Institute, Zhengzhou City, for further examination. Students with a strongly positive PPD test result as well as those with undetermined active TB status were administered preventive medication after written informed consent. The two treatment regimens used were isoniazid at 0.3 g/day for 6 months or Rifapentine and isoniazid combination at 0.6 g twice weekly for 3 months 28 . Confirmed active TB cases were transferred to local TB prevention and control institutions for out-patient or inpatient treatment, and instructed to stay at home for 1 to 3 months. All patients underwent treatment by TB prevention and control institutions until disappearance of clinical symptoms, demonstrated by three consecutive negative sputum smear examinations for acid-fast bacilli (AFB) and lung imaging showing no fibrosis or sclerosis. High prevalence of persistent cough and AFB-positive sputum smears required further exploration. Patients with clinical cure-and restoration class certificates issued by respective TB prevention and control institutions could return to school. The College Hospital Preventive Care Section archived the information of each patient and tracked patient management until recovery.

Statistical analysis
Statistical analyses were performed with SPSS, version 17.0 (SPSS Inc., Chicago, IL, USA). P<0.05 was considered statistically significant. Multiple groups were compared with the χ2 test.

Results
Of the 656,212 students administered the PPD test, 221,292 (33.72%) and 434,920 (66.28%) lived in urban and rural areas, respectively; 341,186 (51.99%) were males, with 315.026 (48.01%) females. A total of 266,992 (40.69%) and 44,563 (6.79%) were positive and strongly positive, respectively. There were 960 diagnosed TB cases, indicating an incidence of 146.29/100,000. Over the 10-year study period, the PPD positive rate and TB prevalence increased annually (Fig 1). A comparison of annual weakly positive rates showed a statistically significant difference (P<0.0001); similar results were obtained for moderately positive PPD, strongly positive PPD, and total positive PPD cases, as well as TB prevalence (P < 0.0001). The total positive and strongly positive rates, as well as prevalence in boys were significantly higher than the values obtained for girls, and significantly higher in rural than urban areas (P<0.0001) ( Table 1). As shown in Figure 1, the rate of confirmed TB cases peaked in 2008, because a high school and a university in Zhengzhou failed to perform PPD tests in 2007, with a TB outbreak in these institutions occurring in 2008. In addition, 2013 marked the final rising trend in total number of confirmed TB cases, because only one university in Zhengzhou performed TB surveillance due to a shortage of funds. We also noticed that many colleges had not administered PPD tests for nearly two years in Henan province.

PPD test results by gender and region
A total of 41.68% males had positive PPD results, with a prevalence of 218.65/100,000. Meanwhile, 39.61% females had positive PPD results, with a prevalence of 67.93/100,000. Total positivity rate, strongly positive rate, and TB prevalence were all significantly higher in males than in females (p<0.0001). Total positivity and prevalence rates in urban students were 38.03% and 80.44/100,000, respectively, while rural students had rates of 42.04% and 179.80/100,000, respectively. Total positivity, strongly positive, and prevalence rates were significantly higher in rural students compared with urban counterparts (p<0.0001) ( Table 2).

Discussion
This study revealed an increase in the prevalence of PPD positivity over 10 years, corroborating other reports in China 29,30 , but different from the decreasing trend found in the 2010 FNTES. College freshmen are active and mobile, increasing the risk of TB transmission. A large number of young adult TB cases constitute an obstacle to TB control 31 . College students undergo physical development and endocrinological changes from adolescence to adulthood, with poor dietary behaviors and less physical activity, which affect long-term health and chronic disease risk 32 .
The students examined had just completed the college entrance examination (CEE), with elevated stress and possibly a weakened immune system. They tended to have less sleep, lived in cramped dormitories, and studied in classrooms with inadequate air quality. Some had poor nutrition, which further contributed to immune suppression. Such factors increase the risk of contracting TB.
Students attending university are required to undergo entrance physical examination and PPD test. With PPD examinations in freshmen, TB epidemic rarely occurs. However, a senior middle school and a university in Zhengzhou in 2007 failed to perform PPD testing, and a TB outbreak occurred at the two institutions. This emphasizes the importance of TB screening in this vulnerable population.

Analysis of PPD test results in boys and girls
Total and strongly positive rates, and the prevalence of positive PPD results in study participants were significantly higher in men compared with women, as previously reported in China 33 . A potential factor contributing to this difference is that males frequent internet cafes more often than females; these cybercafés tend to be crowded, with poor ventilation. Another possible reason is the poorer hygiene in men's dormitories compared with women's, making TB transmission more likely. TB transmission is related to long-term close contact and a dirty living environment 34 . In many low-and middle-income countries women smoke less than men 35 , and smoking increases the risk of pulmonary tuberculosis 36 .

Comparison of PPD test results between urban and rural students
Our survey demonstrated that total and strongly positive PPD results, as well as TB prevalence were higher in students from rural regions than those from urban areas.
Poor economic conditions and nutritional deficiencies in rural areas may lead to lower immunity. Some poor students from rural areas can only afford basic needs, and may have inadequate intake of meat, eggs, milk and fruits.
Rural students may also have less knowledge regarding TB control because health education only comprises a few lectures per semester in many high schools. The lack of basic knowledge of hygiene can result in bad habits such as spitting, which increases the risk of TB transmis-sion. We suggest health education should be provided to students from primary school through university.

Therapeutic measures for individuals with strongly positive PPD tests
Students with strongly positive PPD results, i.e. who have latent TB infection, should be educated about the importance of treatment, and treated to prevent transmission. PPD negative students should be injected BCG vaccine for protection against TB. Strongly positive PPD test students should be immediately treated. According to WHO more than a decade ago, the most cost-effective way to stop TB in communities with high incidence is by curing it. DOTS (Directly-Observed Treatment, Short-Course) is considered the best curative method for TB 37 . However, some students find it difficult to conform to unaffordable TB medication with DOTS standards, and to comply with regimens in developing countries. Irregular medication use can lead to TB drug resistance. Therefore, coordinated efforts should target continuous scale-up of screening, early diagnosis, and proper treatment of TB, in line with DOTS. The ultimate goal is effective prevention and control of TB in this high risk population.

Conclusion
A TB control program includes screening, tracking (such as drugs for prophylaxis and treatment) and re-check, and any disrupted link could increase TB prevalence. Therefore, adequate human and financial resources are needed for TB control programs. Direct and indirect costs, as well as social consequences of TB can be devastating to the patient, family and community 38,39 . Positive PPD rates in the assessed freshmen have increased yearly during the study period. Colleges and the public health department should be aware of this trend and implement adequate measures.
The title of the research topic is "the Medical science and technology research project of Henan Province in 2014" and the research topic number is 201404053.