The global burden of tuberculosis: results from the Global Burden of Disease Study 2015

GBD Tuberculosis Collaborators, Hmwe H Kyu, Emilie R Maddison, Nathaniel J Henry, John Everett Mumford, Ryan Barber, Chloe Shields, Jonathan C Brown, Grant Nguyen, Austin Carter, Timothy M Wolock, Haidong Wang, Patrick Y Liu, Marissa Reitsma, Jennifer M Ross, Amanuel Alemu Abajobir, Kalkidan Hassen Abate, Kaja Abbas, Mubarek Abera, Semaw Ferede Abera, Habtamu Abera Hareri, Muktar Ahmed, Kefyalew Addis Alene, Nelson Alvis-Guzman, Joshua Amo-Adjei, Jason Andrews, Hossein Ansari, Carl Abelardo Antonio, Palwasha Anwari, Hamid Asayesh, Tesfay Mehari Atey, Sachin Atre, Aleksandra Barac, Justin Beardsley, Neeraj Bedi, Isabela Bensenor, Addisu Shunu Beyene, Zahid Ahmad Butt, Pere-Joan Cardona, Devasahayam Christopher, Lalit Dandona, Rakhi Dandona, Kebede Deribe, Amare Deribew, Rebecca Ehrenkranz, Maysaa El Sayed Zaki, Aman Endries, Tesfaye R Feyissa, Florian Fischer, Ruoyan Gai, Alberto L Garcia-Basteiro, Tsegaye Tewelde Gebrehiwot, Hailay Gesesew, Belete Getahun, Philimon Gona, Amador Goodridge, Harish Gugnani, Hassan Haghparast-Bidgoli, Gessessew Bugssa Hailu, Hamid Yimam Hassen, Esayas Hilawe, Nobuyuki Horita, Kathryn H Jacobsen, Jost B Jonas, Amir Kasaeian, Muktar Sano Kedir, Laura Kemmer, Yousef Khader, Ejaz Khan, Young-Ho Khang, Abdullah T Khoja, Yun Jin Kim, Parvaiz Koul, Ai Koyanagi, Kristopher J Krohn, G Anil Kumar, Michael Kutz, Rakesh Lodha, Hassan Magdy And El Razek, Reza Majdzadeh, Tsegahun Manyazewal, Ziad Memish, Walter Mendoza, Haftay Berhane Mezgebe, Shafiu Mohammed, Felix Akpojene Ogbo, In-Hwan Oh, Eyal Oren, Aaron Osgood-Zimmerman, David Pereira, Dietrich Plass, Farshad Pourmalek, Mostafa Qorbani, Anwar Rafay, Mahfuzar Rahman, Rajesh Kumar Rai, Puja C Rao, Sarah E Ray, Robert Reiner, Nickolas Reinig, Saeid Safiri, Joshua A Salomon, Logan Sandar, Benn Sartorius, Morteza Shamsizadeh, Muki Shey, Desalegn Markos Shifti, Hirbo Shore, Jasvinder Singh, Chandrashekhar T Sreeramareddy, Soumya Swaminathan, Scott J Swartz, Fentaw Tadese, Bemnet Amare Tedla, Balewgizie Sileshi Tegegne, Belay Tessema, Roman Topor-Madry, Kingsley Nnanna Ukwaja, Olalekan A Uthman, Vasiliy Vlassov, Stein Emil Vollset, Tolassa Wakayo, Solomon Weldegebreal, Ronny Westerman, Abdulhalik Workicho, Naohiro Yonemoto, Seok-Jun Yoon, Marcel Yotebieng, Mohsen Naghavi, Simon I Hay, Theo Vos, Christopher Jl Murray, GBD Tuberculosis Collaborators, Hmwe H Kyu, Emilie R Maddison, Nathaniel J Henry, John Everett Mumford, Ryan Barber, Chloe Shields, Jonathan C Brown, Grant Nguyen, Austin Carter, Timothy M Wolock, Haidong Wang, Patrick Y Liu, Marissa Reitsma, Jennifer M Ross, Amanuel Alemu Abajobir, Kalkidan Hassen Abate, Kaja Abbas, Mubarek Abera, Semaw Ferede Abera, Habtamu Abera Hareri, Muktar Ahmed, Kefyalew Addis Alene, Nelson Alvis-Guzman, Joshua Amo-Adjei, Jason Andrews, Hossein Ansari, Carl Abelardo Antonio, Palwasha Anwari, Hamid Asayesh, Tesfay Mehari Atey, Sachin Atre, Aleksandra Barac, Justin Beardsley, Neeraj Bedi, Isabela Bensenor, Addisu Shunu Beyene, Zahid Ahmad Butt, Pere-Joan Cardona, Devasahayam Christopher, Lalit Dandona, Rakhi Dandona, Kebede Deribe, Amare Deribew, Rebecca Ehrenkranz, Maysaa El Sayed Zaki, Aman Endries, Tesfaye R Feyissa, Florian Fischer, Ruoyan Gai, Alberto L Garcia-Basteiro, Tsegaye Tewelde Gebrehiwot, Hailay Gesesew, Belete Getahun, Philimon Gona, Amador Goodridge, Harish Gugnani, Hassan Haghparast-Bidgoli, Gessessew Bugssa Hailu, Hamid Yimam Hassen, Esayas Hilawe, Nobuyuki Horita, Kathryn H Jacobsen, Jost B Jonas, Amir Kasaeian, Muktar Sano Kedir, Laura Kemmer, Yousef Khader, Ejaz Khan, Young-Ho Khang, Abdullah T Khoja, Yun Jin Kim, Parvaiz Koul, Ai Koyanagi, Kristopher J Krohn, G Anil Kumar, Michael Kutz, Rakesh Lodha, Hassan Magdy And El Razek, Reza Majdzadeh, Tsegahun Manyazewal, Ziad Memish, Walter Mendoza, Haftay Berhane Mezgebe, Shafiu Mohammed, Felix Akpojene Ogbo, In-Hwan Oh, Eyal Oren, Aaron Osgood-Zimmerman, David Pereira, Dietrich Plass, Farshad Pourmalek, Mostafa Qorbani, Anwar Rafay, Mahfuzar Rahman, Rajesh Kumar Rai, Puja C Rao, Sarah E Ray, Robert Reiner, Nickolas Reinig, Saeid Safiri, Joshua A Salomon, Logan Sandar, Benn Sartorius, Morteza Shamsizadeh, Muki Shey, Desalegn Markos Shifti, Hirbo Shore, Jasvinder Singh, Chandrashekhar T Sreeramareddy, Soumya Swaminathan, Scott J Swartz, Fentaw Tadese, Bemnet Amare Tedla, Balewgizie Sileshi Tegegne, Belay Tessema, Roman Topor-Madry, Kingsley Nnanna Ukwaja, Olalekan A Uthman, Vasiliy Vlassov, Stein Emil Vollset, Tolassa Wakayo, Solomon Weldegebreal, Ronny Westerman, Abdulhalik Workicho, Naohiro Yonemoto, Seok-Jun Yoon, Marcel Yotebieng, Mohsen Naghavi, Simon I Hay, Theo Vos, Christopher Jl Murray

Abstract

Background: An understanding of the trends in tuberculosis incidence, prevalence, and mortality is crucial to tracking of the success of tuberculosis control programmes and identification of remaining challenges. We assessed trends in the fatal and non-fatal burden of tuberculosis over the past 25 years for 195 countries and territories.

Methods: We analysed 10 691 site-years of vital registration data, 768 site-years of verbal autopsy data, and 361 site-years of mortality surveillance data using the Cause of Death Ensemble model to estimate tuberculosis mortality rates. We analysed all available age-specific and sex-specific data sources, including annual case notifications, prevalence surveys, and estimated cause-specific mortality, to generate internally consistent estimates of incidence, prevalence, and mortality using DisMod-MR 2.1, a Bayesian meta-regression tool. We assessed how observed tuberculosis incidence, prevalence, and mortality differed from expected trends as predicted by the Socio-demographic Index (SDI), a composite indicator based on income per capita, average years of schooling, and total fertility rate. We also estimated tuberculosis mortality and disability-adjusted life-years attributable to the independent effects of risk factors including smoking, alcohol use, and diabetes.

Findings: Globally, in 2015, the number of tuberculosis incident cases (including new and relapse cases) was 10·2 million (95% uncertainty interval 9·2 million to 11·5 million), the number of prevalent cases was 10·1 million (9·2 million to 11·1 million), and the number of deaths was 1·3 million (1·1 million to 1·6 million). Among individuals who were HIV negative, the number of incident cases was 8·8 million (8·0 million to 9·9 million), the number of prevalent cases was 8·9 million (8·1 million to 9·7 million), and the number of deaths was 1·1 million (0·9 million to 1·4 million). Annualised rates of change from 2005 to 2015 showed a faster decline in mortality (-4·1% [-5·0 to -3·4]) than in incidence (-1·6% [-1·9 to -1·2]) and prevalence (-0·7% [-1·0 to -0·5]) among HIV-negative individuals. The SDI was inversely associated with HIV-negative mortality rates but did not show a clear gradient for incidence and prevalence. Most of Asia, eastern Europe, and sub-Saharan Africa had higher rates of HIV-negative tuberculosis burden than expected given their SDI. Alcohol use accounted for 11·4% (9·3-13·0) of global tuberculosis deaths among HIV-negative individuals in 2015, diabetes accounted for 10·6% (6·8-14·8), and smoking accounted for 7·8% (3·8-12·0).

Interpretation: Despite a concerted global effort to reduce the burden of tuberculosis, it still causes a large disease burden globally. Strengthening of health systems for early detection of tuberculosis and improvement of the quality of tuberculosis care, including prompt and accurate diagnosis, early initiation of treatment, and regular follow-up, are priorities. Countries with higher than expected tuberculosis rates for their level of sociodemographic development should investigate the reasons for lagging behind and take remedial action. Efforts to prevent smoking, alcohol use, and diabetes could also substantially reduce the burden of tuberculosis.

Funding: Bill & Melinda Gates Foundation.

Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Global age-sex distribution of tuberculosis incidence (A) and deaths (B) in HIV-negative individuals in 2015
Figure 2
Figure 2
Age-standardised rates (per 100 000 population) of tuberculosis incidence (A) and mortality (B) in HIV-negative individuals in 2015 for both sexes ATG=Antigua and Barbuda. FSM=Federated States of Micronesia. LCA=Saint Lucia. Marshall Isl=Marshall Islands. Solomon Isl=Solomon Islands. TLS=Timor-Leste. TTO=Trinidad and Tobago. VCT=Saint Vincent and the Grenadines.
Figure 3
Figure 3
Estimated observed and expected age-standardised rates of tuberculosis incidence (A), prevalence (B), and mortality (C) per 100 000 population among HIV-negative individuals based on SDI, 1990–2015 Each point on a line represents 1 year, starting at 1990 and ending at 2015. In all regions, SDI has increased year on year, so progress in SDI is associated with later years for a given region. The black lines indicate trajectories for each geography expected based on SDI alone. SDI=Socio-demographic Index.
Figure 4
Figure 4
Age-standardised population-attributable fractions of tuberculosis deaths due to diabetes, alcohol use, and smoking among HIV-negative men and women in 1990, 2005, and 2015

References

    1. Murray CJ, Ortblad KF, Guinovart C. Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384:1005–1070.
    1. GBD 2013 Mortality and Causes of Death Collaborators Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–171.
    1. GBD 2015 Mortality and Causes of Death Collaborators Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459–1544.
    1. US Agency for International Development Independent assessment of national TB prevalence surveys conducted between 2009–2015. February, 2016. (accessed Sept 30, 2016).
    1. WHO . World Health Organization; Geneva: 2016. Global tuberculosis report 2016.
    1. Floyd S, Sismanidis C, Yamada N. Analysis of tuberculosis prevalence surveys: new guidance on best-practice methods. Emerg Themes Epidemiol. 2013;10:10.
    1. Anker M, Black RE, Coldham C. A standard verbal autopsy method for investigating causes of death in infants and children. (accessed Oct 18, 2016).
    1. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1545–1602.
    1. GBD 2015 DALYs and HALE Collaborators Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1603–1658.
    1. Lönnroth K, Raviglione M. The WHO's new End TB Strategy in the post-2015 era of the Sustainable Development Goals. Trans R Soc Trop Med Hyg. 2016;110:148–150.
    1. GBD 2015 Risk Factors Collaborators Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1659–1724.
    1. Lozano R, Naghavi M, Foreman K. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study. Lancet. 2010;380:2095–2128.
    1. Foreman KJ, Lozano R, Lopez AD, Murray CJ. Modeling causes of death: an integrated approach using CODEm. Popul Health Metr. 2012;10:1.
    1. Ortblad KF, Lozano R, Murray CJ. The burden of HIV: insights from the Global Burden of Disease Study 2010. AIDS. 2013;27:2003–2017.
    1. Cox JA, Lukande RL, Lucas S, Nelson AM, Van Marck E, Colebunders R. Autopsy causes of death in HIV-positive individuals in sub-Saharan Africa and correlation with clinical diagnoses. AIDS Rev. 2010;12:183–194.
    1. Ford N, Matteelli A, Shubber Z. TB as a cause of hospitalization and in-hospital mortality among people living with HIV worldwide: a systematic review and meta-analysis. J Int AIDS Soc. 2016;19:20714.
    1. Flaxman AD, Vos T, Murray CJ. first edn. University of Washington Press; Seattle: 2015. An integrative metaregression framework for descriptive epidemiology.
    1. Greene WH. Pearson Education; Harlow: 2012. Econometric analysis; pp. 332–344.
    1. Global Burden of Disease Study 2013 Collaborators Global, regional, and national incidence, prevalence, and YLDs for 301 acute and chronic diseases and injuries for 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743–800.
    1. GBD 2013 Risk Factors Collaborators. Forouzanfar MH, Alexander L. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:2287–2323.
    1. Narasimhan P, Wood J, MacIntyre CR, Mathai D. Risk factors for tuberculosis. Pulm Med. 2013;2013:828939.
    1. Cegielski J, McMurray D. The relationship between malnutrition and tuberculosis: evidence from studies in humans and experimental animals. Int J Tuberc Lung Dis. 2004;8:286–298.
    1. Sumpter C, Chandramohan D. Systematic review and meta-analysis of the associations between indoor air pollution and tuberculosis. Trop Med Int Health. 2013;18:101–108.
    1. Food and Agriculture Organization of the UN FAOSTAT statistics database. (accessed Sept 29, 2017).
    1. WHO WHO Global Health Observatory data repository. Global Information System on Alcohol and Health (GISAH) (accessed March 1, 2016).
    1. Global Health Data Exchange (accessed Feb 16, 2016).
    1. WHO Tuberculosis financing and funding gaps. (accessed Oct 14, 2016).
    1. Dieleman J, Campbell M, Chapin A. Evolution and patterns of global health financing 1995–2014. Lancet. 2017;389:1981–2004.
    1. Dye C. Tuberculosis 2000–2010: control, but not elimination. Int J Tuberc Lung Dis. 2000;4(12 suppl 2):S146–S152.
    1. Sreeramareddy CT, Panduru KV, Menten J, Van den Ende J. Time delays in diagnosis of pulmonary tuberculosis: a systematic review of literature. BMC Infect Dis. 2009;9:91.
    1. Storla DG, Yimer S, Bjune GA. A systematic review of delay in the diagnosis and treatment of tuberculosis. BMC Public Health. 2008;8:1.
    1. Sreeramareddy CT, Qin ZZ, Satyanarayana S, Subbaraman R, Pai M. Delays in diagnosis and treatment of pulmonary tuberculosis in India: a systematic review. Int J Tuberc Lung Dis. 2014;18:255–266.
    1. Dye C, Williams BG. The population dynamics and control of tuberculosis. Science. 2010;328:856–861.
    1. Jochem K, Walley J. Determinants of the tuberculosis burden in populations. In: Porter JD, Grange JM, editors. Tuberculosis—an interdisciplinary perspective. Imperial College Press; London: 1999. pp. 33–48.
    1. Golub J, Bur S, Cronin W. Delayed tuberculosis diagnosis and tuberculosis transmission. Int J Tuberc Lung Dis. 2006;10:24–30.
    1. Blumberg HM, Ernst JD. The challenge of latent TB infection. JAMA. 2016;316:931–933.
    1. Hossain S, Quaiyum MA, Zaman K. Socio economic position in TB prevalence and access to services: results from a population prevalence survey and a facility-based survey in Bangladesh. PLoS One. 2012;7:e44980.
    1. Long Q, Li Y, Wang Y. Barriers to accessing TB diagnosis for rural-to-urban migrants with chronic cough in Chongqing, China: a mixed methods study. BMC Health Serv Res. 2008;8:1.
    1. Buu T, Lönnroth K, Quy H. Initial defaulting in the National Tuberculosis Programme in Ho Chi Minh City, Vietnam: a survey of extent, reasons and alternative actions taken following default. Int J Tuberc Lung Dis. 2003;7:735–741.
    1. Botha E, Den Boon S, Verver S. Initial default from tuberculosis treatment: how often does it happen and what are the reasons? Int J Tuberc Lung Dis. 2008;12:820–823.
    1. Afutu F, Zachariah R, Hinderaker S. High initial default in patients with smear-positive pulmonary tuberculosis at a regional hospital in Accra, Ghana. Trans R Soc Trop Med Hyg. 2012;106:511–513.
    1. De Lima YV, Evans D, Page-Shipp L. Linkage to care and treatment for TB and HIV among people newly diagnosed with TB or HIV-associated TB at a large, inner city South African hospital. PLoS One. 2013;8:e49140.
    1. Dobler CC. Screening strategies for active tuberculosis: focus on cost-effectiveness. Clinicoecon Outcomes Res. 2016;8:335–347.
    1. Calligaro GL, Zijenah LS, Peter JG. Effect of new tuberculosis diagnostic technologies on community-based intensified case finding: a multicentre randomised controlled trial. Lancet Infect Dis. 2017;17:441–450.
    1. Lönnroth K, Migliori GB, Abubakar I. Towards tuberculosis elimination: an action framework for low-incidence countries. Eur Respir J. 2015;45:928–952.
    1. Wiker HG, Mustafa T, Bjune GA, Harboe M. Evidence for waning of latency in a cohort study of tuberculosis. BMC Infect Dis. 2010;10:37.
    1. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol. 1974;99:131–138.
    1. Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 2003;167:1472–1477.
    1. Davies P. TB in the elderly in industrialised countries. Int J Tuberc Lung Dis. 2007;11:1157–1159.
    1. Pratt RH, Winston CA, Kammerer JS, Armstrong LR. Tuberculosis in older adults in the United States, 1993–2008. J Am Geriatr Soc. 2011;59:851–857.
    1. Watkins R, Plant A. Does smoking explain sex differences in the global tuberculosis epidemic? Epidemiol Infect. 2006;134:333–339.
    1. Nhamoyebonde S, Leslie A. Biological differences between the sexes and susceptibility to tuberculosis. J Infect Dis. 2014;209(suppl 3):S100–S106.
    1. Neyrolles O, Quintana-Murci L. Sexual inequality in tuberculosis. PLoS Med. 2009;6:e1000199.
    1. Rehm J, Samokhvalov AV, Neuman MG. The association between alcohol use, alcohol use disorders and tuberculosis (TB). A systematic review. BMC Public Health. 2009;9:450.
    1. Oeltmann JE, Kammerer JS, Pevzner ES, Moonan PK. Tuberculosis and substance abuse in the United States, 1997–2006. Arch Intern Med. 2009;169:189–197.
    1. Rehm J, Baliunas D, Borges GL. The relation between different dimensions of alcohol consumption and burden of disease: an overview. Addiction. 2010;105:817–843.
    1. Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis. 2009;9:737–746.
    1. Nelson S, Zhang P, Bagby GJ, Happel KI, Raasch CE. Alcohol abuse, immunosuppression, and pulmonary infection. Curr Drug Abuse Rev. 2008;1:56–67.
    1. O'Leary SM, Coleman MM, Chew WM. Cigarette smoking impairs human pulmonary immunity to Mycobacterium tuberculosis. Am J Respir Crit Care Med. 2014;190:1430–1436.
    1. Szabo G. Alcohol's contribution to compromised immunity. Alcohol Health Res World. 1997;21:30–41.
    1. Uplekar M, Atre S, Wells WA. Mandatory tuberculosis case notification in high tuberculosis-incidence countries: policy and practice. Eur Respir J. 2016;48:1571–1581.
    1. Anderson L, Broekmans J, Floyd K, Glaziou P, Sismanidis B, Zignol M. Strengthening tuberculosis surveillance: rationale and proposed areas of work 2016–2020. (accessed Sept 8, 2017).
    1. Lopez A, Mikkelsen L, Rampatige R. World Health Organization; Geneva: 2013. Strengthening civil registration and vital statistics for births, deaths and causes of death. Resource kit.
    1. Abubakar I, Bassili A, Bierrenbach A. World Health Organization; Geneva: 2012. Assessing tuberculosis under-reporting through inventory studies.
    1. Begg S, Rao C, Lopez AD. Design options for sample-based mortality surveillance. Int J Epidemiol. 2005;34:1080–1087.
    1. WHO . World Health Organization; Geneva: 2015. Global tuberculosis report 2015.
    1. Dodd PJ, Sismanidis C, Seddon JA. Global burden of drug-resistant tuberculosis in children: a mathematical modelling study. Lancet Infect Dis. 2016;16:1193–1201.
    1. Jenkins HE, Tolman AW, Yuen CM. Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates. Lancet. 2014;383:1572–1579.
    1. James SL, Flaxman AD, Murray CJ. Performance of the Tariff Method: validation of a simple additive algorithm for analysis of verbal autopsies. Popul Health Metr. 2011;9:31.
    1. Lozano R, Lopez AD, Atkinson C, Naghavi M, Flaxman AD, Murray CJ. Performance of physician-certified verbal autopsies: multisite validation study using clinical diagnostic gold standards. Popul Health Metr. 2011;9:32.
    1. Murray CJ, Lozano R, Flaxman AD. Using verbal autopsy to measure causes of death: the comparative performance of existing methods. BMC Med. 2014;12:5.
    1. Dowell SF, Blazes D, Desmond-Hellmann S. Four steps to precision public health. Nature. 2016;540:189–191.
    1. Cazabon D, Alsdurf H, Satyanarayana S. Quality of tuberculosis care in high burden countries: the urgent need to address gaps in the care cascade. Int J Infect Dis. 2017;56:111–116.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi