Continuing Education Activity

Tuberculosis is the leading cause of death from an infectious agent worldwide, causing even more deaths in patients with HIV/AIDS. A third of the world's population is said to have contracted the bacteria responsible for tuberculosis, Mycobacterium tuberculosis, with estimates of ten million new infections globally each year. This activity reviews the evaluation and management of primary pulmonary tuberculosis.

Objectives:

• Summarize the etiology of primary pulmonary tuberculosis.
• Outline the evaluation of patients presenting with primary pulmonary tuberculosis.
• Review the management options available for primary pulmonary tuberculosis.
• Describe some interprofessional team strategies that can result in better care coordination for patients presenting with primary pulmonary tuberculosis.

Introduction

Discovered in 1882 by Robert Koch, tuberculosis (TB), one of the oldest known infections, is a major global health problem and one of the top ten causes of death worldwide. It is a disease of humans, as it does not affect animals naturally.[1][2]

Tuberculosis is the leading cause of death from an infectious agent worldwide, causing even more deaths in HIV/AIDS patients. A third of the world's population is said to have contracted the bacteria responsible for tuberculosis, Mycobacterium tuberculosis, with estimates of ten million new infections globally each year.[3][4] The global disease burden of tuberculosis is estimated to be around 24%, with remarkable socioeconomic implications.[5] 

The major pathology in tuberculosis is necrotizing granulomatous inflammation, with the lungs being the primary organs of involvement of the disease in up to 87% of the cases. Having that said, almost any bodily organ could be a site for the disease.[6][7] It commonly affects people living in crowded conditions such as institutionalized patients, immigrants from countries with a high prevalence of tuberculosis, immunocompromised such as patients with HIV, and health care workers.[8][9] 

The worldwide incidence has been steadily decreasing, but it is still a common problem in regions such as Sub-Saharan Africa. It is still a major medical cause of mortality as the global death toll reaches up to 1.5 million deaths a year.[10] Lung function impairment is the major sequel of pulmonary tuberculosis.[11] In this topic, we will review pulmonary tuberculosis covering the main aspects of the disease.

Etiology

Mycobacterium species include a variety of organisms with different genomic structures, morphology, and tropism.[12] The genus itself includes more than 170 species.[13] M. tuberculosis is a gram-negative bacteria. It is a small, aerobic, and nonmotile bacillus. It is characterized by a complex wall structure that is rich in long-chain fatty acids. The genus is divided into two groups: fast-growing and slow-growing organisms. M. tuberculosis belongs to the slow-growing group.[14] M. tuberculosis cell wall is rich in peptidoglycan and complex lipids. These structures are major factors for pathogenesis.[15] The capsule (the outer layer) surrounds the cell wall. It is a main contributor to the bacterium's virulence and survival.

M. tuberculosis is a facultative intracellular bacterium. It acts as an inhibitor of macrophages, proliferates within the macrophages, causing the eventual death of invaded macrophages and the release of the bacillus to the alveolar space.[16] Staining with stains such as Ziehl-Neelsen aid in detecting the acid-fast bacilli using microscopy. Mycobacterium tuberculosis is a very slow-growing organism, taking up to 24 hours to grow.[17]

Epidemiology

Tuberculosis is a reportable disease in almost all world countries. This facilitates more accurate disease tracking and epidemiological studies. The incidence of tuberculosis was slowly decreasing until the surge of HIV infection, which led to this trend reversal.[18][19] Among medical conditions, tuberculosis is now a leading cause of mortality and morbidity across the globe. Different studies estimate that around 1.7 billion individuals have been infected with tuberculosis.[5] TB caused around 2.5% of the world's deaths in 2004.[20]

The WHO estimated that it infected 10 million individuals in the year 2017. Among world countries, India and China are leading in TB deaths.[20] Countries with a high poverty rate are primarily affected, with an estimated incidence of 183 cases per 100,000, compared to less than ten per 100,000 in developed countries.[21] However, the universal incidence is slowly decreasing by 1.6% per year.[22] Among HIV patients, TB is the main culprit for mortality. CD4 cells have a major role in combating HIV infection. Hence advanced HIV disease is typically associated with disseminated disease.[23][24] 

Several other medical conditions and certain medications also increase the risk of developing TB infection. This includes diabetes, chronic corticosteroid use, and the use of anti-TNF biologics. A unique group at risk are patients who underwent gastrectomy, which appears to be due to certain nutritional deficiencies.[25] Some rare genetic defects affecting gamma interferon, IL-12, and IL-23 signaling pathways put patients at increased risk for more severe disease.[26]

Tuberculosis transmits via aerosolized microdroplets. This is classically generated from a coughing patient with active tuberculosis. Other means of generating aerosolized droplets include singing, shouting, and sneezing.[27] Prolonged exposure is the main factor in increasing the risk of transmission. Thus it is a common occurrence among household members and coworkers.[28] Other common places for tuberculosis transmission include prisons, mines, and public transport settings.[29][30] Smear-positive patients are considered highly infectious.[31] The cavitary disease also seems to increase transmission as cavitation erodes the airways the technically facilitates bacterium movement.[32] Children below 5 years and HIV-positive patients are at a higher risk of contracting the disease.[33]

Pathophysiology

Tuberculosis pulmonary inflammation is characterized by lung tissue destruction and necrosis, unlike other lung infections that affect mainly the airways.[34] The main virulence factors that play roles in the pathogenesis of M. tuberculosis include cell wall mycolic acid glycolipids, lipoarabinomannan (LAM), sulfatides, and trehalose dimycolate.[35] The exact role each factor plays is not very understood. The virulence effect varies as there are factors that help evade local immune cells, induce cytokines, and another affecting cellular metabolism.[36] Mce1A protein, although still not clear how plays an important role in tuberculosis cellular transport.[37] 

M. tuberculosis cell wall also contains different kinds of mycolic acids that are integral to the organism growth inside macrophages.[38] Other virulence secretion systems have also been described. Examples are ESX-1, sec, and TAT systems. These systems facilitate the mycobacterium translocation.[39] 

Unlike most gram-negative bacteria, the main virulence factor of tuberculosis evolves around "survival" within its human host, rather than actively attacking the host or evading its defenses. The main example is when it develops cholesterol uptake mechanisms from the host to enhance its survival.[40]

Histopathology

The main pathological feature of tuberculosis is "granuloma formation," a rounded collection of macrophages surrounded by lymphocytes. The unique feature differentiating tuberculous granulomas from other infectious granulomatous conditions (such as Histoplasma and Leishmania) is "caseation" or central necrosis.[34]

History and Physical

After primary infection, the majority of patients remain asymptomatic. Most of these asymptomatic individuals clear the infection. However, a portion enters a "latent" phase with the potential "reactivation" in the future.[41] Symptomatic individuals (around 10 percent) develop primary lung infection with some suffering spread to distant organs, particularly immune-compromised patients (e.g., HIV patients).[42] Prolonged fever is the most commonly reported symptom as only one-third of patients with pulmonary involvement develop respiratory symptoms. This fever usually follows a diurnal pattern. It increased as the day goes and subsides at night, although sometimes it is associated with night sweat.[43] Pulmonary symptoms include chest pain, shortness of breath, and cough. Cough is often mild and non-productive. However, in disease progression, it might produce green or blood-tinged sputum. Other nonpulmonary symptoms may occur, such as lymphadenopathy, fatigue, and pharyngitis.[44] Anorexia, weight loss, and loss of muscle mass could happen in advanced cases.[45] 

Latency is a unique aspect of tuberculosis infection. The majority of infected individuals who get infected do not actually develop symptoms until months to years after their initial exposure. This is known as latent tuberculosis.[46] Research is inconclusive about this stage, but most point towards the bacterium entering a static no-growth state.[47] Reactivation of tuberculosis is a prolonged process that could sometimes take years to progress.[48] Symptoms are not very different from primary disease and classically include fever, cough, shortness of breath, and weight loss.[49]

The physical exam is usually normal in mild disease or shows nonspecific lung findings such as crackles or tubular breath sounds. Absent breath sounds are noted over consolidation areas. Extrapulmonary findings include clubbing and other signs of distant organ involvement.[50]

Evaluation

The workup of suspected TB cases begins with a chest radiograph. The workup should be initiated in any patients with more than three weeks of cough and additional symptoms such as fever, night sweats, hemoptysis, or weight loss. The workup should also be initiated in at-risk groups with prolonged unexplained illnesses. These at-risk groups include the following: HIV-positive patients, individuals with known recent exposure to a case of active tuberculosis, low socioeconomic status, chronic illnesses (such as diabetes, chronic kidney disease, malignancy, or patient on immune suppressive), and IV drug users.[51]

If imaging is suggestive of infection three sputum samples should be collected and sent for acid-fast bacilli (AFB) staining with one sample tested with nucleic acid amplification (NAAT). If both AFB culture and NAAT are positive, TB is likely and treatment should be initiated. Tuberculin skin test (TST) and interferon-gamma release assay (IGRA) should be added to the workup as they support the diagnosis, however, negative results don't exclude the infection.[51] In the case of non-definitive results, a bronchoscopy sample to lung biopsy could be considered.[52]

Radiological Findings

Early in the disease, chest radiographs are usually normal. Hilar lymphadenopathy is a hallmark of radiological findings in tuberculosis. Other common findings include perihilar and right-sided infiltration and pleural effusion.

Treatment / Management

In 2016, international guidelines were developed to treat drug-susceptible tuberculosis, led by the Americal Thoracic Society and Center for Disease Control and Prevention (CDC) with the participation of various US and international organizations.[53] The main goals of treatment are decreasing the burden of growing bacilli, preventing relapse, and decreasing drug resistance. [53] The drug therapy of active tuberculosis is divided into two main phases: the intensive phase (lasting for two months) and followed by the continuation phase (lasting at least four months). The standard drug choice for the intensive phase is isoniazid (INH), ethambutol (EMB), rifampin (RIF), and pyrazinamide (PZA). The continuation phase drugs are usually isoniazid and rifampin.[54][55] Medications should be administered through what is known as directly observed therapy (DOT), which is observing the patient directly ingesting the medicine to enhance patient compliance and therapy adherence.[56] AFB culture should be done monthly during treatment until at least two consecutive negative samples.[53]

The preferred regimen is the combination of INH, RIF, PZA, and EMB for the intensive phase for 8 weeks (56 doses) and INH and RIF for the continuation phase for 18 weeks (126 doses). The medications are given daily, 7 days a week. If there is a concern about compliance or difficulty achieving DOT, the dosing for the continuous phase could be modified to 3 times weekly. When drug sensitivity is available, and the bacterium is susceptible to both INH and RIF, EMB could be stopped.[57] Patients at risk of neuropathy, such as pregnant/lactating mothers, breastfed infants, diabetics, chronic kidney disease, alcoholic, older age, and HIV positive patients, should receive pyridoxine (vitamin B6) supplementation.[58]

Treatment of tuberculosis in HIV-positive patients constitutes a unique challenge due to potential drug interaction with antiretroviral therapy. In general, it is still recommended to use the same duration of treatment for both intensive and continuation phases (two and four months) in HIV-positive patients who are infected with drug-susceptible tuberculosis. The exception is an unusual situation when the patient is not receiving antiretroviral therapy. In this situation, it is suggested that the continuation phase is continued for 3 additional months.[59] The concomitant use of trimoxazole and anti-tuberculous drugs has been shown to improve outcomes in HIV patients with active tuberculosis, particularly those with a CD4 count below 200 cells/µL.[60]

Latent tuberculosis infection (LTBI) is treated with fewer medications for a shorter period of time. 2020 LTBI treatment guidelines include the NTCA- and CDC-recommended treatment regimens that comprise three preferred rifamycin-based regimens and two alternative monotherapy regimens with daily isoniazid. These are only recommended for persons infected with Mycobacterium tuberculosis that is presumed to be susceptible to isoniazid or rifampin. A regimen of 3 months of once-weekly isoniazid plus rifapentine is a preferred regimen that is strongly recommended for children aged more than 2 years and adults. Another option is 4 months of daily rifampin for HIV-negative adults and children of all ages. Three months of daily isoniazid plus rifampin is a preferred treatment that is conditionally recommended for adults and children of all ages and for patients with HIV. Regimens of 6 or 9 months of daily isoniazid are alternative recommended regimens.

In general, severe treatment side effects that warrant cessation of medications occur in 4% to 9% of patients receiving conventional drug therapy.[61] Most commonly reported side effects include nausea, vomiting, and skin rashes.[62] Laboratory monitoring of liver toxicity should be initiated. Significant hepatotoxicity occurs in 2.4% of cases and mandates halting treatment temporarily. Elevated liver enzymes 3 to 5 times above normal limits and elevated serum bilirubin prompt holding therapy until they normalize. According to referenced guidelines, medications are then reintroduced one by one to identify the culprit and substitute it with another medication.[63][61] An optic neuroma is a rare event that could occur with ethambutol. Patients on this medication should have an ophthalmologic exam 4-weeks into treatment.[64] Neuropathy could happen with INH use, and risk could be lowered by concomitant use of pyridoxine.[63]

Drug-resistant Tuberculosis

Drug resistance is a major problem in treating tuberculosis. [65] Patients resistant to INH and RIF are said to have multidrug-resistant (MDR) TB. It is a major challenge that could arise during treatment. The chance of developing MDR TB is around 3.8% in developed countries. However, this number could be much higher in countries with a high TB burden, such as China and India, reaching up to 20%.[66] Drug-resistant TB is categorized into different types:

Mono-resistant TB: Resistance to one of the drugs of standard first-line medications.

Polydrug resistance: Resistance to more than one first-line medication (except the combination of INH and RIF).

Multidrug resistance (MDR): Resistance to both INH and RIF

Extensive drug resistance (XDR): MDR plus resistance to a fluoroquinolone and injectable second-line medications.[67]

There are multiple settings where drug resistance could develop. Nonstandardized treatment protocols among countries or medication shortages in resource-limited countries lead to incomplete treatment.[67] Community and nosocomial transmission are also other major sources of MDR-TB spread.[68] Drug-susceptibility testing (DST) is required to diagnose MDR-TB. Currently, there are different commercially available molecular testing that identify genes conferring drug resistance.[69] 

There are multiple second-line drugs for MDR, but unfortunately, the cure rate is much lower than drug-susceptible tuberculosis. The global cure rate is variable between countries. Surveys reported cure rates between 20 to 48%.[67] As a rule, any medication that was used in first-line regimens should be excluded from second-line therapy. DST and history should guide second-line therapy. Classically the regimen consists of four drugs. The first step is to choose an injectable medication. Examples include kanamycin and capreomycin. Adding a fluoroquinolone such as moxifloxacin or levofloxacin is the next step. The third choice is one of these options: ethionamide, cycloserine, or para-aminosalicylic acid. The last step is to add either PZA or EMB to the regimen.[70] The duration of treatment of MDR-TB is a minimum of 20 months and for an additional 18 months after being culture negative.

Differential Diagnosis

The differential diagnosis can be broad, especially with respiratory involvement, but can include the following:

• Sarcoidosis: Mainly differentiated from tuberculosis by the presence of non-caseating granuloma.
• Fungal infections: Such as  Histoplasmosis, Aspergillosis, Actinomycosis, Blastomycosis, and Nocardiosis. Epidemiological history aid in determining the risk of developing these infections.
• Nontuberculous mycobacterial infections (NTM): such as Mycobacterium kansasii.
• Lung malignancy and lymphoma: Tissue biopsy is needed to role out this diagnosis if suspected
• Lung abscess

Treatment Planning

Patients with active tuberculosis undergoing medical treatment should undergo organized monitoring and follow-up. Sputum sampling and culture with drug susceptibility testing should be done at the third and fourth months into treatment to verify negativity. A sample should also be obtained at the end of treatment. Chest X-rays or equivalent imaging should be obtained two months after treatment initiation and at the end of therapy. Vision assessment should be done monthly, starting the third month till the end of therapy. Screening for hepatitis B and C should be done at baseline for patients at risk (such as IV drug users). Monthly laboratory assessment should start after one month of therapy for blood cells (CBC), liver enzymes, and creatinine. CD4 and RNA viral load should be assessed monthly for HIV-positive patients.[53]

Prognosis

Tuberculosis prognosis is variable as it could be a multi-system disease and is affected by many factors. Patient characteristics such as age, immune status, comorbidities, time of treatment initiation, and compliance have a significant impact on the outcome. In general, treatment is successful in about 85% of cases. The World Health Organization estimates the mortality rate to be at 15 percent.[9]

Complications

Pulmonary tuberculosis has a variety of complications. Bleeding from bronchial, pulmonary, and intercostal arteries lead to hemoptysis. This bleeding is usually minimal and rarely leads to massive blood loss.[71] Rupture of a subpleural focus or a lung cavity could lead to spontaneous pneumothorax.[72] Lymph node inflammation may lead to compression on the bronchial tree and could cause bronchiectasis.[73] Severe untreated pulmonary tuberculosis may lead to extensive lung destruction, necrosis, and gangrene.[74] Tuberculosis has also been reported to increase the risk of lung malignancy.[75] Other less common complications include chronic pulmonary aspergillosis and septic shock.[76][77]

Deterrence and Patient Education

The most effective approach for tuberculosis disease prevention is identifying cases and effective treatment. Medical therapy considerably decreases bacterial load transmission within communities.[78] A vaccine does exist for tuberculosis, known as the BCG vaccine. This is an old vaccine with worldwide use, particularly in developing countries, usually given at birth or in infancy. The vaccine seems to decrease the incidence of tuberculosis in childhood but unfortunately does not affect the incidence of adulthood disease.[78]

Using the FAST approach seems to effectively reduce the burden of nosocomial transmission in a hospital setting. This consists of Finding undiagnosed tuberculosis infections Actively through rapid molecular testing, Separating them safely, and initiating appropriate treatment.[79]

Identifying and mapping "hot sport" within a geographical area and providing preventative INH therapy seems to decrease disease burden within communities.[80]

Socioeconomic development (such as improving public transport settings) and improving nutritional health within communities reduce crowdedness and minimize close contact or prolonged exposure. This reduces the risk of community transmission and decreases the disease burden.[81]

Several vaccine candidates have shown efficacy in animal models compared to the old BCG vaccine. However, none so far have shown efficacy in humans. One trial examined a vaccinia virus-produced M. tuberculosis vaccine has failed to elicit an adequate immune response in human hosts.[82]

Enhancing Healthcare Team Outcomes

A national detection program should be implemented to help curb the disease burden in communities. These programs are responsible for sample processing and result feedback to treating healthcare professionals. Infection control is another integral part of improving the disease outcome. It requires coordination between public health, treating facilities, and the local community. Drug administration under directly observed therapy (DOT) requires feedback pathways between patients, observers, and treating healthcare professionals. In most countries, the patients are assigned a "Case Manager" usually by public health. Communication between the patient and treating professional helps the case manager solve treatment problems and help achieve treatment goals.[83]

Effective patient education about tuberculosis infection, treatment objectives, medications, and their side effects, appropriate infection-control measures vastly improve chances of treatment success and prognosis. Healthy educators and pharmacists play crucial roles here and must be utilized where available.[84]

All these different medical disciplines need to function as a cohesive, collaborative interprofessional healthcare team to improve patient outcomes.

Drug-resistant TB is a major problem now. Communication between clinical pharmacists and treating health professional help in selecting appropriate therapy and minimizes unnecessary drug exposure.

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References

1.

Churchyard G, Kim P, Shah NS, Rustomjee R, Gandhi N, Mathema B, Dowdy D, Kasmar A, Cardenas V. What We Know About Tuberculosis Transmission: An Overview. J Infect Dis. 2017 Nov 03;216(suppl_6):S629-S635. [PMC free article: PMC5791742] [PubMed: 29112747]

2.

Barbier M, Wirth T. The Evolutionary History, Demography, and Spread of the Mycobacterium tuberculosis Complex. Microbiol Spectr. 2016 Aug;4(4) [PubMed: 27726798]

3.

Furin J, Cox H, Pai M. Tuberculosis. Lancet. 2019 Apr 20;393(10181):1642-1656. [PubMed: 30904262]

4.

Sudarsan TI, Thomas L, Samprathi A, Chacko B, Mathuram A, George T, Karthik G, Rajan SJ, Carey RAB, Mahasampath G, Peter JV. Tuberculous ARDS is associated with worse outcome when compared with non-tuberculous infectious ARDS. J Crit Care. 2021 Feb;61:138-143. [PubMed: 33161242]

5.

Houben RM, Dodd PJ. The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS Med. 2016 Oct;13(10):e1002152. [PMC free article: PMC5079585] [PubMed: 27780211]

6.

Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, Parkhill J, Malla B, Berg S, Thwaites G, Yeboah-Manu D, Bothamley G, Mei J, Wei L, Bentley S, Harris SR, Niemann S, Diel R, Aseffa A, Gao Q, Young D, Gagneux S. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet. 2013 Oct;45(10):1176-82. [PMC free article: PMC3800747] [PubMed: 23995134]

7.

Farer LS, Lowell AM, Meador MP. Extrapulmonary tuberculosis in the United States. Am J Epidemiol. 1979 Feb;109(2):205-17. [PubMed: 425959]

8.

Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis. 1982 Mar;125(3 Pt 2):8-15. [PubMed: 7073104]

9.

Dheda K, Barry CE, Maartens G. Tuberculosis. Lancet. 2016 Mar 19;387(10024):1211-26. [PMC free article: PMC11268880] [PubMed: 26377143]

10.

Hagan G, Nathani N. Clinical review: tuberculosis on the intensive care unit. Crit Care. 2013 Sep 27;17(5):240. [PMC free article: PMC4056111] [PubMed: 24093433]

11.

Guirado E, Schlesinger LS. Modeling the Mycobacterium tuberculosis Granuloma - the Critical Battlefield in Host Immunity and Disease. Front Immunol. 2013;4:98. [PMC free article: PMC3631743] [PubMed: 23626591]

12.

Bañuls AL, Sanou A, Van Anh NT, Godreuil S. Mycobacterium tuberculosis: ecology and evolution of a human bacterium. J Med Microbiol. 2015 Nov;64(11):1261-1269. [PubMed: 26385049]

13.

Fedrizzi T, Meehan CJ, Grottola A, Giacobazzi E, Fregni Serpini G, Tagliazucchi S, Fabio A, Bettua C, Bertorelli R, De Sanctis V, Rumpianesi F, Pecorari M, Jousson O, Tortoli E, Segata N. Genomic characterization of Nontuberculous Mycobacteria. Sci Rep. 2017 Mar 27;7:45258. [PMC free article: PMC5366915] [PubMed: 28345639]

14.

Cousins DV, Bastida R, Cataldi A, Quse V, Redrobe S, Dow S, Duignan P, Murray A, Dupont C, Ahmed N, Collins DM, Butler WR, Dawson D, Rodríguez D, Loureiro J, Romano MI, Alito A, Zumarraga M, Bernardelli A. Tuberculosis in seals caused by a novel member of the Mycobacterium tuberculosis complex: Mycobacterium pinnipedii sp. nov. Int J Syst Evol Microbiol. 2003 Sep;53(Pt 5):1305-1314. [PubMed: 13130011]

15.

Converse SE, Mougous JD, Leavell MD, Leary JA, Bertozzi CR, Cox JS. MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6121-6. [PMC free article: PMC156336] [PubMed: 12724526]

16.

Jasmer RM, Nahid P, Hopewell PC. Clinical practice. Latent tuberculosis infection. N Engl J Med. 2002 Dec 05;347(23):1860-6. [PubMed: 12466511]

17.

Allen BW, Mitchison DA. Counts of viable tubercle bacilli in sputum related to smear and culture gradings. Med Lab Sci. 1992 Jun;49(2):94-8. [PubMed: 1487984]

18.

Kwan CK, Ernst JD. HIV and tuberculosis: a deadly human syndemic. Clin Microbiol Rev. 2011 Apr;24(2):351-76. [PMC free article: PMC3122491] [PubMed: 21482729]

19.

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 Oct 08;388(10053):1459-1544. [PMC free article: PMC5388903] [PubMed: 27733281]

20.

Fogel N. Tuberculosis: a disease without boundaries. Tuberculosis (Edinb). 2015 Sep;95(5):527-31. [PubMed: 26198113]

21.

Zaheen A, Bloom BR. Tuberculosis in 2020 - New Approaches to a Continuing Global Health Crisis. N Engl J Med. 2020 Apr 02;382(14):e26. [PubMed: 32242354]

22.

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 Nov 10;392(10159):1789-1858. [PMC free article: PMC6227754] [PubMed: 30496104]

23.

Tiberi S, Carvalho AC, Sulis G, Vaghela D, Rendon A, Mello FC, Rahman A, Matin N, Zumla A, Pontali E. The cursed duet today: Tuberculosis and HIV-coinfection. Presse Med. 2017 Mar;46(2 Pt 2):e23-e39. [PubMed: 28256380]

24.

Khan K, Wang J, Hu W, Bierman A, Li Y, Gardam M. Tuberculosis infection in the United States: national trends over three decades. Am J Respir Crit Care Med. 2008 Feb 15;177(4):455-60. [PubMed: 18029790]

25.

Cheng KC, Liao KF, Lin CL, Lai SW. Gastrectomy correlates with increased risk of pulmonary tuberculosis: A population-based cohort study in Taiwan. Medicine (Baltimore). 2018 Jul;97(27):e11388. [PMC free article: PMC6076070] [PubMed: 29979430]

26.

Boisson-Dupuis S, Bustamante J, El-Baghdadi J, Camcioglu Y, Parvaneh N, El Azbaoui S, Agader A, Hassani A, El Hafidi N, Mrani NA, Jouhadi Z, Ailal F, Najib J, Reisli I, Zamani A, Yosunkaya S, Gulle-Girit S, Yildiran A, Cipe FE, Torun SH, Metin A, Atikan BY, Hatipoglu N, Aydogmus C, Kilic SS, Dogu F, Karaca N, Aksu G, Kutukculer N, Keser-Emiroglu M, Somer A, Tanir G, Aytekin C, Adimi P, Mahdaviani SA, Mamishi S, Bousfiha A, Sanal O, Mansouri D, Casanova JL, Abel L. Inherited and acquired immunodeficiencies underlying tuberculosis in childhood. Immunol Rev. 2015 Mar;264(1):103-20. [PMC free article: PMC4405179] [PubMed: 25703555]

27.

Turner RD, Bothamley GH. Cough and the transmission of tuberculosis. J Infect Dis. 2015 May 01;211(9):1367-72. [PubMed: 25387581]

28.

Kurtuluş Ş, Can R, Sak ZHA. New perspective on rise of tuberculosis cases: communal living. Cent Eur J Public Health. 2020 Dec;28(4):302-305. [PubMed: 33338367]

29.

Hanifa Y, Grant AD, Lewis J, Corbett EL, Fielding K, Churchyard G. Prevalence of latent tuberculosis infection among gold miners in South Africa. Int J Tuberc Lung Dis. 2009 Jan;13(1):39-46. [PubMed: 19105877]

30.

Andrews JR, Morrow C, Walensky RP, Wood R. Integrating social contact and environmental data in evaluating tuberculosis transmission in a South African township. J Infect Dis. 2014 Aug 15;210(4):597-603. [PMC free article: PMC4133578] [PubMed: 24610874]

31.

Zelner JL, Murray MB, Becerra MC, Galea J, Lecca L, Calderon R, Yataco R, Contreras C, Zhang Z, Grenfell BT, Cohen T. Age-specific risks of tuberculosis infection from household and community exposures and opportunities for interventions in a high-burden setting. Am J Epidemiol. 2014 Oct 15;180(8):853-61. [PMC free article: PMC4188339] [PubMed: 25190676]

32.

Kaplan G, Post FA, Moreira AL, Wainwright H, Kreiswirth BN, Tanverdi M, Mathema B, Ramaswamy SV, Walther G, Steyn LM, Barry CE, Bekker LG. Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity. Infect Immun. 2003 Dec;71(12):7099-108. [PMC free article: PMC308931] [PubMed: 14638800]

33.

Martinez L, Cords O, Horsburgh CR, Andrews JR., Pediatric TB Contact Studies Consortium. The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis. Lancet. 2020 Mar 21;395(10228):973-984. [PMC free article: PMC7289654] [PubMed: 32199484]

34.

Elkington P, Lerm M, Kapoor N, Mahon R, Pienaar E, Huh D, Kaushal D, Schlesinger LS. In Vitro Granuloma Models of Tuberculosis: Potential and Challenges. J Infect Dis. 2019 May 24;219(12):1858-1866. [PMC free article: PMC6534193] [PubMed: 30929010]

35.

Rastogi N, David HL. Mechanisms of pathogenicity in mycobacteria. Biochimie. 1988 Aug;70(8):1101-20. [PubMed: 3147701]

36.

Smith I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin Microbiol Rev. 2003 Jul;16(3):463-96. [PMC free article: PMC164219] [PubMed: 12857778]

37.

Casali N, Riley LW. A phylogenomic analysis of the Actinomycetales mce operons. BMC Genomics. 2007 Feb 26;8:60. [PMC free article: PMC1810536] [PubMed: 17324287]

38.

Rao V, Fujiwara N, Porcelli SA, Glickman MS. Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule. J Exp Med. 2005 Feb 21;201(4):535-43. [PMC free article: PMC2213067] [PubMed: 15710652]

39.

Voulhoux R, Ball G, Ize B, Vasil ML, Lazdunski A, Wu LF, Filloux A. Involvement of the twin-arginine translocation system in protein secretion via the type II pathway. EMBO J. 2001 Dec 03;20(23):6735-41. [PMC free article: PMC125745] [PubMed: 11726509]

40.

Pandey AK, Sassetti CM. Mycobacterial persistence requires the utilization of host cholesterol. Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4376-80. [PMC free article: PMC2393810] [PubMed: 18334639]

41.

Milburn HJ. Primary tuberculosis. Curr Opin Pulm Med. 2001 May;7(3):133-41. [PubMed: 11371768]

42.

Stead WW, Kerby GR, Schlueter DP, Jordahl CW. The clinical spectrum of primary tuberculosis in adults. Confusion with reinfection in the pathogenesis of chronic tuberculosis. Ann Intern Med. 1968 Apr;68(4):731-45. [PubMed: 5642961]

43.

POULSEN A. Some clinical features of tuberculosis. Acta Tuberc Scand. 1957;33(1-2):37-92; concl. [PubMed: 13424392]

44.

Long B, Liang SY, Koyfman A, Gottlieb M. Tuberculosis: a focused review for the emergency medicine clinician. Am J Emerg Med. 2020 May;38(5):1014-1022. [PubMed: 31902701]

45.

Schlossberg D. Acute tuberculosis. Infect Dis Clin North Am. 2010 Mar;24(1):139-46. [PubMed: 20171549]

46.

Barry CE, Boshoff HI, Dartois V, Dick T, Ehrt S, Flynn J, Schnappinger D, Wilkinson RJ, Young D. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol. 2009 Dec;7(12):845-55. [PMC free article: PMC4144869] [PubMed: 19855401]

47.

Gill WP, Harik NS, Whiddon MR, Liao RP, Mittler JE, Sherman DR. A replication clock for Mycobacterium tuberculosis. Nat Med. 2009 Feb;15(2):211-4. [PMC free article: PMC2779834] [PubMed: 19182798]

48.

MacGregor RR. A year's experience with tuberculosis in a private urban teaching hospital in the postsanatorium era. Am J Med. 1975 Feb;58(2):221-8. [PubMed: 1115069]

49.

Miller LG, Asch SM, Yu EI, Knowles L, Gelberg L, Davidson P. A population-based survey of tuberculosis symptoms: how atypical are atypical presentations? Clin Infect Dis. 2000 Feb;30(2):293-9. [PubMed: 10671331]

50.

Sgaragli G, Frosini M. Human Tuberculosis I. Epidemiology, Diagnosis and Pathogenetic Mechanisms. Curr Med Chem. 2016;23(25):2836-2873. [PubMed: 27281297]

51.

Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, Keane J, Lewinsohn DA, Loeffler AM, Mazurek GH, O'Brien RJ, Pai M, Richeldi L, Salfinger M, Shinnick TM, Sterling TR, Warshauer DM, Woods GL. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis. 2017 Jan 15;64(2):e1-e33. [PubMed: 27932390]

52.

Malekmohammad M, Marjani M, Tabarsi P, Baghaei P, Sadr Z, Naghan PA, Mansouri D, Masjedi MR, Velayati AA. Diagnostic yield of post-bronchoscopy sputum smear in pulmonary tuberculosis. Scand J Infect Dis. 2012 May;44(5):369-73. [PubMed: 22497518]

53.

Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, Chaisson LH, Chaisson RE, Daley CL, Grzemska M, Higashi JM, Ho CS, Hopewell PC, Keshavjee SA, Lienhardt C, Menzies R, Merrifield C, Narita M, O'Brien R, Peloquin CA, Raftery A, Saukkonen J, Schaaf HS, Sotgiu G, Starke JR, Migliori GB, Vernon A. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016 Oct 01;63(7):e147-e195. [PMC free article: PMC6590850] [PubMed: 27516382]

54.

Johnson JL, Hadad DJ, Dietze R, Maciel EL, Sewali B, Gitta P, Okwera A, Mugerwa RD, Alcaneses MR, Quelapio MI, Tupasi TE, Horter L, Debanne SM, Eisenach KD, Boom WH. Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am J Respir Crit Care Med. 2009 Sep 15;180(6):558-63. [PMC free article: PMC2742745] [PubMed: 19542476]

55.

Small PM, Fujiwara PI. Management of tuberculosis in the United States. N Engl J Med. 2001 Jul 19;345(3):189-200. [PubMed: 11463015]

56.

Chaulk CP, Kazandjian VA. Directly observed therapy for treatment completion of pulmonary tuberculosis: Consensus Statement of the Public Health Tuberculosis Guidelines Panel. JAMA. 1998 Mar 25;279(12):943-8. [PubMed: 9544769]

57.

LoBue PA, Moser KS. Isoniazid- and rifampin-resistant tuberculosis in San Diego County, California, United States, 1993-2002. Int J Tuberc Lung Dis. 2005 May;9(5):501-6. [PubMed: 15875920]

58.

Snider DE. Pyridoxine supplementation during isoniazid therapy. Tubercle. 1980 Dec;61(4):191-6. [PubMed: 6269259]

59.

Vernon A, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium. Lancet. 1999 May 29;353(9167):1843-7. [PubMed: 10359410]

60.

Masur H, Brooks JT, Benson CA, Holmes KK, Pau AK, Kaplan JE., National Institutes of Health. Centers for Disease Control and Prevention. HIV Medicine Association of the Infectious Diseases Society of America. Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Updated Guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014 May;58(9):1308-11. [PMC free article: PMC3982842] [PubMed: 24585567]

61.

Gülbay BE, Gürkan OU, Yildiz OA, Onen ZP, Erkekol FO, Baççioğlu A, Acican T. Side effects due to primary antituberculosis drugs during the initial phase of therapy in 1149 hospitalized patients for tuberculosis. Respir Med. 2006 Oct;100(10):1834-42. [PubMed: 16517138]

62.

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 Jun 01;167(11):1472-7. [PubMed: 12569078]

63.

Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest. 1991 Feb;99(2):465-71. [PubMed: 1824929]

64.

Schaberg T, Bauer T, Brinkmann F, Diel R, Feiterna-Sperling C, Haas W, Hartmann P, Hauer B, Heyckendorf J, Lange C, Nienhaus A, Otto-Knapp R, Priwitzer M, Richter E, Rumetshofer R, Schenkel K, Schoch OD, Schönfeld N, Stahlmann R. [Tuberculosis Guideline for Adults - Guideline for Diagnosis and Treatment of Tuberculosis including LTBI Testing and Treatment of the German Central Committee (DZK) and the German Respiratory Society (DGP)]. Pneumologie. 2017 Jun;71(6):325-397. [PubMed: 28651293]

65.

Seung KJ, Keshavjee S, Rich ML. Multidrug-Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis. Cold Spring Harb Perspect Med. 2015 Apr 27;5(9):a017863. [PMC free article: PMC4561400] [PubMed: 25918181]

66.

Zhao Y, Xu S, Wang L, Chin DP, Wang S, Jiang G, Xia H, Zhou Y, Li Q, Ou X, Pang Y, Song Y, Zhao B, Zhang H, He G, Guo J, Wang Y. National survey of drug-resistant tuberculosis in China. N Engl J Med. 2012 Jun 07;366(23):2161-70. [PubMed: 22670902]

67.

Falzon D, Jaramillo E, Schünemann HJ, Arentz M, Bauer M, Bayona J, Blanc L, Caminero JA, Daley CL, Duncombe C, Fitzpatrick C, Gebhard A, Getahun H, Henkens M, Holtz TH, Keravec J, Keshavjee S, Khan AJ, Kulier R, Leimane V, Lienhardt C, Lu C, Mariandyshev A, Migliori GB, Mirzayev F, Mitnick CD, Nunn P, Nwagboniwe G, Oxlade O, Palmero D, Pavlinac P, Quelapio MI, Raviglione MC, Rich ML, Royce S, Rüsch-Gerdes S, Salakaia A, Sarin R, Sculier D, Varaine F, Vitoria M, Walson JL, Wares F, Weyer K, White RA, Zignol M. WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J. 2011 Sep;38(3):516-28. [PubMed: 21828024]

68.

Lin H, Shin S, Blaya JA, Zhang Z, Cegielski P, Contreras C, Asencios L, Bonilla C, Bayona J, Paciorek CJ, Cohen T. Assessing spatiotemporal patterns of multidrug-resistant and drug-sensitive tuberculosis in a South American setting. Epidemiol Infect. 2011 Nov;139(11):1784-93. [PMC free article: PMC3153578] [PubMed: 21205434]

69.

Iketleng T, Lessells R, Dlamini MT, Mogashoa T, Mupfumi L, Moyo S, Gaseitsiwe S, de Oliveira T. Mycobacterium tuberculosis Next-Generation Whole Genome Sequencing: Opportunities and Challenges. Tuberc Res Treat. 2018;2018:1298542. [PMC free article: PMC6304523] [PubMed: 30631597]

70.

Wells CD, Cegielski JP, Nelson LJ, Laserson KF, Holtz TH, Finlay A, Castro KG, Weyer K. HIV infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis. 2007 Aug 15;196 Suppl 1:S86-107. [PubMed: 17624830]

71.

THOMPSON JR. Mechanisms of fatal pulmonary hemorrhage in tuberculosis. Am J Surg. 1955 Mar;89(3):637-44. [PubMed: 13228824]

72.

WILDER RJ, BEACHAM EG, RAVITCH MM. Spontaneous pneumothorax complicating cavitary tuberculosis. J Thorac Cardiovasc Surg. 1962 May;43:561-73. [PubMed: 14006972]

73.

Rosenzweig DY, Stead WW. The role of tuberculosis and other forms of bronchopulmonary necrosis in the pathogenesis of bronchiectasis. Am Rev Respir Dis. 1966 May;93(5):769-85. [PubMed: 5296012]

74.

Khan FA, Rehman M, Marcus P, Azueta V. Pulmonary gangrene occurring as a complication of pulmonary tuberculosis. Chest. 1980 Jan;77(1):76-80. [PubMed: 7351153]

75.

Brenner AV, Wang Z, Kleinerman RA, Wang L, Zhang S, Metayer C, Chen K, Lei S, Cui H, Lubin JH. Previous pulmonary diseases and risk of lung cancer in Gansu Province, China. Int J Epidemiol. 2001 Feb;30(1):118-24. [PubMed: 11171871]

76.

Page ID, Byanyima R, Hosmane S, Onyachi N, Opira C, Richardson M, Sawyer R, Sharman A, Denning DW. Chronic pulmonary aspergillosis commonly complicates treated pulmonary tuberculosis with residual cavitation. Eur Respir J. 2019 Mar;53(3) [PMC free article: PMC6422837] [PubMed: 30705126]

77.

Kethireddy S, Light RB, Mirzanejad Y, Maki D, Arabi Y, Lapinsky S, Simon D, Kumar A, Parrillo JE, Kumar A., Cooperative Antimicrobial Therapy of Septic Shock (CATSS) Database Group. Mycobacterium tuberculosis septic shock. Chest. 2013 Aug;144(2):474-482. [PubMed: 23429859]

78.

Baily GV. Tuberculosis prevention Trial, Madras. Indian J Med Res. 1980 Jul;72 Suppl:1-74. [PubMed: 7005086]

79.

Barrera E, Livchits V, Nardell E. F-A-S-T: a refocused, intensified, administrative tuberculosis transmission control strategy. Int J Tuberc Lung Dis. 2015 Apr;19(4):381-4. [PubMed: 25859991]

80.

Cegielski JP, Griffith DE, McGaha PK, Wolfgang M, Robinson CB, Clark PA, Hassell WL, Robison VA, Walker KP, Wallace C. Eliminating tuberculosis one neighborhood at a time. Am J Public Health. 2013 Jul;103(7):1292-300. [PMC free article: PMC3682594] [PubMed: 23078465]

81.

Dowdy DW, Azman AS, Kendall EA, Mathema B. Transforming the fight against tuberculosis: targeting catalysts of transmission. Clin Infect Dis. 2014 Oct 15;59(8):1123-9. [PMC free article: PMC4481585] [PubMed: 24982034]

82.

Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, Shea JE, McClain JB, Hussey GD, Hanekom WA, Mahomed H, McShane H., MVA85A 020 Trial Study Team. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet. 2013 Mar 23;381(9871):1021-8. [PMC free article: PMC5424647] [PubMed: 23391465]

83.

Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International standards for tuberculosis care. Lancet Infect Dis. 2006 Nov;6(11):710-25. [PubMed: 17067920]

84.

M'imunya JM, Kredo T, Volmink J. Patient education and counselling for promoting adherence to treatment for tuberculosis. Cochrane Database Syst Rev. 2012 May 16;2012(5):CD006591. [PMC free article: PMC6532681] [PubMed: 22592714]

Disclosure: Zainab Alzayer declares no relevant financial relationships with ineligible companies.

Disclosure: Yasser Al Nasser declares no relevant financial relationships with ineligible companies.