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Primary Lung 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
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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](A1)
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](B2)
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](A1)
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](A1)
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:(B3)
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] (B2)
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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