Tuberculosis Beyond Lungs: An Ancient but Unremitting Problem

“A dread disease in which the struggle between soul and body is so gradual, quiet and solemn and the result so sure that day by day and grain by grain, the mortal part wastes and withers away. A disease … which sometimes moves in giant strides and sometimes at a tardy sluggish pace, but, slow or quick, is ever sure and certain …” Charles Dickens: Nicholas Nickleby Since the beginning of time, tuberculosis (TB) has plagued humanity due to its significant social and economic impact on human existence on a global scale. Over 10 million new cases of TB are reported worldwide each year, affecting over 25% of the world’s population.[1] Thirty high-burden nations account for 87% of all notified cases worldwide. Nearly 28% of all TB cases recorded worldwide are from India.[2] Pulmonary TB is the most common form of TB. Approximately 85% of TB cases that are reported globally involve the lungs.[3] TB can potentially infect organs other than the lungs, known as extrapulmonary TB (EPTB). There are several types of EPTB; some can be fatal, while others cause chronic illness and impairment that lowers quality of life.[4] There are still many difficulties in diagnosing and treating EPTB, despite the fact that we have made great strides in the diagnosis and management of pulmonary TB. Its involvement in nearly every bodily system and the lack of specificity surrounding clinical care has made it a foe in the fight against TB. Early clinical diagnosis of EPTB is hampered by its nonspecific clinical signs, which might mimic those of any other illness. Furthermore, the diagnosis of EPTB is frequently delayed because extra-pulmonary lesions are paucibacillary in nature and sample collection frequently necessitates invasive procedures. As a result, diagnosing and treating EPTB continues to be difficult in the quest to eradicate TB.[5] Hematogenous and lymphatic dispersion of Mycobacterium tuberculosis is the primary mechanism by which EPTB spreads.[6-9] The country’s socioeconomic status and the extent of TB control programs’ execution have a significant impact on EPTB rates. Different populations have seen an increase in the percentage of EPTB among all reported TB cases. Although pulmonary TB could be controlled with the aid of numerous TB control initiatives, EPTB rates are not declining.[10] The ratio of EPTB to pulmonary TB cases in impoverished nations like India is 15%–20%. Among patients who also have HIV, this percentage rises to over 50%, indicating that the host’s immune state is a significant risk factor for EPTB. The prevalence of EPTB varies by age and sex, indicating variations in host characteristics such as immunity.[11,12] The age bracket that is impacted by EPTB varies throughout studies; some reports link it to younger ages, while others link it to older ages. Male patients under 60 years old have been found to have both EPTB and pulmonary TB co-occurring, whereas female patients over 60 years old have isolated EPTB.[13] To determine if an EPTB case is contagious and to aid in diagnosis, all suspected cases must be evaluated for pulmonary TB also.[14] Research continuously demonstrates that pulmonary TB is more common in men, and EPTB is more common in women.[15] While tubercular pleural effusion is more common in men, tubercular lymphadenitis is more common in women. Young females (20–39 years old) were more likely to have genitourinary TB, while male adolescents were more likely to have central nervous system TB.[16] The most often affected site of EPTB is the lymph node, which is followed by the pleural cavity. It is interesting to note that TB of the bones and joints is more prevalent among EPTB cases in Taiwan (24.5%) and Russia (34.5%).[17] Liver illness has been demonstrated to be a risk factor for peritoneal TB on its own, and the risk of disseminated disease was elevated by HIV co-infection and prior TB therapy. The infamous and fatal coinfection of HIV and TB led to a worldwide comeback of TB with the start of the HIV/AIDS epidemic in 1981. Numerous host genes were recognized to play a role in the spread of TB: In a case–control study, the Toll-like receptor 2 genotype T597C was linked to TB meningitis and exacerbated neurologic symptoms.[18] According to the same study, pleural TB was linked to genetic variations in interleukin. People who are homozygous with the interferon-gamma (+874) A allele are 3.75 times more likely to have TB.[19] Diabetes patients with EPTB had a high chance of dying, and TB reactivation appears to happen at least 4 years after the initial diabetes diagnosis.[20] Being the nation with the largest TB burden and having a high population of diabetics provide significant challenges for the healthcare system in India. An estimated 2.7 million incident TB cases occur in India.[21] Kerala, a state in south India with a population of 34.6 million, has a high prevalence of diabetes mellitus, with estimates ranging from 16% to 20%.[21] Because diabetes impairs immunity and pleural effusion is the most frequent location of EPTB involvement, diabetes raises the risk of acquiring TB by almost three times. Similarly, cancer patients have a 9–22 times higher risk of developing EPTB than the general population due to compromised immune systems. Even with a cure and information on how to stop transmission, EPTB is still a major public health concern for a sizable section of the global population. While identifying EPTB is crucial for improving care, programs in underdeveloped nations tend to address it less effectively than PTB. Examining EPTB determinants and identifying people at higher risk for EPTB is essential to improving TB treatment and the prognosis of the disease. Numerous factors, including co-morbidities, HIV coinfection, host factors, genetic variation, and the infection site, influence the spread of TB and the acquisition of EPTB type. The goal of TB treatment is to treat those who have active TB using standardized regimens and follow-up for drug resistance. To prevent the spread of the illness, treating people with active TB should be the top priority for TB control. However, identifying and treating those with latent TB should also be a top priority. Preventive therapy, clinical vigilance, public health initiatives, and health system improvement are all important components of the multi-level approach to EPTB prevention, especially for vulnerable and high-burden groups. Integration across HIV and immunosuppressive treatment programs is also required. Future studies are required to develop new biomarkers and tests that may improve the diagnosis of EPTB. Moreover, clinical suspicion is still necessary for precise identification.