In this cross-sectional study of patients presenting with tuberculous lymphadenitis and clinical signs of TB we found a high prevalence of infection at other sites, with 9 patients with miliary pulmonary TB at the extreme end of the disease spectrum, while only 38% of the patients had single lymphadenitis with no abdominal or pulmonary engagement.
Lymphadenopathy (superficial as well as systemic, including abdominal lymphadenopathy) is regarded as a manifestation of EPTB, where the mode of infection includes haematogenous spread from a primary focus or in miliary TB, lymphatic spread from infected lymph nodes, ingestion of bacilli and direct spread from adjacent viscera . There are indications that the homeostatic immune response in tuberculous lymphadenitis is fundamentally different from that of pulmonary TB .
Tuberculous lymphadenitis patients infected with Uganda genotype strains were significantly less prone to present with abdominal lymphadenopathy (p = 0.014) than those patients infected with non-Uganda strains, even after adjusting for confounding factors including age, sex and HIV co-infection (p = 0.046). Abdominal lymph node enlargement was itself significantly associated with abnormal chest X-ray findings (p = 0.027), one of the features indicative of TB severity or dissemination. Interestingly, the Uganda genotype which is responsible for close to 70% of pulmonary TB disease in our setting , in this study caused only 46% of the 121 cases of tuberculous lymphadenitis. Tuberculous lymphadenitis is the commonest form of extra pulmonary TB in high endemic areas [18, 37]. Previous evidence also suggest that strains of the Euro-American lineage of M. tuberculosis to which M. tuberculosis Uganda genotype belongs less frequently cause EPTB [11, 12].
Thus the Uganda genotype appears to have a reduced potential to disseminate and cause extra-pulmonary disease, and may inversely have a higher potential to cause pulmonary TB. Since pulmonary TB is more contagious than EPTB the Uganda genotype may have an advantage in transmission of TB which is reflected in the high incidence of this genotype in Uganda and surrounding areas . The dominance of the Uganda genotype has however not been associated with pulmonary cavitation , which is associated with tissue liquafactive necrosis and cough generated aerosol, an efficient mechanism by which TB is spread.
A particular strain of Uganda genotype (SIT52) caused a large outbreak of TB in Sweden . This strain exhibited extensive cell death of macrophages infected in vitro, with production of elevated amounts of tumor necrosis factor (TNF) compared to the virulent laboratory H37Rv strain . The interplay of TNF and other cytokines in the early innate immune response is complex, but it is noteworthy that TNF neutralization in animal models including non-human primates resulted in disseminated disease in M. tuberculosis infected animals .
Risk factors for extra pulmonary TB include age, sex and HIV co-infection [21, 43, 44]. Not unexpectedly a high proportion (66%) of the patients in this study were HIV-infected, a figure which is similar to studies of patients with extra-pulmonary TB in other high endemic African countries [45, 46]. It is well known that HIV co-infection represents an increased risk of dissemination of TB involving multiple organs, through several immunological mechanisms not yet quite well understood , and infection with HIV increases the incidence and severity of abdominal TB . Thus 7 patients with miliary TB were HIV-infected while the sero status of the remaining 2 patients was not known. However, HIV-status did not affect the proportion of patients infected with Uganda genotype, and only marginally affected the negative correlation between Uganda genotype and abdominal lymphadenitis, indicating that HIV-status was not important for the differences in clinical manifestations between Uganda and non-Uganda genotypes.
The indication of a lower tendency to form extrapulmonary disease by the Uganda genotype compared with the other genotypes is in line with a recent large study of TB cases that showed a relationship between phylogenetic lineage and clinical site (pulmonary versus extra pulmonary) of TB . In a study from Vietnam disease caused by the Euro-American lineage was significantly more likely to be pulmonary than meningeal, which suggests that this lineage is less capable of extrapulmonary dissemination in this population .
Extrapulmonary disease has been associated with the East Asian/Beijing genotype . Patients infected with strains of Beijing genotype were found to have significantly lower frequency of fever and pulmonary cavitation than those infected with other genotypes of M. tuberculosis, and were associated with characteristic radiological patterns . These associations seem to hold for some populations and not for others [53, 54], and may be explained by the fact that the Beijing lineage has evolved into distinct branches defined by specific RD deletions  with different impact on the immune response . On the other hand there was no difference in lineage distribution between cases of pulmonary and extrapulmonary TB in a study from Ethiopia , a country with a high incidence of tuberculous cervical lymphadenitis , and a study from South Africa  found no significant relationship between mycobacterial genotype and EPTB. Yet, it is increasingly evident that the genetic diversity of M. tuberculosis strains contributes to the wide clinical spectrum of TB [59, 60].
The limitation of this study is the fact that unlike animal models, the patients live in a heterogeneous socio-economic environment which may confer varying susceptibility and resistance to TB. Factors like clinical stages of TB and/or HIV and immunosuppressive states like malnutrition and diabetes mellitus may contribute to disease outcome in TB patients.