TUBERCULOSIS - pediagenosis
Article Update

Thursday, September 10, 2020


Tuberculosis remains a major infectious disease both worldwide and in the United States. The pathogen responsible for most cases, Mycobacterium tuberculosis, infects one third of the world’s population, and it is responsible for over 2 million deaths per year. The incidence of this disease is declining in the United States at a rate of approximately 3% to 6% per year; however, tuberculosis remains an important cause of mortality and morbidity among those in immunocom promised states, especially those coinfected with the human immunodeficiency virus (HIV).

Although a majority of those infected with Mycobacterium tuberculosis develop disease restricted to the lungs, a recent survey of cases in the United States found that 19% had only extrapulmonary disease, whereas 6% had combined pulmonary and extrapulmonary disease. Of those with extrapulmonary disease, 6.5% had urogenital involvement. In addition, the relative proportion of extrapulmonary cases appears to be increasing: despite a steady decline in the number of new pulmonary tuberculosis cases, there has been little change in the number of new extrapulmonary cases. Worldwide, urogenital involvement is even more common, occurring in up to 40% of extrapulmonary cases. There is evidence, however, that even this number may be an underestimate; in one autopsy study, 73% of patients with pulmonary tuberculosis were found also to have a renal focus.
Urogenital tuberculosis affects men twice as often as women, and the average age at presentation is approximately 40 years old. HIV infection is also a major risk factor not only for active tuberculosis in general, but also for extrapulmonary spread and reactivation.
Upon inhalation of airborne bacilli, patients may experience a primary, usually silent, infection that involves formation of granulomas in the pulmonary alveoli. During this initial phase, lymphatic and then hematogenous seeding of distant organs such as the kidneys and reproductive organs can occur. In rare instances, wide and uncontrolled dissemination of mycobacteria may lead to miliary tuberculosis, which can also involve the kidneys (see separate section later).
In the urinary system, the renal cortex is the usual site of primary infection. After initial seeding, the disease course is indolent. Indeed, bacilli can remain latent within granulomas for decades or more, both in the kidneys and elsewhere. Reactivation can occur because of a decline in immunity because of age, disease, or malnutrition. Reactivation of renal tuberculosis may lead to further granuloma formation, parenchymal cavitation, papillary necrosis, calcification, and, in rare cases, tuberculous interstitial nephritis.
As the renal disease becomes advanced, it may spread to the rest of the urinary system by direct extension. In the ureter, strictures and calcification may occur. In the bladder, ulceration and fibrosis may occur, leading to wall contraction and a decrease in storage capacity. Fibrosis adjacent to the ureteric orifice may cause it to become retracted and assume a “golf hole” appearance.
Genital disease may occur either because of hematogenous spread or contiguous extension from the urinary system.

The symptoms of genitourinary tuberculosis can be very nonspecific. Patients often complain of urinary frequency and may, in some cases, experience gross hematuria or flank pain. Some patients may also have constitutional symptoms, including fever and weight loss.
About 90% of patients will have abnormal urinalysis, which may reveal positive leukocyte esterase, hematuria, proteinuria, and low urine pH. About 1 in 10 patients will have only frank hematuria, whereas up to half have microscopic hematuria. As Mycobacterium tuberculosis does not convert urinary nitrates, dipstick is often negative for nitrites.
The classic urinary finding found in up to one quarter of patients is sterile pyuria, where urine contains numerous white blood cells but no bacterial growth is seen on standard cultures. Of note, bacterial growth does not necessarily rule out renal tuberculosis, since secondary bacterial infection is common.
If sterile pyuria is seen, the differential diagnosis also includes chlamydial urethritis, pelvic inflammatory disease, nephrolithiasis, or renal papillary necrosis. If constitutional symptoms and hematuria are present, a malignancy of the urinary or genital system should also be suspected.
A physician may suspect urogenital tuberculosis if the patient has risk factors for tuberculosis exposure, a history of a positive purified protein derivative (PPD) test, a history of immunocompromise, and constitutional symptoms. It is not uncommon, however, for physicians to prescribe antibacterial treatment at first presentation. A lack of positive urine cultures, no response to antimicrobials, or recurrent episodes of cystitis in the setting of suggestive risk factors should raise a suspicion of mycobacterial infection and prompt further evaluation. A radiograph may reveal areas of focal calcification in the kidneys and the lower genitourinary tract. Ultrasonography may reveal calcification, hypoechoic renal abscesses, and shrunken kidneys. CT may demonstrate calcifications, renal scarring and cavitation, papillary necrosis, strictures of the collecting system, and diminution of renal function. Imaging of the thorax should also be performed to rule out concomitant pulmonary or spinal infection. Many patients will have evidence of prior pulmonary infection, and up to 30% to 40% will be found to have active pulmonary disease.
Once tuberculosis is suspected, the bacillus can be identified in urine by acid-fast staining. Because sensitivity is low, multiple early morning midstream voided specimens are often collected to increase detection power. Culture on either liquid broth or solid Löwenstein-Jensen medium remains the gold standard for diagnosis, and it also has the advantage of providing information about mycobacterial drug susceptibilities.
Although culture sensitivity can be as high as 80%, results can take as long as 6 to 8 weeks. For that reason, polymerase chain reaction (PCR) studies may be performed to detect M. tuberculosis in urine earlier in the clinical course. The advantage of this test is not only its high sensitivity (up to 95%), but also its fast turnaround time, with results often obtained within 24 hours.
In situations when there is a high clinical suspicion for tuberculous disease, but microbiologic testing is not definitive, more invasive methods of diagnosis, such as percutaneous tissue biopsy, may be required. Histopathologic examination of the obtained tissue reveals caseating granulomas.
In immunocompetent patients, an intradermal tuberculin test (PPD) can be performed as an additional screen for tuberculosis exposure; however, it is not helpful in diagnosis of the disease because results have been reported as positive in only 60% of patients with urinary tuberculosis. Interpretation of tuberculin test results should follow standard cut-off values: 5 mm or more for immunocompromised patients, 10 mm or more for patients at high risk (inmates, health-care workers, long-term care facility residents, intravenous drug users, and immigrants), and 15 mm or more for patients without any risk factors. A positive tuberculin test result indicates prior exposure but is not diagnostic of active disease. In patients with advanced HIV or other immunocompromising conditions, tuberculin test results may be negative secondary to anergy and should not be used to rule out tuberculosis.
The treatment of urogenital tuberculosis involves a combination of antituberculous therapy and surgical resection, where possible, of local disease. Consultation with experts should be sought, given not only the complexity of the disease course but also the potential adverse effects associated with treatment.
Pending the return of culture and sensitivities, the patient should be initiated on a four-drug regimen that includes isoniazid, ethambutol, rifampin, and pyrazinamide. If cultures indicate the organism is sensitive to isoniazid, rifampin, and pyrazinamide, the ethambutol can be stopped. After 8 weeks, pyrazinamide is usually stopped, because it has an early bactericidal effect.
The duration of therapy with the remaining two agents depends on the patient’s immune status. Therapy may also need to be adjusted if infection occurs in an area with high levels of multidrug-resistant or extensively drug-resistant tuberculosis.

In the developed world, tuberculosis is rarely a cause of chronic kidney disease. Preservation of renal function, however, depends on early detection to limit renal parenchymal destruction. In developing countries, where diagnosis and treatment are more likely to be delayed, permanent loss of renal function is more common.

In addition to being the site of locally reactivating granulomas, as described previously, the kidneys may rarely be involved in the disseminated disease known as miliary tuberculosis.
Miliary tuberculosis results from widespread hematogenous dissemination of tuberculous bacilli after invasion of the pulmonary circulation. It may occur during the time of primary infection or at reactivation, and it is often associated with the extremes of age and other conditions that compromise the immune system. Patients have more pronounced constitutional systems and extensive pulmonary disease. Overwhelming systemic illness may overshadow the effects of renal involvement. The workup of miliary tuberculosis includes acid-fast bacillus smears, culture, PCR, and histopathologic examination of affected tissues (e.g., bone marrow, lymph nodes, liver). If the kidney is affected, numerous granulomatous lesions may be present throughout the cortex and, less commonly, the medulla. On microscopic examination these granulomas reveal central caseous necrosis.
Rapid diagnosis of military tuberculosis is essential, and treatment with the combination regimen described above should be promptly initiated.

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