Tuberculosis: The leading infectious killer

Prof. Ekaterina Kulchavenya Head of Urogenital Department of Novosibirsk TB Research Institute Novosibirsk (RU)

ku_ekaterina@ mail.ru

Dr. Denis Kholtobin Head of Urogenital Department of MC “Avicenna” Novosibirsk (RU)

Tuberculosis (TB) is a communicable disease that is one of the top 10 global causes of death, and the leading cause of death from a single infectious agent, ranking above HIV/AIDS. This was the case before the COVID-19 pandemic started in March 2020. In 2019, 10 million people developed TB and 1.4 million died from the disease (see figure 1).

Throughout history, TB has claimed lives; even now it accounts for 5,000 deaths on a daily basis. TB kills more young and adults than any other infectious disease. Many well-known and distinguished persons were victims of TB: Pharaoh Tutankhamun (1358 - 1340 BC), Cardinal Richelieu (1581 - 1642), Baruch Spinoza (1632 - 1677), Anders Celsius (1701 - 1744), Jean-Jacques Rousseau (1712 - 1778), Robert Burns (1759 - 1796), Frederic Chopin (1810 - 1849), Napoleon II of France (1811 - 1832), Anton Chekhov (1860 - 1904), Amedeo Modigliani (1884 - 1920), George Orwell (1903 - 1950), Anna Eleanor Roosevelt (1884 - 1962) Franz Kafka (1883 - 1924), Vivien Leigh (1913 - 1967) and many, many others.

According to the World Health Organization’s (WHO) latest global TB report, an estimated 1.8 million people could die from TB in 2020 (numbers were last seen in 2012). The statistics were based on WHO’s modelling which estimated an additional 200,000 to 400,000 TB deaths in 2020 if the number of people with TB detected and treated falls by 25% to 50% over a three-month period. In 2019, an estimated 1.4 million people died from TB-related illnesses.

The WHO emphasised that the COVID-19 pandemic threatens to reverse recent progress in reducing the global burden of TB disease. The global number of TB deaths could increase by around 0.2–0.4 million in 2020 if health services are disrupted and the number of people who are treated for TB falls by 25–50% over a period of 3 months. [1]

Urogenital tuberculosis TB is caused by the bacillus Mycobacterium tuberculosis (Mtb). The disease typically affects the lungs (pulmonary TB) but can also affect other parts of the body (extrapulmonary TB).

TB can affect anyone but most people who develop the disease (about 90%) are adults. Of those who fell sick with TB in 2019, 87% were in one of 30 high TB-burden countries. [1] The risk of TB is significantly increased in chronic kidney disease. The link between chronic kidney disease and TB has been known for more than 40 years, but the pathophysiological interaction between these two diseases is still poorly understood. Dialysis and renal transplant patients appear to be at a higher risk of TB, in part related to immunosuppression along with socioeconomic, demographic, and comorbid factors.

In some regions of high TB-burden countries, urogenital tuberculosis (UGTB) is the second most common form of TB and in other regions, the third most common form of TB. A large proportion of patients is underdiagnosed; hence, untreated. The continuing spread of multidrug-resistant TB (MDR-TB) is also a growing concern. According to WHO, only 38% of the estimated number of people with MDR-TB were enrolled in treatment programmes in 2019. [2]

UGTB includes urinary tract TB and genital TB and is associated with pulmonary or other localizations of TB in 40 - 65% of cases. Male genital tuberculosis (MGTB) is associated with pulmonary or renal TB in 50% of cases, but isolated forms also occur. Usually the epididymis and prostate are involved together. [3-4] Diagnosis of UGTB remains an enigma; sometimes it is even more art than science. The related symptoms are nonspecific, including frequency, microscopic haematuria, flank pain, and acidic urine; also urinary TB showed a wide variety of findings on x-ray examination. [5] If there is no other evidence of Mtb, UGTB may be diagnosed based on skin-test, histological picture, caverns revealed by urography and sterile pyuria, but last point has more and more contraversions.

‘Since symptoms are non-specific, UGTB often hides under a mask of another disease. This is a reason why UGTB is often called as “great imitator”, “great mystificator”, or “great hoaxer”.’

In the past, the diagnosis may have been based on sterile pyuria – but now the paradigm has changed: the detection of bacteria in patients with no urinary tract infections indicated that the dogma that “urine is sterile” was false. We have found non-specific microbes in 75% patients with UGTB. Although acid fast bacilli microscopy and Lowenstein-Jensen culture remains the cornerstone of the diagnosis of TB as whole, these traditional bacteriological methods are either slow or their sensitivity is low, especially with clinical samples like urine that contain small number of micro-organisms. [6]

UGTB is followed by a number of problems and paradoxes. There is no consensus on a terminology, diagnostic criteria and criteria of healing. Since symptoms are non-specific, UGTB often hides under a mask of another disease. This is a reason why UGTB is often called as “great imitator”, “great mystificator”, or “great hoaxer”. [7] Clinical features, diagnostic tools, and possibilities of anti-Tb therapy and surgery for UGTB have changed during last decades significantly. Surgery for UGTB patients may be performed in department of general urology, but neoadjuvant anti-TB therapy for at least two months should be provided. MC “Avicenna” in Novosibirsk, Siberia, performed laparoscopic operations for UGTB patients alongside with Novosibirsk Research TB Institute.

We would like to illustrate challenges in urogenital TB with the following case [4]:

A 60-year old female patient had her first episode of gross haematuria in 2015. The symptoms cleared on their own. For two years she had no complaints. In 2017, haematuria, dysuria and flank pain appeared on her right side. A cystoscopy revealed strong inflammation and therefore, a biopsy of the bladder wall was performed. Histological investigation showed TB granuloma; DNA Mtb was found in urine by polymerase chain reaction. The x-ray examination revealed stricture of the right ureter, destruction of renal parenchyma and hydronephrosis on the right kidney, an afunctional left kidney, and Microcystis.

The diagnosis was: UGTB, kidney TB 4th stage on left, kidney TB 3rd stage on right, bilateral TB of ureter, bladder TB 4th stage. To preserve the right kidney, nephrostomy was performed. Standard anti-TB therapy with four drugs was prescribed for four months, then Dr. Kholtobin performed nephroureterectomy on the left kidney, cystectomy and enteroplasty by laparoscopy.

What lesson can we learn from this clinical case? Although the first symptoms reoccurred after two years, the patient was not fully examined and UGTB was not suspected despite her living in a TB-epidemic region. Gross haematuria may be the only manifestation of renal TB, and UGTB should be suspected especially in a patient who, without any other reason, has the symptoms and lives in a TB-epidemic region.

For two years, the patient appeared well and had no complaints, but latent torpid TB inflammation severely damaged her kidney and bladder. She had the so-called “open form” of UGTB; she was contagious and possibly infected her family as well.

Figure 2: A kidney and a bladder affected by UGTB

Figure 3: A section of the TB bladder in figure 2 showing total fibrosis and obliteration of the bladder

References:

1. Global tuberculosis report 2020. Available on https://www.who.int/publications/i/item/9789240013131 2. WHO consolidated guidelines on tuberculosis 2020.

Module 4: treatment. Available on https://www.who.int/ publications/i/item/9789240007048 3. Kulchavenya E., Naber K., Bjerklund Johansen T.E.

Urogenital tuberculosis: classification, diagnosis, and treatment. European Urology Supplement, 2016; 15(4): 112-121 4. Kulchavenya E, Kholtobin D, Shevchenko S. Challenges in urogenital tuberculosis. World J Urol. 2020 Jan;38(1):8994. doi: 10.1007/s00345-019-02767-x. 5. Sallami S, Ghariani R, Hichri A, Zrayer O. Imaging findings of urinary tuberculosis on computerized tomography versus excretory urography: through 46 confirmed cases. Tunis Med. 2014 Dec;92(12):743-7. 6. Ghaleb K, Afifi M, El-Gohary M (2013) Assessment of diagnostic techniques of urinary tuberculosis. Mediterr J

Hematol Infect Dis. J 3;5(1):e2013034. doi: 10.4084/

MJHID.2013.034. 7. Choreño Parra JA, Martínez Zúñiga N, Salinas Lara C.

Tuberculosis “the great imitator”: False healing and subclinical activity. Indian J Tuberc. 2017; 64(4):345-348. doi: 10.1016/j.ijtb.2017.05.006.

Saturday 10 July, 15.15 – 16.15 CEST Thematic Session 12 Emerging threats by infectious diseases Virtual Room 5