Andrew Symes1 and Abhay Rané2
(1)
Department of Urology, Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
(2)
Department of Urology, Surrey and Sussex Healthcare NHS Trust, Maple House, East Surrey Hospital, Canada Avenue, Redhill, RH1 5RH, UK
Abhay Rané
Email: a.rane@btinternet.com
Abstract
This chapter looks at uncommon urinary tract infections such as TB, fungal, and parasitic; it discusses the significance of conditions such as sterile pyuria and how to investigate this finding.
Keywords
UncommonUrinaryInfections
What Is Sterile Pyuria, Is It Significant, and How Should It Be Investigated?
Sterile pyuria is the presence of significant white blood cells (WBC) in the urine, without bacteruria. It can be defined as ≥5 WBC per high-powered field (HPF) in a centrifuged specimen or >10 WBC/mm3of urine. Sterile pyuria is always significant and should trigger appropriate investigations to determine the possible cause, some of which are listed below:
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Possible causes of sterile pyuria |
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Genitourinary tuberculosis (TB) |
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Urolithiasis |
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Recently treated urinary tract infection (UTI) |
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Urinary tract malignancy |
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Chlamydial urethritis |
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Papillary necrosis |
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Prostatitis |
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Interstitial cystitis |
Investigations should include a comprehensive targeted history and examination, aimed at excluding the above diagnoses. Specific investigations should include the following, but further, more specialized investigations should be guided by initial findings:
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Midstream urine for microscopy, culture, and sensitivities |
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At least three early-morning urines (ideally five) for TB |
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A cystoscopy +/− biopsy |
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Upper urinary tract imaging – usually an ultrasound +/− intravenous urogram/CT scan |
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Urine cytology |
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Routine blood tests |
What Is Tuberculosis, and How Does It Cause Disease?
Mycobacteria are gram-resistant, nonmotile, pleomorphic rods that are often found in habitats such as water or soil. One type is Mycobacterium tuberculosis, responsible for the development of tuberculosis (TB) in humans. It is an intracellular pathogen usually infecting mononuclear phagocytes (e.g., macrophages) and is termed an “acid-fast bacillus”; once stained, it resists decolorization with acidified organic solvents.
The World Health Organization (WHO) estimates that approximately one-third of the world’s population is infected with Mycobacterium tuberculosis, with around ten million new cases per year (WHO 1997). Genitourinary TB is uncommon, accounting in the UK for only 2.6 % of all tuberculous infections [1]. The vast majority of infections are acquired through inhalation of the organism into the lungs via airborne droplet nuclei, after close contact with an actively infectious individual. Most individuals are easily able to control the initial infection and are asymptomatic, with bacilli either killed off or lying dormant.
Development of symptoms depends on both the organism and, more importantly, the host immune response, and thus, disease may occur many years later due to immunosuppression secondary to trauma, AIDS, diabetes, steroids, and other immunosuppressive agents. Prior to the advent of antibiotic therapy, the case fatality was 50 %, but this has now fallen to approximately 4 % per newly identified case.
Genitourinary TB is caused by metastatic spread of the organism through the bloodstream during the initial infection. The kidney is usually the primary organ infected with urinary disease, and other parts of the urinary tract become involved by direct extension. The initial infection occurs in the renal cortex, where the bacilli can remain dormant within granulomata for decades. This dormant infection then becomes activated due to failure of the local immune response. The primary site for infection of the genital tract is often the epididymis in men and the fallopian tubes in women, also by hematogenous spread. Similar to urinary disease, the infection then spreads to adjacent organs by direct extension.
How Does TB Present in the Urinary Tract?
TB should always be suspected in the urinary tract when a patient presents with vague, long-standing urinary symptoms without obvious cause [1]. Men are affected more commonly than women (2:1), and most patients are aged between 20 and 40 years. It is rare in children.
Infection of the kidney, ureter, and bladder usually results in urinary frequency without urgency, classically associated with sterile pyuria (not present in 20 % cases). Microscopic hematuria is also often present (50 %), but visible hematuria is rare (10 %). Symptoms are often intermittent and pain is rare, although recurrent cystitis may be an early warning sign.
Recurrent hematospermia is a rare presenting symptom, but tuberculous epididymitis may be the first and only presenting symptom of genitourinary TB, which may involve the testis by direct extension. Clinically it is often identical to acute epididymo-orchitis, with a painful, inflamed scrotal swelling.
How Should the Diagnosis Be Confirmed?
The tuberculin test involves intradermal injection of a purified protein derivative of tuberculin, which, when positive, causes an inflammatory reaction at the site. A positive reaction only signifies previous infection and is not synonymous with active infection. Diagnosis therefore relies on urine examination.
Sterile pyuria is the classic urine analysis finding with microscopic hematuria present 50 % of the time. Routine urine culture may show secondary bacterial infection (20 %); however, cultures for M. tuberculosis take 6–8 weeks, as the organism is slow growing. As the organism is only intermittently excreted, at least three early morning urine specimens (pooled over night) should be sent and inoculated on Lowenstein-Jensen culture media.
The Ziehl-Neelsen stain used diagnostically on sputum, however, is not commonly employed in urine due to false positives. More recently a polymerase chain reaction method on pooled urine samples has been developed and appears to offer sensitivity and specificity of 96 and 98 %, respectively [2].
Imaging has an important role to play in diagnosis. Intravenous urogram, or more commonly CT urogram, can be used to provide functional information about:
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1. Renal lesions – infundibular stenosis, calyceal and parenchymal destruction, and calcification. |
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2. Ureters – strictures and dilatation and the condition of the bladder wall. |
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3. Cystoscopy and biopsy are not essential tests in diagnosing genitourinary TB but are often employed in ruling out other conditions such as malignancy. |
What Complications Does TB Infection Cause in the Urinary Tract?
Renal
Caseating granulomata occur in the kidney, and when healing occurs, fibrous tissue is left with calcium deposition resulting in calcified lesions. If extensive this may lead to parenchymal destruction and even “autonephrectomy” [3]. In addition calyceal strictures, papillary necrosis, and ureteropelvic junction obstruction may occur.
Ureter
In a similar process strictures may occur anywhere in the ureter causing obstruction. Most commonly these occur at the vesicoureteric junction.
Bladder
Lesions are initially centered around the ureteric orifice and may be discrete ulcers or inflamed edematous tissue. If untreated they may become extensive, resulting in a fibrotic and contracted bladder.
Epididymis
Infection of the epididymis presents as an epididymo-orchitis and sometimes even as a fistula.
How Is TB Treated?
Treatment of active M. tuberculosis infection is with a combination of antituberculous drugs such as isoniazid, rifampicin, streptomycin, pyrazinamide, and ethambutol. Multidrug therapy aims to diminish the likelihood of drug-resistant organisms developing. Therapy is continued for 6 months in most cases [4]. The role of surgery has declined with the successes of medical treatment and is now largely centered on organ preservation and reconstruction, as opposed to excision [5]. It is usually delayed until at least 4–6 weeks of medical therapy has been administered.
What Is AIDS and How Is It Diagnosed?
Acquired immunodeficiency syndrome (AIDS) refers to the disorder caused by HIV (human immunodeficiency virus) infection. HIV is a retrovirus that infects and kills T-helper cells, one of the body’s main cellular defenses against infection. HIV is spread through contact with blood, semen, and vaginal secretions – for example, by sexual intercourse, use of contaminated needles or blood products, or from mother to baby during childbirth.
The course of HIV infection is very variable and typically occurs over 8–12 years [6]. Three distinct phases exist:
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1. Primary infection – a self-limiting syndrome lasting less than 14 days and mimicking many acute febrile illnesses. |
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2. Chronic asymptomatic infection – lasting around 10 years. |
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3. Overt AIDS – defined by the development of serious opportunistic infections, neoplasms, or other life-threatening conditions resulting from immunosuppression caused by HIV infection. It usually occurs when CD4+ counts fall below 200 cells/mm3 and leads to death within 2–3 years if untreated. |
Standardized laboratory assays are available for HIV testing and screening for HIV antibodies using an enzyme-linked immunosorbent assay (ELISA). Testing is a two-step process, with the initial screening assay retested to exclude laboratory error. If positive, a confirmatory assay is also performed to confirm the diagnosis [6].
What Are the Urological Complications of HIV/AIDS
The two most common sequelae of AIDS are infections and malignancy; however, numerous other complications can occur. These are summarized in the table below.
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Infections |
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Genitourinary tuberculosis |
Papillary necrosis, autonephrectomy, strictures |
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Renal |
CMV, aspergillosis, toxoplasmosis |
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Penile and urethral |
Genital herpes, warts, pelvic inflammatory disease, Reiter’s disease (uveitis, arthritis, urethritis) |
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Prostate |
Prostatitis (common organisms + fungal, TB) |
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Testis and epididymis |
Epididymo-orchitis (common organisms + fungal, TB) |
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Syphilis |
Resurgent in the UK |
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Fournier’s gangrene |
Fulminant necrotizing fasciitis of scrotum |
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UTIs |
Usual urinary tract pathogens, e.g., E. coli |
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Malignancy |
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Kaposi’s sarcoma |
Assoc with herpes virus infection, genital skin |
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Squamous cell carcinoma |
Also assoc with HPV infection, penile or genital skin |
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Testicular cancer |
50× increased risk of germ cell and non-germ cell tumors |
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Non-Hodgkin’s lymphoma |
Lymph nodes primarily but can be genitourinary organs/genital skin |
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Renal dysfunction and/or failure |
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HIV-associated nephropathy |
Proteinuria and renal insufficiency/end-stage renal failure |
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Stones |
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Protease inhibitors |
Indinavir/atazanavir |
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Radiolucent and may not be seen on CT |
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Management is temporary cessation of drug with hydration |
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Voiding dysfunction |
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Voiding dysfunction |
Most common is urinary retention 54 %, detrusor overactivity 27 %, bladder outflow obstruction 18 % |
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Erectile dysfunction/infertility |
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Erectile dysfunction |
Worsen as disease progresses. HIV infection is also cytotoxic to sertoli/germ cells – testicular atrophy |
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Infertility |
Abnormal semen parameters assoc with testicular atrophy. Risk of HIV transmission |
Should Men Be Routinely Circumcised to Reduce Risk of HIV Transmission?
Three prospective randomized clinical trials of adult male circumcision in South Africa, Kenya, and Uganda reported highly significant reductions in risk of HIV infection among participants randomly assigned to circumcision [7–9], and indeed, the trials were stopped early in some cases due to the overwhelming demonstration of the significant advantage for the circumcised group. This is mirrored by a meta-analysis of studies that demonstrated a highly significant reduced risk of HIV infection in circumcised men [10].
Despite this strong evidence, the issue remains contentious, as many would argue that in the UK, the relatively low rates of HIV in non-high-risk populations do not justify the invasive nature of the procedure and may indeed encourage risky behavior (i.e., lack of condom use).
What Is Schistosomiasis and Its Life Cycle?
Schistosomiasis is a chronic disease caused by parasitic infection with schistosomes, parasitic trematodes. Paired adult male and female worms reside in the venous plexuses of the abdominal viscera. S. haematobium worms live mainly in the venous plexuses around the bladder and are responsible for urinary schistosomiasis. Other types will not be discussed here. S. haematobium worms are endemic to tropical areas of Southeast Asia, Africa, South America, the Middle East, and the Caribbean, with 80–90 million persons infected. Of these, up to 40 million people have complications secondary to the disease.
The life cycle of S. haematobium is complex and can be divided into an asexual, snail phase and a sexual, human phase (see text and figure below).
Snail phase – asexual
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• Free swimming miracidium enters snail. |
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• Becomes sporocyst (one miracidium makes 40 sporocysts). |
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• Each sporocyst forms ~400 active parasites called cercariae – released into water. |
Human phase – sexual
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• Cercariae penetrate skin to become schistosomulum in liver. |
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• Adults pair up and move to bladder vesical veins. |
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• Copulate 3–6 years, ~500 eggs/day. |
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• Eggs migrate into bladder, penetrate mucosa, and flush out miracidium larvae. |
Schistosomiasis Life Cycle (CDC/Alexander J. da Silva, PhD/Melanie Moser)
What Are the Clinical Manifestations of Schistosomiasis, and How Is It Diagnosed and Treated?
Clinically, schistosomiasis can be divided into an active and chronic phase. Active infection, Katayama fever, is rare among endemic populations and is more commonly seen in noninfected travelers. It may result in fever, lymphadenopathy, splenomegaly, and urticaria [11].
Chronic schistosomiasis is much more common and has several different manifestations. The classical initial clinical presentation is hematuria with terminal dysuria. This can be severe enough to produce anemia and clot retention [12]. Next, patients enter a chronic active phase where symptoms are largely related to a contracted bladder and consist of pelvic pain, urgency, frequency, and urinary incontinence. During this phase, the ureters may become obstructed resulting in hydroureteronephrosis. Finally, the chronic inactive phase is where the infection has burnt out and symptoms result from complications, such as nonfunctioning obstructed kidneys.
The diagnosis is made in a patient who has had exposure to an endemic area. The presence of terminally spined eggs in the urine is diagnostic of active S. haematobium infection. As excretion peaks between 10 a.m. and 2 p.m., a midday urine is sent for microscopy. If eggs are not seen, either bladder or rectal mucosal biopsy may show the presence of eggs, with cystoscopy often reported as showing sandy patches. In the inactive form of the disease, eggs are not excreted, and the diagnosis is made radiographically. Plain X-ray may show a calcified bladder, with calcification seen anywhere along the urinary tract. CT or IVU may help diagnose ureteric obstruction, strictures, and nonfunctioning kidneys.
Praziquantel is the drug of choice for treatment of schistosomiasis. Cure rates approach 100 % and it is given in two divided oral doses of 40 mg/kg. Side effects are mild and self-limiting. Surgery is now reserved for complications that have not resolved after medical therapy (e.g., ureteric obstruction).
What Fungal Infections of the Urinary Tract Are You Aware of?
With the exception of Candida species, the urinary tract is rarely involved in fungal infections. Rare diseases, such as aspergillosis, cryptococcus, histoplasmosis, and coccidioidomycosis, may involve the urinary tract but are often part of disseminated disease in immunocompromised patients.
Candida albicans is responsible for the majority of fungal infections in the urinary tract. The number of these infections has risen dramatically with the increasing use of broad-spectrum antibiotics, indwelling vascular and urinary catheters, and immunosuppressants. Candidal infection is commonly seen on the penis, vulva and vagina, and on the skin around stomas. The majority of patients with candiduria are asymptomatic, although emphysematous cystitis has been seen in diabetic patients with candida. Infection of the upper urinary tract with candida can also occur and may present like acute pyelonephritis. Infection can arise either through hematogenous spread in systemic infection or via ascendance from the lower urinary tract. Renal abscesses, pyelonephritis, urinary obstruction, and fungal balls requiring surgical removal can all occur. Diagnosis is made by direct microscopy of urine, with cultures usually unhelpful. Radiographic imaging is directed at identifying complications.
Candiduria may reflect contamination or colonization, but persistence requires evaluation and consideration of treatment [13]. Not all patients require treatment, and in many instances, removal of a catheter or discontinuation of antibiotic therapy may be enough to clear the infection [14]. Patients who are undergoing urinary tract instrumentation should, however, be treated. Systemic treatment with oral or intravenous fluconazole achieves high urinary concentration and is the first line if treatment is required. Intravenous amphotericin has also been used in difficult to treat infections but comes at the price of toxicity. Local irrigation with antifungals to bladders and kidneys via catheters and nephrostomies has also been used with varying degrees of success.
What Is Emphysematous Pyelitis/Pyelonephritis?
Emphysematous pyelitis is an infection of the renal collecting system by gas-forming bacteria. It is often associated with diabetes mellitus (50 %) and, if untreated, has a mortality of up to 20 %. It presents in a similar fashion to acute pyelonephritis, with systemic symptoms and loin pain, and is often preceded by lower urinary tract symptoms such as cystitis. Management involves fluid resuscitation, intravenous antibiotics, strict diabetic control, and if necessary, urinary tract drainage via retrograde ureteric stenting or nephrostomy.
Emphysematous pyelonephritis is an acute, severe, necrotizing infection of the renal parenchyma and perirenal tissue, which results in the presence of gas within the renal parenchyma, collecting system, or perinephric tissue. It is associated with diabetes 90 % of the time and has a mortality of 50 %. Presentation is of an acutely unwell septic patient, often with poorly controlled diabetes or even as a diabetic ketoacidosis. The management is along ABC principles and should be considered as a surgical emergency. Broad-spectrum antibiotics and tight diabetic control is essential, and these patients often require emergency nephrectomy.
Emphysematous pyelonephritis is different to xanthogranulomatous pyelonephritis which is a chronic severe infection leading to destruction of renal tissue and eventually resulting in a nonfunctioning kidney. It is usually seen with upper urinary tract obstruction and stones and may be difficult to distinguish from renal cell carcinoma on CT scanning, thus often ending up in a nephrectomy.
How Do You Manage a Systemically Unwell Diabetic with Cellulitis of the Scrotum?
This patient should be seen immediately and an assessment made along ABC principles. He should be admitted to hospital and fully resuscitated with oxygen and IV fluids and should also be given broad-spectrum intravenous antibiotics, as guided by local microbiological advice. Blood tests should be sent off for renal function, glucose, full blood count, C-reactive protein, and clotting. Diabetics who have a source of illness, especially sepsis, are at increased risk of developing diabetic ketoacidosis, and in that instance, a sliding scale should be commenced to control blood sugar. He should be regularly reviewed, and if any clinical signs of deterioration present, then early involvement of ITU/HDU is essential. With scrotal cellulitis, there is no role for surgical management. If the diagnosis were unclear, an urgent ultrasound of the scrotum would help rule out an underlying abscess requiring drainage.
What Is Fournier’s Gangrene, and How Is It Treated?
Fournier’s gangrene is a polymicrobial necrotizing fasciitis of the perianal, perineal, or genital areas. The bacteria involved act synergistically to invade and destroy fascial planes and are composed of aerobes (e.g., E. coli) and anaerobes (e.g., bacteroides). Predisposing factors include diabetes, alcoholism, steroids, malnutrition, and HIV infection. Trauma, recent surgery, and the presence of foreign bodies may be inciting events, and causative factors are found in more than 75 % of cases. It often starts insidiously and extreme pain is an early finding along with systemic upset. As the disease progresses, skin overlying the affected region becomes discolored, eventually becoming gangrenous. Crepitus may be present, and by this stage, the patient usually shows signs of severe sepsis or even septic shock.
Fournier’s gangrene is a true surgical emergency necessitating radical debridement in theater, which is often repeated at second look 24–48 h later. Urinary and fecal diversion may be required depending on the source of infection. Broad-spectrum antibiotic cover is given with aggressive resuscitation, usually on a high-dependency/intensive care unit. Once the infection has settled, these patients often require plastic surgery consultation to cover the large defects left by debridement. Mortality from this condition can be as high as 75 % [15].
Key Points
· Sterile pyuria is a significant finding and should trigger appropriate investigations. It may be the only presenting sign of genitourinary tuberculosis.
· Genitourinary TB is uncommon and usually arises through hematogenous spread first to the kidney and then down through the urinary tract.
· Genitourinary TB should be suspected in any patient with vague, poorly defined, long-standing urinary symptoms without an obvious cause.
· Diagnosis of urinary tract TB requires at least three early-morning urine specimens; however, pooled urinary PCR may speed up diagnosis.
· AIDS sufferers can manifest numerous differing urinary tract symptoms, but generally infections, which may be atypical, and malignancies are the most common.
· Circumcision significantly reduces the risk of HIV transmission but is controversial, and not part of current UK practice.
· Schistosomiasis is a parasitic infection not endemic to the UK. It has a complex life cycle involving humans and snails.
· Candidal urinary tract infections are associated with immunocompromise, either systemic or through breach of natural host defense mechanisms, e.g., urinary catheter.
· Candida does not always require treatment; with cessation of antibiotics sometimes, this is all that is required to terminate the infection.
· Emphysematous pyelitis/pyelonephritis, scrotal cellulitis, and Fournier’s gangrene are rare urinary tract infections, but potentially life-threatening and require urgent urological referral and management.
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