Cystitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Steven C. Campbell, M.D., Ph.D.; Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3], Sadaf Sharfaei M.D.[4]

Cystitis is defined as inflammation of the urinary bladder. When caused by an infection, cystitis is classified as a type of the lower UTI. Cystitis results mostly from ascending infections from the urethra but can also result from descending infections from the blood or the lymphatic system. The condition more often affects women, but can affect either gender and all age groups. Urinary tract infections have been described since 1550 BC. In 1836 the earliest record of interstitial cystitis without the presence of a bladder stone were published. Cystitis may be classified according to the etiology and therapeutic approach into various subtypes including: traumatic, interstitial, eosinophilic, hemorrhagic cystitis, and cystitis cystica. For the purpose of treatment, cystitis may also be classified into acute uncomplicated, complicated, and recurrent cystitis. Cystitis occurs when the normally sterile lower urinary tract (urethra and bladder) is infected by bacteria, which leads to irritation and inflammation. Females are more prone to the development of cystitis because of their relatively shorter urethra. Complicated cystitis is due to the obstruction and stasis of urine flow. More than 85% of cases of cystitis are caused by escherichia coli (E. coli), a bacterium found in the lower gastrointestinal tract. Other causes of cystitis include certain medications, diabetes, crohn’s disease, iatrogenic causes, endometriosis, pelvic inflammatory disease, urinary obstruction, and bladder incontinence. Cystitis must be differentiated from other causes of dysuria. Approximately 50% of patients with acute uncomplicated cystitis will recover without treatment within a few days or weeks. If left untreated, some patients with cystitis may progress to develop recurrent infection, pyelonephritis, hematuria, and rarely renal failure. Prognosis is generally good. The majority of patients with cystitis do not have recurrence or complications after treatment. Patients with cystitis are usually well-appearing. Common physical examination findings of cystitis include fever and suprapubic tenderness. Antimicrobial therapy is indicated in cystitis. The treatment of cystitis depends on the disease course (acute uncomplicated vs. complicated) and the rates of resistance in the community. Preventative measures to avoid cystitis include abstinence from sexual activity, use of barrier contraception during sexual intercourse, increasing fluid intake and frequency of urination, and use of estrogen (among postmenopausal women).

Urinary tract infections have been described since ancient times with the first documented description in the Ebers Papyrus dated to 1550 BC. In 1836, Joseph Parrish published about interstitial cystitis by describing three cases of severe lower urinary tract symptoms without the presence of a bladder stone. Dr. Alexander Skene in 1887 used the term “interstitial cystitis” to describe the disease.

Cystitis may be classified according to the etiology and therapeutic approach into various subtypes such as traumatic, interstitial, eosinophilic, hemorrhagic cystitis, foreign body, emphysematous, and cystitis cystica. Cystitis can also be classified as acute or chronic depending on the duration of the infection. For the purpose of treatment, cystitis may also be classified into acute uncomplicated, complicated, and recurrent cystitis. It can be classified as bacterial, viral, fungal or parasitic depending on the causative pathogen.

Urine is normally sterile due to the low pH and unidirectional flow of urine that does not allow bacteria to grow and invade the urinary tract. Cystitis occurs when the normally sterile lower urinary tract (urethra and bladder) is either infected by bacteria or rarely a fungus, which leads to irritation and inflammation. Irritation followed by inflammation can also occur in response to trauma, chemicals or foreign bodies. Females are more prone to the development of cystitis because of their relatively shorter and straighter urethra. Bacteria does not have to travel as far to enter the bladder, which is in part due to the relatively short distance between the opening of the urethra and the anus. The pathogenesis of complicated cystitis include obstruction and stasis of urine flow. Normal flow of urine washes away the pathogens and clears the tract. Obstruction leads to overdistension and bacterial growth is facilitated by the residual urine. Stasis of urine flow allows entry of pathogens into the urinary tract.

Infections are the most common cause of cystitis. More than 80% of cases of cystitis are caused by Escherichia coli (E. Coli), a bacterium found in the lower gastrointestinal tract. Some viruses, fungi and parasites can rarely cause cystitis. Other causes of cystitis include certain medications, iatrogenic causes, pelvic inflammatory disease, trauma, and radiation therapy.

Cystitis must be differentiated from other causes of dysuria such as acute pyelonephritis, urethritis, prostatitis, vulvovaginitis, urethral strictures or diverticula, benign prostatic hyperplasia and neoplasms such as renal cell carcinoma and cancers of the bladder, prostate, and penis.

Urinary tract infections are found more frequently in women than in men. It is estimated that more than 30% of women will experience at least one episode of cystitis. Of these 30%, 20% women will have recurrent cystitis. The case-fatality rate/mortality rate of uncomplicated cystitis is approximately zero. Females are more commonly affected with cystitis than males. The female to male ratio is 4 to 1. Acute uncomplicated cystitis commonly affects women ages 18-39 years. There is no racial predilection to cystitis. Cystitis is a common disease that affect everyone, mostly women, worldwide.

Common risk factors in the development of cystitis include female gender, sexual intercourse, diabetes, pregnancy, catheterization, fecal incontinence, old age, and immobility. Some foods are thought to have a role in increasing the risk of cystitis such as vitamin C, coffee or tea, carbonated and alcoholic drinks, citrus fruit, or spicy foods.

Screening is not recommended for cystitis in a general population. However, pregnancy is an indication for screening for the presence of bacteria in the urine, as this may require aggressive treatment unlike other settings. Other situations that require screening for asymptomatic bacteriuria are prior to urologic surgery or for the research purposes.

Approximately 50% of patients with acute uncomplicated cystitis will recover without treatment within a few days or weeks. If left untreated, some patients with cystitis may progress to develop recurrent infection, pyelonephritis, hematuria, and rarely renal failure. Prognosis is generally good. The majority of patients with cystitis do not have recurrence or complications after treatment.

Acute uncomplicated typical cystitis is mainly diagnosed based on clinical presentation. Patients with classic symptoms including dysuria, frequency, urgency, and/or suprapubic pain may not need any diagnostic studies. Patients with atypical symptoms might require urinalysis and urine culture to confirm cystitis.

A detailed and thorough medical history from the patient is necessary. Specific areas of focus when obtaining a history from the patient include use of urinary catheters,pregnancy, sexual history, diabetes, recent antibiotic use, history of renal disease, urinary incontinence, and urinary retention. Symptoms of cystitis include painful urination, abnormal urine color (cloudy), blood in the urine, frequent urination or urgent need to urinate, or pressure in the lower pelvis.

Patients with cystitis are usually well-appearing. Common physical examination finding of cystitis includes suprapubic tenderness. A focused physical examination is helpful in confirming the suspicion of cystitis and in ruling out alternate pathology.

Presence of signs and symptoms of cystitis like dysuria, nocturia, frequency and urgency increase the probability of confirmation of cystitis as the diagnosis. Laboratory tests used in the diagnosis and confirmation of cystitis include urinalysis and urine culture. Laboratory findings consistent with the diagnosis of cystitis include pyuria and either white blood cells (WBCs) or red blood cells (RBCs) on urinalysis and a positive urine culture.

There are no ECG findings associated with cystitis.

X ray is not usually done to diagnose cystitis. An x ray of KUB (Kidneys, ureters, and bladder) is done to probe the suspicion for emphysematous cystitis. In case of emphysematous cystitis, it can show presence of gas in the bladder wall. Sometimes, an x ray that is taken for another reason, might reveal gas in the urinary bladder and thus lead to the diagnosis of emphysematous cystitis.

There are no echocardiography findings associated with cystitis. Ultrasonography is not done routinely to diagnose cystitis. Ultrasonography is sometimes done to diagnose the suspicion of emphysematous cystitis and for detecting the presence of tumors or stones. Imaging findings for chronic hemorrhagic cystitis due to radiation or chemotherapyinclude a small fibrosed bladder with a thick wall and resultant hydronephrosis. Calcification is only rarely seen.

In case of emphysematous cystitis, a CT scan of the abdomen can show presence of gas in the bladder wall. CT scan done while looking for other causes of abdominal pain, sometimes reveal gas directing the bladder wall and thus the diagnosis of emphysematous cystitis. CT scan may not be that useful in other causes of cystitis.

MRI is not used in the routine diagnosis of cystitis. An MRI can help diagnose a tumor or a stone in the bladder that is leading to stasis and thus to the inflammation and infection of the bladder. Inflammation and edema can also be noticed by the help of an MRI. MRI is sometimes used to diagnose cystitis glandularis. Imaging findings for chronic hemorrhagic cystitis due to radiation include a fibrosed bladder with a thick wall, hydronephrosis and rarely, calcifications.

There are no other imaging findings associated with cystitis.

Cystoscopy is not usually done to diagnose cystitis. Cystoscopy is recommended in recurrent cystitis, emphysematous cystitis, cystitis in children less than 2 years or in any kind of cystitis with normal routine tests. Hunter lesions can be identified using cystoscopy in patient with interstitial cystitis or bladder pain syndrome. Cystoscopy may sometime require the administration of local anaesthesia to facilitate the process. Mass spectrometry based metabolomic analysis is useful in detecting urinary metabolites in Interstitial cystitis.

A major proportion of the urinary tract infections resolves on its own if left untreated. Complications can occur but not very frequently. Cystitis can though increase morbidity and the goal of therapy is early resolution of infectious symptoms. Antimicrobial therapy is indicated in cystitis. The treatment of cystitis depends on the disease course (acute uncomplicated vs complicated) and the rates of resistance in the community. Due to the risk of the infection spreading to the kidneys (complicated UTI) and the high complication rate in diabetics and the elderly population, prompt treatment is almost always recommended. The increasing resistance to various drugs is a growing challenge. One aspect of increasing drug resistance is the gram negative bacteria population that produces extended spectrum beta lactamase. Hyperbaric oxygen is used to treat hemorrhagic cystitis associated with exposure to radiation and emphysematous cystitis, as presence of gas in the bladder wall interferes with the tissue oxygenation. Proper oxygenation may help to curtail the associated damage.

There are no recommended therapeutic interventions for the management of cystitis.

Surgery is not the primary treatment for cystitis and is not required most of the times. Surgery can be done for associated pathologies leading to cystitis like a tumor or a stone leading to obstruction of the bladder and thus encouraging growth of pathogens and thus cystitis.

Preventative measures to avoid cystitis include the measures for preventing a urinary tract infection which include voiding after intercourse, use of barrier contraception, increasing fluid intake and frequency of urination, and use of estrogen (among postmenopausal women). Single-dose prophylactic antimicrobial therapy prior to sexual intercourse may be administered to patients who have recurrent episodes of cystitis that are associated with sexual activity. Cleaning the urethral meatus after intercourse has also shown to be effective in preventive recurrent cystitis.

Secondary prophylaxis of cystitis is useful to prevent recurrent cystitis. It is more beneficial in patients in which cystitis is associated with sexual intercourse, a structural defect or a disease like diabetes that can lead to recurrent infections.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

Urinary tract infections have been described since ancient times with the first documented description in the Ebers Papyrus dated to 1550 BC. In 1836, Joseph Parrish published about interstitial cystitis by describing three cases of severe lower urinary tract symptoms without the presence of a bladder stone. Dr. Alexander Skene in 1887 used the term “interstitial cystitis” to describe the disease.

• Urinary tract infections was first described and documented in the Ebers Papyrus dated to 1550 BC.^[1]

• In 1836, Joseph Parrish, a surgeon from Philadelphia, published the earliest document on interstitial cystitis describing three cases of severe lower urinary tract symptoms without the presence of a bladder stone.
• The term “interstitial cystitis” was used by Dr. Alexander Skene in 1887 to describe the disease.^[2]
• In 2003-2004, researchers suggested that milder cases of interstitial cystitis should be known as painful bladder syndrome (PBS).^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

Cystitis may be classified according to the etiology and therapeutic approach into various subtypes such as traumatic, interstitial, eosinophilic, hemorrhagic cystitis, foreign body, emphysematous, and cystitis cystica. Cystitis can also be classified as acute or chronic depending on the duration of the infection. For the purpose of treatment, cystitis may also be classified into acute uncomplicated, complicated, and recurrent cystitis. It can be classified as bacterial, viral, fungal or parasitic depending on the causative pathogen.

Cystitis may be classified into several subtypes based on:^[1]

• Etiology
  • Traumatic cystitis
  • Interstitial cystitis
  • Eosinophilic cystitis
  • Hemorrhagic cystitis
  • Foreign body cystitis
  • Cystitis cystica
  • Emphysematous cystitis
  • Cystitis glandularis
• Pathogen
  • Bacteria
  • Fungi
  • Viruses
  • Parasites
• Duration and treatment
  • Acute uncomplicated cystitis
  • Complicated cystitis
  • Recurrent/Chronic cystitis

There are several medically distinct types of cystitis, each having a unique etiology and therapeutic approach:

It is probably the most common form of cystitis in the female, and is due to bruising of the bladder, usually by abnormally forceful sexual intercourse. This is often followed by bacterial cystitis, frequently by coliform bacteria being transferred from the bowel through the urethra into the bladder. Lack of circumcision and intercourse are important risk factors for traumatic cystitis.^[1][2]

Interstitial cystitis is considered more of an injury to the bladder resulting in constant irritation and rarely involves the presence of infection. IC patients are often misdiagnosed with UTI/cystitis for years before they are told that their urine cultures are negative. Antibiotics are not used in the treatment of IC. The cause of IC is unknown, though some suspect it may be autoimmune where the immune system attacks the bladder. Certain urinary metabolites are being associated with the diagnosis of interstitial cystitis. Chronic interstitial cystitis can lead to changes in the expression of the neuropeptides leading to defected visceral sensations and hyperreflexia of the urinary bladder. Several therapies are now available.^[3][4][5]

It is a rare form of cystitis that is diagnosed by biopsy. In these cases, the bladder wall is infiltrated with a high number of eosinophils. The cause of EC may be attributed to infection by Schistosoma haematobium or by certain medications in afflicted children. Some consider it a form of interstitial cystitis.^[6][7][8]

Blood in the bladder due to rupture of vessels, trauma, or tumour can act as an irritant and cause cystitis. Hemorrhagic cystitis can occur as a side effect of cyclophosphamide, ifosfamide, exposure to environmental toxins like aniline dyes, pesticides, and radiation therapy.^[9] Radiation cystitis, one form of hemorrhagic cystitis is a rare consequence of patients undergoing radiation therapy for the treatment of cancer.^[10] Several adenovirus serotypes have been associated with an acute, self-limited hemorrhagic cystitis, which occurs primarily in boys. It is characterized by hematuria, and virus can usually be recovered from the urine.^{[11][12][13][14]}

This is the kind of inflammation of the urinary bladder that can result from foreign bodies like a kidney stone, tumour, contraceptive device, foley catheter, or an infection associated with these foreign bodies. When caused by a benign lesion obstructing the bladder, foreign body cystitis is called papillary or polypoid cystitis.^{[15][16][17][18]}

This is a chronic cystitis glandularis accompanied by the formation of cysts. This disease can cause chronic urinary tract infections. It appears as small cysts filled with fluid and lined by one or more layers of epithelial cells. These are due to hydropic degeneration in the center of Brunn’s nests.^[19][20]

Emphysematous cystitis is associated with production of gas and is mostly caused by E Coli and klebsiella pneumoniae.^[21]

This is a premalignant type of cystitis. It is considered to be a precursor of adenocarcinoma of the bladder.^[22]

This kind of cystitis is caused by the anaesthetic agent, ketamine, which causes urothelial dysfunction.^[23]

Cystitis can be classified according to the causative organisms.^{[24][25][26][27][28]}

• Bacteria
  • E.coli (80-85%)^[24][25][29]
  • Enterococcus faecalis^[30]
  • Proteus Mirabilis^[31]
  • Klebsiella
  • Staphylococcus Saprophyticus
  • Staphylococcus Aureus^[32]
  • Lactobacillus
  • Group B Streptococci
  • Pseudomonas
• Fungi
  • Candida
• Viruses
  • HIV^[33]
  • Adenovirus^[34]
  • Cytomegalovirus^[35]
  • Polyoma viruses (JC and BK)
• Parasite
  • Toxoplasma Gondii^[33]

Cystitis may be classified based on the duration of infection and the treatment:

• Patients with acute uncomplicated cystitis have an infection that is restricted to the lower urinary tract and is most commonly seen in women with normal structure and function of the genitourinary tract and children older than age 2 years. Acute Urinary infections in men are always managed as complicated infections.
• Patients with acute uncomplicated cystitis may be treated using a single antimicrobial therapy using either a single dose or a 3-day regimen.

• Complicated urinary tract infections occur irrespective of age and gender in people who have either functional or structural malformations. Urinary tract infection in elderly men is always considered complicated.
• Patients with complicated cystitis generally require a longer duration of therapy compared with patients with uncomplicated cystitis.

• Repeated urinary tract infections are commonly seen in children and the elderly. Many factors like use of oestrogen, antimicrobials, and immunodeficiency are some factors contributing to the recurrent urinary tract infections. Long term inflammation and infection can lead to hyperreflexia of the bladder and altered sensations also known as allodynia.
• Patients with recurrent cystitis may require prolonged prophylactic antimicrobial therapy for 6-12 months.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Steven C. Campbell, M.D., Ph.D. Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2], Maliha Shakil, M.D. [3]

Urine is normally sterile due to the low pH and unidirectional flow of urine that does not allow bacteria to grow and invade the urinary tract. Cystitis occurs when the normally sterile lower urinary tract (urethra and bladder) is either infected by bacteria or rarely a fungus, which leads to irritation and inflammation. Irritation followed by inflammation can also occur in response to trauma, chemicals or foreign bodies. Females are more prone to the development of cystitis because of their relatively shorter and straighter urethra. Bacteria does not have to travel as far to enter the bladder, which is in part due to the relatively short distance between the opening of the urethra and the anus. The pathogenesis of complicated cystitis include obstruction and stasis of urine flow. Normal flow of urine washes away the pathogens and clears the tract. Obstruction leads to overdistension and bacterial growth is facilitated by the residual urine. Stasis of urine flow allows entry of pathogens into the urinary tract.

• Acute uncomplicated cystitis is an inflammation of the urinary bladder that occurs in the absence of any structural or functional pathology. In women, vaginal colonization of the uropathogens leads to the development of a urinary tract infection.
• Cystitis occurs when the normally sterile lower urinary tract (consisting of urethra and bladder) is infected by bacteria and becomes irritated and inflamed.
• Once bacteria enter the bladder, they are normally removed through urination. When bacteria multiply faster than they are removed by urination, it results in their accumulation leading to an infection.^[1][2]

Cystitis is rare in males but when occurs, is predominantly found in homosexual or uncircumscribed individuals.

• Females are more prone to the development of cystitis because of their relatively shorter urethra.
• Bacteria do not have to travel as far to enter the bladder, which is in part due to the relatively short distance between the opening of the urethra and the anus.^[3][4]

The pathogenesis of complicated cystitis include obstruction and stasis of urine flow.

• Complicated cystitis is usually a result of an abnormality in the structure or function of the urinary tract.
• This abnormality can result from various causes like foreign bodies such as:
  • kidney stones
  • Urinary catheters or other draining devices
  • Structural defects
  • renal failure
  • pregnancy
  • immunosuppression.
• Any process leading to the obstruction leads to over distension and so bacterial growth is facilitated by the residual urine.
• Stasis of urine flow allows entry of pathogens into the urinary tract and also hinders the natural preventive mechanism by which urine flushes away the pathogens and prevents colonisation in the urinary tract.^[1][5][6][7]

Recurrent inflammation of the bladder that is usually due to an infection, needs intensive investigation. Recurrent urinary infections may result from:

• Immunodeficiency
• contraceptive device
• Sexual intercourse
• Structural defecct
• genetic defect

The most common pathogen involved in recurrent infections resulting in inflammation of the bladder is E.coli.

• Chronic inflammation of the urinary bladder can cause alterations in the functional mechanisms and may lead to structural changes.
• It is understood that recurrent or chronic cystitis can lead to changes in the expression of the neuropeptides like substance P and calcitonn gene-related peptide (CGRP).
• This manifests as altered sensation of bladder filling called allodynia and hyperreflexia of the urinary bladder due to defect in the agents responsible for regular sensing ability of the bladder. ^{[8][9][10][11][12]}

The pathogenesis of Interstitial cystitis also known as bladder pain syndrome, includes:^{[13][14][15][16]}

• Epithelial dysfunction
• Mast cell activation
• Bladder sensory nerve up-regulation
• Organ cross talk

Certain foods have been associated with the interstitial cystitis, some of these include:

• Spicy foods
• Citrus fruit
• Tomatoes
• Carbonated and alcoholic drinks
• Coffee or tea
• Vitamin C

The urothelium acts as a barrier against damage to the bladder. The urothelium produces a mucous layer which regulates the entry of potassium in the bladder interstitium.

• Damage to the urothelium results in the production of cytokines which activate mast cells in the interstitium.
• Mast cell activation is further triggered by the diffusion of excess potassium into the bladder interstitium.^[17]

Chronic irritation from infection, calculi or even tumors results in metaplasia of the urothelium, which proliferates into buds, which grow down into the connective tissue beneath the epithelium in the lamina propria.

• In the case of cystitis cystica, the buds then differentiate into cystic deposits.
• The pathogenesis of cystitis cystica follows a positive feedback mechanism where with each infection there is a greater chance of subsequent changes in the bladder mucosa.
• Long term chemoprophylaxis and transurethral resection of the bladder are amongst the possible treatment options for cystitis cystica.^{[18][19][20][21]}

Inflammation of the urinary bladder by infiltration of eosinophils is the core of the process.

• Schistosoma haematobium is strongly associated with the development of eosinophilic cystitis.
• Infection with Schistosoma haematobium is generally associated with excessive presence of eosinophilic leukocytes and cytokines.
• Eosinophiliac cystitis can also be caused by certain medications that can have allergic manifestation and thus increase the number of eosinophils.
• Eosinophilic cystitis is sometimes confused with invasive bladder carcinoma and can be differentiated by demonstrating the presence of eosinophilia. ^[22]

Hemorrhagic cystitis is associated with hematuria.

• The hematuria results from rupture of the small mucosal blood vessels that are damaged due to:
  • Radiation exposure
  • Medications such as:
    • cyclophosphamide
    • ifosfamide
    • penicillin G
  • Viruses such as:
    • adenovirus
  • Accumulation of metabolites from chemotherapeutic drugs
• Treatments targeting eradication of the causative viruses, drugs or metabolites and intravenous hydration that flushes the urinary tract are very effective in treating hemorrhagic cystitis.^[23]
• Several adenovirus serotypes have been associated with an acute, self-limited hemorrhagic cystitis, which occurs primarily in boys.
• It is characterized by hematuria, and virus can usually be recovered from the urine.^{[24][25][26][27][28][29]}

Traumatic cystitis is caused by trauma to the bladder.

• Damage to the bladder predisposes it to invasion by pathogens that are normally not able to infect the bladder.
• Traumatic cystitis is a common phenomenon in females and follows invasion of a bruised bladder that follows an abnormally forceful sexual intercourse.
• Absence of circumcision increase chances of the normal pathogen in the skin to be lodged into the urinary tract, though the evidence is not convincing.
• Traumatic cystitis can also occur postoperatively in children.
• Trauma can also lead to stricture formation which in turn leads to stasis of urine and growth of bacteria or viruses in the bladder. ^[30][31]

Foreign bodies like kidney stones, indwelling catheters, and contraceptive devices can either result in:

• Mechanical damage to the epithelium leading to inflammation or
• Cause stasis of urine due to adhesion formation leading to pathogen invasion and ultimately cystitis
• Foreign bodies like catheters can grow bacteria like E.Coli, pseudomonas and staphylococcus saprophyticus leading to cystitis.

Removal of the foreign body and flushing the urinary tract with fluids are very effective treatment options.

• Polypoid/Papillary cystitis is caused by obstruction of the bladder by a benign tutor that leads to stasis leading to infection and inflammation of the bladder.^{[32][33][34][35][36][37]}

Gas production inside the bladder is the key feature to diagnose emphysematous cystitis. Diabetes has been strongly associated with this emphysematous cystitis.

• Though the pathogenesis is not exactly understood, high tissue glucose content in a patient with diabetes mellitus and fermentation of glucose in urine are considered to be important mechanisms that facilitate invasion of gas forming bacteria.
• E.Coli and Klebsiella are amongst the found pathogens.
• Another important aspect in the pathogeneses of emphysematous cystitis is the imbalance between the accumulation of gas and its clearance.
• Emphysematous cystitis can be an incidental finding on abdominal imaging done for abdominal pain or any other suspected pathology.
• Abdominal pain and hematuria can be seen in patients with this disease due to damage caused by gas forming bacteria.
• Since air accumulation interferes with normal oxygenation of the tissues, provision of hyperbaric oxygen has been associated with improvement of symptoms in patients with emphysematous cystitis.^{[38][39][40][41][42]}

Cystitis glandularis is considered a premalignant condition. The following are some significant aspects in the pathogenesis of cystitis glandularis:

• This abnormal disorder of proliferation involves glandular metaplasia of transitional cells in the bladder epithelium.
• Cystitis glandularis has two types, the typical, involving the urinary bladder and the intestinal/colonic type.
• Cystitis glandularis is considered to be a precursor of bladder adenocarcinoma.
• The intestinal component is considered to be more premalignant of the two types.
• Tumor necrosis factor alpha is considered a mediator of chronic inflammation.
• TNF-a causes induction of nuclear localisation of beta-catenin which is a component of adherents junction. This pathway is similar to the pathogenesis of barret’s esophagus. ^{[43][44][45][46]}

Ketamine cystitis is a complication of procedures where ketamine is used as anaesthetic agent. Ketamine cystitis differs from other drugs that cause cystitis like cyclophosphamide, ifosfamide and penicillin G, in that it does not cause haemorrhage. The pathogeneses of ketamine cystitis includes urothelial dysfunction by the following mechanisms:^[47]

• Inflammation mediated by mast cells
• Increased expression of M3
• Increased expression of B3-AR
• Decreased expression of ZO-1 and E-cadherin in bladder mucosa
• Increased TUNNEL expression and high Tryptase activity in the mucosa
• Increased cell apoptosis in the urothelium

Though the genetics of cystitis have not been studied extensively. It is understood that family history of urinary tract infection is a strong risk factor recurrent urinary infections in relatives. This risk is stronger in closer than distant relatives suggesting the role of a genetic component.^[8][48]

The following conditions can be associated with cystitis.^{[1][4][49][50]}

• Immunodeficiency
• Diabetes
• Pregnancy
• Benign prostatic hyperplasia
• Renal Stones
• Post menopausal status
• Toxoplasmosis
• HIV

The gross pathology of cystitis does not yield any findings.

The microscopic pathology helps to confirm the diagnosis and to differentiate different types of cystitis.^[51][52]

• 
  Cystitis Cystica. Source: Libre Pathology^[51]
• 
  Cystitis Glandularis. Source: Libre Pathology^[52]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Steven C. Campbell, M.D., Ph.D. Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

Infections are the most common cause of cystitis. More than 80% of cases of cystitis are caused by Escherichia coli (E. Coli), a bacterium found in the lower gastrointestinal tract. Some viruses, fungi and parasites can rarely cause cystitis. Other causes of cystitis include certain medications, iatrogenic causes, pelvic inflammatory disease, trauma, and radiation therapy.

Infections are the most common cause of cystitis. More than 80% of cases of cystitis are caused by Escherichia coli (E. Coli), a bacterium found in the lower gastrointestinal tract. Pathogens causing cystitis include: ^{[1][2][3][4][5]}

• Gram negative bacteria
  • Escherichia Coli
  • Klebsiella
  • Enterobacter
  • Proteus species

• Gram positive bacteria
  • Enterococci
  • Staphylococcus saprophyticus

Some less common or rare causes of cystitis may include:^[6][7]

• HIV
• Ketamine
• Tranilast
• Trauma

Hemorrhagic cystitis can be caused by:^[4][8][9][5]

• Medications such as:
  • Cyclophosphamide
  • Ifosfamide
  • Penicillin G
  • Ketamine
• Procedures
• Radiation therapy
• Adenovirus infection

The causes of cystitis with rest to organ system can be classified as:^{[7][10][11][12][13][4][5][8][14][15][3][16][17][18][19]}

Cardiovascular	No underlying causes
Chemical / poisoning	Chemical cystitis
Dermatologic	No underlying causes
Drug Side Effect	Allopurinol, BCG vaccine, Cetirizine, Cyclophosphamide, Cytarabine, Danazol, Doxorubicin, drug induced cystitis, hexaminolevulinate, Ifosfamide, Leflunomide, Methotrexate, NSAIDs, Oxaprozin, Pramipexole, Sertraline, Tiagabine, Tiaprofenic acid, Ticarcillin, Topiramate, Tranilast
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	Cystoscopy, radiotherapy
Infectious Disease	Candida, chlamydia, E. coli, enterobacter, gonorrhea, klebsiella, prostatitis, pseudomonas aeruginosa, schistosomiasis, serratia, staphylococcus saprophyticus, trichomoniasis, tuberculosis
Musculoskeletal / Ortho	No underlying causes
Neurologic	No underlying causes
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Opthalmologic	No underlying causes
Overdose / Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal / Electrolyte	No underlying causes
Rheum / Immune / Allergy	Autoimmune interstitial cystitis
Sexual	No underlying causes
Trauma	Physical trauma
Urologic	Autoimmune interstitial cystitis, interstitial cystitis, urethritis
Dental	No underlying causes
Miscellaneous	Foreign body cystitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

Cystitis must be differentiated from other causes of dysuria such as acute pyelonephritis, urethritis, prostatitis, vulvovaginitis, urethral strictures or diverticula, benign prostatic hyperplasia and neoplasms such as renal cell carcinoma and cancers of the bladder, prostate, and penis. It must also be differentiated from sexually transmitted diseases such as syphilis.^[1][2][3]

• Cystitis must be differentiated from other diseases that cause lower abdominal pain and fever like appendicitis, diverticulitis, inflammatory bowel disease, colorectal cancer, and endometritis.^{[4][5][6][7][8][9]}

Diseases		Symptoms		Signs			Diagnosis		Other Features
		Abdominal pain	Bowel habits	Rebound tenderness	Guarding	Genitourinary signs	Lab findings	Imaging
GI diseases	Colorectal cancer	LLQ	Constipation	–	–	–	Serum carcino-embryogenic antigen  Low Vit b12 Hypercalcemia	CT scan, x-ray and MRI used to show metastasis
	Inflammatory bowel disease	LLQ	Bloody diarrhea	–	–	–	Leukocytosis		Colonoscopy and tissue sampling are recommended for differentiating between Crohn’s disease and ulcerative colitis.
	Diverticulitis	LLQ	Constipation Or Diarrhea	–	+	+	Leukocytosis	CT scan shows evidence of inflammation
	Appendicitis	LLQ / RRQ	Constipation	+	+	–	Leukocytosis	Ultrasound shows evidence of inflammation	Nausea & vomiting,decreased appetite
	Strangulated hernia	LLQ	–	–	–	–	No specific tests	CT scan used to detect the hernia and to show if it is single or multiple
Gentiourinary diseases	Cystitis	LLQ	–	+	–	Suprapubic tenderness	Pyuria Presence of nitrites and leukocyte estrase	X ray is done to probe the suspicion of emphysematous cystitis. CT scan shows gas in the bladder in cases of emphysematous cystitis.
	Prostatitis	LLQ Groin pain	–	–	–	Tender and enlarged	Serum PSA elevated Leukocytosis Elevated CRP	CT scan shows edema and enlarged prostate Abscess may be observed
	Pelvic inflammatory disease	Bilateral	–	+	–	Purulent vaginal discharge	Nucleic acid amplification tests is the best laboratory test for PID.	Transvaginal utrasonography
Gynecological diseases	Endometritis	LLQ	–	+	–	+	No specific tests	Ultrasound is helpful to rule out other differential diagnosis such as pelvic abscess, thrombosis and masses	Vaginal discharge Vaginal bleeding
	Salpingitis	LLQ/ RLQ		+/-	+/-		Leukocytosis	Pelvic ultrasound	Vaginal discharge

• The differential diagnoses of Cystitis include:^[2][3][10]

• Acute pyelonephritis
• Ureteritis
• Urethritis
• Prostatitis
• Vulvovaginitis
• Cervicitis
• Urethral strictures or diverticula
• Benign prostatic hyperplasia
• Syphilis
• Genital Herpes
• Neoplasms such as renal cell carcinoma and cancers of the bladder, prostate, and penis

Cystitis must also be differentiated from sexually transmitted diseases, such as syphilis.^[1]

Cystitis can be differentiated from other diseases that cause lower urinary tract irritation symptoms, such as: dysuria, urgency and frequency in addition to urethral dyscharge , the differential list include: urethritis, cervicitis, vulvovaginitis, epididimitis, prostatitis , and syphilis.^{[3][11][12][13]}

Disease	Findings
Cystitis	Bladder inflammation, Features with increased frequency and urgency, dysuria, and suprapubic pain. Is more common among women. E.coli is the most common pathogen[14][15][16][17].
Urethritis	infection of the urethra,causes dysuria and urethral discharge[12][18][19]
Bacterial vulvovaginitis	Presents with dysuria and pruritus, Vaginal discharge and odor are almost always present, caused by Gardnerella species[20].
Cervicitis	Often asymptomatic,some women have an abnormal vaginal discharge and vaginal bleeding (especially after sexual intercourse)[21]
Prostatitis	bacterial infection of the prostate,causes discomfort during ejaculation[22]
Epididymitis	Presents with scrotal pain and swelling accompanied by fever and lower urinary tract irritation symptoms(dysuria and frequency)[23].
Syphilis	Presents with generalized systemic symptoms such as malaise, fatigue, headache and fever. Skin eruptions may be subtle and asymptomatic. It is classically described as 1) non-pruritic bilateral symmetrical mucocutaneous rash; 2) non-tender regional lymphadenopathy; 3) condylomata lata; and 4) patchy alopecia.[11]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

Urinary tract infections are found more frequently in women than in men. It is estimated that more than 30% of women will experience at least one episode of cystitis. Of these 30%, 20% women will have recurrent cystitis. The case-fatality rate/mortality rate of uncomplicated cystitis is approximately zero. Females are more commonly affected with cystitis than males. The female to male ratio is 4 to 1. Acute uncomplicated cystitis commonly affects women ages 18-39 years. There is no racial predilection to cystitis. Cystitis is a common disease that affect everyone, mostly women, worldwide.

• It is estimated that one third of the women population has at least one episode of cystitis in their lifetime. Of these many will have recurrent cystitis.

• 81% of the total UTIs in the world occur in women.
• 27% of women with an episode of UTI have another episode within the next 6 months while 48% within the next 12 months.^[1][2]
• More than 7 million uncomplicated UTIs occur in the US per year.^[3]
• Sexually active women are known to have a higher incidence of UTIs than women of other categories.
• The incidence of cystitis in women is 5-7 per year per 100,000 while that in same age men is 50-80 per 100000.^[4][5]
• The incidence of UTI is higher in sexually active women than postmenopausal women.^[6][7][4]
• There is a higher incidence of urinary tract infection in immunocompromised, elderly, diabetic, and individuals with indwelling catheters.^[8][9]

• Almost 30% of the women will experience at least one episode of cystitis during their life span. Of these 30%, 20% of these women will have recurrent cystitis.^[1]

• The case-fatality rate/mortality rate of uncomplicated cystitis is approximately zero.^[10]

• Acute uncomplicated cystitis commonly affects women ages 18-39 years.^[11][3][12]
• UTIs are less frequent in 2-13 years old girls.
• Urinary tract infections can rarely occur in boys in the first year after birth in the presence of a structural defect or due to lack of circumcision.

• There is no racial predilection to cystitis.

• Females are more commonly affected with cystitis than males. The female to male ratio is 4 to 1.^[13][14]

• Cystitis is a common disease that affect everyone, mostly women, worldwide.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Steven C. Campbell, M.D., Ph.D. Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

Common risk factors in the development of cystitis include female gender, sexual intercourse, diabetes, pregnancy, catheterization, fecal incontinence, old age, and immobility. Some foods are thought to have a role in increasing the risk of cystitis such as vitamin C, coffee or tea, carbonated and alcoholic drinks, citrus fruit, or spicy foods.

Common risk factors in the development of cystitis include:^{[1][2][3][4][5][6][7][8][9][10]}

• Female gender
  • Shorter urethra
  • Less distance between the urethra and anus
• History of urinary tract infections
• Recent sexual intercourse (introduction of bacteria in the urethra)
• Use of a diaphragm with spermicide
• Post menopausal status (low oestrogen so loss of protective vaginal flora)
• Homosexual men
• Genetic predisposition or family history
• Lack of circumcision
• Old age
• Immobility

• Any blockage of the bladder or urethra
• Diabetes Mellitus (hyperglycemia inhibits neutrophil migration and phagocytosis)
• Benign prostatic hypertrophy
• Fecal incontinence
• Pregnancy
• Systemic Lupus Erythematosus
• Urinary retention
• HIV
• Toxoplasmosis

• Antimicrobial drugs
• Estrogen use
• Catheterization
• Procedures that involve the urinary tract

The following foods are thought to have a role in increasing the risk of cystitis:^[11]

• Spicy foods
• Citrus fruit
• Carbonated and alcoholic drinks
• Coffee or tea
• Vitamin C

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2]

Screening is not recommended for cystitis in a general population. However, pregnancy is an indication for screening for the presence of bacteria in the urine, as this may require aggressive treatment unlike other settings. Other situations that require screening for asymptomatic bacteriuria are prior to urologic surgery or for the research purposes.

• Screening is not recommended for cystitis in a general population.
• Screening is recommended to detect bacterial presence in the urine of pregnant women. Urine culture is done to screen this population for bacterial presence.^[1][2]

• Asymptomatic bacteriuria is only screened for in the following circumstances:^[3]
  • Pregnancy
  • Before urologic surgery
  • Research purposes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

Approximately 50% of patients with acute uncomplicated cystitis will recover without treatment within a few days or weeks. If left untreated, some patients with cystitis may progress to develop recurrent infection, pyelonephritis, hematuria, and rarely renal failure. Prognosis is generally good. The majority of patients with cystitis do not have recurrence or complications after treatment.

• Approximately 50% of patients with acute uncomplicated cystitis will recover without treatment within a few days or weeks.
• If left untreated, some patients with cystitis may progress to develop recurrent infection, pyelonephritis, hematuria, and rarely renal failure.^[1][2]

Complications of cystitis include:^{[1][2][3][4][5][6][7][8]}

• Chronic or recurrent urinary tract infections
• Hematuria
• Pyelonephritis
• Acute renal failure
• Adhesions in the urinary bladder
• Candidemia
• Sepsis
• Bladder rupture
• Adenocarcinoma of the bladder

• Prognosis is generally good.
• The majority of patients with cystitis have a complete resolution of symptoms after treatment.^[9]
• Recurrence is the most common complication of cystitis.
• Every UTI increases the risk of subsequent UTI.
• An E.Coli increases the chance or recurrent infection at least three times.
• Following the first UTI, 27% of women during the first 6 months and 48% of women during the first 12 months are considered to undergo another urinary tract infection.^[10][11]

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