Infectious Proctitis

10 Infectious Proctitis Andreia Albuquerque FA CU LTY O F MEDI CINE O F THE UNIV ERS ITY OF P ORT O, PO RTO , P ORT UGAL HOME RTO N ANAL NEOPLASIA SERVICE (HANS), HOMERTON UNIVERSITY HOSPITAL, L ONDON, UNITED K INGDOM

10.1 Definition and General Concepts Proctitis is an inflammation of the rectum, typically involving the last 15 cm1 and can have noninfectious (e.g., inflammatory bowel disease, radiation proctitis) or infectious causes. Most of the infections are sexually transmitted diseases (STDs) and common pathogens are Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, and herpes simplex virus (HSV).1–3 Other pathogens also exist, although they are less frequently described, like cytomegalovirus (CMV) and amebiasis. Transmission can occur during sexual anal intercourse. Men who have sex with men (MSM) are a high-risk group, but other practices and routes of infection can also be implicated. In some studies gonorrhea and chlamydia were the most frequent causes of proctitis in MSM, followed by herpes and syphilis,4 but in other settings HSV was the most common pathogen implicated in HIV-positive MSM.5 HIV-positive MSM frequently have multiple infections compared with HIV-negative MSM.5 In developed countries outbreaks of lymphogranuloma venereum (LGV) in MSM with proctitis as the form of presentation6 have been reported. There are several symptoms that suggest proctitis; however, in many cases, patients can be asymptomatic.7 The pathogen’s primary infection site is related to the patient’s symptoms. In cases involving the rectum, few sensory nerve endings are present, so frequently there are no symptoms (e.g., gonorrhea and chlamydia). Infections of the stratified squamous epithelium of the perianal area and anal verge are more commonly painful (e.g., in HSV).8 The presence of anal or perianal ulcers in a young sexually active patient is frequently associated with HSV or syphilis, and HIV should always also be excluded.9 In this chapter, proctitis due to chlamydia, gonorrhea, HSV, syphilis, CMV, and Entamoeba histolytica will be described in more detail (Table 10.1).

10.2 Herpes Simplex Virus There are two types of HSV: type 1 (HSV-I) and type 2 (HSV-2). Most cases of HSV proctitis are caused by HSV-2,10 but the first-episode of anogenital herpes due to HSV-1 is significantly increased among younger MSM and heterosexual women.11 Herpetic infections can be primary or a reactivation.1 In 20% of the cases infection has a chronic and Anorectal Disorders. https://doi.org/10.1016/B978-0-12-815346-8.00010-2 © 2019 Elsevier Inc. All rights reserved.

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Table 10.1

Causes of Infectious Proctitis

Etiology

Symptoms

Endoscopy/Anoscopy Diagnostic Tests

Herpes simplex virus type 1 and type 2

Severe pain, tenesmus, constipation, anal discharge, sacral paresthesia, difficulty urinating

Ulcers, purulent exudate Herpes simplex virus DNA detection in rectal biopsies or exudate from lesions

Neisseria gonorrhoeae

Most patients asymptomatic Tenesmus, pruritus, thick purulent anal discharge

Thick purulent anal discharge, friability, erythema

Treponema pallidum

Primary syphilis: chancre, discharge, bleeding, pain, itching Secondary syphilis: discharge, bleeding, pain, anorectal condylomata lata Most asymptomatic Pain, discharge, rectal bleeding

Mucous membrane, friability, erythema, ulceration

Chlamydia trachomatis serovars D-K Chlamydia trachomatis serovars L1, L2, or L3

Friability, ulceration, mild erythema

Pain, rectal bleeding, Normal or mild fever, tenesmus erythematous, friable mucosa, deep ulcers, granulomas, mucopurulent exudates, strictures Cytomegalovirus Most asymptomatic Mucositis, ulceration, Mononucleosis-like polypoid, and mass illness with rectal lesions bleeding, after unprotected anal intercourse Entamoeba Bloody diarrhea, Edematous mucosa, histolytica fever and abdominal ulcers pain

Therapy

Acyclovir 400 mg orally three times daily, acyclovir 200 mg orally five times daily, valacyclovir 1 g orally twice daily or famciclovir 250 mg orally three times a day for 7–10 days (CDC) or 5–10 days (European guidelines) NAATs Ceftriaxone 250 mg IM + Culture for azithromycin 1 g orally antimicrobial sensitivity single dose (CDC) (treatment failure) Ceftriaxone 500 mg IM + azithromycin 2 g single dose (European guidelines) Nontreponemal tests Benzathine penicillin G 2.4 (e.g., VDRL, RPR): million units IM single dose screening and monitoring therapy response Treponemal test (e.g., FTA-ABS): confirmation of diagnosis NAATs Azithromycin 1 g orally once or doxycycline 100 mg orally twice a day for 7 days NAATs Doxycycline 100 mg orally twice daily for 21 days

PCR in blood and mucosa or immunohistochemistry of the mucosa

Ganciclovir 5 mg/kg IV twice daily for 2–3 weeks or foscarnet 90 mg/kg IV twice daily

Antigen assays, PCR, serology

Metronidazole 750 mg orally three times daily for 5–10 days plus paromomycin 10 mg/kg/ day three times daily for 5– 10 days or diloxanide furoate 500 mg three times daily for 10 days orally

CDC, Centers for Disease Control and prevention; FTA-ABS, fluorescent treponemal antibody absorption; IM, intramuscular; IV, intravenous; NAATs, Nucleic acid amplification tests; PCR, polymerase chain reaction; RPR, rapid plasma reagin; VDRL, venereal disease research laboratory.

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FIG. 10.1 Immunocompetent women presenting with symptoms of pain and rectal bleeding. (A) Proctoscopy revealing an ulcer extending from the pectin line to the distal rectum. (B) Extensive ulceration in the perianal area. (C) Perianal area 14 days after acyclovir therapy was started.

recurrent course.12 Sexual transmission can occur during anal intercourse or oral-anal contact, especially in MSM.7 The seroprevalence for HSV-1 and/or HSV-2 in MSM is around 95%.10 HSV proctitis is more common in HIV-positive MSM5 and the incubation period is around 1–3 weeks after exposure.1 Severe pain, tenesmus, constipation, anal discharge, sacral paresthesia, and difficulty urinating can be the presenting symptoms.1,2 Only one-third of the MSM have external ulceration.5 Ulcers and purulent exudate can be seen in the endoscopy/proctoscopy1 (Fig. 10.1A–C). The biopsies in the ulcer’s base can reveal nuclear inclusions or multinucleate cells.1 HSV DNA detection from rectal biopsies or exudate from lesions is a rapid detection method with high sensitivity and specificity, and it should be used routinely for diagnosis.13,14 Serology is of limited value for acute infection diagnosis. The detection of IgG antibodies indicates previous infection and IgM is unreliable for diagnosing acute infection, although seroconversion might be an indicator of a primary infection. The Centers for Disease Control and Prevention (CDC) STDs treatment guidelines9 (published in 2015) recommended treating the first genital HSV infection (there are no specific recommendations for HSV proctitis) with either acyclovir 400 mg orally three times daily, acyclovir 200 mg orally five times daily, valacyclovir 1 g orally twice daily, or famciclovir 250 mg orally three times a day for 7–10 days. These drugs can help control the symptoms (first episode or recurrences) and decrease the duration of viral shedding, but they do not eradicate the virus nor interfere with subsequent recurrences.2 The 2017 European guidelines for the management of genital herpes14 suggested treatment with the same drugs for 5–10 days. Patients with proctitis due to HSV should be screened for HIV, and abstinence is recommended when lesions are present.2 HIV-positive patients can have prolonged or more severe episodes and HSV shedding is increased.9

10.3 Gonorrhea Gonorrhea is caused by N. gonorrhoeae, and common infection routes are oral-anal, anal sexual intercourse, and, in women, cervical/urethral dissemination. MSM and women are high-risk groups.1,2

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The incubation period is around 5–7 days, but most patients are asymptomatic.7 Tenesmus, pruritus, and a typically thick purulent anal discharge in the anoscopy can be reported.1,2 Other findings in the anoscopy, like friability and erythema, are nonspecific.2 N. gonorrhoeae can be detected by nucleic acid amplification tests (NAATs) or by culture. The culture should be performed for antimicrobial sensitivity testing in patients with treatment failure. Gram-negative diplococci are suggestive of a diagnosis, but microscopy sensitivity is low in rectal infection15; therefore, it is not recommended in the rectum.9 NAATs can provide results quicker, with higher sensitivity and are the first option in rectal infections,15 although no information on antibiotic susceptibility is provided. The CDC recommended intramuscular (IM) ceftriaxone 250 mg plus azithromycin 1 g orally in a single dose (similar for HIV-positive and negative patients) as first-line therapy for uncomplicated rectal infections (cure rates are 99.2%).9 Doxycycline 100 mg orally twice a day for 7 days can be used in cases of azithromycin allergy. This regimen can treat both gonorrhea and chlamydia, co-infections are commonly seen. No test-of-cure is needed for uncomplicated rectal infection treated with any of the recommended or alternative regimens, but patients should be re-tested 3 months after treatment (re-infection risk). Testing for other STDs, including chlamydia, syphilis, and HIV, should also be done. There is a threefold risk of HIV infection in MSM with gonorrhea.2 The 2012 European guidelines on the diagnosis and treatment of gonorrhea in adults recommended the same drug regimen, but with different doses: ceftriaxone 500 mg IM as a single dose plus with azithromycin 2 g as single oral dose.15 If the patient is asymptotic a NAAT should be done and in cases where there are persistent symptoms a culture is recommended with antimicrobial sensitivity testing.15 Sexual partners need to be tested and treated.9,15 Patients should abstain from sexual activity for 7 days after they and their partners have completed treatment and symptoms have resolved.

10.4 Syphilis Syphilis is an infection due to T. pallidum with several different stages of the disease. Acquired syphilis is divided into early and late stages. Early syphilis includes primary, secondary, and early latent syphilis. The European Centre for Disease Prevention and Control defines early syphilis as syphilis acquired <1 year previously and for the World Health Organization it is <2 years previously. Late syphilis includes late latent and tertiary syphilis.16 In acquired disease, transmission occurs through sexual contact12 and most cases of primary and secondary syphilis are in MSM. Mucocutaneous lesions predispose to infection and they are uncommon after the first year of infection.9 Anorectal involvement can be seen in the primary and secondary stages. In primary syphilis, painless anal ulcers can appear 2–6 weeks after infection, typically as an isolated anal or rectal ulcer (chancre) with indurated edges and a clean base. One or multiple lesions can be present,1 usually with concomitant regional lymphadenopathy. Perianal involvement can be seen, especially in MSM (Fig. 10.2). Proctitis with or without

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FIG. 10.2 Perianal syphilis in a man who have sex with men.

chancres,3 symptoms of discharge, bleeding, significant pain, and itching are also other possible symptoms.1 Untreated syphilis can evolve to secondary syphilis, where mucous membrane lesions of the anus and rectum, proctitis, and anorectal condylomata lata can appear.1,2 Condyloma lata are warty, mucoid, plaque-like perianal lesions.17 The Venereal Disease Research Laboratory (VDRL) test and the Rapid Plasma Reagin (RPR) test (nontreponemal tests) are often used for screening and monitoring response to therapy. If reactive, the patient should undergo a treponemal test, like the Fluorescent Treponemal Antibody Absorption (FTA-ABS) test, to confirm the diagnosis. This test remains positive in most patients after the first infection, so it is not appropriate for disease treatment monitoring. There are several situations that can lead to a false-positive results in a nontreponemal test, namely infections (e.g., HIV), autoimmune conditions, immunizations, pregnancy, injection-drug use, and older age, therefore this test needs to be confirmed.9 A decline of nontreponemal test titers is usually seen after treatment (in some cases it can persist for a long period of time) and might become nonreactive with time.9 T. pallidum-specific NAATs of the ulcer exudate, condylomata lata, and rectal biopsies might allow direct pathogen detection.12 The CDC guidelines9 and the 2014 European guidelines for treatment of adults with early syphilis16 recommended as first-line therapy benzathine penicillin G 2.4 million

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units IM in a single dose (both HIV-positive and HIV-negative patients). In early stages, syphilis has a good response to curative treatment.2 Follow-up and test-of-cure should be done with nontreponemal tests at 6 and 12 months after treatment, according to the CDC9; and at 1 month, 3 months, 6 months, and 12 months after treatment, according to the European guidelines.16 Failure of nontreponemal test titers to decline fourfold at 6–12 months might be indicative of treatment failure. For re-treatment, weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks is recommended.9,16 Sexual partners should be identified: 46%–60% of traced sexual contacts of patients with early syphilis are likely to be infected and need to be tested at the first visit and repeated at 6 weeks and 3 months.16 Syphilis increases the risk of HIV transmission (by two to five times) and patients should also be tested for HIV and other STDs,2,16 hepatitis C included.16

10.5 Non-LGV Chlamydia Infections caused by C. trachomatis are the most commonly reported bacterial STDs in Europe12 and in North America.1,3 The frequent transmission routes are anal sexual intercourse and cervico/vaginal dissemination in women. C. trachomatis serovars D-K can cause proctitis. The latency period is around 7–10 days after infection and most of patients are asymptomatic. Pain, discharge, and rectal bleeding can be reported with several endoscopic patterns, like friability, ulceration, and mild erythema.3 The 2015 European guidelines on the management of C. trachomatis infections recommended using a NAAT for the diagnosis of rectal infection, although the sensitivity and specificity in rectal specimens are lower compared to urogenital specimens.18 The recommended first-line therapy is azithromycin 1 g orally once a day or doxycycline 100 mg orally twice a day for 7 days (similar for HIV-positive and negative patients).9,18 There are some studies suggesting a lower efficacy of azithromycin in rectal infection,19–21 but more data are needed. The CDC9 and the 2015 European guidelines18 recommend both drugs as first-line therapy,9,18 although the European guidelines recommended a test-of-cure if azithromycin is used. A NAAT should be performed 4 weeks after completion of therapy.18 A test-of-cure is not recommended according to the CDC.9 Patients should be instructed to abstain from sexual intercourse for 7 days after singledose therapy or until completion of a 7-day regimen and until all of their sex partners are treated.9 Testing for HIV, gonorrhea, and syphilis is also needed. Sexual partners should be referred for evaluation, testing, and presumptive treatment.9,18

10.6 Lymphogranuloma Venereum LGV is a STD caused by C. trachomatis serovars L1, L2, or L3. Since 2003 there has been a rising incidence in MSM, most of whom are HIV-positive, with several outbreaks reported in different developed countries presenting as a severe proctitis.6 Some sexual behaviors, like anal enemas, sex with a HIV-positive partner, and sex in sex parties were associated

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with LGV proctitis.22 Anorectal manifestations normally occur after inoculation via the rectum. A systematic review and meta-analysis showed that the prevalence of HIV among LGV cases was 67% to 100%.23 LGV normally corresponds to an invasive infection affecting the submucosa and with lymphatic dissemination to loco regional lymph nodes; serovars D-K infections are confined to the mucosal layer with more mild to asymptomatic clinical presentations.22 The classical presentation with tender inguinal and/or femoral lymphadenopathy is now uncommon.24 Proctitis and proctocolitis are currently the most frequently reported clinical manifestations of LGV, especially in MSM.24 This disease can be misdiagnosed as inflammatory bowel disease (IBD),25,26 due to the similarities in clinical manifestations, complications, and endoscopic and histologic appearance. Symptoms of pain, rectal bleeding, fever, and tenesmus can occur. There are several endoscopic patterns described, from normal or mild erythematous and friable mucosa to deep ulcers or granulomas with mucopurulent exudates.25 Complications might arise, like strictures, fistulas, and abscesses, similar to Crohn’s disease. The recommended tests for rectal specimens are NAATs (which are positive in both LGV and non-LGV chlamydial infections).9,18 Positive rectal specimens for C. trachomatis should be characterized further (genotyping for LGV), to differentiate LGV from nonLGV,13 because this has implications for the recommended treatment duration. Empiric treatment for LGV should start when compatible symptoms are present.9 The CDC9 and the 2013 European Guideline on the Management of Lymphogranuloma Venereum27 recommended doxycycline 100 mg orally twice daily for 21 days (similar for HIVpositive and HIV-negative patients). The duration of treatment is different from other chlamydia infections (serovars D-K), where treatment is only 7 days. An alternative regimen is erythromycin 500 mg orally four times a day for 21 days. Screening for HIV and other STDs should be done, including hepatitis B and C.27 There should be no sexual contact until therapy is complete, and sexual partners should be tested and presumptively treated.27

10.7 Cytomegalovirus The rectum is an area less frequently affected by CMV, compared with the colon, which is the most commonly affected area of the gastrointestinal tract.28 This infection can be a reactivation or a primary infection, and cases were described in both immunosuppressed (transplant patients, HIV-positive, chemotherapy)29 and immunocompetent patients.30,31 There were cases associated with nonprotected anal sex in MSM and women32; however, there were situations where this association was not found, especially in the elderly and/or patients with comorbidities (e.g., diabetes mellitus and IBD).30,31 In immunocompetent patients, CMV infection is normally asymptomatic, and clinically significant disease is most often seen in the immunosuppressed.33 Mononucleosis-like illness with rectal bleeding, after unprotected anal intercourse, is suggestive of sexually transmitted CMV proctitis.32 Endoscopy can reveal mucositis, ulceration, polypoid, and mass lesions.32

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CMV serology is of limited value for diagnosis due to the high seroprevalence of CMV in the adult population, although a recent infection can be suggested by a positive CMV IgM.34 DNA detection by polymerase chain reaction (PCR) in the blood and mucosa allows rapid quantitative and qualitative results with high sensitivity.33 Histopathological findings including ulcerations, enlarged cells with intracytoplasmic and intranuclear inclusion bodies, and a positive CMV histochemistry can be helpful for diagnosis.32 This infectious proctitis generally resolves spontaneously and does not require antiviral therapy,32 but in severe cases, normally in immunosuppressed patients, therapy needs to be considered.29 Intravenous (IV) ganciclovir 5 mg/kg twice daily for 2–3 weeks is the first-line therapy for gastrointestinal infection. Foscarnet 90 mg/kg IV twice daily can be used as a first option or an alternative in cases of intolerance or ganciclovir failure.28,34 The presence of sexually transmitted CMV proctitis should raise the suspicion of other STDs, including HIV, which should be excluded.32 Regarding IBD, subclinical reactivation of CMV during immunomodulator or biological therapy is common but is normally self-limited.34 The prevalence of CMV is 21%–34% in acute severe colitis and, in the steroid refractory group, around 33%–36%.35 The Second European evidence-based consensus on the prevention, diagnosis, and management of opportunistic infections in IBD recommended that in cases of acute steroid-resistant colitis/proctitis, CMV should be excluded, and when identified during immunomodulator therapy, antiviral therapy should be initiated and the discontinuation of immunomodulators considered.34 CMV diagnoses should be done preferably by PCR in blood and mucosa or immunohistochemistry of the mucosa.34

10.8 Amebiasis Amebiasis is caused by E. histolytica, a protozoan parasite. Other Entamoeba species have been identified, but E. histolytica is the only one that can cause human disease.36 Infection occurs primarily through fecal-contaminated food or water containing cysts, but also by sexual transmission (oral-anal sex).37,38 Invasive infections have an increasing prevalence in developed countries in MSM who engage in oral-anal sex.37 In developing countries the risk in MSM is less studied.37 Most E. histolytica infections are asymptomatic (80%–90%)36 and 4%–10% of asymptomatic subjects will develop disease over a year.38 Colitis and liver abscess are the most common complications of invasive infections, and bloody diarrhea, fever and abdominal pain39 are often reported symptoms. Pregnancy, immunosuppression, and corticosteroids intake are risk factors associated with more severe disease.38 Different patterns of endoscopic appearance for right-side colitis (more commonly affected) and proctosigmoiditis were described.39 Aphthae, erosions, ulcers, exudates, or edematous swollen mucosa in the cecum are normally present in a right-sided colitis. An edematous swollen mucosa with bloody exudate is the most frequently seen pattern in proctosigmoiditis, although ulcers and aphthae can also occur, mimicking ulcerative colitis.39 Amebiasis and ulcerative colitis have different therapeutic approaches (corticosteroids are contraindicated in amebiasis); therefore differential diagnosis is important.

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The sensitivity and specificity for detection of E. histolytica in stool are low and microscopy cannot differentiate between the several types of Entamoeba. Antigen assays and PCR40 can be used with better sensitivity and specificity.37 Antibodies (serology) can be negative in the acute phase or persist for a long period.37 In a pilot study including five patients with suspected amoebic colitis, in vivo visualization of trophozoites by using an endocytoscope was described (all cases had rectum involvement).40 These findings need to be confirmed in a larger study; therefore this method is not currently recommended for diagnosis. There are no specific recommendations for proctitis therapy due to this pathogen, but the first-line treatment for invasive amoebiasis are nitroimidazole derivatives (e.g., metronidazole and tinidazole), followed by a luminal agent to eradicate colonization.37,38 Metronidazole given in an oral dose of 750 mg three times daily for 5–10 days is the drug of choice. For a luminal agent, paromomycin 10 mg/kg/day three times daily for 5–10 days or diloxanide furoate 500 mg three times daily for 10 days13 orally can be used. Asymptomatic carriers of (only) E. histolytica should receive treatment with luminal agents, to prevent development of invasive disease and the spread of the infection.37,38

10.9 Conclusions It is important to recognize infection as a cause of proctitis, the high-risk groups for the disease and the most commonly involved pathogens (N. gonorrhoeae, C. trachomatis, T. pallidum, and HSV). A higher index of suspicion should exist in MSM and patients with IBD that do not respond to therapy. Endoscopy/anoscopy, serology, culture, and, in most cases, NAATs are important for diagnosis. Diligent and appropriate treatment is necessary to control the symptoms and disease transmission; most infections have a high cure rate with therapy. The presence of HIV and other STDs need to be excluded. An increased risk of HIV transmission is normally present in patients with infectious proctitis. In several countries, the reporting of many of these infections (e.g., syphilis, gonorrhea, and chlamydia) to a health authority is required and should not be neglected.

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