Case 2-2006 — A 31-Year-Old, HIV-Positive Man with Rectal Pain
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《新英格兰医药杂志》
Presentation of Case
A 31-year-old man with the acquired immunodeficiency syndrome (AIDS) was evaluated at the infectious disease clinic of this hospital because of rectal pain and a mucopurulent rectal discharge.
Four days before this evaluation, the patient first noticed rectal discharge, pain on defecation, and blood in his stools. He described pelvic pain, nausea, and generalized weakness but no fever, chills, or emesis. He had regular anal-receptive intercourse without condoms with his usual partner, who was also infected with the human immunodeficiency virus (HIV), and with other partners.
In the patient under discussion, HIV infection had been diagnosed 12 years earlier. He had received sporadic medical care over the course of the following 10 years and had taken antiretroviral therapy (including zidovudine, lamivudine, nelfinavir, and ritonavir–lopinavir) inconsistently. Approximately 1 year before the current evaluation, he had been admitted to this hospital for 10 days with fever, diarrhea, rash, a CD4 cell count of six per cubic millimeter, and an HIV viral load of 207,000 copies of RNA per milliliter of plasma. Diagnoses of disseminated infection with Mycobacterium avium–intracellulare and staphylococcal ecthyma were made, and the conditions were treated with cephalexin, clarithromycin, and ethambutol.
After discharge, the patient was seen in the infectious disease clinic, and antiretroviral therapy with didanosine, stavudine, and efavirenz was begun. Cutaneous Kaposi's sarcoma, oral thrush, rectal herpes simplex, and anal condylomas developed over the course of the next year. Treatment with acyclovir, fluconazole, and dapsone was given. His CD4 cell count rose to 175 per cubic millimeter, and his HIV viral load fell to less than 50 copies of RNA per milliliter over the course of the year before this evaluation.
He smoked one pack of cigarettes per day, used no alcohol, and was a regular user of marijuana and methamphetamine. He was unemployed. His aunt had Crohn's disease.
On examination, the blood pressure was 122/88 mm Hg, the pulse 88 beats per minute, the respiratory rate 10 breaths per minute, and the temperature 36.8°C. The weight was 86.8 kg. There were flat, pigmented skin lesions over the right tibia and left shoulder consistent with inactive Kaposi's sarcoma. There was no thrush or oral hairy leukoplakia. Small cervical and inguinal lymph nodes were palpable. The lungs and heart were normal. The abdomen was soft and nontender, without hepatosplenomegaly. On rectal examination, there were bulky perianal condylomas but no external ulcerations. Digital rectal examination and anoscopy were not possible because of rectal pain.
The results of a complete blood count, the levels of serum electrolytes, and tests of renal and liver function were normal. The CD4 cell count was 188 per cubic millimeter and the viral load fewer than 50 copies of RNA per milliliter. Ceftriaxone and azithromycin were prescribed. Rectal-swab cultures for Neisseria gonorrhoeae and herpes simplex virus were negative, as was the serum rapid plasma reagin.
Two weeks later at a follow-up visit, the pain on defecation had improved, but mucus and blood were still seen in the stools. Anoscopy showed mucus but no blood or ulcerations. There were no internal hemorrhoids or anal-canal condylomas. A stool culture grew scant normal enteric flora without enteric pathogens or N. gonorrhoeae. Five days later, rectal pain had increased. A diagnostic procedure was performed.
Differential Diagnosis
Dr. Benjamin T. Davis: This young man with clinically advanced AIDS presented to my clinic with rectal pain and discharge of four days' duration, with some nausea and weakness but without other systemic symptoms or fever. Approximately one year after the institution of highly active antiretroviral therapy, his immunologic recovery is evident not only by the rise in his CD4 cell count but also by the resolution of disseminated infection with M. avium complex and the regression of Kaposi's sarcoma. Clinically, he now has proctitis. This is the patient's first episode of such a condition and, as such, it is important. He is at high risk for a sexually transmitted infection by virtue of his history of sexually transmitted diseases (HIV, herpes simplex virus, human papillomavirus, Kaposi's sarcoma–associated herpesvirus), his ongoing unprotected anal intercourse with multiple partners, and his regular use of methamphetamine.
The differential diagnosis of proctitis is broad but may also be fairly quickly narrowed in this case. Noninfectious causes of proctitis are less common than infectious ones and include radiation-induced, ischemic, and inflammatory causes. Ischemic proctitis is infrequently seen because of extensive collateral blood supply to the rectum. Inflammatory bowel disease, both ulcerative proctitis and Crohn's proctitis, may present initially with this constellation of symptoms. However, the two types of proctitis are distinguished by their chronicity, and the first requirement of both diagnoses is that an infectious cause must be ruled out.
The four most prevalent infectious causes in men who have sex with men are, in descending order of incidence, gonorrhea, herpes simplex, chlamydia, and syphilis.1 When evaluated systematically, almost half of cases remain undiagnosed, and as many as 10 percent are caused by multiple coincident infections. There may be clinical overlap between causes of proctitis and causes of colitis, which include bacterial pathogens such as shigella, Escherichia coli, and Clostridium difficile; protozoal causes such as amoebiasis; and viral pathogens such as cytomegalovirus. The prominence of this patient's painful purulent discharge, the paucity of systemic symptoms, and the absence of fever narrow the list of likely diagnoses to the four sexually transmitted infections: gonorrhea, herpes simplex, chlamydia, and syphilis.
This illness is a critical sentinel event with important implications for this patient and for the public health. Proctitis is a marker for other sexually transmitted diseases, and its presence increases the risk of their transmission, including HIV infection. Patients such as this man should be broadly screened for sexually transmitted diseases, including HIV, syphilis, gonorrhea, chlamydia, human papillomavirus, and viral hepatitis. A thorough contact investigation should be initiated, and sexual partners should be evaluated and offered early or prophylactic therapy where appropriate. The Internet is increasingly being used by patients as a means to find sexual partners, often across great geographic distance. It has also become a tool for public health officials to identify contacts and to conduct epidemiologic research.
For the treatment of sexually transmitted diseases to be successful for both the patient and his or her sexual contacts, it is important that treatment be given at the time of the initial evaluation. Diagnostic testing is important, but empirical therapy for clinical syndromes such as proctitis should be administered without delay while testing for specific agents is pending. Patients with proctitis should always be offered empirical therapy for gonorrhea and chlamydia and also for herpes simplex virus if clinically warranted, as was done in this case. This patient was evaluated for gonorrhea, herpes simplex virus, and syphilis, and none of these infections were found. A DNA-amplification test for chlamydia on the rectal swab was not available in our clinic at the time this patient was seen, in 2002. The patient improved somewhat over the two weeks after the evaluation, but then returned to the clinic because of worsening symptoms. This scenario usually implies either reinfection or inadequate treatment.
If his continued symptoms represent primary treatment failure, what other organisms should be considered? The initial rectal swab was not tested for Chlamydia trachomatis DNA. Most cases of C. trachomatis proctitis are relatively mild and respond well to a single dose of azithromycin. The serotypes D through K are the most common causes of nongonococcal urethritis and mucopurulent cervicitis. In contrast, lymphogranuloma venereum, caused by C. trachomatis serovars L1, L2, and L3, may cause more extensive infection and respond poorly to single-dose azithromycin. Could this patient have lymphogranuloma venereum?
There are three stages of lymphogranuloma venereum that produce distinct clinical syndromes. In the primary stage, a small, painless mucosal or cutaneous ulcer occurs at the site of inoculation and resolves spontaneously. The secondary stage of infection begins 10 to 30 days later, as the obligate intracellular pathogen travels through lymphatics, usually to draining lymph nodes. The hallmark of this stage is lymphadenitis, and it is often distinguished by a vigorous and severe inflammatory reaction, which may suppurate and extend to structures adjacent to the lymph nodes and lymphatics. When the primary inoculation is in the penis or vagina, inguinal or femoral lymphadenitis or both develop, with a severe inflammatory reaction that may suppurate and extend to adjacent structures. Clinically, a fluctuant mass, or bubo, is seen, which may lead to abscesses, fistulae, and sinus tracts. However, when the rectum is the site of primary inoculation, in both men and women, proctitis is the most common manifestation of the secondary stage. Systemic symptoms such as fever and malaise are common. This patient's clinical symptoms and signs are entirely consistent with this manifestation of secondary lymphogranuloma venereum.
If left untreated, tertiary-stage lymphogranuloma venereum, which is marked by fibrosis and strictures, may develop in a minority of patients. Late complications include chronic genital ulceration, genital elephantiasis, anal fistulae and strictures, frozen pelvis, and infertility.
The timely diagnosis of lymphogranuloma venereum can be challenging, and in most cases is made on clinical grounds. Serologic tests (complement fixation and immunofluorescence) are limited because they do not distinguish among different serotypes, do not differentiate past from present infection, and, most important, are not available at the time of clinical presentation. Culture of the organisms from clinical specimens is expensive, and sensitivity is generally low. Nucleic acid testing of clinical specimens has emerged as a promising technique that is both sensitive and convenient. Specialized laboratories can further amplify sequences in the major outer-membrane protein and reliably distinguish among lymphogranuloma venereum serotypes.
Lymphogranuloma venereum is endemic in Africa, the Indian subcontinent, Southeast Asia, and parts of Central and South America. The illness occurs sporadically in North America, Europe, and Australia; until recently, most cases had been linked to travel in endemic areas. In the past three years, however, clustered cases of lymphogranuloma venereum proctitis have been identified in men who have sex with men, in an outbreak that appears to be centered in the Netherlands, but which has spread to other cities in Western Europe and to the United States. Characteristics of patients associated with this outbreak include a high rate of HIV-seropositivity; a high rate of concomitant sexually transmitted diseases, including gonorrhea, syphilis, and herpes simplex virus; severe proctitis without inguinal lymphadenopathy; and predominance of the L2 serotype.2,3 The patient under discussion today shares many of the clinical and epidemiologic features of other patients affected by this outbreak.
Because of his persistent symptoms and the high clinical suspicion of chlamydial proctitis, I referred him to Dr. Thiim for sigmoidoscopy and rectal biopsy.
Dr. Michael Thiim: The digital examination was very painful, as it is in most patients with proctitis; in contrast to the usual smooth texture of the mucosa in acute inflammation, I was able to palpate firm, scar-like material in the rectum, suggesting a stricture. The endoscopic examination showed mucosal erythema with edema, linear ulcerations, and a creamy, yellowish-white exudate for the first 8 to 9 cm (Figure 1); the colon was normal beyond that. Rectal swabs and biopsy specimens were obtained and sent for bacterial culture, viral culture, and for pathological examination.
Figure 1. Endoscopic Image of the Rectum.
There is a large ulcer with a yellowish-white exudate. The remaining epithelium is erythematous.
Dr. Benjamin T. Davis's Diagnosis
Lymphogranuloma venereum proctitis.
Pathological Discussion
Dr. Lawrence R. Zukerberg: Microscopical examination of the rectal-biopsy specimen showed surface injury with an inflammatory exudate and extensive crypt injury associated with lamina propria and crypt inflammation. The lamina propria contained lymphocytes, plasma cells, and neutrophils. Neutrophils were especially prominent around the crypts, and neutrophilic cryptitis was present, with injury and crypt loss (Figure 2). The active (neutrophilic) inflammation in the absence of crypt distortion, lymphoid aggregates, and plasma-cell aggregates suggested an acute or infectious colitis rather than chronic inflammatory bowel disease. No granulomas were seen, and special stains for acid-fast bacilli, cytomegalovirus, and herpes simplex virus were negative.
Figure 2. Rectal-Biopsy Specimen (Hematoxylin and Eosin).
There is inflammation in the lamina propria, with prominent neutrophilic infiltration of crypts (cryptitis).
When this biopsy was performed three years ago, a specific diagnosis was not made. Recently, the paraffin block was sent for C. trachomatis testing. The test (performed at Esoterix Laboratories, based on the Cobas Amplicor CT/NG assay, Roche Diagnostic Systems) is a qualitative polymerase-chain-reaction (PCR) test. Unstained tissue sections are digested and detergent treated to release chlamydial DNA that is contained in the chlamydial reticulate bodies. In addition to chromosomal DNA, C. trachomatis has an approximately 7500-base-pair cryptic plasmid that is common to all C. trachomatis isolates.4,5 The PCR reaction uses biotinylated primers to define a sequence of approximately 207 nucleotides within the cryptic plasmid. After PCR, the amplicon is captured by hybridization to a specific oligonucleotide probe, which increases the overall specificity of the test. Detection is by colorimetric absorbance after avidin–horseradish peroxidase conjugate binds to the biotin-labeled amplicon and catalyzes the oxidation of 3,3',5,5'-tetramethylbenzidine to a colored complex that is measured at 660 nm. The test in this patient's rectal-biopsy specimen was interpreted as positive, with absorbance greater than 2.0.
Chlamydia6 is a small bacterium that cannot grow outside a living cell because it cannot synthesize its own ATP. There are numerous factors that contribute to the pathogenicity of C. trachomatis. Colonization of chlamydia persists at sites that are inaccessible to phagocytes and immune cells. The surface of chlamydia does not contain proteins that are distinctive enough to induce a full immune response, allowing it to persist and making the development of a vaccine difficult. The life cycle consists of two stages: the elementary body and the reticulate body. The elementary body is the dispersal form and is analogous to a spore. It induces its own endocytosis, and once inside the endosome, it "germinates" into the reticulate body. This forms replicates by binary fission, dividing every two to three hours. After division, the reticulate body transforms back to the elementary form and is released by exocytosis, producing 100 to 1000 elementary bodies. The word "chlamys" is Greek for "cloak draped around the shoulder," which describes how the intracytoplasmic inclusions caused by the bacterium are "draped" around the nucleus of the infected cell.
Both lymphogranuloma venereum and non–lymphogranuloma venereum serotypes are known to affect the large intestine, with severe anal pain and discharge, including hemorrhagic enterocolitis.7 The recent appearance of cases of lymphogranuloma venereum in men who have sex with men in continental Europe, the United Kingdom, and the United States has brought renewed attention to lymphogranuloma venereum.8 The men in these cases most often presented with hemorrhagic proctitis, and many of the cases were initially mistaken for inflammatory bowel disease or other conditions.
The main pathological differential diagnosis of lymphogranuloma venereum proctitis or colitis includes other forms of infectious colitis and early idiopathic inflammatory bowel disease.9,10 Many pathogenic bacteria, including salmonella, shigella, enterohemorrhagic E. coli, campylobacter, yersinia, and clostridium, as well as chlamydia may cause hemorrhagic enterocolitis and have similar pathologic findings on biopsy. Viral infections, especially cytomegalovirus, may have a similar presentation, but viral inclusions can often be identified and cytomegalovirus infection can be confirmed by immunohistochemical staining. Syphilis and tuberculosis may cause proctocolitis, and are included in the differential diagnosis, although granulomas are not prominent in lymphogranuloma venereum colitis.
The discontinuous nature of the colitis helps to distinguish lymphogranuloma venereum colitis from idiopathic ulcerative colitis, and the proximal-to-distal gradient of severity, in turn, helps distinguish this colitis from Crohn's disease. However, many of the histopathological features overlap between infectious colitis and inflammatory bowel disease. The Centers for Disease Control and Prevention and some commercial laboratories perform nucleic acid amplification on anorectal swabs, but biopsy tissue may also be useful in confirming the diagnosis, as in this case.
Dr. Davis: Treatment with doxycycline, 100 mg twice daily for 21 days, is curative in secondary-stage lymphogranuloma venereum. We treated this patient with doxycycline, and his symptoms of proctitis resolved entirely within three or four days. On the day that I prescribed doxycycline for the patient, his partner began having similar rectal symptoms, although not as severe. We treated him as well, and his symptoms resolved promptly. Blood tests for chlamydia serology were sent for analysis and came back three or four weeks later as seropositive. At that point, we felt comfortable with the diagnosis on the basis of his clinical response. As Dr. Zukerberg has noted, the diagnosis was recently confirmed by DNA analysis on the biopsy specimen.
Anatomical Diagnosis
Lymphogranuloma venereum proctitis.
Dr. Davis reports having received consulting fees from Gilead Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Infectious Disease Unit (B.T.D.), the Gastrointestinal Unit (M.T.), and the Department of Pathology (L.R.Z.), Massachusetts General Hospital; and the Departments of Medicine (B.T.D., M.T.) and Pathology (L.R.Z.), Harvard Medical School.
References
Klausner JD, Kohn R, Kent C. Etiology of clinical proctitis among men who have sex with men. Clin Infect Dis 2004;38:300-302.
Spaargaren J, Fennema HS, Morre SA, de Vries HJ, Coutinho RA. New lymphogranuloma venereum Chlamydia trachomatis variant, Amsterdam. Emerg Infect Dis 2005;11:1090-1092.
Nieuwenhuis RF, Ossewaarde JM, Gotz HM, et al. Resurgence of lymphogranuloma venereum in Western Europe: an outbreak of Chlamydia trachomatis serovar L2 proctitis in the Netherlands among men who have sex with men. Clin Infect Dis 2004;39:996-1003.
Palmer L, Falkow S. A common plasmid of Chlamydia trachomatis. Plasmid 1986;16:52-62.
Peterson EM, de la Maza LM. Restriction endonuclease analysis of DNA from Chlamydia trachomatis biovars. J Clin Microbiol 1988;26:625-629.
DeMets A. Chlamydia trachomatis. Madison: University of Wisconsin Department of Bacteriology, 1998. (Accessed December 27, 2005, at http://www.bact.wisc.edu/Bact330/lecturechlamydia.)
Lymphogranuloma venereum among men who have sex with men -- Netherlands, 2003-2004. MMWR Morb Mortal Wkly Rep 2004;53:985-988.
Blank S, Schillinger JA, Harbatkin D. Lymphogranuloma venereum in the industrialized world. Lancet 2005;365:1607-1608.
de la Monte SM, Hutchins GM. Follicular proctocolitis and neuromatous hyperplasia with lymphogranuloma venereum. Hum Pathol 1985;16:1025-1032.
Ina K, Kusugami K, Ohta M. Bacterial hemorrhagic enterocolitis. J Gastroenterol 2003;38:111-120.(Benjamin T. Davis, M.D., )
A 31-year-old man with the acquired immunodeficiency syndrome (AIDS) was evaluated at the infectious disease clinic of this hospital because of rectal pain and a mucopurulent rectal discharge.
Four days before this evaluation, the patient first noticed rectal discharge, pain on defecation, and blood in his stools. He described pelvic pain, nausea, and generalized weakness but no fever, chills, or emesis. He had regular anal-receptive intercourse without condoms with his usual partner, who was also infected with the human immunodeficiency virus (HIV), and with other partners.
In the patient under discussion, HIV infection had been diagnosed 12 years earlier. He had received sporadic medical care over the course of the following 10 years and had taken antiretroviral therapy (including zidovudine, lamivudine, nelfinavir, and ritonavir–lopinavir) inconsistently. Approximately 1 year before the current evaluation, he had been admitted to this hospital for 10 days with fever, diarrhea, rash, a CD4 cell count of six per cubic millimeter, and an HIV viral load of 207,000 copies of RNA per milliliter of plasma. Diagnoses of disseminated infection with Mycobacterium avium–intracellulare and staphylococcal ecthyma were made, and the conditions were treated with cephalexin, clarithromycin, and ethambutol.
After discharge, the patient was seen in the infectious disease clinic, and antiretroviral therapy with didanosine, stavudine, and efavirenz was begun. Cutaneous Kaposi's sarcoma, oral thrush, rectal herpes simplex, and anal condylomas developed over the course of the next year. Treatment with acyclovir, fluconazole, and dapsone was given. His CD4 cell count rose to 175 per cubic millimeter, and his HIV viral load fell to less than 50 copies of RNA per milliliter over the course of the year before this evaluation.
He smoked one pack of cigarettes per day, used no alcohol, and was a regular user of marijuana and methamphetamine. He was unemployed. His aunt had Crohn's disease.
On examination, the blood pressure was 122/88 mm Hg, the pulse 88 beats per minute, the respiratory rate 10 breaths per minute, and the temperature 36.8°C. The weight was 86.8 kg. There were flat, pigmented skin lesions over the right tibia and left shoulder consistent with inactive Kaposi's sarcoma. There was no thrush or oral hairy leukoplakia. Small cervical and inguinal lymph nodes were palpable. The lungs and heart were normal. The abdomen was soft and nontender, without hepatosplenomegaly. On rectal examination, there were bulky perianal condylomas but no external ulcerations. Digital rectal examination and anoscopy were not possible because of rectal pain.
The results of a complete blood count, the levels of serum electrolytes, and tests of renal and liver function were normal. The CD4 cell count was 188 per cubic millimeter and the viral load fewer than 50 copies of RNA per milliliter. Ceftriaxone and azithromycin were prescribed. Rectal-swab cultures for Neisseria gonorrhoeae and herpes simplex virus were negative, as was the serum rapid plasma reagin.
Two weeks later at a follow-up visit, the pain on defecation had improved, but mucus and blood were still seen in the stools. Anoscopy showed mucus but no blood or ulcerations. There were no internal hemorrhoids or anal-canal condylomas. A stool culture grew scant normal enteric flora without enteric pathogens or N. gonorrhoeae. Five days later, rectal pain had increased. A diagnostic procedure was performed.
Differential Diagnosis
Dr. Benjamin T. Davis: This young man with clinically advanced AIDS presented to my clinic with rectal pain and discharge of four days' duration, with some nausea and weakness but without other systemic symptoms or fever. Approximately one year after the institution of highly active antiretroviral therapy, his immunologic recovery is evident not only by the rise in his CD4 cell count but also by the resolution of disseminated infection with M. avium complex and the regression of Kaposi's sarcoma. Clinically, he now has proctitis. This is the patient's first episode of such a condition and, as such, it is important. He is at high risk for a sexually transmitted infection by virtue of his history of sexually transmitted diseases (HIV, herpes simplex virus, human papillomavirus, Kaposi's sarcoma–associated herpesvirus), his ongoing unprotected anal intercourse with multiple partners, and his regular use of methamphetamine.
The differential diagnosis of proctitis is broad but may also be fairly quickly narrowed in this case. Noninfectious causes of proctitis are less common than infectious ones and include radiation-induced, ischemic, and inflammatory causes. Ischemic proctitis is infrequently seen because of extensive collateral blood supply to the rectum. Inflammatory bowel disease, both ulcerative proctitis and Crohn's proctitis, may present initially with this constellation of symptoms. However, the two types of proctitis are distinguished by their chronicity, and the first requirement of both diagnoses is that an infectious cause must be ruled out.
The four most prevalent infectious causes in men who have sex with men are, in descending order of incidence, gonorrhea, herpes simplex, chlamydia, and syphilis.1 When evaluated systematically, almost half of cases remain undiagnosed, and as many as 10 percent are caused by multiple coincident infections. There may be clinical overlap between causes of proctitis and causes of colitis, which include bacterial pathogens such as shigella, Escherichia coli, and Clostridium difficile; protozoal causes such as amoebiasis; and viral pathogens such as cytomegalovirus. The prominence of this patient's painful purulent discharge, the paucity of systemic symptoms, and the absence of fever narrow the list of likely diagnoses to the four sexually transmitted infections: gonorrhea, herpes simplex, chlamydia, and syphilis.
This illness is a critical sentinel event with important implications for this patient and for the public health. Proctitis is a marker for other sexually transmitted diseases, and its presence increases the risk of their transmission, including HIV infection. Patients such as this man should be broadly screened for sexually transmitted diseases, including HIV, syphilis, gonorrhea, chlamydia, human papillomavirus, and viral hepatitis. A thorough contact investigation should be initiated, and sexual partners should be evaluated and offered early or prophylactic therapy where appropriate. The Internet is increasingly being used by patients as a means to find sexual partners, often across great geographic distance. It has also become a tool for public health officials to identify contacts and to conduct epidemiologic research.
For the treatment of sexually transmitted diseases to be successful for both the patient and his or her sexual contacts, it is important that treatment be given at the time of the initial evaluation. Diagnostic testing is important, but empirical therapy for clinical syndromes such as proctitis should be administered without delay while testing for specific agents is pending. Patients with proctitis should always be offered empirical therapy for gonorrhea and chlamydia and also for herpes simplex virus if clinically warranted, as was done in this case. This patient was evaluated for gonorrhea, herpes simplex virus, and syphilis, and none of these infections were found. A DNA-amplification test for chlamydia on the rectal swab was not available in our clinic at the time this patient was seen, in 2002. The patient improved somewhat over the two weeks after the evaluation, but then returned to the clinic because of worsening symptoms. This scenario usually implies either reinfection or inadequate treatment.
If his continued symptoms represent primary treatment failure, what other organisms should be considered? The initial rectal swab was not tested for Chlamydia trachomatis DNA. Most cases of C. trachomatis proctitis are relatively mild and respond well to a single dose of azithromycin. The serotypes D through K are the most common causes of nongonococcal urethritis and mucopurulent cervicitis. In contrast, lymphogranuloma venereum, caused by C. trachomatis serovars L1, L2, and L3, may cause more extensive infection and respond poorly to single-dose azithromycin. Could this patient have lymphogranuloma venereum?
There are three stages of lymphogranuloma venereum that produce distinct clinical syndromes. In the primary stage, a small, painless mucosal or cutaneous ulcer occurs at the site of inoculation and resolves spontaneously. The secondary stage of infection begins 10 to 30 days later, as the obligate intracellular pathogen travels through lymphatics, usually to draining lymph nodes. The hallmark of this stage is lymphadenitis, and it is often distinguished by a vigorous and severe inflammatory reaction, which may suppurate and extend to structures adjacent to the lymph nodes and lymphatics. When the primary inoculation is in the penis or vagina, inguinal or femoral lymphadenitis or both develop, with a severe inflammatory reaction that may suppurate and extend to adjacent structures. Clinically, a fluctuant mass, or bubo, is seen, which may lead to abscesses, fistulae, and sinus tracts. However, when the rectum is the site of primary inoculation, in both men and women, proctitis is the most common manifestation of the secondary stage. Systemic symptoms such as fever and malaise are common. This patient's clinical symptoms and signs are entirely consistent with this manifestation of secondary lymphogranuloma venereum.
If left untreated, tertiary-stage lymphogranuloma venereum, which is marked by fibrosis and strictures, may develop in a minority of patients. Late complications include chronic genital ulceration, genital elephantiasis, anal fistulae and strictures, frozen pelvis, and infertility.
The timely diagnosis of lymphogranuloma venereum can be challenging, and in most cases is made on clinical grounds. Serologic tests (complement fixation and immunofluorescence) are limited because they do not distinguish among different serotypes, do not differentiate past from present infection, and, most important, are not available at the time of clinical presentation. Culture of the organisms from clinical specimens is expensive, and sensitivity is generally low. Nucleic acid testing of clinical specimens has emerged as a promising technique that is both sensitive and convenient. Specialized laboratories can further amplify sequences in the major outer-membrane protein and reliably distinguish among lymphogranuloma venereum serotypes.
Lymphogranuloma venereum is endemic in Africa, the Indian subcontinent, Southeast Asia, and parts of Central and South America. The illness occurs sporadically in North America, Europe, and Australia; until recently, most cases had been linked to travel in endemic areas. In the past three years, however, clustered cases of lymphogranuloma venereum proctitis have been identified in men who have sex with men, in an outbreak that appears to be centered in the Netherlands, but which has spread to other cities in Western Europe and to the United States. Characteristics of patients associated with this outbreak include a high rate of HIV-seropositivity; a high rate of concomitant sexually transmitted diseases, including gonorrhea, syphilis, and herpes simplex virus; severe proctitis without inguinal lymphadenopathy; and predominance of the L2 serotype.2,3 The patient under discussion today shares many of the clinical and epidemiologic features of other patients affected by this outbreak.
Because of his persistent symptoms and the high clinical suspicion of chlamydial proctitis, I referred him to Dr. Thiim for sigmoidoscopy and rectal biopsy.
Dr. Michael Thiim: The digital examination was very painful, as it is in most patients with proctitis; in contrast to the usual smooth texture of the mucosa in acute inflammation, I was able to palpate firm, scar-like material in the rectum, suggesting a stricture. The endoscopic examination showed mucosal erythema with edema, linear ulcerations, and a creamy, yellowish-white exudate for the first 8 to 9 cm (Figure 1); the colon was normal beyond that. Rectal swabs and biopsy specimens were obtained and sent for bacterial culture, viral culture, and for pathological examination.
Figure 1. Endoscopic Image of the Rectum.
There is a large ulcer with a yellowish-white exudate. The remaining epithelium is erythematous.
Dr. Benjamin T. Davis's Diagnosis
Lymphogranuloma venereum proctitis.
Pathological Discussion
Dr. Lawrence R. Zukerberg: Microscopical examination of the rectal-biopsy specimen showed surface injury with an inflammatory exudate and extensive crypt injury associated with lamina propria and crypt inflammation. The lamina propria contained lymphocytes, plasma cells, and neutrophils. Neutrophils were especially prominent around the crypts, and neutrophilic cryptitis was present, with injury and crypt loss (Figure 2). The active (neutrophilic) inflammation in the absence of crypt distortion, lymphoid aggregates, and plasma-cell aggregates suggested an acute or infectious colitis rather than chronic inflammatory bowel disease. No granulomas were seen, and special stains for acid-fast bacilli, cytomegalovirus, and herpes simplex virus were negative.
Figure 2. Rectal-Biopsy Specimen (Hematoxylin and Eosin).
There is inflammation in the lamina propria, with prominent neutrophilic infiltration of crypts (cryptitis).
When this biopsy was performed three years ago, a specific diagnosis was not made. Recently, the paraffin block was sent for C. trachomatis testing. The test (performed at Esoterix Laboratories, based on the Cobas Amplicor CT/NG assay, Roche Diagnostic Systems) is a qualitative polymerase-chain-reaction (PCR) test. Unstained tissue sections are digested and detergent treated to release chlamydial DNA that is contained in the chlamydial reticulate bodies. In addition to chromosomal DNA, C. trachomatis has an approximately 7500-base-pair cryptic plasmid that is common to all C. trachomatis isolates.4,5 The PCR reaction uses biotinylated primers to define a sequence of approximately 207 nucleotides within the cryptic plasmid. After PCR, the amplicon is captured by hybridization to a specific oligonucleotide probe, which increases the overall specificity of the test. Detection is by colorimetric absorbance after avidin–horseradish peroxidase conjugate binds to the biotin-labeled amplicon and catalyzes the oxidation of 3,3',5,5'-tetramethylbenzidine to a colored complex that is measured at 660 nm. The test in this patient's rectal-biopsy specimen was interpreted as positive, with absorbance greater than 2.0.
Chlamydia6 is a small bacterium that cannot grow outside a living cell because it cannot synthesize its own ATP. There are numerous factors that contribute to the pathogenicity of C. trachomatis. Colonization of chlamydia persists at sites that are inaccessible to phagocytes and immune cells. The surface of chlamydia does not contain proteins that are distinctive enough to induce a full immune response, allowing it to persist and making the development of a vaccine difficult. The life cycle consists of two stages: the elementary body and the reticulate body. The elementary body is the dispersal form and is analogous to a spore. It induces its own endocytosis, and once inside the endosome, it "germinates" into the reticulate body. This forms replicates by binary fission, dividing every two to three hours. After division, the reticulate body transforms back to the elementary form and is released by exocytosis, producing 100 to 1000 elementary bodies. The word "chlamys" is Greek for "cloak draped around the shoulder," which describes how the intracytoplasmic inclusions caused by the bacterium are "draped" around the nucleus of the infected cell.
Both lymphogranuloma venereum and non–lymphogranuloma venereum serotypes are known to affect the large intestine, with severe anal pain and discharge, including hemorrhagic enterocolitis.7 The recent appearance of cases of lymphogranuloma venereum in men who have sex with men in continental Europe, the United Kingdom, and the United States has brought renewed attention to lymphogranuloma venereum.8 The men in these cases most often presented with hemorrhagic proctitis, and many of the cases were initially mistaken for inflammatory bowel disease or other conditions.
The main pathological differential diagnosis of lymphogranuloma venereum proctitis or colitis includes other forms of infectious colitis and early idiopathic inflammatory bowel disease.9,10 Many pathogenic bacteria, including salmonella, shigella, enterohemorrhagic E. coli, campylobacter, yersinia, and clostridium, as well as chlamydia may cause hemorrhagic enterocolitis and have similar pathologic findings on biopsy. Viral infections, especially cytomegalovirus, may have a similar presentation, but viral inclusions can often be identified and cytomegalovirus infection can be confirmed by immunohistochemical staining. Syphilis and tuberculosis may cause proctocolitis, and are included in the differential diagnosis, although granulomas are not prominent in lymphogranuloma venereum colitis.
The discontinuous nature of the colitis helps to distinguish lymphogranuloma venereum colitis from idiopathic ulcerative colitis, and the proximal-to-distal gradient of severity, in turn, helps distinguish this colitis from Crohn's disease. However, many of the histopathological features overlap between infectious colitis and inflammatory bowel disease. The Centers for Disease Control and Prevention and some commercial laboratories perform nucleic acid amplification on anorectal swabs, but biopsy tissue may also be useful in confirming the diagnosis, as in this case.
Dr. Davis: Treatment with doxycycline, 100 mg twice daily for 21 days, is curative in secondary-stage lymphogranuloma venereum. We treated this patient with doxycycline, and his symptoms of proctitis resolved entirely within three or four days. On the day that I prescribed doxycycline for the patient, his partner began having similar rectal symptoms, although not as severe. We treated him as well, and his symptoms resolved promptly. Blood tests for chlamydia serology were sent for analysis and came back three or four weeks later as seropositive. At that point, we felt comfortable with the diagnosis on the basis of his clinical response. As Dr. Zukerberg has noted, the diagnosis was recently confirmed by DNA analysis on the biopsy specimen.
Anatomical Diagnosis
Lymphogranuloma venereum proctitis.
Dr. Davis reports having received consulting fees from Gilead Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Infectious Disease Unit (B.T.D.), the Gastrointestinal Unit (M.T.), and the Department of Pathology (L.R.Z.), Massachusetts General Hospital; and the Departments of Medicine (B.T.D., M.T.) and Pathology (L.R.Z.), Harvard Medical School.
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