What’s bugging the gut? A team approach

Cryptosporidium is not detected well in a routine ova and parasite exam, “which is something we don’t teach medical students very well,” Dr. Wojewoda said, adding, “I’m working on it.” In a routine O&P exam, Cryptosporidium can look like yeast, which are normal in stool. “This is a time when you can work with your GI, family medicine, and infectious diseases colleagues. Make sure they know that either a Cryptosporidium exam, antigen assay, or PCR assay is a better test.”

If they do an O&P exam, a modified acid-fast stain would be used to differentiate Cryptosporidium from yeast. “When we observe them, the oocysts are approximately four to six microns and very round.”

Multiple Cryptosporidium species can cause disease, she said, but Cryptosporidium parvum and Cryptosporidium hominis are the most common. “We get this via ingestion of unclean food or water that’s been contaminated with stool,” the latter often encountered in water parks. In 2018 there were 748,000 cryptosporidiosis cases.

Cryptosporidium organisms show small basophilic round bodies protruding from the apex of enterocytes, highlighted with Giemsa stain. “Interestingly, they are considered intracellular but extracytoplasmic in location,” Dr. Iuga said. They are located within parasitophorous vacuoles covered by the host’s microvillous membranes. “Histologically,” she said, “the small intestine mucosa can show variable villous atrophy, variable inflammation including cryptitis and lamina propria neutrophilic infiltrate, as well as intraepithelial lymphocytosis and eosinophil infiltrate.”

Cryptosporidium can be found in lakes and rivers, especially when the water is contaminated with sewage and animal waste, and it’s resistant to chlorine disinfection and therefore can be present in drinking water. The disease is caused by ingesting infectious oocytes followed by the release of sporozoites that invade enterocytes, primarily in the small intestine. The most common sites of infection are the small intestine and proximal colon, “but they can also infect the distal colon, pancreas, respiratory tract, and, interestingly, the gallbladder and biliary tree. And there are reported cases of sclerosing cholangitis associated with Cryptosporidium infection,” Dr. Iuga said.

Cryptosporidium can cause self-limited diarrhea in immunocompetent patients and chronic diarrhea in immunocompromised patients. “It can also be a cause of malabsorption, lactose intolerance, dehydration, weight loss, and malnutrition in severe cases,” she noted. Infection is managed with supportive therapy, antiprotozoal medication, or antiretroviral therapy in HIV patients or by reducing immunosuppression in other settings.

The third case is that of a 42-year-old man who presented with lower abdominal pain and hematochezia. On physical examination there were a few slightly raised, painful perianal tags. Colonoscopy revealed erythema and discrete ulcers in the rectum. Abdominal CT scan revealed circumferential thickening of the rectal wall and numerous enlarged perirectal lymph nodes, concerning for malignancy.

H&E sections from the perianal tags (Figs. 10 and 11) showed psoriasiform epidermal hyperplasia with superficial and deep perivascular and periadnexal chronic inflammatory infiltrate, Dr. Zenali explained.

Chronic inflammatory infiltrate is often lymphoplasmacytic with scattered histiocytes and eosinophils. Another histologic finding in syphilis is obliterative endarteritis, characterized by concentric endothelial swelling, fibroblastic thickening, and narrowing of the vascular lumen. Fig. 12 is a photomicrograph of Treponema pallidum immunostain highlighting the presence of spirochetes in the epithelium.

Microscopic examination raises a diagnosis of condyloma lata, which is distinct from the more commonly encountered anogenital condyloma (condyloma acuminatum). Condyloma lata occur in the setting of secondary syphilis. “On H&E alone,” Dr. Zenali said, “we cannot entirely exclude other venereal disease such as lymphogranuloma venereum [LGV] or granuloma inguinale [donovanosis], and immunostaining or silver impregnation methods can aid in further delineation.”

A biopsy was needed, Dr. Woje­woda said, in addition to a syphilis serology workup for confirmation. The nontreponemal serology (Venereal Disease Research Laboratory, rapid plasma reagin) used to be performed first, “and if that was positive, you would confirm with treponemal-specific serology,” such as the fluorescent treponemal antibody absorbed (FTA-ABS) test or T. pallidum particle agglutination (TPPA).

The treponemal serology is now automated and it’s therefore easier to do the treponemal serology as the first line. “If that serology is positive, we reflex to a nontreponemal serology, such as the RPR.” If tissue is available, Treponema pallidum would be positive by Warthin-Starry stain, and there’s also an organism-specific immunohistochemical stain that can be performed on tissue,” Dr. Wojewoda said.

Almost 130,000 cases of syphilis were diagnosed in 2019, a 74 percent increase since 2015. “And the scary part,” she said, “is that we saw a 279 percent increase since 2015 in congenital syphilis cases,” with 1,870 cases diagnosed in 2019, “and that trend is continuing today.”

In the digestive tract, Dr. Zenali said, syphilitic disease more frequently manifests in the anorectal region, but it can also affect other sites. “Case studies of syphilitic hepatitis and severe gastritis have been reported. Due to its variable presentations, syphilis is known as the great imitator. Thus, underdiagnosis or misdiagnosis rates can be high,” she said.

In primary syphilis, the lesions generally appear at the site of first inoculation, and so-called chancre(s) can be single or multiple. In secondary syphilis, there is rash and adenopathy, and condyloma lata is the characteristic lesion, often occurring about six to eight weeks after the primary infection. Features of primary and secondary syphilis can coexist. Patients with syphilis may even remain asymptomatic for long periods. Neurological disorders, arthritis, and a distinctive lesion called gumma are seen in tertiary syphilis, she explained.

On histology, in nearly any stage of syphilis, there is increased chronic inflammation and obliterative endarteritis, Dr. Zenali said. “In the luminal GI tract, secondary syphilis can manifest as ulcers, cryptitis, mass-like chronic inflammation, or even granulomatous inflammation.” The spirochete organism can be identified in primary and secondary lesions, “but it can be difficult to demonstrate in the gummas.”

“We always want to see a lot of plasma cells in syphilis, but occasionally they are few if any,” Dr. Zenali said, adding, “Sometimes you just see a lot of eosinophils and lymphocytes or histiocytes.” It’s something to keep in mind, she said: “If you don’t have a lot of plasma cells, that doesn’t rule out syphilis histologically. If there is any suspicion, get the appropriate stains.”

Of the differential, Dr. Zenali said condyloma acuminatum is typically a firm, raised, keratinized anogenital lesion, and HPV-associated cytopathic effect can be seen in many, if not all, cases.

Like syphilis, Chlamydia trachomatis can cause coloproctitis. At the inoculation site it often forms papules and ulcers, which quickly disappear and become fibrotic; it may become a stricturing disease or develop fistulae. “You may find enlarged inguinal lymph nodes with stellate abscess inside of them.”

The perianal disease in donovanosis or granuloma inguinale (caused by Klebsiella granulomatis) forms nodular or ulcerated lesions. The condition can clinically mimic syphilis and lymphogranuloma venereum, she cautions. In granuloma inguinale, lesions contain pathognomonic inclusions called Donovan bodies within the mononuclear cells. “They are distinctive in that they are bipolar-staining intracellular densities on standard Giemsa or silver stains.”

Penicillin is the treatment of choice for syphilis, Dr. Zenali said, but the regimen is stage dependent. The RPR test can be used to monitor treatment, she said, and it is important to be familiar with the caveats of post-treatment RPR levels to avoid misinterpretation. “For treatment purposes, knowing the patient’s HIV status is important and typically assessed due to risk of co-infection.”

Karen Lusky is a writer in Brentwood, Tenn.