Etiology and PathogenesisTop
The most frequent sign of gastrointestinal (GI) infection in immunocompromised patients is chronic diarrhea.
1) Viruses: Cytomegalovirus (CMV), herpes simplex virus (HSV), adenoviruses, noroviruses (previously known as Norwalk virus), rotaviruses, and other.
2) Bacteria: Mycobacterium avium complex (MAC), Mycobacterium tuberculosis, Clostridium difficile, Salmonella spp, Shigella spp, Campylobacter jejuni, bacterial overgrowth syndrome.
3) Protozoa: Microsporidia, Cryptosporidium parvum, Cystoisospora belli (formerly Isospora belli), Giardia intestinalis, Entamoeba histolytica, Blastocystis hominis, Cyclospora spp, Toxoplasma gondii, Pneumocystis jirovecii (previously carinii), Leishmania donovani.
4) Fungi: Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis.
The predominant etiologic agents depend on the type of immunodeficiency (see Immunodeficiency Disorders); for instance, the most common pathogens in HIV-infected patients are mycobacteria (predominantly MAC), cryptosporidia, microsporidia, and CMV.
Clinical Features and DiagnosisTop
Frequent diarrhea, usually chronic.
To confirm the etiology, test ≥3 stool samples (bacteriological, virological, and parasitological tests should be performed on each sample). Testing for microsporidiosis and cryptosporidiosis is indicated in significantly immunocompromised patients (CD4+ cell count <200/microL). In patients with fever and CD4+ cell counts <100/microL, mycobacterial blood culture should be performed. If stool test results do not identify the pathogen and diarrhea does not contain blood, perform upper and lower GI endoscopy. The risk of CMV infection is high in patients with CD4+ cell counts <100/microL; in such cases perform colonoscopy and obtain mucosal biopsy specimens for histologic examination and virological tests.
1. CMV infection: Clinical manifestations range from an asymptomatic CMV carrier status to diffuse ulcerative lesions of the colonic mucosa accompanied by abdominal pain, dysentery, and in some cases also by intestinal perforation.
Diagnosis: Lower GI endoscopy with collection of biopsy specimens for histologic examination; identification of CMV (immunohistochemical studies [characteristic viral inclusion bodies], polymerase chain reaction [PCR]) in specimens.
2. HSV infection: In patients with AIDS, HSV causes persistent chronic proctitis with painful ulcerations (also involving skin in the anal area).
Diagnosis: GI endoscopy with collection of biopsy specimens for histologic examination; detection of HSV antigens (or HSV DNA detection using PCR) in specimens.
3. Infections with intestinal bacteria: In severely immunocompromised patients infections with Salmonella spp and frequently also with C jejuni may lead to bacteremia and sepsis.
Diagnosis: Based on results of stool cultures.
4. MAC infection: White papules 1 to 3 millimeters in diameter forming in the intestinal mucosa, most frequently in the duodenum (~90% of cases); these are a result of accumulation of macrophages in the lamina propria.
Diagnosis: Diagnosis is difficult to establish and based on detection of mycobacteria in blood and stool specimens (cultures, PCR).
5. Cryptosporidiosis is caused by an intracellular protozoan C parvum, which typically infects jejunal enterocytes. The incubation period lasts 7 to 10 days. Signs and symptoms include watery diarrhea, abdominal cramping, fever, asthenia, and rarely manifestations from the biliary tract, liver, or pancreas; chronic diarrhea with a significant loss of water and electrolytes develops when the CD4+ cell count falls <100/microL.
Diagnosis: Detection of antigens (enzyme-linked immunosorbent assay [ELISA]) and oocysts (modified Ziehl-Neelsen staining) in stool samples or antibodies in serum (ELISA). Histologic examination of intestinal mucosal biopsy specimens is rarely performed.
6. Microsporidiosis is caused by various intracellular protozoa, most commonly Enterocytozoon bieneusi and Encephalitozoon intestinalis. Signs and symptoms include watery diarrhea, low-grade fever, asthenia, nausea, and vomiting.
Diagnosis: Detection of the protozoa by histologic examination of intestinal mucosal biopsy specimens (preferably using electron microscopy); detection of spores in stool.
7. Cystoisosporiasis: Infections in humans are caused by the protozoan C belli. The source of infection is water or food contaminated by oocysts. C belli multiplies in enterocytes of the small intestine, leading to destruction of the epithelium and the intestinal villi. Clinical features are similar to cryptosporidiosis.
Diagnosis: Repeated microscopic examinations of stool for the presence of parasites (fecal smear, direct or stained with brilliant green).
8. Candidiasis: Candidiasis is most frequently caused by C albicans, Candida krusei, Candida glabrata, or Candida tropicalis. It affects 75% to 90% of patients with AIDS. Signs and symptoms include lesions that may develop on the oral mucosa (these may take 4 forms: acute pseudomembranous lesions [thrush], acute atrophic lesions, chronic hypertrophic lesions, chronic atrophic lesions), pharyngeal mucosa, and esophageal mucosa (often asymptomatic; ~50% of patients develop dysphagia and chest pain).
Diagnosis: Esophageal lesions found on endoscopy (characteristic whitish patches that adhere to the surface and may involve the entire esophagus) and oral swab/brush cytology followed by microbiological tests (culture and antifungal susceptibility profile). Isolation of the fungi in the absence of clinical features is not sufficient to diagnose fungal infection and start treatment.
1. Symptomatic treatment: As in acute infectious diarrhea.
2. Antimicrobial treatment:
1) M tuberculosis (see Tuberculosis: Active Disease): Combined treatment with isoniazid, rifampin (INN rifampicin), pyrazinamide, and ethambutol for 9 to 12 months.
2) MAC (see Nontuberculous Mycobacterium Diseases): Multidrug therapy of symptomatic infection for 9 to 12 months.
3) CMV: IV ganciclovir 5 mg/kg every 12 hours (or valganciclovir 900 mg orally bid) as the first-line therapy. An alternative therapy is IV foscarnet 60 mg/kg over 1 hour every 8 hours for 14 to 28 days.
4) HSV: Acyclovir (INN aciclovir) 200 mg orally 5 times a day for 5 to 10 days, valacyclovir 1 g orally bid, or famciclovir 500 mg orally tid.
5) Cryptosporidium spp: Paromomycin for 14 to 28 days.
6) Cyclospora spp: Sulfamethoxazole/trimethoprim or ciprofloxacin for 14 to 28 days.
7) C belli: Sulfamethoxazole/trimethoprim, ciprofloxacin, or pyrimethamine for 14 to 28 days.
8) E intestinalis: Albendazole. E bieneusi: Fumagillin is the drug of choice. Alternative agents include metronidazole and atovaquone. Therapy lasts 14 to 28 days.
9) Candida spp: In patients with mild oral candidiasis, use nystatin 200,000 to 600,000 U qid for 7 to 14 days. In patients with moderate or severe candidiasis, use oral fluconazole 100 to 200 mg/d for 7 to 14 days (if ineffective, use oral itraconazole, voriconazole, or amphotericin B; IV administration may be considered in patients with recurrent candidiasis). In patients with pharyngeal candidiasis, use oral fluconazole 200 to 400 mg/d (in the case of intolerance, administer IV fluconazole; in patients resistant to fluconazole, use itraconazole, posaconazole, or voriconazole).