Oesophageal Candidiasis [Candida Esophagitis] Dr. Riina Rautemaa-Richardson Infectious Diseases Consultant Wythenshawe Hospital, Manchester University NHS FT, UK Intended Learning Outcomes To be aware of the pathogenesis of oesophageal candidiasis To be familiar with the clinical presentation of oesophageal candidiasis To be able to diagnose oesophageal candidiasis and rule out differential diagnoses To be aware of the treatment options available for treating oesophageal candidiasis To be aware of the treatment outcome and complications of oesophageal candidiasis Introduction Candida esophagitis is an opportunistic infection that complicates disorders associated with granulocyte and/ or lymphocyte numbers and dysfunction It is the most common infection of the oesophagus and the most common gastrointestinal opportunistic disorder among individuals infected with HIV Oesophageal candidiasis is an AIDS-defining opportunistic infection with
prevalence >40% in pre-ART era With the advent of ART, the prevalence of oesophageal candidiasis increased in non-HIV-infected patients compared to HIV-infected patients HIV infection with low CD4 counts (fewer than 50 cells/L) and broad-spectrum antibiotic exposure are the most prominent risk factors for development of oesophageal candidiasis Monkemuller et al. Dig Dis Sci. 2005; 50: 230234. Nkuize et al. HIV Med. 2010; 11: 412417 Takahashi et al. PLoS One. 2015; 10(7): e0133589 Pathogenesis Candida spp. are yeasts found in normal oral and oesophageal flora Colonization entails superficial adherence and proliferation of Candida on the oesophageal mucosa Defences against colonization include normal salivation, oesophageal motility, a healthy oesophageal epithelium, and a balance between oral bacterial and fungal flora Infection results when Candida invades into oesophageal epithelial cell layer, a process that usually requires defective mucosal immunity Fungal virulence factors includes the ability to colonize and adhere to oesophageal mucosa by undergoing morphogenesis to the hyphal form or ability to secrete proteinases to lyse host cell membranes.
Vazquez JA. Drugs. 2003;63:971989 Pathogenesis Primary or acquired immunodeficiency leads to impaired defences against Candida Broad-spectrum antibiotics may eliminate certain bacteria that inhibit fungal growth, thereby enhancing Candida overgrowth. Oesophageal disease, such as non-infectious esophagitis (including GORD) or achalasia may favour the development of oesophageal candidiasis However, except for HIV infection, there are few data to prove a causative effect with oesophageal candidiasis Choi et al. Yonsei Med J. 2013; 54(1): 160 165. Takahashi et al. PLoS One. 2015; 10(7): Risk factors Key risk factors Other risk factors HIV/AIDS
Smoking Most common Low CD4 counts High HIV-RNA viral load ART nave patients Cancer Irradiation (radiotherapy) Chemotherapy Diabetes Hyperglycaemia Immunodeficiency Alcoholism Wearing dentures or partials Inhaled corticosteroid use
Xerostomia Inadequate saliva Chronic diseases (heart, liver etc.) Long-term oral antibiotic use High sugar diet Proton pump inhibitors Increasing age Chocarro-Martinez et al. Eur J Clin Microbiol Infect Dis. 2000;19: 96100. Presence of oral candidiasis (in children)Weerasuriya et al. Dis Esophagus. 2006;19: 189192. Yakoob et al. World J Gastroenterol. 2003;9: 23282331 Takahashi et al. PLoS One. 2015; 10(7): e0133589 Transplant recipients Clinical manifestation Oral thrush (indicator sign)
Odynophagia Painful swallowing Dysphagia Difficulty in swallowing Retrosternal burning pain or discomfort Nausea/vomiting Upper gastrointestinal bleeding Fever Dehydration Weight loss Oral thrush is a frequent findings indicative of an underlying oesophageal candidiasis It is more common (>90%) in children with oesophageal candidiasis than its is in adults (<25%) ~50% of patients with severe
oesophageal candidiasis by endoscopy may be asymptomatic Clinical manifestation: Children Oral thrush (94%) Nausea/vomiting (24%) Odynophagia (80%) Dehydration (12%), and Refusal to (breast)feed Cries while swallowing Gastrointestinal (GI) bleeding (6%) Retrosternal chest pain (57%), Fever (29%) Concurrent oropharyngeal candidiasis was the most common clinical presentation
Saeed & Boyle:Pediatric Gastrointestinal and Liver Disease (4ed, 2011): 255260 Chiou et al. Pediatr Infect Dis J. 2002;21(5):388-92. Diagnosis: Confirmatory Histology Presence of yeasts and pseudohypahe invading oesophageal mucosae Culture Revealing Candida spp. Candida albicans - most common, other species rare Antifungal sensitivity testing Require if previous triazole exposure or in those failing therapy Grocott methanamine silver stain preparation of oesophageal biopsy sample showing hyphal invasion
Diagnosis Gold standard diagnosis Upper gastrointestinal endoscopy + Brushings and biopsy Findings Raised, white candidal plaques Plagues cannot be washed away with water Bleeding of attachment site following brushings Antinori et al. Endoscopy.1995; 27(5):371-6. The white plaques represents desquamated epithelial cells with fungal yeasts and hyphae,
inflammatory cells, and bacteria Differential diagnosis Viral oesophagitis Herpes simplex Cytomegalovirus HIV esophagitis (primary HIV infection) Varicella-zoster virus Epstein-Barr virus Malignancies Oesophageal Kaposi's sarcoma Superficial spreading carcinoma Oesophageal carcinoma Gastric carcinoma Others All these conditions present with: Dysphagia
Odynophagia Retrosternal chest pain +/- weight loss Mycobacterium tuberculosis esophagitis Drug-induced esophagitis Crohns disease Ulceration in Candida esophagitis occurs on a background of extensive plaque formation. Bacterial esophagitis Radiation and chemoradiation esophagitis Plaques of candidiasis
are more linear Human papillomavirus (Myco)bacterial Actinomycosis Reflux esophagitis (GORD) Peptic ulcers diseases Differential diagnosis Other fungal causes of esophagitis Mucormycosis Cryptococcus spp Pneumocystis jirovecii Aspergillosis Histoplasmosis Blastomycosis Grading oesophageal candidiasis: Endoscopic Kodsi endoscopic severity grading
Grade 0: Normal oesophageal mucosa Grade 1: Raised white plaques are 2 mm or less in size Grade 2: Raised white plaques greater than 2 mm in size Grade 3: Mucosal ulceration is present or a confluent, thick plaque like membrane coats the oesophageal mucosa Grade 4: Finding of grade III with increased friability of the mucous membranes and occasional narrowing of the lumen Nishimura et al. PLoS One. 2013; 8(3): e58217. Kodsi et al. Gastroenterology. 1976; 71(5):715-9.
Endoscopic severity of Kodsi's grading A: Grade I, a few raised white plaques up to 2 mm in size without oedema or ulceration. B: Grade II, multiple raised white plaques greater than 2 mm in size without ulceration. C: Grade III, confluent, linear, and nodular elevated plaques. D: Grade IV, finding of grade III with increased friability of the mucous membranes and occasional narrowing of the lumen. E: White carpet appearance, thick white plaque cover on esophageal mucosa circumferential narrowing the lumen. F: Oral candidiasis, for which endoscopy can detect laryngopharyngeal candidiasis. Nishimura et al. PLoS One. 2013; 8(3): e58217.
Treatment: 2-3 weeks Mild disease Fluconazole, PO Key information Moderate Fluconazole/Itraconazole IV or PO Itraconazole suspension for fluconazole resistance Severe disease (HIV/AIDs) Fluconazole, IV (preferred ) Amphotericin B, IV de Wet NEchinocandins et al. Clin Infect Dis. 2004; 39:8429 Krause et al. Clin Infect Dis. 2004; 39:7705 Voriconazole Posaconazole
Amphotericin B (either deoxycholate or lipid formulations) and Echinocandins All effectively treat oesophageal candidiasis Oesophageal candidiasis appears to have a higher relapse rate after treatment with the AIDS info,echinocandins Mucocutaneous candidiasis. 2017 (update) Treatment: Dosing and dosages Preferred therapy Alternative therapy Fluconazole, IV or PO Voriconazole, PO or IV
200 mg BID 200 mg (up to 400 mg) daily Isavuconazole, PO Itraconazole, oral solution (PO) 200-400 mg daily Refractory disease Posaconazole immediaterelease oral suspension 400 mg twice daily for 28 days 200-400 mg as a loading dose (LD), followed by 50100mg daily or 400 mg PO once-weekly Caspofungin/Micafungin, IV 50-150 mg daily Anidulafungin, IV 100 mg for one dose, then 50 mg daily Amphotericin B deoxycholate 0.6 mg/kg IV daily, or
Lipid formulation of amphotericin B 3-4 mg/kg IV daily Clinical response and relapse rates Adapted from Vazquez. HIV ther. 2010; 4 (3): Clinical response and relapse rates Prophylaxis with oral antifungals significantly reduced symptomatic relapses of oesophageal candidiasis in AIDS patients Cumulative probability of relapse at 12 months being ~40 % with prophylaxis , compared with 80-90% in the untreated group Recurrence occurs , usually within 2-3 months after successful antifungal treatment Fluconazole is highly effective , but risk of resistance is increased with prolonged use Secondary prophylaxis should be instituted until ART produces immune et al.(CD4>100 Am J Gastroenterol. reconstitution in patientsParente with relapse cells/L)
1994;89(3):416-20. Laine L. Gastroenterology. 1994;107(3):7446 Complications Life-threatening upper gastrointestinal bleeding Oesophagotracheal fistula (rare) Posaconazole immediate-release oral suspension is effective in 75% of patients with azolerefractory oesophageal candidiasis Refractory disease (4-5%) Risk factors Echinocandins and voriconazole are alternative agents Oesophageal stenosis Oesophageal perforation (rare)
CD4 <50 cells/mm3 Multiple azole antifungals Relapse Amphotericin B is used for multidrug refractory disease Risk factors Azole refractory disease Initial response to echinocandins Gaissert et al. Ann Thorac Surg. 1999; 67: 231233. Kanzaki et al. Surg Today. 2009; 39: 972978. Prevention of oesophageal candidiasis AIDS patients General measures Anti-retroviral therapy Good oral hygiene practices
No evidence to support the use Regula dental check ups of primary prophylactic Treat vaginal candidiasis antifungals Limit sugary food intake Diabetics Blood sugar control Regular HbA1c monitoring Encourage yogurt intake for at risk individuals Avoid yeast containing foods Summary Candida esophagitis is the most common infection of the oesophagus
and its an AIDS-defining opportunistic infection HIV/AIDs, cancers and its associated treatment, and diabetes are the most common risk factors Fluconazole and itraconazole are the preferred systemic antifungals for the treatment of oesophageal candidiasis Echinocandins and amphotericin B are useful in patients with refractory disease or patients with recurrence For patients with recurrent disease, discontinue secondary prophylaxis when the CD4 count has risen to >200 cells/mm3 following initiation of ART END
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