Oesophageal Candidiasis Candida Esophagitis Dr Riina RautemaaRichardson Infectious

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-HIVinfected patients compared to HIV-infected patients • HIV infection with low CD 4 counts (fewer than 50 cells/µL) and broad-spectrum antibiotic exposure are the most prominent risk factors for development of oesophageal candidiasis Monkemuller et al. Dig Dis Sci. 2005; 50: 230– 234. Nkuize et al. HIV Med. 2010; 11: 412– 417 Takahashi et al. PLo. S One. 2015; 10(7): e 0133589

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: 971– 989

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. PLo. S One. 2015; 10(7): e 0133589

Risk factors Key risk factors • • Other risk factors HIV/AIDS • Most common • Low CD 4 counts • High HIV-RNA viral load • ART naïve patients • Smoking • Alcoholism • Wearing dentures or partials Cancer • Irradiation (radiotherapy) • Chemotherapy • Inhaled corticosteroid use • Xerostomia • Inadequate saliva Diabetes • Hyperglycaemia • Immunodeficiency • Chronic diseases (heart, liver etc. ) • Long-term oral antibiotic use • High sugar diet • Proton pump inhibitors • Increasing age • Transplant recipients • Presence of oral candidiasis (in children) • Chocarro-Martinez et al. Eur J Clin Microbiol Infect Dis. 2000; 19: 96– 100. Weerasuriya et al. Dis Esophagus. 2006; 19: 189– 192. Yakoob et al. World J Gastroenterol. 2003; 9: 2328– 2331 Takahashi et al. PLo. S One. 2015; 10(7): e 0133589

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 (4 ed, 2011): 255– 260 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 • Human papillomavirus (Myco)bacterial • • • Mycobacterium tuberculosis esophagitis Bacterial esophagitis Actinomycosis Malignancies • Oesophageal Kaposi's sarcoma • Superficial spreading carcinoma • Oesophageal carcinoma • Gastric carcinoma Others • Reflux esophagitis (GORD) • Peptic ulcers diseases • Drug-induced esophagitis • Crohn’s disease • Radiation and chemoradiation esophagitis • All these conditions present with: • Dysphagia • Odynophagia • Retrosternal chest pain • +/- weight loss • Ulceration in Candida esophagitis occurs on a background of extensive plaque formation. • Plaques of candidiasis are more linear

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. PLo. S One. 2013; 8(3): e 58217. 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. PLo. S One. 2013; 8(3): e 58217.

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 • Echinocandins de Wet N et al. Clin Infect Dis. 2004; 39: 842– 9 Krause et al. Clin Infect Dis. 2004; 39: 770– 5 • 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 echinocandins AIDS info, Mucocutaneous candidiasis. 2017 (update)

Treatment: Dosing and dosages Preferred therapy • Fluconazole, IV or PO • 200 mg (up to 400 mg) daily • Itraconazole, oral solution (PO) • 200 -400 mg daily Refractory disease Alternative therapy • Voriconazole, PO or IV • 200 mg BID • Isavuconazole, PO • 200 -400 mg as a loading dose (LD), followed by 50 -100 mg daily or • 400 mg PO once-weekly • Caspofungin/Micafungin, IV • 50 -150 mg daily • Posaconazole immediate-release • Anidulafungin, IV oral suspension • 100 mg for one dose, then 50 mg daily • 400 mg twice daily for 28 days • 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): 1 -19

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 reconstitution in patients with relapse (CD 4>100 cells/µL) Parente et al. Am J Gastroenterol. 1994; 89(3): 416 -20. Laine L. Gastroenterology. 1994; 107(3): 744 -6

Complications • Life-threatening upper gastrointestinal bleeding • Oesophageal stenosis • Oesophageal perforation (rare) • Oesophagotracheal fistula (rare) • Refractory disease (4 -5%) • Risk factors • CD 4 <50 cells/mm 3 • Multiple azole antifungals • Posaconazole immediate-release oral suspension is effective in 75% of patients with azole-refractory oesophageal candidiasis • Echinocandins and voriconazole are alternative agents • Amphotericin B is used for multi-drug refractory disease • Relapse • Risk factors • Azole refractory disease • Initial response to echinocandins Gaissert et al. Ann Thorac Surg. 1999; 67: 231– 233. Kanzaki et al. Surg Today. 2009; 39: 972– 978.

Prevention of oesophageal candidiasis • AIDS patients • Anti-retroviral therapy • No evidence to support the use of primary prophylactic antifungals • Diabetics General measures • Good oral hygiene practices • Regula dental check ups • Treat vaginal candidiasis • Limit sugary food intake • Blood sugar control • Encourage yogurt intake for at risk individuals • Regular Hb. A 1 c monitoring • 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 CD 4 count has risen to >200 cells/mm 3 following initiation of ART

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