Infectious oesophagitis

• Infectious oesophagitis is the second most common kind of oesophagitis, after reflux; it means an organism has settled in and inflamed the lining of the oesophagus.
• Almost always the cause is one of three: living yeast, above all Candida albicans; herpes simplex virus (HSV); or cytomegalovirus (CMV).
• These three look different on endoscopy: Candida leaves creamy or yellow-white plaques that cling to the mucosa; HSV produces small, deep, punched-out or volcano-like ulcers; CMV produces larger, deeper ulcers that run along the oesophagus and often have little surrounding inflammation.
• They occur when host defences fail, most often in people living with HIV, people who are immunosuppressed after transplantation, people with blood cancers receiving chemotherapy, and people taking corticosteroids, antibiotics or acid-suppressing drugs.
• In someone with classic thrush and odynophagia, a trial of systemic antifungal treatment is justified; symptoms should start to improve within three to five days. If they do not, or the picture is atypical, an upper endoscopy with biopsies and brushings is required, because the probability of a viral co-infection is high.

By the end of this page you should be able to:

1. Say who is at risk of infectious oesophagitis and why, including the role of HIV-related immune depletion.
2. Distinguish Candida, HSV and CMV oesophagitis by their endoscopic and histologic appearances.
3. Plan the investigation of a patient with odynophagia in an immunocompromised host, including when to scope and what to take.
4. Prescribe appropriate antifungal and antiviral treatment, with route, dose, duration and what to do when first-line therapy fails.
5. Advise on complications, recurrence, prevention and care in settings where endoscopy is not available.

Infection is the second most common cause of oesophagitis, after gastro-oesophageal reflux disease.^[1] The normal oesophagus defends itself well: swallowed organisms are flushed by peristalsis and saliva, stomach acid and pepsin kill many that survive, and mucosal IgA and cell-mediated immunity handle the rest. Infectious oesophagitis develops when one or more of these barriers fails, or when an organism already in the gut overgrows faster than the host can contain it. Many infections are therefore opportunistic, but HSV in particular can produce oesophagitis even in people with apparently normal immunity.^[4]

Infectious oesophagitis is predominantly a disease of people with impaired immunity.^[4] There are no reliable worldwide incidence figures for the condition as a whole; what does exist is the size of the groups at risk. Yeast of the genus Candida lives as a harmless commensal in the mouth and gut of most healthy people, so candidal oesophagitis is not so much caught as allowed to happen when cell-mediated immunity falters. It is the commonest type of infectious oesophagitis in adults, and Candida albicans is by far the commonest species isolated.^[5]

Cytomegalovirus is even more widely carried: studies suggest roughly 80% of the world's population has been infected at some time.^[4] In people with normal immunity infection is usually silent or causes a mild mononucleosis-like illness, and the virus then lies latent in many organs. In an immunocompromised host it reactivates, and after the bowel, the oesophagus is the second most common target organ.^[3] CMV oesophagitis is the leading form of infectious oesophagitis in people with advanced HIV disease, that is, those with AIDS.^[1]

Herpes simplex virus oesophagitis is reported most often in recipients of solid organ or bone marrow transplants, where 1 to 6% of solid organ and 10 to 15% of bone marrow recipients are said to be affected.^[3] It is almost always HSV-1; HSV-2 has been reported, but is uncommon.^[1][4]

Young adults with apparently intact immunity can develop HSV oesophagitis, often resolving on its own. Self-limiting episodes aside, most adults who develop any infectious oesophagitis have at least one underlying risk factor.

The lifetime risk of Candida oesophagitis in people with AIDS is estimated at around 10 to 15%.^[5]

A useful way to remember the risks is to think of them as either removing a normal barrier or disturbing the resident flora. The same patient often has more than one.

• Immunodeficiency of every kind. Advanced HIV infection is the classic setting. Corticosteroids (systemic, inhaled and topical), chemotherapy, radiotherapy, organ and bone marrow transplantation, haematologic cancers and immunosuppressive drugs (methotrexate, cyclosporine and biologics that block tumour necrosis factor) all depress the cell-mediated immunity that keeps fungi and herpesviruses in check.
• Corticosteroids inhaled for asthma or chronic lung disease. Local deposition of steroid in the oropharynx and oesophagus suppresses local immunity and allows yeast to overgrow, and swallowed residue can do the same lower down.
• Antibiotics. Broad-spectrum antibiotics disrupt the bacterial flora that normally competes with Candida in the gut and mouth, opening space for yeast overgrowth.
• Acid suppression and conditions that alter motility. Reduced gastric acid removes a major barrier to swallowed organisms, and abnormal oesophageal emptying traps organisms and residue against the mucosa. Reflux oesophagitis can coexist and may damage the mucosa first.
• Diabetes mellitus. Hyperglycaemia impairs neutrophil function, and glucose in saliva and tissue fluids feeds yeast.
• Haematologic malignancy and its treatment. This is the classic setting for the most severe bacterial, fungal and viral oesophagitis.
• Indwelling devices and proximity to the microbiome. Dentures are the commonest local risk for oral candidiasis; dental disease, oral hygiene and biofilm formation on appliances also matter.

Candidal oesophagitis is found most often in people with haematologic malignancy, people on corticosteroids or people living with AIDS, and the absence of oral thrush does not exclude it.^[4] In the commonly encountered situation of an immunocompromised patient with AIDS or chemotherapy, studies report CD4 counts under 200 cells per µL in people with viral and fungal co-infection.^[4] In advanced HIV disease these are the two figures that matter clinically: Candida causes most oesophageal disease once the CD4 count falls below about 200 cells per µL, and CMV disease usually appears at counts under 50 cells per µL.^[3]

Less common organisms appear when the defect is deep or specific. Of these, Cryptococcus, Histoplasma, Blastomyces and Aspergillus are reported from time to time, mycobacteria can involve the oesophagus as part of tuberculosis or non-tuberculous disease, and Mucor is a rare, rapidly fatal cause in diabetic ketoacidosis.^[4] HIV-related ulcers, thought to be idiopathic or related to HIV itself, also belong in the differential and may coexist with any of the above.

The clinical picture follows from three facts: each organism has a preferred tissue target in the oesophagus, the immune defect determines which organism gets ahead, and the resulting mucosal damage is what hurts.

Candida is a yeast. In health it colonises the oropharynx and gut without invasion, held in check by salivary defences, competing bacteria and T-cell immunity. When these fail it grows, forms pseudohyphae that pierce the superficial squamous epithelium, and triggers a neutrophilic inflammatory response. Infection usually spreads contiguously from the mouth into the oesophagus, which is why oral thrush so often accompanies it; it can reach the oesophagus even when the mouth looks clear.

HSV infects squamous epithelial cells. It arrives either by reactivation of latent virus in sensory ganglia with spread along the vagus nerve, or by direct extension from the mouth into the oesophagus during a primary or recurrent infection. The virus lyses cells at the surface; ulcers form where the epithelium dies, and local replication can extend them at the edges.

CMV has a tropism for mesenchymal and endothelial cells rather than the squamous surface. It causes a vasculitis and focal tissue necrosis at the base of an ulcer. That is why CMV ulcers are characteristically deep, often linear or longitudinal, and have surprisingly little inflammatory change in the surrounding mucosa. Reactivation, rather than new acquisition, drives most adult disease.

The key distinction for the clinician is not between species names but between surface infection and submucosal infection, because it determines where to aim the biopsy.

Histologic examination shows Candida as budding yeast and pseudohyphae invading viable squamous epithelium, usually with an accompanying neutrophilic infiltrate and necrotic debris. The appearance of squamous cells disrupted at the surface, sometimes described as "shredded wheat", is classic. Special stains (periodic acid-Schiff, Gomori methenamine silver) highlight the fungal cell wall.

HSV produces multinucleated squamous epithelial cells with ground-glass nuclei, nuclear moulding and marginated chromatin at the ulcer edge, plus eosinophilic or basophilic intranuclear inclusions known as Cowdry type A inclusions. The relevant material is at the margin of the ulcer, in viable squamous epithelium; the ulcer bed itself is mostly necrotic debris.

CMV leaves enlarged endothelial and stromal cells at the base of the ulcer containing basophilic intranuclear inclusions surrounded by a clear halo, the "owl's eye", sometimes with intracytoplasmic granules. These are easily missed if the biopsy is taken from the edge rather than the ulcer base.

The symptoms of infectious oesophagitis are those of any oesophagitis, but their suddenness and intensity in an immunocompromised patient, or after recent antibiotics or steroids, should raise the possibility. The main features are:

• Odynophagia, pain on swallowing, the most characteristic symptom for infectious oesophagitis generally, and for CMV in particular.
• Dysphagia for solids, sometimes progressing to liquids.
• Retrosternal or substernal chest pain, often worsened by hot drinks.
• Associated oral thrush with creamy white plaques that scrape off to leave a red, raw surface; absence of thrush never excludes oesophageal infection.^[4]
• Fever, anorexia, weight loss, nausea, vomiting and, occasionally, haematemesis or melena.

Candida usually produces a rapid onset of odynophagia and retrosternal pain, sometimes with feeding difficulty, because the inflamed mucosa stings with every swallow.^[5] HSV adds a systemic viral prodrome in many patients: fever, extra-oesophageal herpetic lesions, lip vesicles and oral ulcers are clues to the diagnosis but are not always present. CMV more often brings constitutional symptoms (fever, weight loss, anaemia) than severe local ones; odynophagia and dysphagia may be a smaller part of the picture than overall decline.

On examination, look at the mouth carefully, check temperature and weight, record the HIV and transplant status and medications, and arrange an HIV test if the diagnosis would be new. Ask about pill swallowing habits, recent medication changes, and whether symptoms worsen with acid.

The causes of dysphagia and odynophagia overlap, and infectious oesophagitis is rarely the only possibility.

When a patient presents with odynophagia, distinguishing these clinically is difficult; the response to a diagnostic trial of treatment, and endoscopy when that fails, sorts most of them out.

Upper endoscopy is the test that confirms and classifies. Candida produces raised, creamy or yellow-white plaques adherent to an erythematous, oedematous mucosa, sometimes severe enough to line the whole oesophagus. HSV produces vesicles in the early stage and multiple superficial, well-circumscribed ulcers, usually under 2 cm and often described as volcano-like or punched-out.^[5] CMV produces fewer, larger, deeper ulcers that may be linear, longitudinal or serpiginous, often in the distal oesophagus, with a relatively normal surrounding mucosa.

Because each organism lives in a different tissue layer, taking biopsies from the wrong place misses the diagnosis. Brushings as well as biopsies are supported by the HIV and transplant literature, because brushings often contain more cells than forceps samples.

• Candida: biopsy the plaques and the mucosa, looking for organisms invading epithelium.^[1][5]
• HSV: biopsy the margin of an ulcer where viable squamous epithelium still harbours virus; immunohistochemistry for viral antigen confirms it.
• CMV: biopsy the ulcer base where stromal and endothelial cells reside; the characteristic inclusions are here, not at the edge.

• HIV testing and CD4 count when the diagnosis might represent advanced immunosuppression.
• Viral load and (in transplant recipients) CMV antigenaemia or CMV DNA in blood, which can support, but not replace, tissue diagnosis.
• Blood cultures and chest imaging as part of a general work-up when the system is unwell.
• Swabs and KOH preparations for oral candidiasis when thrush is present. Histology rather than culture usually clinches invasive oesophageal disease.^[5]

The practical problem is to avoid scoping every patient, without delaying diagnosis in those who need it.

A diagnostic trial of antifungal therapy before endoscopy is endorsed by current candidiasis guidelines.^[2] It should not be used as a substitute for endoscopy when there is bleeding, a mass on imaging, rapidly worsening symptoms, severe pain out of proportion, or a known immunocompromised patient failing treatment.

Co-infection is common rather than rare: in one series of HIV-positive patients with infectious oesophagitis, 20% had simultaneous Candida and CMV infection, and a few had three organisms together; Candida with HSV alone, without CMV, was not seen.^[1] When empiric antifungal treatment is started, any clinical non-response within three to five days should trigger endoscopy, because the chance of a co-existing viral infection is around half.^[1][4]

Systemic antifungal therapy is always required; topical agents do not reach the oesophagus in sufficient concentration. Oropharyngeal and oesophageal disease are co-managed.

Preferred therapy. IDSA guidelines (the 2016 update, still the widely cited standard):^[2]

• Oral fluconazole 200 to 400 mg (3 to 6 mg/kg) daily for 14 to 21 days, strong recommendation. A 400 mg loading dose followed by 200 to 400 mg daily for two to three weeks is commonly used.^[4]
• If oral intake is not possible, intravenous fluconazole 400 mg (6 mg/kg) daily, or an echinocandin: micafungin 150 mg daily, caspofungin with a 70 mg loading dose then 50 mg daily, or anidulafungin 200 mg daily.^[2]
• Amphotericin B deoxycholate 0.3 to 0.7 mg/kg daily is a less preferred alternative for patients unable to take oral therapy.^[2]
• De-escalate to oral fluconazole 200 to 400 mg (3 to 6 mg/kg) daily once the patient can swallow.^[2]

Fluconazole-refractory disease. When symptoms persist despite 3 to 5 days of appropriate therapy, do not simply prolong the same drug. Options derive from the IDSA 2016 guideline:^[2]

• Itraconazole solution 200 mg daily, or voriconazole 200 mg (3 mg/kg) twice daily by mouth or intravenously, for 14 to 21 days.^[2]
• An echinocandin as above for 14 to 21 days.^[2]
• Amphotericin B deoxycholate 0.3 to 0.7 mg/kg daily for 21 days.^[2]
• Posaconazole suspension 400 mg twice daily, or extended-release tablets 300 mg once daily, as a possible option.^[2] Escalation matters most in non-albicans Candida (such as C. glabrata) which carry higher azole resistance rates, and in patients with prior azole exposure.

Recurrent disease and prevention of recurrence. Chronic suppressive fluconazole 100 to 200 mg three times weekly for recurrent oesophagitis, and antiretroviral therapy in people with HIV, because restoring immunity is what truly prevents recurrence.^[2]

Pregnancy. Azoles are teratogenic and should not be used in pregnancy, especially in the first trimester, so amphotericin B becomes the drug of choice for oesophageal candidiasis in pregnancy.^[4]

The immune status decides everything.

• People with apparently normal immunity: HSV oesophagitis is uncommon and usually self-limited; antiviral therapy is considered case by case.^[4]
• Immunocompromised patients: oral acyclovir 400 mg five times a day for two to three weeks; alternatives are famciclovir 500 mg three times a day or valaciclovir 1 g three times a day.^[4]
• Severe odynophagia or inability to swallow: hospitalise for intravenous acyclovir 5 mg/kg three times a day for one to two weeks, switching to oral therapy once swallowing returns.^[4]
• Acyclovir-resistant disease (suspected after no improvement after an adequate course): foscarnet, with specialist supervision and attention to renal toxicity.
• Relapse: common in profoundly immunocompromised patients; consider long-term suppressive acyclovir or valaciclovir if episodes recur often.
• Prophylaxis: transplant programmes commonly use aciclovir prophylaxis around the time of transplantation according to local protocol.

Untreated CMV oesophagitis progresses to transmural disease with bleeding, perforation and stricture, and even with treatment reported mortality is substantial.^[3]

• Normal immune status: CMV oesophagitis is exceptionally rare in immunocompetent adults; ulceration seen in association with CMV may be related to reflux and may respond to a proton pump inhibitor, with antiviral therapy reserved for non-response.^[3]
• Immunocompromised patients: induction therapy with ganciclovir 5 mg/kg or foscarnet 90 mg/kg (both intravenously) for three to six weeks. Ganciclovir is given 5 mg/kg per dose every twelve hours; if improvement occurs, valganciclovir 900 mg by mouth every twelve hours can be used when swallowing permits.^[3][4]
• Ganciclovir intolerance (for example, severe neutropenia) calls for foscarnet instead; cidofovir and specialised combinations remain salvage options.
• Valganciclovir 900 mg twice daily by mouth is also used for maintenance in relapsing patients after induction, though maintenance therapy is controversial and where response is expected, a defined 3 to 6 week course is often sufficient.^[4]
• Testing for resistance is appropriate when there is no clinical or virologic response after two weeks of therapy.^[3]
• Antiretroviral therapy for HIV, and reduction of iatrogenic immunosuppression where this is safe.
• Eye examination: CMV can involve the retina in the same patient, so ophthalmologic assessment is sensible whenever GI CMV is found.

A single organism is often not the whole story, particularly in advanced AIDS. Endoscopy is the only way to make sure a second organism is not missed when the first treatment fails. Repeat endoscopy and biopsy are warranted for bleeding, clinical deterioration, or therapy not working within the time frames above.

• Stricture formation from repeated or circumferential ulceration, which can present as progressive dysphagia even after infection has cleared.
• Gastrointestinal bleeding, from eroded vessels within ulcers.
• Perforation (rare but reported, particularly in CMV) with mediastinitis, sepsis and a high mortality.
• Malnutrition and weight loss from odynophagia severe enough to stop eating.
• Failure to clear the infection producing chronic disease, nodular or proliferative oesophagitis and long-term carriage.
• HIV recognition: infectious oesophagitis, particularly Candida, can be the event that reveals previously undiagnosed, advanced HIV disease.^[5]

Prognosis is excellent when the immune defect is reversible (a course of steroids finished, an infection treated, chemotherapy completed) or when effective antiretroviral therapy is started. In immunocompetent or mildly immunocompromised hosts HSV and Candida usually resolve with or without brief courses of treatment, and CMV episodes in the immunocompetent are rare and usually self-limiting. In people with advanced, untreated HIV or persistent transplant immunosuppression, recurrence is frequent until immunity improves; suppressive courses and switching to maintenance therapy are then worth discussing.^[2][4]

Patient advice that is both practical and low-cost:

• For anyone on inhaled corticosteroids, rinse the mouth, gargle and spit after each dose, use a spacer, and report hoarseness or white patches early. This reduces throat and gut deposition without changing the required treatment.
• Keep oral hygiene and clean dentures daily; remove and soak prostheses at night to disrupt Candida biofilms.
• Review antibiotics and acid-suppressing drugs before prescribing, using the narrowest spectrum that fits, for the shortest time.
• In HIV, effective antiretroviral therapy is the single best prevention against all forms of infectious oesophagitis; measure and monitor the CD4 count and viral load.
• Transplant and chemotherapy protocols include prophylactic antimicrobials (aciclovir for HSV, and fluconazole where local policy supports it), given before rather than after the event.

• Pregnancy. Avoid azoles, especially in the first trimester, because they are teratogenic; use amphotericin B for Candida oesophagitis.^[4] For viral disease in pregnancy, specialist advice is needed.- Children. HIV-related candidiasis in children follows the same treatment principles with weight-based dosing (see product information). CMV in neonates is a different disease (congenital) and is not covered here.
• Older adults. Candida oesophagitis is common in people over 65; in this group six-month mortality is around 47% compared with around 5% in people without oesophageal candidiasis; early diagnosis and treatment, and swallowing assessment, matter.^[3]

Where endoscopy is not available, the clinical picture is usually enough to start treatment:

• In a patient with known HIV, recent weight loss, fever and odynophagia, with or without thrush, start fluconazole if available and arrange HIV care and antiretroviral therapy; if there is no improvement within three to five days, suspect viral co-infection and refer for specialist assessment.
• HSV is suspected on the basis of oral ulcers and the typical acute odynophagia; aciclovir is inexpensive and oral.
• CMV is suspected when the patient is profoundly immunosuppressed with fever, weight loss and large oesophageal ulcers on contrast imaging or referred endoscopy; ganciclovir requires referral.
• Oral rinsing, spacer use and denture hygiene cost very little and prevent much of the disease.
• Referral for endoscopy remains appropriate when bleeding, suspicion of malignancy, or failure of empiric therapy is present, even if it takes time to arrange.

• Infectious oesophagitis is the second most common cause of oesophagitis: almost always Candida, HSV or CMV.
• It reflects failed barriers: cell-mediated immunosuppression, disturbed flora, reduced acid, altered motility, or hyperglycaemia.
• Candida gives yellow-white plaques; HSV small deep, punched-out or volcano ulcers; CMV large, deep, often linear or longitudinal ulcers with little surrounding inflammation.
• Thrush is a clue, but its absence never excludes oesophageal disease; co-infection with two or three organisms is common.
• Where classic thrush plus odynophagia are present in an immunocompromised host, give systemic antifungal therapy first and reassess within three to five days; otherwise, or on failure, scope with biopsies taken from the right place and with brushings.
• Candida: fluconazole 200 to 400 mg (3 to 6 mg/kg) daily for 14 to 21 days; escalate to echinocandins, voriconazole, itraconazole, posaconazole or amphotericin B on failure; chronic suppression 100 to 200 mg fluconazole three times weekly when needed.^[2]
• HSV: aciclovir 400 mg five times daily for two to three weeks, or aciclovir 5 mg/kg intravenously three times a day for one to two weeks if severe; alternatives famciclovir or valaciclovir; foscarnet for resistant virus.^[4]
• CMV: ganciclovir 5 mg/kg or foscarnet 90 mg/kg intravenously for three to six weeks; valganciclovir 900 mg twice daily when stable.^[3][4]- In pregnancy, avoid azoles and use amphotericin B.
• Restoring immunity (ART, reducing immunosuppression) is the real cure; drugs alone lead to relapse.

• HIV infection and advanced HIV disease
• Transplant medicine and immunosuppressive drugs
• Gastro-oesophageal reflux disease
• Pill oesophagitis and drug-induced oesophagitis
• Eosinophilic oesophagitis
• Oropharyngeal candidiasis
• Cytomegalovirus disease
• Oesophageal strictures and dilatation
• Antiretroviral therapy and immune reconstitution
• Pathogen-specific therapy for fungal infections