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Each infection or injury in this episode is explained by where the agent acts and how long it stays. Candida takes hold when local defenses fail, so unexplained disease prompts an HIV test, and severe or atypical cases are scoped before treatment. Persistent pain after Candida clears suggests cytomegalovirus, biopsied at the ulcer base, while herpes is biopsied at the ulcer edge. Chemical injury follows the chemical and contact time: alkali penetrates the esophagus, the airway comes first, nothing is given that adds injury, and endoscopy at 24 to 48 hours grades the damage and sets disposition. Survivors need stricture care and long-term cancer surveillance. Pill esophagitis is prevented by upright dosing with a full glass of water.
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Welcome to Board Pearls. This is episode two of two of the Eosinophilic and Infectious Esophagitis chapter, in the Esophageal Disorders module. This episode covers infection and chemical injury of the esophagus, through four patients. A thirty-four-year-old man with painful swallowing and thrush has Candida esophagitis that turns out to be the first sign of HIV, and then cytomegalovirus esophagitis once the Candida clears. His case teaches why Candida takes hold, when to treat empirically and when to scope, how white plaques are confirmed, and why persistent pain after treatment means a second infection biopsied at the ulcer base. A twenty-two-year-old woman with herpes simplex esophagitis after a cold sore teaches why herpes is biopsied at the ulcer edge instead. A forty-six-year-old man who swallowed drain cleaner teaches what the chemical predicts, what is done in the first hour and what must never be done, how the endoscopic grade decides where he goes, and why the injury is a lifelong condition. A seventy-four-year-old woman with doxycycline pill esophagitis teaches how the same principle of chemical and contact time applies to a single tablet.
Here's the first patient. A thirty-four-year-old man has three weeks of painful swallowing, now bad enough that he's barely drinking. He's lost twelve pounds. He has thrush on his tongue. He has no known medical history, takes no medications, and has never been tested for human immunodeficiency virus, HIV.
Painful swallowing with thrush points to Candida esophagitis, an overgrowth of Candida albicans, or less often another Candida species, on esophageal lining whose local defenses have failed. The presentation is painful swallowing, difficulty swallowing, discomfort behind the breastbone, and sometimes weight loss from eating less, which fits his twelve pounds. Thrush is present in many patients but not all, particularly in HIV, and its absence doesn't exclude esophageal disease, especially in a patient on an inhaled steroid who rinses after each dose. The first thing to ask is why Candida took hold, because the answer says what else to look for. Candida lives in the mouth and esophagus of many healthy adults. It's held in check by the antimicrobial peptides of saliva and the esophagus, by gastric acid, by peristalsis, and by intact cell-mediated immunity. Disease appears when one or more of those defenses fail.
Each risk factor is a failed defense. HIV with a CD4, cluster of differentiation four, count under two hundred cells per microliter weakens cell-mediated immunity. So do solid organ and stem cell transplantation on calcineurin inhibitors or other immunosuppression, chronic steroids whether systemic or inhaled, poorly controlled diabetes, and blood and solid cancers. Long courses of broad-spectrum antibiotics remove the bacteria that compete with Candida. Proton pump inhibitors, PPIs, lower the gastric acid that is one of the built-in antifungal barriers. And stasis, from achalasia, scleroderma, a peptic stricture, or radiation injury, keeps the organism in contact with the lining. An asthmatic on an inhaled steroid and a PPI is the typical primary care case.
He has none of those, and that absence is the clue. Esophageal candidiasis can be the first sign of HIV, the illness that establishes the diagnosis of acquired immunodeficiency syndrome, AIDS, in a previously healthy adult. So any unexpectedly severe Candida esophagitis without an obvious cause warrants an HIV test. His is positive, with a CD4 count of sixty.
That result changes how he's evaluated. An empiric fluconazole trial is reasonable in a low-risk patient with classic symptoms and oral thrush. But a patient with severe painful swallowing, immunocompromise, or atypical findings goes straight to upper endoscopy with biopsy before any antifungal is started, because a viral infection or a pill injury can produce the same symptoms and needs different treatment. He has severe pain and a CD4 count of sixty, so he goes to endoscopy.
His endoscopy shows discrete white and yellow-white plaques stuck to the lining throughout the mid and distal esophagus. They don't wash off with water, which separates them from food. They can be pushed with the scope tip but don't lift off easily, and the lining bleeds a little at the base when one is dislodged. Brushings stained with Gram, periodic acid-Schiff, or Grocott methenamine silver stain show pseudohyphae and yeast forms. Pseudohyphae are the tissue signature of Candida invasion. True hyphae would point toward Aspergillus or another mold and would reopen the diagnosis.
Brushing matters because several other conditions also turn the esophagus white. Leukoplakia is rough, keratinized lining from chronic injury or tobacco, and it can't be scraped off. Esophagitis dissecans superficialis is the squamous lining peeling off in sheets, linked to bisphosphonates, celiac disease, autoimmune blistering skin diseases, and some psychiatric drugs, and it's benign once the cause is removed. Parakeratosis is white lining associated with head and neck cancer or chronic injury. And severe cytomegalovirus can produce a thick, adherent exudate that looks like confluent Candida; there the biopsy shows inclusions in stromal and endothelial cells rather than pseudohyphae. In any white esophagus, a brushing or a biopsy decides.
With Candida confirmed, fluconazole, two hundred to four hundred milligrams daily for fourteen to twenty-one days, is first line for esophageal disease in an immunocompetent or moderately immunocompromised patient. That's a higher dose than for thrush alone, because the esophageal lining needs higher tissue levels. It's given intravenously at the same dose when the patient can't swallow or can't absorb it, and he can't swallow, so he starts it intravenously.
Fluconazole isn't enough for everyone. Echinocandins, such as caspofungin, micafungin, or anidulafungin, are kept for disease that doesn't respond to fluconazole, for severe disease in critically ill patients, and for documented or suspected azole-resistant species; Candida glabrata in particular is increasingly resistant to fluconazole. Voriconazole and posaconazole are other options when azoles fail from resistance, and amphotericin B is rarely needed now.
A week later, his thrush is gone, but swallowing still hurts badly. Candida that responds to fluconazole should be improving by now, and his mouth shows the drug is working. In a patient this immunosuppressed, persistent pain after the Candida clears means a second infection until proven otherwise, not a fluconazole failure. So he's scoped again. The plaques are gone, but there are two large, deep ulcers in the distal esophagus.
Which virus it is, and where to biopsy, have the same answer: where the virus lives. In a patient with HIV and a CD4 count under one hundred, large deep ulcers point to cytomegalovirus. The other hosts are solid organ transplant recipients, especially in the first six months when reactivation is most common, stem cell transplant recipients, and patients with chemotherapy-induced neutropenia. Cytomegalovirus ulcers may be single or multiple, are often serpiginous or geographic, sit mostly in the distal esophagus, and in severe cases join into broad areas of bare lining. They're deep because the virus infects the endothelial cells and fibroblasts beneath the lining, not the squamous cells. That's also why the biopsy has to come from the ulcer base, where the infected stromal cells are exposed. A biopsy from the edge would show inflamed squamous lining and miss the virus.
The pathologist looks for cytomegalic cells in the granulation tissue at the base: markedly enlarged endothelial cells or fibroblasts with a large, dark-staining inclusion in the nucleus surrounded by a clear halo, the owl's eye, often with a more variable ground-glass inclusion in the cytoplasm. Immunohistochemistry for cytomegalovirus antigens confirms it. His biopsies from the ulcer bases show owl's-eye inclusions. He has cytomegalovirus esophagitis, which followed his Candida.
A blood test for cytomegalovirus by polymerase chain reaction, PCR, doesn't settle it either way. A positive result supports systemic infection but doesn't prove the virus caused the ulcer, because a patient with virus in the blood can have another cause for the esophageal lesion. A negative result doesn't exclude tissue disease. The tissue makes the diagnosis.
His treatment starts with induction: intravenous ganciclovir, five milligrams per kilogram every twelve hours, for fourteen to twenty-one days. Oral valganciclovir, nine hundred milligrams daily, then completes treatment and continues as maintenance while he remains severely immunosuppressed. Intravenous ganciclovir is the standard induction for moderate to severe disease like his; oral valganciclovir alone may be reasonable for milder disease in selected outpatient transplant recipients who absorb it well. Foscarnet is the alternative for ganciclovir resistance, which can develop with prolonged ganciclovir exposure and occurs in some primary strains, and for patients whose bone marrow suppression from ganciclovir limits the dose.
He also needs an eye exam. Cytomegalovirus retinitis commonly accompanies invasive disease and threatens sight if it's missed. So any patient with documented invasive cytomegalovirus is referred to ophthalmology.
Preventing his next infection depends on antiretroviral therapy, not more antimicrobials. Restoring his CD4 count prevents recurrence far better than lifelong fluconazole, which selects for resistant Candida. Maintenance antifungal prophylaxis isn't routine after one episode; it's considered in patients with HIV whose CD4 count stays low and in transplant recipients on heavy immunosuppression with recurrent disease. He starts antiretroviral therapy, and over the next months his CD4 count climbs.
The biopsy rule for cytomegalovirus has a mirror image, and the second patient shows it. A twenty-two-year-old woman, otherwise healthy, had a cold sore a week ago and now has sudden, severe pain on swallowing. Endoscopy shows several small, shallow, well-circumscribed ulcers with raised, rolled, volcano-like edges scattered through the mid and distal esophagus.
She has herpes simplex esophagitis. Each lesion starts as a small blister that ruptures and leaves a shallow ulcer with a raised margin and a clean fibrin base. Herpes infects the squamous epithelial cells, so its ulcers are shallow, and the biopsy has to come from the heaped-up edge, where infected epithelial cells are still alive. The base is only granulation tissue, with no viable infected cells. So herpes is biopsied at the edge and cytomegalovirus at the base, for the same reason: that's where each virus lives.
Under the microscope, the epithelial cells at the edge show three nuclear changes: multinucleation, margination of chromatin, and nuclei molded against each other. Cowdry type A inclusions sit inside the nucleus as pink globules surrounded by a clear halo. Multinucleated giant cells with those features are diagnostic. When the histology is suggestive but not definitive, immunohistochemistry for herpes simplex types one and two confirms it, and viral culture or PCR of the biopsy tissue supports it. Her edge biopsies show multinucleated cells with Cowdry type A inclusions.
Herpes esophagitis is mainly a disease of transplant recipients and patients on chemotherapy, but it also occurs in healthy young adults like her, often after a cold sore or lip lesion, and in them it's usually self-limited. In an immunocompetent patient, treatment is acyclovir two hundred milligrams five times a day or four hundred milligrams three times a day for seven to ten days, and many cases resolve without antivirals if she can be supported through the pain. She takes the shorter acyclovir course and recovers within days. In an immunocompromised patient, treatment is acyclovir four hundred milligrams five times a day for fourteen to twenty-one days, or intravenous acyclovir, five to ten milligrams per kilogram every eight hours, when the patient can't swallow or has severe disease. Foscarnet covers acyclovir-resistant herpes, which is uncommon but increasingly recognized in heavily immunosuppressed patients with prior acyclovir exposure.
The two viruses don't always arrive separately. A heavily immunosuppressed patient can have both on biopsy, and then both regimens are given. And when biopsies are negative but suspicion stays high in an immunocompromised patient with severe pain, treatment can start while pathology and immunohistochemistry are pending.
Infection is one way the esophageal lining fails; chemical injury is the other, and it follows a single rule. In both caustic ingestion and pill injury, the depth and extent of damage depend on the chemical and on how long it touches the lining. The agents differ, a corrosive liquid or a slowly dissolving tablet, and so do the contact times, but management in each case limits further contact, assesses the depth, and follows the long-term consequences of a deep wound. The third patient is the severe end of that rule. A forty-six-year-old man reached for a water bottle in his garage and took a large mouthful of liquid drain cleaner that a neighbor had stored in it. He spat some out but swallowed some. He arrives an hour later drooling, with chest pain and a hoarse voice. His lips and mouth have white patches.
He has a caustic ingestion, and what he swallowed comes first, because the chemistry predicts where the injury is and how deep it goes. Drain cleaner is a strong alkali, sodium hydroxide, commonly called lye; potassium hydroxide is the other common one, and oven cleaners and some industrial cleaners contain them too.
Alkali causes liquefactive necrosis. It turns the fats in cell membranes into soap and dissolves structural proteins, so nothing stops it at the surface. It keeps penetrating, through the mucosa and the muscle toward the mediastinum, until tissue fluids buffer it. It hits the esophagus hardest, because it passes the mouth and throat quickly and concentrates in the esophagus, and once it reaches the stomach, gastric acid partly neutralizes it and limits gastric injury. For him, that chemistry predicts deep esophageal injury.
Strong acid behaves differently, which is why the label matters. Hydrochloric, sulfuric, and phosphoric acids are found in toilet bowl cleaners, pool chemicals, and some battery products. They cause coagulative necrosis: they denature proteins into a crust, an eschar, that often limits deeper penetration. Acid also moves through the esophagus faster and pools in the stomach and at the pylorus, where the narrow outflow concentrates it. So as a rule, alkali injures the esophagus and acid injures the stomach, though a severe ingestion of either can injure anywhere.
Two common household exposures fall outside that rule. Liquid bleach, around five percent sodium hypochlorite, is a frequent ingestion in children and in deliberate ingestions, and it rarely causes severe esophageal injury, because it's too dilute and more irritant than caustic. A swallowed button battery in a child is a separate emergency: the battery generates hydroxide at its negative pole, causes rapid alkaline injury within hours, and needs urgent endoscopic removal.
His first priority is the airway, ahead of breathing and circulation. Swelling of the throat and larynx can progress fast after a caustic ingestion. Drooling, stridor, a changed voice, or extensive burns in the mouth and throat mean the airway is threatened, and intubation is done early, before the swelling makes it difficult or impossible. He's drooling and hoarse, so he's intubated now. Then he's kept nothing by mouth, with intravenous access, fluid resuscitation, and pain control.
What isn't done matters as much, and each prohibition has a reason. No emetics, because vomiting brings the caustic back over the injured esophagus and can perforate weakened tissue. No neutralizing agents, such as a weak acid for an alkali or a weak base for an acid, because neutralization releases heat and adds a thermal burn to the chemical one. No blind nasogastric tube, because it can trigger retching and vomiting and perforate injured lining; a feeding tube can be placed under direct vision during the staging endoscopy when nutrition access is needed. No activated charcoal, because it doesn't work for caustics. And no routine antibiotics; they're given only for documented or strongly suspected perforation or aspiration.
Once he's stable, the next decision is whether and when to scope, because depth decides everything that follows. Endoscopy is done within twenty-four to forty-eight hours of the ingestion, to see how deep the injury is and how far it extends. It's contraindicated in a patient who is hemodynamically unstable, has signs of perforation, is in severe respiratory distress, or has throat swelling and necrosis too severe for safe instrumentation. In those patients, computed tomography, CT, is the imaging test, and surgery is consulted directly. He's stable on the ventilator, with no signs of perforation, so he's scoped the next morning.
The endoscopic findings are graded with the Zargar classification. Grade zero is normal lining. Grade one is swelling and redness. Grade two A is superficial ulceration, with bleeding, blisters, or white exudate. Grade two B is deep ulceration, focal or circumferential. Grade three A is focal necrosis, and three B is extensive necrosis. Grade four is perforation.
The grade decides where the patient goes and how he does. Grades zero and one get a liquid diet advanced as tolerated, observation, and outpatient follow-up. Grade two A is similar, with a longer period of observation. Grade two B and grade three go to the intensive care unit, ICU, nothing by mouth, with parenteral nutrition or a nasojejunal feeding tube, often placed endoscopically past the injury, and surgery is consulted. Grade three B carries high mortality, because the necrosis extends through much of the wall, and esophagectomy is sometimes needed for dead tissue or established perforation. Grade four is established perforation and a surgical emergency.
His endoscopy shows deep circumferential ulceration in the mid and distal esophagus: grade two B. He goes to the ICU, and a feeding tube is placed past the injury during the same endoscopy.
Medicine adds little once the injury is graded. A PPI reduces acid's contribution to ongoing injury and helps healing, and sucralfate is sometimes added. Systemic steroids have been studied repeatedly to prevent strictures after grade two B injury, and the evidence doesn't support routine use, though some centers still use them selectively for grade two B after weighing benefit and risk. They're never used for grade three, because they impair healing and raise the risk of infection. Topical mitomycin C during early dilation has been used to reduce stricture recurrence in some pediatric series but isn't standard adult care. So he gets a PPI, nutrition through his tube, and time.
His recovery doesn't end at discharge, because a caustic ingestion is a lifelong premalignant condition, and he needs counseling about that, ongoing surveillance, and care with a gastroenterologist indefinitely. The first long-term problem is stricture. It develops in about a third of patients with grade two B injury and most with grade three, usually two to eight weeks after the ingestion, as the lining heals with scar. It's treated with gradual endoscopic dilation, often repeated over months to years. Strictures that keep coming back may need steroid injection or a stent, and esophagectomy with reconstruction is kept for strictures that can't be dilated or that leave the patient unable to eat enough. He develops a mid-esophageal stricture five weeks later and needs four dilations over six months before he can eat normally.
The second long-term problem is cancer. Squamous cell carcinoma develops in the scarred esophagus after a long latency, typically twenty to forty years after the injury, at a risk reported in some series as about a thousand times that of the general population. The cause is chronic inflammation, scarring, and dysplasia in the regenerating squamous lining. So a patient with significant initial injury needs surveillance endoscopy starting about fifteen to twenty years after the ingestion and continuing after that. For him, that means surveillance starting in his early sixties, and he needs to understand why, because he'll feel well for a long time before it matters.
Pill esophagitis is the same rule at small scale, and the fourth patient shows it. A seventy-four-year-old woman takes doxycycline for a skin infection. Last night she took it at bedtime with a sip of water and lay straight down. This morning she has sudden, sharp pain behind the breastbone every time she swallows, with some difficulty swallowing.
She has pill esophagitis: a tablet that lodged against the esophageal wall dissolved there and injured the lining where it sat. The dissolved drug injures the surface, and into the lamina propria with longer contact, in one of three ways. Some drugs are acidic when dissolved: doxycycline and tetracycline, the most common culprits because they're widely prescribed, plus ferrous sulfate and ascorbic acid. Some are concentrated enough to injure, like extended-release potassium chloride. And some are directly toxic: nonsteroidal anti-inflammatory drugs, NSAIDs, aspirin, oral bisphosphonates such as alendronate, risedronate, and ibandronate, clindamycin, quinine and quinidine, and the oral anticoagulant dabigatran.
Her risk factors are both behavioral and anatomical. A pill taken with a sip of water instead of a full glass stays poorly hydrated and sticks as it dissolves. A pill taken lying down, or just before lying down, loses gravity as a propellant. Older adults are overrepresented, with more pills, less saliva, and more time lying down. Achalasia, scleroderma, ineffective esophageal motility, and pre-existing strictures or rings prolong contact at the abnormal segment. The pill sticks most often at the level of the aortic arch, where the left mainstem bronchus indents the esophagus, and sometimes at the lower esophageal sphincter, where peristalsis slows.
Her history usually makes the diagnosis before any scope, so the questions are about the pill, the volume of water, and her posture. Symptoms classically begin hours to days after the pill. When endoscopy is done, it shows discrete, often shallow ulcers with normal lining between them, and the classic pattern is a kissing pair facing each other on opposite walls where the tablet sat between them. The biopsy shows ulceration with mixed inflammation including neutrophils and reactive epithelial change, without the eosinophils of eosinophilic esophagitis or the viral inclusions of herpes and cytomegalovirus.
Her treatment removes the cause and protects the lining while it heals. The doxycycline is stopped and her skin infection is treated with another drug. Sucralfate slurry coats the injured lining and speeds healing. Viscous lidocaine and systemic pain relief help in the first days, and a brief course of a PPI is added if the ulcer is severe or reflux is contributing. Symptoms usually resolve within one to two weeks. Prevention is the real treatment: take pills upright, with at least eight ounces, about two hundred forty milliliters, of water, and stay upright for at least thirty minutes after the dose. In patients with a motility disorder or stricture, a different formulation or a different way of giving high-risk drugs is considered. If pill esophagitis recurs in the same patient, the next step is to look for a motility disorder or a stricture that's holding pills up.
Here are the traps the boards set in these patients.
In Candida, missing HIV in a patient with unexplained esophageal candidiasis is the first trap. Giving empiric fluconazole to a severely immunocompromised patient, or to one with severe pain or atypical findings, skips the endoscopy that would find a viral or pill cause. Using the thrush dose of fluconazole undertreats esophageal disease. And lifelong fluconazole in HIV selects for resistance, when antiretroviral therapy is what prevents recurrence.
In the viruses, calling persistent pain after Candida treatment a fluconazole failure misses the second infection. Biopsying the edge of a cytomegalovirus ulcer or the base of a herpes ulcer samples the wrong cells. Relying on blood cytomegalovirus PCR, instead of tissue, can both overcall and miss esophageal disease. And forgetting the eye exam in invasive cytomegalovirus risks blindness from retinitis.
In caustic ingestion, delaying intubation in a patient with drooling, stridor, or a changed voice lets the airway close. Giving an emetic, a neutralizer, charcoal, or a blind nasogastric tube adds injury or does nothing. Scoping a patient with suspected perforation, instability, or severe airway swelling is dangerous, and CT with a surgical consult is the alternative. Sending a grade two B or three injury home, or giving steroids for grade three, are both errors. And forgetting that stricture follows within weeks and cancer decades later leaves the patient without dilation or surveillance.
In pill esophagitis, missing the bedtime pill taken with a sip of water misses the diagnosis. And in a patient whose pill esophagitis recurs, missing the motility disorder or stricture behind it leaves the cause in place.
So, start to finish.
Candida grows when the defenses fail: HIV with a CD4 count under two hundred, transplant, steroids including inhaled ones, diabetes, cancer, antibiotics, PPIs, and stasis. Unexplained disease needs an HIV test. A low-risk patient with thrush can have an empiric trial, but severe pain, immunocompromise, or atypical findings go to endoscopy first. Adherent white plaques with pseudohyphae are Candida, treated with fluconazole two hundred to four hundred milligrams daily for two to three weeks, with echinocandins for resistance or critical illness. Long-term prevention in HIV is antiretroviral therapy.
Cytomegalovirus infects the stroma, so its ulcers are large and deep, the biopsy comes from the base, and owl's-eye inclusions make the diagnosis. Treatment is intravenous ganciclovir and then valganciclovir, with an eye exam. Herpes infects the epithelium, so its ulcers are shallow with raised edges, the biopsy comes from the edge, and multinucleated cells with Cowdry type A inclusions make the diagnosis. Treatment is acyclovir. Foscarnet covers resistance to either drug.
In chemical injury, the chemical and the contact time set the depth. Alkali penetrates deeply and injures the esophagus; acid forms a crust and injures the stomach. The airway comes first, and emetics, neutralizers, charcoal, and blind tubes are never given. Endoscopy at twenty-four to forty-eight hours grades the injury unless the patient is unstable or perforated, and grade two B and higher go to the ICU with surgical input. Steroids aren't routine and are never given for grade three.
Survivors face strictures within weeks and squamous cell cancer decades later, so surveillance starts fifteen to twenty years out. Pill esophagitis follows a specific drug taken with too little water or before lying down: stop the drug, coat the ulcer, and teach upright dosing with a full glass of water.
That completes the esophagus. The next chapter moves to the stomach: peptic ulcer disease and Helicobacter pylori, from diagnosis through first-line and salvage treatment.