The Spectrum of Esophagitis in Patients Living with HIV—A Scoping Review

Abstract

Esophageal lesions are common findings in disorders of the digestive tract in patients living with HIV, the most typical symptoms being odynophagia and/or dysphagia. This article provides a narrative review of the spectrum of esophagitis in patients living with HIV, focusing on fungal, viral, bacterial and non-infectious etiologies, as well as co-infections with viral hepatitis viruses. The article provides a comprehensive approach to the strategy of diagnosis and the role of upper digestive endoscopy and histopathological examination in the evaluation of esophageal pathology in patients living with HIV.

Introduction

The epidemiological profile of the human immunodeficiency virus (HIV) infection is in a continuous dynamic. With improved diagnostic and improved access to highly effective antiretroviral treatment (ART), a total of 39.9 million people are reported to be living with HIV worldwide [1].

Highly active antiretroviral therapy (HAART) is an evolving concept, which has revolutionized HIV care and has transformed HIV into a chronic, manageable infection. However, despite important improvements in diagnosis and screening rates in recent years, many newly diagnosed patients still present late, with the European Center for Disease Prevention and Control (ECDC) reporting that 50.6% of all new cases in 2022 were classified as late presenters [2]. Late presenters and patients who disengage from care are at risk of progression of HIV infection, which in turn associates the risk of developing opportunistic infections (OIs). OIs represent the hallmark of advanced stages of HIV infection and are the most frequent causes of morbidity and mortality in patients with advanced HIV infection.

Predictive factors in the occurrence of esophagitis

Several factors may contribute to the pathogenesis of esophagitis in patients living with HIV. On the one hand, they can develop any kind of esophageal disorder seen in the general population, for example, gastroesophageal reflux disease (GERD), and on the other hand, in the presence of immunosuppression as seen in patients with advanced HIV infection, they are at risk for opportunistic causes of infectious esophagitis, which commonly occur when the CD4 T lymphocyte levels are below 200 cells/µL; a CD4 cell count below 100 cells/µL further represents a risk factor for idiopathic HIV esophagitis [3].

Main types of esophageal lesions in patients living with HIV

Many patients living with HIV will experience upper gastrointestinal symptoms at some point during the course of the disease but a lot of these symptoms are non-specific and multifactorial (pyrosis, dyspepsia, anorexia, weight loss). The most typical symptoms of esophagitis are odynophagia (retrosternal pain with swallowing) and/or dysphagia (difficulty with ingestion of food from the oropharynx through the esophagus). Indications for upper endoscopy in patients living with HIV are reviewed in Figure 1.

In patients living with HIV, esophageal lesions can result from a variety of infectious, neoplastic, and idiopathic conditions. The main etiologies of esophageal lesions include fungal, viral, bacterial, neoplastic or idiopathic causes (Figure 2) [3,4,5,6,7,8].

Fungal causes of esophagitis

Candida esophagitis.

Fungal causes of esophagitis include Candida spp., which is the most common cause of esophagitis in patients living with HIV, particularly those with advanced HIV infection, as well as the most common cause of infectious esophagitis in the general population [9]. In healthy individuals, this yeast is a normal part of the microbiota of the gastrointestinal and genital tracts. However, in patients with antibioticassociated dysbiosis, or in those with immunosuppression, Candida can overgrow and invade the mucosa, generating infection.

Esophageal candidiasis typically presents with odynophagia and dysphagia and may be accompanied by oral candidiasis. Retrosternal pain in patients with oral candidiasis should prompt further investigation to rule out Candida esophagitis, particularly in the presence of specific risk factors, such as HIV infection, immunosuppression, diabetes, chronic corticosteroid treatment, or chronic treatment with proton pump inhibitors [9,10]. However, the absence of thrush should not rule out a diagnosis of Candida esophagitis. In a report by Bonacini et al., 38% of the patients with Candida esophagitis did not present concomitant thrush [6].

The endoscopic features of Candida esophagitis are very distinctive, showing white or pale yellowish plaque-like lesions and exudates that cling to the esophageal mucosa. Confirmation is achieved histologically by obtaining biopsies or brush samples that reveal the presence of yeast and pseudohyphae infiltrating the mucosal cells.

Prior to the introduction of HAART, the rate of endoscopic findings suggestive for Candida esophagitis in patients living with HIV was reported to be as high as 42% [11]. In a previous study performed in our center, 88 patients were evaluated endoscopically and among them 31.5% had Candida esophagitis and 8.1% had esophageal ulcers associated with herpes simplex or CMV [7]. Another study, involving 629 patients with esophageal disease linked to HIV, refractory to initial antifungal treatment, found that Candida was the predominant cause, detected in 21.9% of the cases [12]. In a comparative study by Takahashi et al., the prevalence of Candida esophagitis was reported to be 11.2% in patients living with HIV, compared to 2.9% in the general population [13]. The number of cases of esophageal candidiasis in patients living with HIV may be underestimated as in many cases presenting with odynophagia or dysphagia, empirical treatment may be initially instituted and upper endoscopy postponed for a later time, only in case of unfavorable response to treatment.

Interestingly, in the study by Takahashi et al., patients living with HIV displayed a higher burden of symptoms, in particular for the following complaints: retrosternal burn, hunger cramps, nausea, early satiety, odynophagia, dysphagia, and belching. While none of these symptoms was directly predictive of Candida esophagitis in this patient population, overall higher symptom scores were reported when compared to patients without HIV infection [13].

Candida albicans remains the predominant species implicated in fungal esophagitis. However, other non-albicans species, such as Candida glabrata [6,14], Candida krusei [6], and Candida nivariensis[15] are increasingly being reported.

Other fungal causes of esophagitis

Apart from Candida spp., other fungi such as Histoplasma capsulatum can occasionally cause esophageal lesions. The geographical distribution of Histoplasma esophagitis follows the epidemiology of the pathogen, which is rarer in Europe, and more frequent in the Americas. The features of Histoplasma esophagitis include nonspecific symptoms that generally occur in the presence of systemic symptoms suggestive of disseminated histoplasmosis, occurring in a patient with immunosuppression. Upper endoscopy can reveal ulcerative lesions that may appear as deep, necrotic ulcers [16]. Early recognition and treatment are essential, as the condition can be severe, especially in immunocompromised patients.

Viral causes of esophagitis

The main culprits of viral esophagitis among patients living with HIV include herpes simplex virus (HSV) and cytomegalovirus (CMV). The hallmark of HSV esophagitis is represented by endoscopic findings of vesicles and ulcers, while CMV esophagitis usually shows large linear ulcers.

Herpetic esophagitis

The causative organism of herpetic esophagitis is almost always HSV type-1 although HSV-2 has been occasionally identified [17]. Patients commonly exhibit symptoms such as odynophagia and dysphagia, with the typical onset of HSV infection being sudden and severe. Fever, nausea, vomiting and heartburn are less frequent. Intractable hiccups have been reported in connection with HSV esophagitis [18]. Some patients may have concurrent herpes labialis or ulcers in the oropharynx but the absence of cutaneous HSV lesions does not preclude the diagnosis of esophagitis.

In a historical (1991) study by Bonacini et al. involving 110 patients living with HIV who were diagnosed with ulcerative esophagitis, HSV was identified through viral culture in 23.3% of cases, while CMV in 76.7% of the cases [6]. Among individuals with advanced acquired immunodeficiency syndrome (AIDS), Candida is frequently cited as the primary cause of esophagitis, whereas cytomegalovirus (CMV) is commonly identified as the leading viral etiology [12]. Importantly, the cited study by Bonacini et al. has also highlighted a high rate of coinfections in historical cohorts of patients living with HIV; specifically, 45.8% had fungal esophagitis alone, 20.8% had viral esophagitis alone, while the remaining 33.4% had double etiology, fungal and viral [6].

Typically, the diagnosis of HSV esophagitis relies on endoscopic observations which are further validated through histopathological examination. HSV esophagitis is marked by numerous, well circumscribed, small (<2 cm in size) ulcers, often with apparently normal adjacent mucosa. These lesions are primarily found in the mid to distal esophagus. Although this initial phase is seldom observed during endoscopic examination, vesicles or bullae help differentiate HSV from CMV esophagitis. Another differentiating element is that the ulcers in CMV esophagitis are deeper and tend to be linear or longitudinal. Biopsies or brushings are mandatory because CMV esophagitis frequently presents with symptoms that can overlap with those of HSV esophagitis, and antiviral treatment is different for these two etiologies. It is advisable to obtain up to ten biopsies, preferably from the periphery of an ulcer. Histological examination typically reveals multinucleate giant cells with ground-glass nuclei and intranuclear eosinophilic inclusions, occupying approximately half of the nuclear volume [19]. Immunohistochemical staining for HSV glycoproteins can provide additional diagnostic assistance [19], but is not commonly used in routine clinical practice. In certain instances, qualitative and quantitative polymerase chain reaction (PCR) testing may be employed to detect HSV DNA in tissue specimens.

Cytomegalovirus esophagitis

Cytomegalovirus (CMV) stands as the predominant viral opportunistic infection in patients with advanced HIV infection. The majority of CMV disease instances arise in the context of significant immunosuppression, typically characterized by very low CD4 cell counts, often below 50 cells/µL [20]. The hallmark of CMV disease includes CMV retinitis, as well as extraocular disease. In a comprehensive multinational prospective study conducted in Europe, the occurrence and outcomes of invasive CMV disease were investigated among patients with AIDS, both before and after the advent of ART. Out of a total of 8556 patients, 707 (8.3%) were diagnosed with CMV disease, and among these, 449 (63.5%) had CMV retinitis. Among extraocular CMV disease, the gastrointestinal tract was reported as the leading location of disease (reported in up to 66% of extraocular cases), followed by the CNS (in 17% of cases) [21]. As patients diagnosed with extraocular CMV disease frequently exhibit concurrent CMV retinitis, ophthalmologic assessment should be performed in all individuals with CMV disease, regardless of the site involved.

CMV esophagitis is one of the clinical syndromes classified under gastrointestinal disease. It typically manifests with symptoms such as odynophagia and dysphagia. Additionally, patients may experience fever, nausea, and epigastric pain. Upper endoscopy may reveal large, linear, well-demarcated, deep, single or multiple esophageal ulcers. These ulcers commonly appear in the mid to distal portion of the esophagus and may be accompanied by mucosal edema and nodularity. Histopathological analysis typically reveals cytomegalic cells, which are large cells containing eosinophilic intranuclear inclusions and often basophilic intracytoplasmic inclusions. These cells are identified within the densely inflamed granulation tissue at the base of the ulcer. In cases where CMV esophagitis is suspected, it is recommended to obtain multiple deep biopsies from the central base of the ulcerated lesion for further examination. Serological studies may be unreliable in the extremely immunosuppressed. The presence of anti-CMV IgM antibodies may indicate recent infection, but can also persist for several years following acute infection. Their presence cannot confirm tissue invasive disease. Furthermore, antibodies can be absent in patients with marked immunodepression. IgG antibodies, while commonly found in adults, offer limited diagnostic utility. In cases where typical histological lesions are observed, a tissue CMV PCR test may aid diagnosis [22].

Bacterial esophagitis

The relative incidence of bacterial esophagitis in patients with HIV infection remains underexplored, with current literature reporting only sporadic cases. In the context of immunosuppression, invasive bacterial esophagitis has been documented in 11% to 16% of infectious esophagitis cases [6].

The bacteria implicated in these infections may belong to the oropharyngeal flora, (Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus viridans), or may be opportunistic pathogens such as Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) [23]. In certain cases, a polymicrobial etiology can also be observed. Additionally, in patients with AIDS, instances of esophagitis caused by Actinomyces israelii complex and Nocardia asteroides have been documented [23]. In certain cases, a polymicrobial etiology can also be observed.

In 1999, Mastroiani et al. published a report of three patients with HIV infection who had been diagnosed with esophagitis following upper digestive endoscopy. The three patients were all young, male, and consumed drugs, they presented with odynophagia and/or dysphagia, and had CD4 counts <50 cells/µL. Endoscopic lesions were located in the distal third of the esophagus. Cultures from the biopsies were negative for viruses, fungi, and mycobacteria, but positive for Proteus mirabilis in two cases, and polymicrobial in the third case, with the presence of Stenotrophomonas maltophilia, Serratia spp., and Staphylococcus aureus [8].

The endoscopic presentation of bacterial esophagitis can range from nonspecific inflammatory changes, such as hyperemia and mucosal friability, to more severe manifestations including exudates, erosions, and ulcerations. Although cultures from biopsies can be performed, this method is not consistently available. Nevertheless, it has been suggested that simultaneous blood cultures and esophageal tissue cultures can confirm the esophagus as the primary source of bacterial infection. Moreover, identifying bacteria within the subepithelial tissues or deeper layers of the esophagus, in the absence of other microorganisms or neoplastic infiltration, may be considered diagnostic for bacterial esophagitis.

Neoplastic lesions

Neoplastic lesions include Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and different types of carcinomas. Kaposi’s sarcoma is an AIDSdefining illness that can also affect the esophagus in its visceral form, presenting as red to purple vascular lesions. Non-Hodgkin’s lymphoma is also an AIDS-defining malignancy that can involve the esophagus, often presenting with mass lesions or ulcerations. Squamous cell carcinoma and adenocarcinoma are not directly associated with HIV infection, but are seen with increased frequency in patients with immune suppression.

Since the advent of HAART, a shift has been seen from AIDS-defining cancers to non-AIDSdefining ones. The results of a retrospective study from Tanzania, which included 3398 patients with HIV, reported a prevalence of 72% of nonAIDS defining cancers, the most common neoplasia being esophageal cancer (11.1%), while AIDS-defining cancers represented 28%, with Kaposi’s sarcoma as the dominant pathology (13.2%) [24].

Data from a retrospective cohort study of American veterans showed that for patients with HIV infection there is a higher risk of developing esophageal squamous cell carcinoma, especially for CD4 cell counts below 200 cells/µL, while for esophageal adenocarcinoma, the risk is similar to that of patients without HIV infection [25].

Other causes of esophageal lesions

Idiopathic esophageal ulcers

Idiopathic esophageal ulcers refer to a clinical syndrome characterized by large ulcerations in the esophagus, observed primarily in patients with HIV infection. These ulcers tend to occur during severe immunodeficiency, typically when CD4 cell counts drop below 50 cells/µL, in the absence of an identifiable infectious agent. The pathogenesis of idiopathic esophageal ulcers may involve immune dysregulation associated with HIV or direct involvement of the virus itself. Bei et al. have reported a strong association between HIV infection and giant idiopathic esophageal ulcers in patients with AIDS, with HIV detected in ulcer samples from the majority of cases [26]. Symptoms commonly observed in these patients include odynophagia, substernal chest pain, and weight loss. Given the broad differential diagnosis for esophageal ulcerations in patients with HIV, endoscopic evaluation is essential for accurate diagnosis and to rule out other potential causes.

Esophageal strictures

Esophageal strictures are rare complications of ulcerative esophagitis secondary to opportunistic infections in patients living with HIV. In a study conducted by Wilcox et al., 160 patients with HIV and esophageal ulcers were identified, with approximately 8% of them presenting esophageal strictures [27].

Gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is common in the general population, but also affects patients living with HIV, potentially leading to erosive esophagitis when left untreated.

Drug-induced esophagitis

Different medications used to treat HIV infection, opportunistic infections, or patient comorbidities, can cause drug-induced esophagitis, which presents with esophageal irritation and ulceration.

Historically, the first antiretrovirals commonly produced digestive adverse effects such as nausea or vomiting, and some were also associated with esophagitis in isolated cases. For example, esophageal ulcerations and druginduced esophagitis were reported in patients receiving zidovudine or zalcitabine [28]. However, neither GERD nor erosive esophagitis have been reported to be associated with specific antiretrovirals (ARVs) [29]. Boosting agents such as ritonavir or cobicistat may be associated with gastrointestinal intolerance manifesting as nausea and diarrhea, but no cases of esophagitis have been reported. Among currently used ARVs, reports of esophagitis remain extremely rare.

Patients living with HIV may experience polypharmacy, cumulating several other chronic medications in addition to ART. These concomitant medications can at times induce additive toxicities. Several drug classes have been reported to be associated with drug-induced esophagitis, including but not limited to: antibiotics such as tetracyclines, clindamycin, or co-trimoxazole; nonsteroidal anti-inflammatory drugs such as aspirin, ibuprofen, naproxen, or indomethacin; bisphosphonates; anticholinergics; as well as oral potassium or iron supplements, especially in extended-release formulations, or when not taken with adequate water [30].

Esophageal pathology in patients living with HIV and viral hepatitis

Patients living with HIV may associate coinfections with viral hepatitis viruses, in which case there is a risk of accelerated progression of liver fibrosis, with advanced or end-stage liver disease occurring earlier in the course of infection, and with increased risk of development of hepatocellular carcinoma. Esophageal varices can be the hallmarks of advanced liver disease, with the occurrence of portal hypertension. These varices can carry a risk of bleeding and can prove to be important causes of morbidity or even mortality in these patients. Splenomegaly identified on ultrasound exam, increased liver stiffness along with the presence of esophageal varices on upper endoscopy are very useful markers of portal hypertension and advanced liver disease [25].

Highly effective antivirals are now widely available for the treatment of viral hepatitis. With these therapeutic instruments, HBV infection can now be well controlled, HCV infection can be cured, and HDV can be better managed. However, the management of infection with hepatitis viruses is most effective when started earlier during the course of infection, ideally before the occurrence of liver disease and of significant fibrosis. This advocates for universal screening against hepatitis viruses in patients living with HIV, in order to institute early treatment and prevent progression of liver disease.

Conclusions

In patients living with HIV, the differential diagnoses for upper digestive symptoms such as dysphagia, odynophagia or retrosternal pain should include fungal, viral or bacterial infections, as well as neoplasias, idiopathic ulcers, strictures, gastroesophageal reflux disease or druginduced esophagitis. Diagnosis of esophageal lesions typically involves endoscopy with biopsy and, in certain instances cultures, to determine the exact cause and the appropriate treatment. The management of these lesions depends on the underlying etiology, with antifungal, antiviral, antibiotic, or antineoplastic therapies being used accordingly.