REVIEW Herpes esophagitis: a comprehensive review Thievvy Ginkreau ’, Flove Roxenbey’, Olivier Bouchaud”, Claudie Mavche4 and Olivier Lovtholary” ‘Service de Mkdecine Interne, La Salpgtri&re,Paris, ’Service de Bactkriologie-Virologie-Hygi&ie, H6pital Saint-Vincent-de-Paul, Paris, 3Service des Maladies Infectieuses et Tropicales, Groupe Hospitalier Bichat-Claude-Bernard, Paris, 4Service d’Anatomopathologie, Groupe Hospitalier Bichat- Claude-Bernard, Paris, and 5Service de MCdecine Interne, H6pital Avicenne, Universiti. Paris Nord, Bobigny, France Key words: Herpes simplex virus, esophagitis, immunodepression INTRODU CTl ON POPULATIONS AT RISK Herpes esophagitis (HE) was first described by Pearce Several types of immunodeficiencies have been and Uagradi in 1943 [I]. For 30 years the diagnoses described as risk factors for HE (Table l), but cellular were made in post niortern studies of immuno- iniinunity is the key factor for the control of herpes compromised patients 12-41. Then, the developement simplex infection, while the role of antibodies and of endoscopy allowed an earlier diagnosis [5,6]. complement is less important [I 6,171. Thus, patients HE is a well-known complication of imniuno- with quantitative defects of T-lymphocytes are particu- depression, and the esophagus is the viscus most often larly prone to develop HSV infections. Indeed, we involved during the dissemination of herpes simplex recently reported such a complication during the late virus (HSV) infection 171. HE is observed in up to 5% stages of HIV infection [18]. Qualitative defects of T- of patients treated for malignant hematologic diseases lymphocytes also represent a risk factor; this is parti- [8], 1-6% of solid organ transplant recipients [9,10] and cularly true for liver and renal transplant patients [19]. 10-1 5% of bone marrow-transplanted patients [ll]. Furthermore, cellular immunodepression favors the HE is also an AIDS-defining condition [12] and a presence of HSV in the saliva [ZO], which may be a frequent site of disseminated neonatal HSV infection potential source of esophageal infection during swallow- [13,14]. Interestingly, HE has also been anecdotically ing [7,21]. described in imniunocoinpetent patients, in whom it is Corticosteroids and anticancer chemotherapy are a self-limited illness [15]. We give here an extensive also well-known risk factors for visceral HSV infection review of HE, including its pathophysiology, clinical [7]. Indeed, corticosteroids are able to inhibit the manifestations, treatment and outcome. activation, proliferation, differentiation and functions of virtually all cells involved in the immune response, but particularly T-cell proliferation [22-241. Anti- cancer chemotherapy and radiotherapy have imniuno- suppressive effects but are also associated with the Corresponding author and reprint requests: loss of normal esophageal mucosal integrity, which 0. Lortholary, Service de Medecine Interne, enhances the risk of HSV reactivation [25]. HBpital Avicenne, Universite Paris Nord, Previous upper digestive tract endoscopy or 125 Route de Stalingrad, 93009 Bobigny, France insertion of gastric tube are reported in 33-7 1% of cases Tel: 33 1 48 95 54 51 Fax: 33 1 48 95 54 50 during the weeks before HE [4,7,18,26]. Nasogastric e-mail: [email protected] intubation may favor the development of HE by Accepted 12 March 1997 trauma and/or viral autoinoculation 17,271. However, 397 398 Clinical Microbiology and Infection, Volume 3 Number 4, August 1997 Table 1 Populations at risk for HE associated with an increased frequency of HSV reacti- vation, including HE [32]. Hematologic malignancies, with or without neutropenia [6-8,27,62,65,75,79,82,87,95,97,102,107.109,117,118] Solid tumors [3,7,27,57,62,65,68,78,87,88,97,102,107,116, Herpes esophagitis during bone marrow transplantation 119,120] There is no significant difference in HE incidence Systemic or inflanimatory diseases [24]: systemic lupus between autologous and allografted bone marrow erytheniatosus [62,120,121], recipients [33].Prior to the prophylactic use of acyclovir, Wegener’s granulomatosis [7,62], polyarteritis nodosa [7], giant cell arteritis [27], rheumatoid arthritis [27,68.75,102], 80% of seropositive patients excreted HSV during the polymyositis [102], Crohn’s disease [7,62], ulcerative colitis first SO days after bone marrow transplantation, with a [57], rapidly progressive glomerulonephritis [7], tuberculosis [2] peak excretion during the second or third week 1331. HIV infection [18,27,38-44,62,55,92,102,107,109,120] By contrast, fewer than 2% of seronegative patients Extensive burns (271-Recent trauma (71 excrete HSV after transplantation, suggesting that Alcoholism [102,120] Diabetes mellitus [27,57,102,120,122] HSV infection after transplantation is mostly due to Cystic fibrosis [lZO] reactivation [33,34]. During a prospective study of 44 Heart insufficiency [57] episodes of unexplained nausea and vomiting after Renal insufficiency 1781 allogeneic bone marrow transplantation, Spencer et a1 Gastro-esophageal acid reflux [29,78,120] [31] documented HE in five cases occurring 1-4 Mental retardation [123] Iatrogenic factors months after transplantation. HSV infection was less Radiation therapy (particularly for mediastinal tumors) common than cytomegalovirus (CMV) infection in [6,27,75,87,102,119] two series [11,31], probably because of the frequent Solid organ transplantation-cyclosporin [ 19,Z7,62,107,124-127] use of prophylactic acyclovir. Among 39 bone marrow Bone marrow transplantation [80,95,102,109] transplant recipients, 21 had infectious esophagitis, Anti-CD3 monoclonal antibodies [32] Immunosuppressive agents: cyclophosphamide, azathioprine including six isolated HE cases and four co-infections [68,120] with CMV or Candida sp. HE occurred mostly in non- Systemic steroid therapy [27,57,68,75,87,102,120,12 11 neutropenic patients within a mean of 72 days after Inhaled steroids [128] transplantation and earlier than fungal esophagitis [ 111. Recent surgery [129]-trigeminal nerve surgery [21] Surveillance cultures of the oropharynx obtained 1-7 days before the endoscopy were not useful in predicting the organism causing esophagitis [l 11. Three of six patients with HE died without resolution of their no definitive conclusion concerning its role in favoring esophagitis. The same authors reported postmortem HE can be drawn in the absence of case-control data showing evidence of esophageal infection in 25/59 studies in immunocompromised patients. Endotracheal patients, including six due to HSV [ll]. In the intubation and nasogastric tubes should be avoided in neutropenic population, herpetic ulcerations have been such patients in case of patent labial or buccal herpetic reported to be a portal of entry for various bacterial and infection [28]. Gastroesophageal reflux has also been fungal infections [35]. cited as a possible risk factor for HE [29]. Herpes esophagitis in AIDS patients Herpes esophagitis in solid organ transplant recipients [281 During HIV infection, HSV seroprevalence is 80-95% HSV reactivation is mostly observed during the first for type 1 and 20-30% for type 2 [36]. HIV and HSV- month post-transplantation, and HSV infections occur 1 enhance reciprocally their replication in macrophages within the first 2 months after transplantation [30]. In and keratinocytes [37]. During HIV-1 infection, HE a prospective study of infectious esophagitis following has been considered to be relatively uncommon and liver and renal transplantation, the authors discovered classically less frequent than esophagitis due to CMV HE in 3/47 liver transplants post-transplantation (6%) [38-401, in contrast to results reported in other studies and in 1/21 renal transplants post-transplantation (5%). [41-431. In HIV-1 patients, HE was the cause of4-16% These data showed a lower prevalence of HE than that of esophageal symptoms [38,39,41-431 and occurred in observed after marrow transplantation [11,31]. In the four out of 154 patients (2.5%) followed prospectively latter paper [31], no association between HE and [43]. We recently reported 34 AIDS patients with HE administration of prednisone or blood level of cyclo- [18]. In that paper, the mean CD4 cell count was sporin A was found. HE has also been reported after 15/mm3 and recent predisposing factors (nasogastric cardiac transplantation, but no clear data on the pre- procedures, steroid therapy, anticancer therapy) were valence were reported [lo]. Mter transplantation, the noted in 47% of patients. Only 15% of our patients use of anti-CD3 monoclonal antibodies has also been relapsed, most of them having an iatrogenic pre- Genereau et al: Herpes esophagitis 399 disposing factor (steroids, anticancer therapy). HE has mented in adults, and does not represent a significant also been reported during HIV primary infection [44]. route of viral replication. However, viremia occurs in neonates infected at birth with HSV-2 [69], and has Herpes esophagitis during disseminated neonatal HSV been reported in HSV-1-infected children receiving infection immunosuppressive therapy [70]. Therefore, esophageal In neonates, the esophagus is frequently involved in infection is most often secondary to a viral recurrence, the dissemination of HSV infection 1141. The exact most of the time by regional extension of buccal or prevalence has not been precisely described, but histo- pulmonary localization 1711. It is now well established logic changes consistent with HE were demonstrated that after infection of the oral epithelium, viral