{"id":60711,"date":"2024-09-30T11:30:11","date_gmt":"2024-09-30T11:30:11","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=60711"},"modified":"2024-10-09T18:03:08","modified_gmt":"2024-10-09T18:03:08","slug":"clinicopathological-study-of-herpes-simplex-esophagitis-in-a-tertiary-centre-in-india","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no3\/clinicopathological-study-of-herpes-simplex-esophagitis-in-a-tertiary-centre-in-india\/","title":{"rendered":"Clinicopathological Study of Herpes Simplex Esophagitis in a Tertiary Centre in India"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

The most common\ncauses of infectious esophagitis are Candida<\/em> (88%), herpes\nsimplex virus (10%) and cytomegalovirus (2%). \nHerpes simplex virus (HSV) is the most common cause of viral\nesophagitis. Histopathological evaluation forms an unusual\narmamentarium in the evaluation of viral infections. The many cytopathic effects\nof viruses are sometimes the earliest manifestation of an ongoing disease\nprocess. One such is Herpes Simplex Virus (HSV). The word \u201cherpes\u201d (from the\nGreek, \u201cto creep\u201d) has been around in medical literature since time immemorial.1<\/sup>\nThe Roman physician Herodotus in 100 AD described cold sores (herpes febrilis)\nin his anecdotes.1<\/sup> In 1976, John Astruc, a French physician first\ndescribed genital herpes.1<\/sup> Among the\nimmunocompetent individuals, HSV esophagitis typically occurs as a primary\ninfection with a self-limited course.2<\/sup> There is evidence that impaired mucosal barrier may augment oesophageal\nHSV infection.2 <\/sup>The part of the gastrointestinal tract that\nis commonly affected is the oesophagus, with an incidence of 0.5% to 2% based\non an autopsy series.3-6 <\/sup>The\ncorrelation between the clinical manifestations, endoscopic and\nhistopathological findings, and the viral antibodies has not been widely\ndescribed in literature. Therefore, in the present study we aimed to\ninvestigate the clinical manifestations and associated comorbidities of\npatients diagnosed to have herpes simplex esophagitis based on findings of\nendoscopy, serology, and histopathology.<\/p>\n\n\n\n

Materials and Methods<\/strong><\/p>\n\n\n\n

Study design and population – laboratory\nbased, retrospective study, done on rural population in Coastal Karnataka,\nSouth India, <\/p>\n\n\n\n

Methods: From a total of 6,782 esophageal\nbiopsies received in the department of Pathology, between November 2011-\nJanuary 2017, 5683 were endoscopically found to have an ulcerated esophageal\nmucosa. Of these 5683 cases, filters were given in the laboratory information\nsystem to isolate cases with a clinical suspicion of HSV infection, which gave\na total of 173 cases, owing to the endoscopic findings and in correlation with\nthe underlying comorbidities. Inclusion criteria was biopsy proven cases of\nherpes simplex esophagitis. Exclusion criteria: Biopsy negative for HSV\nchanges. <\/p>\n\n\n\n

Ethical consideration: This study was\nconducted according to the WMA Declaration of\nHelsinki, after approval of\nscientific review committee. The data collected was coded to maintain the\nconfidentiality of the patients. The demographic and clinical\ndetails like alcohol consumption, smoking habits, underlying comorbidity,\nimmunocompromised state, retroviral disease status, were collected from patient\nrecords from the archives. Direct and indirect identifiers were avoided by\ncoding the sample population case wise (e.g. case 1, 2, etcetera). The\nindications for an upper gastrointestinal (GI) endoscopy including dysphagia\nand\/or odynophagia, heartburn, epigastric pain, nausea\/vomiting, GI bleeding\nand endoscopic findings like friable mucosa, erosions\/ ulcers, polypoid\/ nodular\npattern and site of involvement were noted. Biopsy should be performed from the margin \/ edge of\nthe ulcer rather than from the base. Serological\nparameters like anti-HSV 1 IgM and anti-HSV 2 IgM were also recorded. The\nbiopsy slides were reviewed for the cytopathic effects and the characteristic\ninclusions of HSV. The slides were reviewed independently by two pathologists.\nSpecial stains including periodic acid Schiff (PAS) and\/ or Gomori\u2019s methenamine silver (GMS) stains\nwere performed to rule out concomitant fungal infection. <\/p>\n\n\n\n

Data analyses: The data on categorical\nvariables is shown as in (% of cases) and the data on normally distributed\ncontinuous variables is presented as Mean and Standard deviation (SD). For\nnon-normally distributed continuous variables, median (min \u2013 max) was used. The\ninter-group statistical comparison of distribution of categorical variables is\ntested using Chi-Square test or Fisher\u2019s exact probability test.<\/p>\n\n\n\n

Results<\/strong><\/p>\n\n\n\n

27 of the 173 clinically suspected patients were diagnosed as HSV esophagitis based on histological and\/or serological investigation. The median age of the study population was 50 years (range 34-71 years) while the male to female ratio was 2.3:1. The most common clinical manifestations amongst the diagnosed cases, were epigastric pain (21\/27 patients, 77.8%), odynophagia\/dysphagia (16\/27 patients, 59.2%), heartburn (15\/27 patients, 55.5%) and nausea\/vomiting (11\/27 patients, 40.7%). Cigarette smoking and alcohol consumption were present among (11\/27 patients, 40.7%) and (12\/27 patients, 44.4%), respectively (table1). Of the 27 diagnosed patients, 8 (29.6%) had Type 2 DM, 5 (18.5%) had COPD, 2 (7.4%) had end stage renal disease, 1 (3.7%) had cirrhosis of liver, 5 (18.5%) had a diagnosed malignancy and were under chemotherapy and\/or irradiation or both for the same. 17 (62.9%) were under steroid therapy while none had undergone an organ transplantation. HIV co-infection was present among 11 cases. Upper GI endoscopy reports revealed erosions and ulcers with surrounding erythema of the mucosa in 19\/27 patients (70.3%), friable mucosa in 5\/27 patients (18.5) and polypoid\/nodular pattern in 3\/27 patients (11.1%). 18.5% of patients (5\/27) had lesions on the upper third of the oesophagus, 59.2% (16\/27) in the middle third, while 22.2% (6\/27) on the distal third. None of our patients had HSV lesions involving the entire oesophagus. The CD4 counts were available in 11 cases with HIV coinfection with all patients having a count > 200\/\u03bcL. Anti-HSV 1 IgM antibodies were positive among 20\/27 patients, negative among 2\/27 patients and not done among 5\/27 patients. Anti-HSV 2 IgM antibodies were positive among 15\/27 patients, negative among 7\/27 patients and not done among 5\/27 patients. There were 48.1% (13\/27) patients who had antibodies present against both HSV 1 and HSV 2 (Table 2). With respect to the HIV coinfected population, all cases (n=11) showed anti-HSV 1 IgM positivity (11\/11) and 6\/11 also showed anti-HSV 2 IgM positivity. However, there was no significant relation with the CD4 counts in these patients. HSV usually affects the epithelial cells of the oesophagus, hence histologic examination reveals large intranuclear inclusion bodies, commonly referred to as Cowdry A bodies, (Figure 1 A and B) and\/or multinucleated giant cells (Figure 2) with ground glass nuclei and marginated chromatin in the epithelial cells (9). The surrounding mucosa may show necro-inflammatory slough, mixed inflammatory infiltrate and reactive atypia with few koilocytes (Figure 3).<\/p>\n\n\n\n

Table 1: Clinical Characteristics and Underlying Risk Factors with respect to the type of ulcer on Endoscopy findings in patients with Herpes Simplex Infection<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

 <\/strong><\/p>\n

 <\/strong><\/p>\n<\/td>\n

\n

Type 1 (n=5)<\/strong><\/p>\n<\/td>\n

\n

Type 2 (n=19)<\/strong><\/p>\n<\/td>\n

\n

Type 3 (n=3)<\/strong><\/p>\n<\/td>\n

\n

Total (N=27)<\/strong><\/p>\n<\/td>\n

\n

P<\/em><\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Age > 60 years<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n

\n

6<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

7<\/p>\n<\/td>\n

\n

0.48<\/p>\n<\/td>\n<\/tr>\n

\n

Male sex<\/p>\n<\/td>\n

\n

4<\/p>\n<\/td>\n

\n

15<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

19<\/p>\n<\/td>\n

\n

0.01*<\/p>\n<\/td>\n<\/tr>\n

\n

Personal Habits<\/p>\n<\/td>\n<\/tr>\n

\n

Smoking<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

9<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

11<\/p>\n<\/td>\n

\n

0.30<\/p>\n<\/td>\n<\/tr>\n

\n

Alcohol<\/p>\n<\/td>\n

\n

4<\/p>\n<\/td>\n

\n

8<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

12<\/p>\n<\/td>\n

\n

0.08<\/p>\n<\/td>\n<\/tr>\n

\n

Underlying Disease Condition<\/p>\n<\/td>\n<\/tr>\n

\n

DM<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

6<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

8<\/p>\n<\/td>\n

\n

0.45<\/p>\n<\/td>\n<\/tr>\n

\n

COPD<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n

\n

5<\/p>\n<\/td>\n

\n

0.25<\/p>\n<\/td>\n<\/tr>\n

\n

ESRD<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

0.63<\/p>\n<\/td>\n<\/tr>\n

\n

Cirrhosis<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n

\n

0.80<\/p>\n<\/td>\n<\/tr>\n

\n

Malignancy<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n

\n

4<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

5<\/p>\n<\/td>\n

\n

0.68<\/p>\n<\/td>\n<\/tr>\n

\n

HIV infection<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n

\n

9<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n

\n

11<\/p>\n<\/td>\n

\n

0.52<\/p>\n<\/td>\n<\/tr>\n

\n

Status of Infection<\/p>\n<\/td>\n<\/tr>\n

\n

Sepsis<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

5<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

5<\/p>\n<\/td>\n

\n

0.27<\/p>\n<\/td>\n<\/tr>\n

\n

Other Factors<\/p>\n<\/td>\n<\/tr>\n

\n

Steroids<\/p>\n<\/td>\n

\n

5<\/p>\n<\/td>\n

\n

11<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n

\n

17<\/p>\n<\/td>\n

\n

0.11<\/p>\n<\/td>\n<\/tr>\n

\n

WBC<\/p>\n<\/td>\n

\n

7140 \u00b1 5326<\/p>\n<\/td>\n

\n

10110 \u00b1 4759<\/p>\n<\/td>\n

\n

9166 \u00b1 1800<\/p>\n<\/td>\n

\n

9455 \u00b1 4652<\/p>\n<\/td>\n

\n

0.46<\/p>\n<\/td>\n<\/tr>\n

\n

DM \u2013 Diabetes Mellitus, COPD \u2013 Chronic Obstructive Pulmonary Disease, ESRD \u2013 End Stage Renal Disease, HIV \u2013 Human Immunodeficiency Virus<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n

Table 2: Correlation of CD4 counts with the type of anti-HSV IgM antibody in patients with HIV coinfection (n=11)<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Anti-HSV 1 IgM<\/strong><\/p>\n<\/td>\n

\n

Anti-HSV 2 IgM<\/strong><\/p>\n<\/td>\n

\n

CD4 cell count (\/\u03bcl)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

Negative<\/p>\n<\/td>\n

\n

477.82<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

Positive<\/p>\n<\/td>\n

\n

432.67<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

Negative<\/p>\n<\/td>\n

\n

272<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

Positive<\/p>\n<\/td>\n

\n

384.65<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

Positive<\/p>\n<\/td>\n

\n

354.45<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

Positive<\/p>\n<\/td>\n

\n

276.84<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

Negative<\/p>\n<\/td>\n

\n

456.66<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

Positive<\/p>\n<\/td>\n

\n

475.66<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

Positive<\/p>\n<\/td>\n

\n

478.99<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

Negative<\/p>\n<\/td>\n

\n

479.08<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

Negative<\/p>\n<\/td>\n

\n

485.56<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n

Discussion<\/strong><\/p>\n\n\n\n

The\nmain aim is to study the clinical features, including comorbidities and\nendoscopic findings, diagnosed to have herpes simplex esophagitis based on\nhistopathology along with correlation of serological findings.<\/p>\n\n\n\n

HSV esophagitis is known to occur in\nimmunocompromised individuals including those affected with AIDS; however there\nhave been reports of its occurrence in the immunocompetent as well.1 <\/sup>The hallmark of HSV esophagitis\nendoscopically are multiple, small, superficial ulcers most commonly along the\ndistal third of the oesophagus7 <\/sup>whereas in our study the most\nfrequent site was the middle third. Viral culture of the biopsy sample is the\nmost sensitive diagnostic modality for HSV-18-10<\/sup>, however in our\nstudy we could not employ the same. <\/p>\n\n\n\n

HSV esophagitis, per se,\nshows a slight male predilection (4, 10-14) and affects individuals in the 5th<\/sup> to 6th<\/sup>\ndecades of their lives owing to increasing risk factors. In our study group\nalso, the median age was found to be 50 years with a male preponderance (M:F –\n2.3:1) which was in concordance with two studies (M:F \u2013 3:1, mean age 63.1\nyears and M:F – 4.7:1, mean age 38 years). 4,10<\/sup> However, this may\nrepresent just the tip of the iceberg as most infections may remain subclinical\nor latent. The most common risk factors include male sex (P <\/em>< 0.01), age > 60 years, personal habits like cigarette\nsmoking and alcohol consumption, underlying comorbidities like Type 2 DM, COPD,\nESRD, cirrhosis of liver, malignancy, and HIV coinfection and other\npredisposing factors like steroid intake and chemoradiation, as compared to another\nstudy which reported chemoradiation as a risk factor (P < 0.05) 7<\/sup>\nas also associated co-infections like fungal, bacterial etc.11<\/sup><\/p>\n\n\n\n

The most common clinical manifestations in\nour study were odynophagia\/dysphagia (59.2%) which is concordant with several contemporary\nreports of 61% 2<\/sup>, 71%13<\/sup> and 76%.12<\/sup> GI bleeding has\nbeen reported to occur in HSV esophagitis; however, none of our patients had\nfrank GI bleeding in contrast to a study11<\/sup> which reported GI\nbleeding in 30% of their study group (n=23). This may be attributed to the\nunderlying comorbidities, the severity of infection and sociodemographic\ndiversities. <\/p>\n\n\n\n

The three types of HSV esophagitis,\nobserved endoscopically4<\/sup>, include: Type 1 – small, punched-out\nlesions with raised margins having a yellowish exudate, Type 2 – small,\npunched-out lesions without raised margins or exudate, Type 3 – multiple,\nconfluent ulcers with a map-like appearance; all the three types were recorded\nin our series.<\/p>\n\n\n\n

The CD4 counts in\nthose with HIV coinfection (n=11), based on literature is usually <200 for\nHSV infection to set in. In our study, all the patients had a CD4 count of over\n200, which may be attributable to racial and geographic differences with\ndifferent immunological constitution, and to the small sample size.<\/p>\n\n\n\n

All the patients in\nour study were subjected to an upper GI endoscopic biopsy which on routine\nhaematoxylin and eosin-stained microscopic examination revealed ulcerated oesophageal\nmucosae with necro-inflammatory slough. The squamous epithelial cells showed\nperinuclear clearing (koilocytosis) along with intranuclear inclusions (Cowdry\nA) (Figure 1 and 2) suggesting a viral aetiology, possibly HSV. This was in\nconcordance with other studies. 4,7,9,13<\/sup> Ancillary\nimmunohistochemistry specific for HSV could not be done due to unavailability\nof the antibody. The diagnosis was rendered based on morphology with clinical\nsuspicion and serological evidence. The serology for anti-HSV 1 and 2 IgM were\ndone for all the cases in the study group; however, to the best of our\nknowledge no other study has compared or studied the relation of positive\nantibody serology with histological evidence.<\/p>\n\n\n\n

Antiviral\ntherapy, including acyclovir, famciclovir, and Val acyclovir, is used to treat HSV\nesophagitis in immunocompromised hosts.15, 16<\/sup> However, the benefit\nof antiviral therapy for HSV esophagitis is controversial in immunocompetent\npatients because of reported rare complications.12,13,17<\/sup> In our\nretrospective study, 22\/27 patients (81.5%) received antiviral therapy, and\ntheir symptoms, especially dysphagia and\/or odynophagia showed an obvious\nimprovement within 3 to 5 days as documented in the medical charts. <\/p>\n\n\n\n

The present retrospective study has some limitations. First, laboratory data about immune status such as CD4 count were not checked on all HSV esophagitis patients, and only in those with HIV coinfection. Second, typically endoscopic typing includes type 1, type 2, and type 3 may not be mutually exclusive with overlapping or combined lesions in the same patient, which did not yield statistically significant results. Third, the small sample size of biopsy proven cases restricted comparison with clinically suspected cases. Fourth, immunohistochemistry could not be specifically carried out on the biopsies due to unavailability. Fifth, an adequate follow up was not available to carry out survival and mortality related studies. Although the mortality of the disease per se, is low, but when compounded by the underlying disease status, it may increase.<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: A and B. Intranuclear inclusions in the squamous epithelial cells with ground glass appearance (H and E, x400, x200).<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
\"\"<\/td>\n\n

Figure 2: Giant cell formation with nuclear features (H and E, x200)<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
\"\"<\/td>\n\n

Figure 3: Acanthotic squamous epithelium with koilocytosis (H and E, x100)<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

In\nconclusion, HSV esophagitis primarily affects males and immunocompromised hosts.\nAn early laboratory work-up of the at-risk population and those with typical\nclinical manifestations can help improve the detection rates. Early and correct\ndiagnosis based on histopathological evaluation of characteristic inclusions by\nthe pathologist is useful for appropriate treatment.<\/p>\n\n\n\n

Acknowledgement<\/strong><\/p>\n\n\n\n

We would like to acknowledge the technical staff of departments of Microbiology and Pathology, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India for the retrieval of data and conducting of the procedures.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The author(s) declares no conflict of interest<\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

The author(s) received no financial support for the research, authorship, and\/or publication of this article. <\/strong><\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

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