Triple infection of gastric syphilis, Helicobacter pylori and human immunodeficiency virus: A case report

Abstract

BACKGROUND

Gastric syphilis (GS) is a rare infection caused by Treponema pallidum (T. pallidum) and may mimic neoplasia or be overlooked. Co-infection with Helicobacter pylori (H. pylori) and human immunodeficiency virus (HIV) has not previously been reported.

CASE SUMMARY

A 17-year-old woman presented with upper abdominal pain for two weeks. A large irregular-shaped ulcer on the antrum was identified by endoscopy and the C-14 breath test was positive. Quadruple therapy was given to eradicate H. pylori, but her symptoms persisted after treatment. No significant improvement in the antral ulcer was found on secondary gastroscopy. Gynecologic examination observed characteristic vulvar syphilis. Serum tests revealed that she was co-infected with syphilis and HIV. Immunohistochemistry (IHC) staining confirmed the coexistence of H. pylori and T. pallidum in gastric mucosa biopsy. The gastric symptoms rapidly disappeared after anti-syphilis treatment, and she was finally diagnosed with GS, H. pylori and HIV triple infection.

CONCLUSION

GS should be considered in any patient with an atypical or therapy-refractory gastric ulcer, particularly when serological syphilis positivity exists. IHC is a reliable method for confirming intra-gastric T. pallidum. Clinical doctors need to collaborate with pathologists to clarify diagnosis.

Key Words: Gastric syphilis; Helicobacter pylori; Human immunodeficiency virus; Immunohistochemistry; Differential diagnosis; Case report

Core Tip: We describe the first case of gastric syphilis, Helicobacter pylori (H. pylori) and human immunodeficiency virus triple infection. The report highlights that syphilis can produce severe “tumor-like” gastric ulceration; moreover, co-infection must be identified when H. pylori eradication fails.

INTRODUCTION

Syphilis, caused by Treponema pallidum (T. pallidum), is a sexually transmitted infection, which has re-emerged globally in the past decade worldwide[1,2]. Gastric syphilis (GS) remains exceptionally rare, even in China where the incidence of syphilis is high[3]. Non-specific epigastric pain, nausea or occult bleeding frequently leads to misdiagnosis as peptic disease, malignancy or lymphoma[4,5]. To date, no report has documented the simultaneous presence of GS, Helicobacter pylori (H. pylori) and human immunodeficiency virus (HIV). Through integrated endoscopic, pathological, and serological analysis, this case highlights the importance of considering syphilis in atypical gastric manifestations.

CASE PRESENTATION

Chief complaints

A 17-year-old Tibetan woman complained of persistent abdominal pain for approximately 2 weeks.

History of present illness

The patient developed progressive epigastric pain unresponsive to traditional medicines. She denied diarrhea, fever or hematemesis.

History of past illness

The patient had pulmonary tuberculosis 5 years earlier (completed treatment, documented cure). No prior sexually transmitted diseases.

Personal and family history

The patient stated that there was no family history of gastric tumors.

Physical examination

Vital signs were stable. Soft abdomen with localized epigastric tenderness and no guarding was observed. Gynecological inspection revealed painless, indurated, moist papules on the labia majora (Figure 1A).

Figure 1 Manifestations on the vulva and back before and after anti-Treponema pallidum treatment. A: Pale, tough papules could be seen on the vulva before anti-Treponema pallidum (T. pallidum) treatment; B: The papules disappeared after anti-T. pallidum treatment; C: Severe herpes zoster virus infection led to a large ulcer on the back.

Laboratory examinations

Laboratory test results included hemoglobin 113 g/L, C-14 urea breath test was positive, serological tests revealed positive results for T. pallidum (rapid plasma reagin 1:128) and HIV. Eight months later, serological testing showed that T. pallidum specific antibody was also positive.

Imaging examinations

Gastroscopic inspection revealed extensive mucosal erosion, and a large irregular-shaped ulcer with bleeding in the antrum, which was approximately 3 cm × 2 cm in size, the bottom of the ulcer was uneven and the mucosa surrounding the ulcer was thickened with a nodular appearance. The manifestations of the ulcer were similar to that of a gastric tumor (Figure 2A). Quadruple therapy (lansoprazole 30 mg bid; bismuth pectin 200 mg bid; furazolidone 0.1 g bid; clarithromycin 0.5 g bid) was given to eradicate H. pylori. However, her symptoms persisted after treatment and a second gastroscopy showed an unchanged antral ulcer with reduced mucosal swelling (Figure 2B). Following anti-syphilis therapy, she declined repeat endoscopy.

Figure 2 Gastroscopy findings before and after treatment. A: A large exudative ulcer was found in the antrum with swelling and bulging margins before treatment; B: The ulcer did not shrink significantly after Helicobacter pylori eradication therapy.

Hematoxylin-eosin staining revealed inflammatory infiltration predominantly consisting of dense lymphocytes and plasma cells, gland destruction, granulation tissue and follicular hyperplasia (Figure 3A and B). Immunohistochemistry (IHC) revealed scattered rod-shaped H. pylori on surface epithelium (Figure 3C) and numerous spiral T. pallidum within the mucosa, muscularis mucosae and exudate (Figure 3D).

Figure 3 Hematoxylin-eosin staining and immunohistochemistry staining of biopsy tissues. A: Gastric mucosa revealed severe inflammation [Hematoxylin-eosin (HE) staining, 100 ×]; B: Mainly lymphocyte and plasma cell infiltration (HE staining, 400 ×); C: Helicobacter pylori immunohistochemistry (IHC) staining showing pathogens on the superficial mucosa (IHC staining, 400 ×, blue arrows); D: IHC staining of Treponema pallidum showed thread-like pathogens distributed in the tissue and mucus (IHC staining, 400 ×, orange arrows).

MULTIDISCIPLINARY EXPERT CONSULTATION

The patient had a large irregular ulcer in the gastric antrum, and the C-14 urea breath test was positive. The gastric lesion extended beyond the typical presentation of H. pylori gastritis and the treatment for H. pylori eradication was ineffective. The non-specific antibody titer for syphilis was 1:128, with vulvar syphilis, suggesting a current syphilis infection. The histopathological examination revealed non-specific inflammatory changes, mucosal erosion, and dense inflammatory cell infiltration, with predominantly lymphocytes and plasma cells. In this case, the possibility of GS was suggested. Subsequent IHC staining confirmed the presence of both H. pylori and T. pallidum within the gastric mucosa.

FINAL DIAGNOSIS

The final diagnosis was triple infection of GS, H. pylori and HIV.

TREATMENT

The patient initially received H. pylori eradication therapy without relief of her symptoms. Following the diagnosis of GS, she was treated with doxycycline (100 mg, bid, 30 days) due to penicillin allergy.

OUTCOME AND FOLLOW-UP

After anti-syphilis treatment, her gastric symptoms disappeared entirely, and the vulva papules gradually disappeared (Figure 1B). The patient suffered a serious herpes zoster virus infection with a large ulcer on her back 8 months later (Figure 1C), and it was speculated that this might have been related to HIV infection. Gastroscopy was declined by the patient at the 8-month visit and she remained asymptomatic regarding the upper-gastrointestinal tract. The patient was subsequently lost to follow-up. The timeline of the patient's progression is shown in Figure 4.

Figure 4 Timeline of the patient's progression. H. pylori: Helicobacter pylori; HIV: Human immunodeficiency virus.

DISCUSSION

GS is a rare disease that can mimic malignancy, lymphoma, or peptic ulcer disease, often leading to missed or delayed diagnosis[6,7]. The reported age of GS patients ranges from 21 years to 78 years[6,7]. In this case, the large solitary antral ulcer with rolled margins and surrounding nodularity initially raised oncological suspicion. Co-existence of H. pylori, found in up to 58% of gastric ulcer patients, further obscured the underlying syphilitic etiology, particularly in a young, immunocompromised woman without prior history of previous sexually transmitted infections[7,8].

To date, this is the first reported triple infection of GS, H. pylori and HIV in an adolescent. Isolated dual infections have been reported, but never both concurrently[9,10]. In addition, 8 months later she developed herpes-zoster eruption, which might have been related to immune reconstitution. Early antiretroviral therapy can substantially reduce the risk of herpes zoster among individuals living with HIV[11]. At 17 years old, our patient is the youngest reported with GS, underscoring that age alone should not exclude syphilis in sexually active adolescents with atypical gastrointestinal symptoms.

Endoscopically, GS is termed the “great imitator” owing to deep ulcers, nodularity, thickened folds or linitis-like rigidity[2,8,12]. These features overlap with adenocarcinoma, lymphoma, MALToma, cytomegalovirus infection, tuberculosis, and Crohn’s disease[2,8,12]. In our patient, the ulcer size, depth, and marginal elevation strongly suggested malignancy. GS typically masquerades as gastric cancer or lymphoma, with ulcerative, nodular or infiltrative patterns[5,6]. Our patient’s large solitary ulcer and marginal nodularity simulated malignancy, prompting oncological concern. The additional presence of H. pylori is not unexpected, up to 58% of gastric-ulcer patients harbor the bacterium[6,10], which can mask the syphilitic etiology and delay appropriate treatment. Young age and female gender further lowered clinical suspicion.

Histopathology of GS is non-specific, chronic active gastritis shows dense lymphocyte and plasma cell infiltration[6]. Histological biopsy is prone to miss the diagnosis. GS should be differentiated from diseases such as H. pylori infection, cytomegalovirus infection, fungal infection and lymphoma, which are shown in Table 1. Diagnosis requires detection of T. pallidum in gastric biopsy and IHC staining has higher sensitivity and specificity[13,14]. Moreover, H. pylori colonizes the mucosal surface, whereas T. pallidum invades the full mucosal thickness. Thus, in this case, inflammation persisted after H. pylori eradication, and the patient’s symptoms were not relieved.

Table 1 Endoscopic and histopathological characteristics of different gastric lesions.

Diseases	Endoscopic characteristics	Histopathological characteristics
Gastric syphilis[6,17,18]	Common site is the antrum with multiple ulcers or giant ulcers. Nodular mucosal elevations and thickening of gastric folds that are similar to gastric carcinoma. Fibrotic narrowing and rigidity occur in the late-stage	Non-specific inflammation mainly plasma cells and lymphocytes. IHC staining for T. pallidum in all layers of mucosa
H. pylori-associated gastritis[19]	Common site is the junction of the gastric antrum and body. Congestion, edema, erythema, and ulcers appear on the gastric mucosa, usually superficial	Non-specific inflammation mainly neutrophils and lymphocytes on the surface of gastric mucosa. Specific IHC staining for H. pylori
Gastric carcinoma[20,21]	Mostly shows as a huge ulcer that is stained with moss adhered to the surface of the ulcer, and the edge of the ulcer is raised like a dam	Hyperplasia of atypical epithelial cells, with a glandular, patchy, or scattered distribution, with special markers, such as CK, P53, and Ki67
Gastric lymphoma[22,23]	Common site is the antrum. Mucosal erosion, ulceration, mucosal nodules or thickening, presenting as flat or polypoid elevations	Large sheets of monotonous cells within the mucosa; specific IHC staining helps the diagnosis
Gastric tuberculosis[24]	Common sites are the gastric antrum and lesser curvature. Nodular hypertrophic mass may mimic carcinoma, some present with antrum deformation and obstruction	Granulomatous inflammation with stenosis, perforation, or fistula, and positive staining for acid fast bacilli
Gastric cytomegalovirus[25,26]	Common site is the antrum. Punched-out ulcers with partial mucosal thickening and inflammation, which are similar to gastric carcinoma	Eosinophilic inclusions visible in epithelium or stroma. Specific IHC staining for cytomegalovirus

H. pylori: Helicobacter pylori; T. pallidum: Treponema pallidum; IHC: Immunohistochemistry.

At present, there is no conclusive evidence to confirm a clear correlation between HIV infection and gastric lesions. It was reported that gastrointestinal opportunistic infections exist in a small number of late-stage HIV infected individuals receiving highly active antiretroviral therapy[15]. Yet the incidence of chronic active gastritis does not differ between HIV-positive patients with or without H. pylori infection[16].

In our case, missed diagnosis might be attributable to: (1) The rarity of GS; (2) Young age and the absence of a sexually transmitted infection history; (3) Antral predilection and nonspecific endoscopy; (4) Positive C-14 breath test diverting attention; and (5) Non-specific histology. Thus, GS is easily overlooked by both gastroenterologists and pathologists. Multidisciplinary evaluation of symptoms, history, serology, endoscopy and histology reduced the misdiagnosis of GS.

Therefore, we propose a stepwise method for patients with refractory gastric ulcers and HIV or high-risk sexual history. Firstly, initial workup includes serology for syphilis and HIV, and the C-13/14 breath test. Secondly, if the patient is H. pylori-negative or treatment fails, then repeat endoscopy with multipoint biopsies and targeted IHC for T. pallidum, cytomegalovirus, Epstein-Barr virus, tuberculosis, and fungal stains should be carried out. Moreover, if syphilis serology is positive, penicillin or doxycycline therapy can be initiated. Finally, clinical symptoms and serology for syphilis should be followed and observed.

This report has a few limitations, as it was a single case that lacked generalizability. However, we hope that this case may contribute to the recognition and management of GS in the context of multiple concurrent infections, and enhance clinical awareness of this rare condition.

CONCLUSION

This case highlights the diagnostic complexity of triple infection in an immunocompromised woman. GS should be considered in patients with atypical or refractory gastric ulcers, especially after failed H. pylori eradication. IHC staining is a convenient and low-cost method to confirm T. pallidum. Finally, multidisciplinary collaboration between gastroenterologists, infectious-disease specialists and pathologists is essential to avoid misdiagnosis.