Acute hepatitis and pancytopenia related to non-typhoidal salmonella infection in a human immunodeficiency virus-infected patient

Introduction

Non-typhoidal salmonellae (NTS) organisms including Salmonella Typhimurium, Salmonella Dublin, Salmonella Enteritidis, Salmonella Virchow, and Salmonella Choleraesuis are gaining importance as a cause of bacteremia. ¹ Although the most common clinical manifestation of these food-borne pathogens is self-limiting acute gastroenteritis, a more severe, invasive, and sometimes recurrent presentation in immunocompromised adults, particularly people living with human immunodeficiency virus (PLWH) (HIV)-infected ones, also occurs.^1–4

NTS has not been associated with hepatitis in the literature, although a co-infection of NTS and hepatitis E virus was shown in an immunocompetent acute hepatitis patient. ⁵ Pancytopenia, on the other hand, was associated with invasive NTS in an immunocompetent patient and only leucopenia and thrombocytopenia were associated with invasive NTS in immunocompromised patients with different malignancies, but not in HIV infection.^6,7 Here we present a case of acute hepatitis and pancytopenia related to a non-typhoidal agent in an HIV-infected patient, the first case in the literature.

Case

A 22--year-old healthy Kenyan man was admitted with fever, weight loss, fatigue, and jaundice. He had lived in Kenya until 21 years old, and started living in Turkey 12 months previously. His last visit to Kenya was two months prior to admission. Physical examination showed icterus and hepatomegaly. The laboratory investigations revealed white blood cell count (WBC) 3880/µL, absolute neutrophil count (ANC) 2530/µL, absolute lymphocyte count (ALC) 980/µL, hemoglobin (Hb) 11.8 g/dL, platelets (plt) 117,000/µL, aspartate aminotransferase (AST) 398 U/L, alanine aminotransferase (ALT) 290 U/L, alkaline phosphatase (ALP) 242 U/L, gamma-glutamyl transpeptidase (GGT) 263 U/L, lactate dehydrogenase (LDH) 267 U/L, total bilirubin 5.71 mg/dL, direct bilirubin 4.66 mg/dL, and serum ammonia 85.8 μg/dL. His electrolytes, albumin, coagulation parameters, and urine analysis were with in the normal range.

He was hospitalized and received supportive treatment. After four days of follow-up, laboratory tests showed WBC 3130/µL, ANC 1720/µL, ALC 1090/µL, Hb 12.6 g/dL, plt 48,000/µL, AST 752 U/L, ALT 517 U/L, ALP 222 U/L, GGT 204 U/L, total bilirubin 7.08 mg/dL, direct bilirubin 6.8 mg/dL, and C-reactive protein 0.82 mg/dL. On the tenth day of hospitalization, his WBC decreased to 1650/μL, and the percentage of monocytes increased from 8.2% (320/μL) to 16.2% (500/μL). The peripheral blood smear showed no other pathological finding or sign of malarial infection.

Considering these findings, the differential diagnosis included acute viral hepatitis, autoimmune hepatitis, hepatobiliary sepsis/cholangitis, and drug toxicity. He denied any herbal, alcohol, or drug use. Abdominal ultrasonography showed hepatomegaly with mildly reduced echogenicity and normal biliary structure and splenomegaly.

On serological evaluation, both anti-HIV ½ ELISA test and confirmatory Western blot test were positive. Tests including hepatitis B surface antigen (HBsAg), antiHBc IgM, hepatitis C virus antibody (anti-HCV), HCV-RNA, hepatitis A virus antibody (anti-HAV) IgM, Epstein-Barr Virus Viral Capsid antibody (anti-EBV) VCA IgM, EBV-DNA, cytomegalovirus (CMV)-DNA, venereal disease research laboratory (VDRL), Treponema pallidum hemagglutination (TPHA), Brucella tube agglutination, anti-parvovirus IgM, parvovirus-DNA, autoantibodies (anti-nuclear antibody, anti-liver kidney microsomal antibody, anti-smooth muscle antibody), and T-Spot-TB test were negative and antiHBs was positive (240 IU/mL), having been vaccinated for HBV.

While the patient was under supportive care, blood culture taken during fever episodes became positive for two sets (six bottles) and Salmonella enterica subspecies enterica serovar Enteritidis was isolated. Antibiogram showed ampicillin, ciprofloxacin, and trimethoprim-sulfamethoxazole susceptibility. Because stool culture was also positive for the same agent, ciprofloxacin was administered 400 mg IV two times a day. He became afebrile at the third day of treatment with sterile blood culture. Ciprofloxacin was given for 14 days. Stool culture became negative after six weeks. Elevated transaminases started to resolve after the tenth day and normalized at the sixth week.

Because his HIV viral load was 285,000 copies/mL, CD4 cell count was 86 cells/µL, and CD8 count was 450 cells/μL, antiretroviral therapy (ART) (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate) and trimethoprim-sulfamethoxazole (800/160 mg tb, po, three times in a week), azithromycin (500 mg tb, three times in a week) prophylaxis were started, three weeks after the control of bacteremia. No resistance was found in primary resistance test for selected ART. Pancytopenia improved and normalized eight weeks after the start of antibacterial and three weeks of ART. At the sixth month of diagnosis, stool culture was negative, HIV RNA was undetectable, and CD4 cell count was 228 cells/μL. The etiology of the acute hepatitis was accepted as Salmonella enterica subspecies enterica serovar Enteritidis.

Discussion

NTS has a diverse distribution and there are endemic areas, especially in Asia and Africa. Living in and travel to those regions, and other risks facilitating transmission via the fecal-oral route should alert for NTS.^2,8 Owing to food-borne pathogenicity of NTS, patients commonly present with self-limiting acute gastroenteritis, but also more severe, invasive, and sometimes recurrent bacteremia in immunocompromised adults, particularly PLWH.^1,4

Unlike in typhoid fever and gastroenteritis, NTS bacteremia in PLWH has been associated with aggressive systemic infections like meningitis, endocarditis, aortic mycotic aneurysm, splenic abscess, spontaneous peritonitis, pyomyositis, other soft tissue infections, intracranial infections (particularly brain abscess, meningitis and cerebral empyema), septic arthritis, and a few case of acalculous cholecystitis.^1–4

Invasive NTS infection and related pancytopenia is scarce in the literature. In a case-based search, NTS was associated with pancytopenia in an immunocompetent patient with sepsis. ⁶ However, only bicytopenia, including leucopenia and thrombocytopenia, was found in a malignancy-related immunocompromised patient cohort infected with NTS. ⁷ Even though pancytopenia shown in the current case might be the result of both uncontrolled HIV and invasive NTS infection; earlier response to treatment supports the association between NTS infection and pancytopenia.

Hepatitis secondary to NTS is not a common presentation and this is the first case of NTS hepatitis in an HIV-infected patient in the literature. The absence of any other underlying cause for hepatitis and prompt response to antibacterial treatment suggests that the hepatitis was indeed due to Salmonella enterica subspecies enterica serovar Enteritidis isolated from both blood and stool culture, albeit with the limitation of a lack of hepatitis E evaluation. However, because the responsible microorganism was isolated and the patient responded to targeted treatment, hepatitis E infection would be unlikely. Although we have no clear explanation for the mechanism of liver injury, owing to work addressing increased aggressiveness and fatality of NTS in immunosuppressed patients, impaired host defense, in addition to NTS microorganismal factors, could be a predisposing factor.^7,9

Host defense against intracellular bacteria like Salmonella requires a functional cell-mediated immunity and lymphocytes. ⁴ HIV infection presents with significantly lower lymphocyte counts and cytokine response.^3,4 Gordon ² and Feasey et al. ¹⁰ explained the invasive pathogenesis and high rate of NTS recurrence in HIV-infected patients. Firstly, the deterioration of gastrointestinal mucosa caused by CD4 T-cell depletion, especially interleukin-17-producing T cells (Th17 cells) in HIV infection, results in impairment of integrity, repair, and maintenance of the epithelial mucosal barrier and epithelial cell expression of antimicrobial peptides, increasing susceptibility for local invasion by Salmonella. Secondly, HIV causes dysregulated cytokine response during intracellular Salmonella infection.

In NTS infection, the first target is the control of bacteremia. The first-line treatment of choice in NTS bacteremia is ceftriaxone or fluoroquinolones. ⁸ Studies showed that administration of ART was associated with reduction in both recurrence and incidence of NTS infection.^2,9,11 Therefore, it is important to initiate or continue ART in NTS bacteremia as soon as possible.

In conclusion, underlying immunosuppression should be excluded in patients presenting with NTS bacteremia, especially in the absence of typical presentation, namely gastroenteritis. On the other hand, atypical organ involvement and abnormal laboratory findings in HIV should prompt investigations for opportunistic pathogens. In the NTS infection of immunocompromised patients, the first target should be control of bacteremia and then administration of antiretroviral therapy to improve patients’ immunity.