Introduction

Salmonella is the most complex genus in the Enterobacterales family, with a wide range of serotypes; more than 2600 serotypes have been isolated globally1 and it is a widely spread zoonotic pathogen that spreads mainly through oral infection of contaminated food and water sources.2 Human Salmonella infections are divided into typhoid fever, also known as enteric fever, caused by Salmonella typhi and Salmonella paratyphi, and a series of clinical syndromes caused by many nontyphoidal Salmonella serotypes (NTSs).3 Most patients present with acute gastroenteritis with a self-limiting course.4 A small percentage of patients develop extraintestinal disseminated infections manifesting as bacteraemia with secondary migratory lesions (eg, bone marrow, joints, heart valves, arteries, etc.) with high morbidity and mortality rates.5,6 HIV-infected patients are at high risk for the development of invasive Salmonella infections and for severe adverse outcomes due to the presence of immunodeficiency.7,8 Even in the era of combination antiretroviral therapy, nontyphoidal Salmonella remains one of the most important pathogens causing bloodstream infections in HIV-infected patients.9

Globally, there are approximately 10.9 million cases of enteric fever, resulting in approximately 116,800 deaths annually.10 Invasive nontyphoidal Salmonella infections account for approximately 3.4 million cases and more than 680,000 deaths annually.11,12 Looking further down the road, Salmonella typhimurium and Salmonella enteritidis, in particular, are increasingly becoming important public health threats in middle- and lower-income countries in Asia and Africa.13 China has a population of 1.4 billion, of which approximately 70–80% of bacterial food poisoning is caused by Salmonella.14 One study analyzed clinical data on Salmonella infections in 137 hospitals in Zhejiang Province, China, between 2018 and 2020 and reported that invasive Salmonella infections occurred in 20.9% of 6,111 patients in Zhejiang Province, of which bloodstream infections accounted for 52.8%.15 Thus, the prevalence of invasive Salmonella infections in China is not low; however, very little data from epidemiological investigations of HIV patients with coinfections of invasive Salmonella infections in China are available.

The issue of drug resistance in Salmonella, especially nontyphoidal Salmonella, has also become another major global concern. Multidrug-resistant Salmonella typhi is considered endemic in many developing countries, such as Southeast Asia,16 and drug resistance in nontyphoidal Salmonella is also high. Multidrug resistance has been reported in the literature in ≥80% of 784 NTS isolates.17 The situation in China is not encouraging either, with a total of 178 iNTS isolates in one study, and 53.4% of the isolates showed multidrug resistance.18 However, there are very few data on the drug resistance profile of invasive Salmonella infections in Chinese HIV patients.

We therefore retrospectively analyzed data on HIV-infected patients coinfected with invasive Salmonella infections at a hospital in Hangzhou, Zhejiang Province, China, analyzing the prevalence of serotypes, patient clinical presentations, outcomes, and Salmonella resistance profiles in the region to provide a baseline for the assessment of this serious disease in the Hangzhou area of China.

Materials and MethodsStudy Design and Patient Population

We retrospectively investigated all Salmonella infection patients admitted and hospitalized from January 2012 to August 2023 at Xixi Hospital, Hangzhou, China. A total of 29 cases of Salmonella infection in HIV patients were retrieved, among which 3 cases with positive stool culture only were considered noninvasive infection cases and were excluded. A total of 26 nonduplicate patients were ultimately included. Clinical information, including age, sex, season of onset, underlying disease, symptoms, laboratory results, treatment, outcome, bacterial antimicrobial susceptibility and serotypes, was collected. Meteorological information was obtained from the China Meteorological Administration. Details are shown in the flow chart (Figure 1).

Figure 1 Flow chart of the study design.

This study was performed at Xixi Hospital in Hangzhou, Zhejiang Province, China, which is a region located on the southeast coast of China with a subtropical monsoon climate. The Centre is the Hangzhou Public Health Clinical Centre, one of the key national tertiary teaching hospitals specialising in infectious diseases, and undertakes the clinical diagnosis and treatment of AIDS cases assigned by the Government.

Inclusion Criteria Patients >18 years old; Patients infected with HIV(confirmed to be positive by a primary HIV screening test in the laboratory department and HIV antibody testing in the CDC laboratory); Meets the definition of invasive Salmonella infection: symptoms consistent with invasive bacterial infection and positive cultures or metagenomic next-generation sequencing of Salmonella enterica species isolated from normally sterile body sites such as blood, cerebrospinal fluid (CSF), and bronchoalveolar lavage fluid (BALF).19 Culture and Identification

The patient’s venous blood was collected by bilateral puncture with 2 vials per side (aerobic vials(BACT/ALERT FA Plus, BioMérieux, France)+anaerobic vials(BACT/ALERT FN Plus, BioMérieux, France)) of 8–10 mL of blood per vial, or 2–3 mL of the patient’s cerebrospinal fluid was withdrawn from the bedside, inoculated directly into microbial culture vials(BACT/ALERT PF Plus, BioMérieux, France), and sent to the laboratory within 2 hours. The laboratory staff placed the culture bottles in a fully automated bacterial mycobacterial culture detection instrument (BACT/ALERT 3D, BioMérieux, France) and incubated them for 5 days. The blood culture bottles were removed immediately after the blood culture was reported to be positive, and the alarm time and growth curve were recorded immediately after smear microscopy was performed by transferring the blood plate. Alternatively, under strict aseptic operation, the BALF was collected, and the precipitate was cultured and inoculated on a blood plate. After both were cultured for 18–24 hours, the typical colonies on the plate were used for the preliminary identification of Salmonella with a fully automated microbial mass spectrometry detection system (VITEK MS, BioMérieux, France), and Isolates identified as the genus Salmonella were further investigated to detect the somatic (O) antigen and flagellar (H) antigen by slide agglutination with commercial antisera (Lanzhou Biological Products Research Institute Limited Liability Company, Lanzhou, China), and the serotype was determined according to the White-Kauffmann-Le Minor scheme. OLYMPUS CX21 microscopy was employed.

Antimicrobial Susceptibility Tests

The antimicrobial susceptibility testing in this study was done using the automated instrumental method of the MIC method. Salmonella was added to a bacterial suspension(prepared as 3.0mL 0.45% NaCL solution + 145µL 0.5–0.63 McF units)and put into an automatic bacterial analyzer(VITEK 2 COMPACT, BioMérieux, France) for detection of the relative minimum inhibitory concentration (MIC) values of different antibiotics for bacteria, and the susceptible (S), intermediate (I), and resistant (R) values for different antibiotics were obtained according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Antimicrobial susceptibility testing was performed using standard strains (A TCC700323, A TCC700327, A TCC29213 and A TCC25922) for microbiological quality control.

Antimicrobial sensitivity card using VITEK 2 AST-GN13, antibiotic discs include amikacin, ampicillin, ampicillin-sulbactam, aztreonam, cefazolin, cefepime, cefotetan, ceftazidime, ceftriaxone, ciprofloxacin, ertapenem, gentamicin, imipenem, levofloxacin, furantoin, piperacillin-tazobactam, tobramycin, cotrimoxazole. Notably, Salmonella can exhibit activity in vitro against first- and second-generation cephalosporins, cephamycin, and aminoglycosides, but clinical treatment is not effective.20 Therefore, the above categories of drugs were not included in the analysis.

Definitions

Multidrug resistance (MDR) was defined as resistance to three or more antimicrobial drugs, such as aminopenicillins (ampicillin), beta-lactam combinations (ampicillin-sulbactam, piperacillin-tazobactam), cephalosporins (ceftriaxone, ceftazidime, cefepime), monocyclic beta-lactams (aminoglycoside), carbapenems (imipenem), dihydrofolate reductase inhibitors (cotrimoxazole) and fluoroquinolones (ciprofloxacin, levofloxacin). Isolates with intermediate resistance were considered insensitive.

Community-acquired episodes were defined as episodes of illness prior to and within 48 hours of admission to the hospital. Otherwise, the episode was defined as a hospital episode.

Statistical Analysis

The data were entered into Microsoft Excel and analyzed by SPSS version 22.0 software. Continuous variables that were not normally distributed are described as medians with interquartile ranges (IQRs) and were compared using the Kruskal‒Wallis H-test. A p<0.05 was considered to indicate a statistically significant difference. The correlation between the number of cases and the mean monthly rainfall was tested using Spearman’s rank correlation coefficient.

ResultsSociodemographic and Clinical Characteristics

A total of 26 patients with invasive Salmonella infection and HIV were identified during the 11-year study period (1 in 2012, 2 in 2013, 3 in 2014, 4 in 2015, 2 in 2016, 0 in 2017,4 in 2018, 1 in 2019, 2 in 2020, 1 in 2021, 4 in 2022, and 2 in 2023) (Figure 2).

Figure 2 Distribution of the 26 invasive Salmonella cases by year of admission and serovar. The bar chart shows the number of invasive Salmonella cases diagnosed in Hangzhou in each year from 2012 to 2023, according to serovar.

Twenty-five (96.2%) of the 26 HIV patients with invasive Salmonella infection were male, and one was female (3.8%), with a mean age of 33.5 years (26.75, 46.75). Twenty-three of the patients(88.5%) presented before the initiation of highly active antiretroviral therapy. Highly active antiretroviral therapy used in the remaining three patients before the onset of the disease were tenofovir, lamivudine and efavirenz Two cases occurred in January, one in February, two in March, two in April, two in June, three in July, two in August, two in September, five in October, two in November, and three in December (Figure 3). Although the number of cases of invasive Salmonella infections occurring in the summer and fall seasons was greater, with a total of 16 cases (61.5%), there was no significant correlation between the number of cases and the average monthly rainfall (rs=0.069, P=0.841).

Figure 3 Distribution of the 26 invasive Salmonella cases and average rainfall by month. The bar chart shows the distribution of the 26 invasive Salmonella cases according to the month of admission. The average monthly rainfall over the 11-year period (January 2012–August 2023) in Hangzhou is shown in the line graph.

Symptoms were recorded in a total of 25 out of 26 patients, with 12 having diarrhea (48%), 2 having nausea (8%), 2 having vomiting (8%), and 2 having abdominal pain (8%). Abnormalities in routine stool test results at admission were present in 7 (26.9%) out of 26 patients; erythrocytes and pus cells were present in 3 (11.5%) patients; fecal occult blood was present in 4 (15.4%) patients; and a normal fecal result was observed in 13 (50%) patients. Additionally, 6 (23.1%) patients did not undergo a routine fecal test.

Eleven of the 26 patients (42.3%) were admitted to the hospital with respiratory symptoms as the main complaint, and 16 (61.5%) had lung lesions on admission computed tomography (CT); 10 of those patients had diffuse infectious lesions in both lungs and were considered to have clinical complications combined with Pneumocystis carinii pneumonia. Cavitary lesions were present in 2 patients on admission CT; in 1 patient, BALF NGS found the Salmonella enteritidis 601 sequence, and in the other patient, BALF NGS revealed a novel cryptococcal complex group 3656 sequence.

Eight of the 26 patients (30.8%) had combined intestinal lesions, including one with incomplete intestinal obstruction, three with perianal acrocyanosis, one with perianal abscess, one with adenoma of the transverse colon and duodenal bulbous ulcer, and one with a giant ulcer at the ileocecal end. The pathology was consistent with cytomegalovirus infection, which was later confirmed by perforation of the ulcer of the intestinal wall with peritonitis, and the patient was referred for surgery. One patient suffered from immunologic thrombocytopenic purpura with gastrointestinal bleeding manifested by black stools on admission to the hospital. Two patients (7.7%) had mesenteric lymphadenopathy; CT of one patient suggested multiple necrotic enlarged lymph nodes in the posterior peritoneum and mesenteric hiatus, and CT of one patient suggested multiple enlarged and necrotic lymph nodes in the posterior peritoneum and root of the mesentery. Patients were clinically diagnosed with tuberculosis in the abdominal lymph nodes, and diagnostic antituberculosis treatment was effective.

Among the 26 patients, there were 11 cases of comorbid chronic underlying diseases, including 4 cases of comorbid chronic viral hepatitis B, 1 case of comorbid chronic viral hepatitis C, 1 case of comorbid chronic viral hepatitis B and chronic viral hepatitis C, 1 case of comorbid immune thrombocytopenic purpura, 1 case of comorbid Kaposi’s sarcoma at final diagnosis, 1 case of comorbid type 2 diabetes mellitus, 1 case of comorbid hypertension and type 2 diabetes mellitus, and 1 case of combined bilateral cerebral infarct sequela, hypertension, and type 2 diabetes mellitus.

Twenty-three of the 26 patients had community-acquired infections, and three patients had nosocomial infections. The time from admission to diagnosis of invasive Salmonella infection in the three patients who developed nosocomial infections ranged from 12 to 78 days.

A total of 7 patients (26.9%) were identified as having multiple bacterial infections or even multiple opportunistic pathogen infections by culture. Cryptococcus neoformans was found in one cerebrospinal fluid culture, C. neoformans was found in two blood cultures, Cyanobacterium marneffei was found in one blood culture, C. marneffei was found in one sputum culture, Bacillus antacidus was found in one blood culture, and B. antacidus and C. marneffei were found in another blood culture.

All 26 patients were treated with parenteral antibiotics for a mean duration of 21 days (13.75, 27.25). The final outcome of treatment was assessed on the basis of the discharge record and categorised as (1) improvement: including recovery or discharge with symptomatic improvement and is able to take care of himself/herself;(2) deterioration: including death or hopeless discharge. Of these, 22 (84.6%) were discharged with improvement, 4 deteriorated, including 3 (11.6%) who were automatically discharged because of the hopelessness of treatment for deterioration, and 1 (3.8%) died. The main cause of death in these patients was respiratory failure. Detailed clinical characteristics are shown in Table 1.

Table 1 Presentation of HIV with Invasive Salmonella Infections by Serovar in the 26 Whose Isolates Were Serotyped

Isolation and Identification of Salmonella Serotypes

Twenty-four of the patients provided blood samples (92.3%), and the mean time to report positive blood cultures was 6 days (4,7.25%). In 1 patient, in addition to a positive blood culture, a cerebrospinal fluid culture revealed Salmonella group D; 3×10^2 copies/mL of Salmonella were found after arthritic fluid puncture using GenSeizer™-based metagenomic next-generation sequencing (mNGS) results. In addition, 2 patients provided alveolar lavage samples (7.7%), and the time to report positivity in the alveolar lavage fluid was 3 days in both patients.

Of the 26 serotyped isolates, 1 (3.8%) was Salmonella typhi, 5 (19.2%) were Salmonella paratyphi, and 16 (61.6%) were NTS, with 6 (23.2%) being Salmonella enteritidis and 6 (23.2%) being Salmonella Dublin; these were the most common serotypes. Another 4 strains (15.4%) had unspecified serotypes (Table 2).

Table 2 Serogroups, Serotypes and Distribution of 26 Cases of Invasive Salmonella Infections in HIV Patients

Antimicrobial Resistance Profiles

Drug sensitivity was detected for 24 of the 26 strains. Of these, 6 were TS, 15 were NTS and 3 were untyped. The in vitro resistance rates of the 6 TS isolates to ampicillin, ampicillin-sulbactam, and cotrimoxazole were 50% (3/6), 33.3% (2/6), and 50% (3/6), respectively. Overall, 16.7% (1/6) of the isolates were sensitive to ciprofloxacin, and 16.7% (1/6) were affected by ampicillin-sulbactam. All the strains were susceptible to ceftriaxone, cefepime, aztreonam, imipenem, levofloxacin, and piperacillin-tazobactam.

The in vitro resistance rates of 15 NTS isolates to ampicillin, ampicillin-sulbactam, aztreonam and ceftriaxone were 86.7% (13/15), 78.6% (11/14), 6.7% (1/15), and 6.7% (1/15), respectively. Additionally, 6.7% (1/15) of the isolates were sensitive to cefepime, 26.7% (4/15) were sensitive to levofloxacin, and 7.1% (1/14) were sensitive to ampicillin sulbactam. All the strains were susceptible to imipenem, ciprofloxacin, cotrimoxazole, and piperacillin-tazobactam. One patient had no drug sensitivity to ampicillin-sulbactam.

In vitro resistance to ampicillin and ampicillin-sulbactam was 100% (3/3) in all 3 untyped isolates. Overall, 66.7% (2/3) of the isolates were susceptible to levofloxacin. The isolates were sensitive to ceftriaxone, cefepime, aztreonam, imipenem, cotrimoxazole, and piperacillin-tazobactam; one patient had no drug sensitivity to ciprofloxacin; and two patients were sensitive to ciprofloxacin (Table 3, Figure 4).

Table 3 Study of Salmonella Serotype Resistance in 24 HIV Patients with Invasive Salmonella Infection

Figure 4 Antibiotic sensitivity pattern of the 24 invasive Salmonella cases.

Abbreviations:AMP, ampicillin; SAM, ampicillin-sulbactam; CRO, ceftriaxone; FEP, cefepime; ATM, aztreonam; IPM, imipenem; CIP, ciprofloxacin; LEV, levofloxacin; SXT, trimethoprim-sulfamethoxazole; TZP, Piperacillin-tazobactam.

Notes:*There was 1 case without ampicillin-sulbactam and 1 case without ciprofloxacin in the NTS.There was 1 case without ciprofloxacin in Untyped.

Among the MDR strains detected in 8 cases, 2 were Salmonella paratyphi C, 1 of which was resistant to ampicillin, ampicillin-sulbactam, and cotrimoxazole and was susceptible to ciprofloxacin; 1 was resistant to ampicillin and cotrimoxazole and was susceptible to ampicillin-sulbactam; 3 were Salmonella Dublin, 1 of which was resistant to ampicillin, ampicillin-sulbactam, ceftriaxone, and aztreonam and was susceptible to levofloxacin and cefepime; 2 were resistant to both ampicillin and ampicillin-sulbactam and susceptible to levofloxacin; and 1 was Salmonella enteritidis and resistant to ampicillin and ampicillin-sulbactam and susceptible to levofloxacin. Two Salmonella group D strains were susceptible to ampicillin, ampicillin-sulbactam, and levofloxacin.

Discussion

To our knowledge, this study is the first detailed report on invasive Salmonella infections in HIV-infected patients in Hangzhou, China. Previously, we focused on Cryptococcus, Mycobacterium tuberculosis, nontuberculous Mycobacteria, C. marneffei and cytomegaloviruses among the types of opportunistic infections occurring in HIV patients, and the burden of Salmonella, a large group of gram-negative bacilli, on HIV patients may be underestimated.

Salmonellosis is usually characterized by fever, abdominal pain, diarrhea, nausea and vomiting.5 In contrast, the current study showed that many patients did not experience gastrointestinal symptoms. This finding is similar to that of previous studies showing that the lack of typical diarrhea symptoms in many immunosuppressed patients with invasive nontyphoidal Salmonella infections is associated with severe cellular immune abnormalities.21 In this study, we found that many patients even started with respiratory symptoms, and a total of 7 patients clearly presented with multiple bacterial infections or even multiple opportunistic pathogen infections through multisite sampling and examination. This finding suggested that mixed infections caused by the other pathogens in HIV-infected patients tend to mask the Salmonella infection itself and are easily missed. Four out of the 26 patients had poor treatment outcomes; 3 were automatically discharged due to deterioration of their condition, and 1 died. Among these four patients, blood cultures revealed both C. marneffei and B. antacidus in one patient, blood cultures revealed B. antacidus in another patient, and lung CT suggested diffuse infection in both lungs in one patient; these findings were considered associated with Pneumocystis jiroveci pneumonia, suggesting that the prognosis of patients with mixed infections may be worse.

Twenty-three of the 26 infections in this study occurred prior to the initiation of highly active antiretroviral therapy. CD4+ T-cell counts were <200 cells/µL in all 25 patients for whom data were available, and 23 of these patients had CD4+ T-cell counts <100 cells/µL, which is similar to the findings of a previous study.22,23 The main mechanism is an imbalance in the function of monocytes and macrophages, which results in defects in effector functions such as phagocytosis, microbicidal activity and cytokine production.24 Additionally, immune evasion fails to properly phagocytose and kill bacteria in the presence of microorganisms associated with opportunistic infections. Eight of the 26 patients had combined intestinal lesions, and the gastrointestinal tract is a site of early and severe CD4+ T-cell depletion in HIV infection,25 in particular interleukin-17-producing T cells (Th17 cells). Loss of intestinal mucosal interleukin-17 cells during HIV infection may be a key mechanism by which Salmonella transmission from the gut leads to invasive disease in these patients.23 Two of the 26 patients had combined mesenteric lymphadenopathy, as demonstrated in a previous study.26 Surgical removal of mouse mesenteric lymph nodes (MLNs) led to an increase in the number of Salmonella typhimurium strains reaching systemic sites early after infection. This finding suggested that MLNs are important sites of immune protection during Salmonella infection,27 and highly active antiretroviral therapy has been shown to prevent intestinal infections by inhibiting viral replication and restoring immunity.28

In our study, Salmonella enteritidis and Salmonella Dublin were the most common serotypes, and both serotypes together caused 46.4% of the invasive infections. Previous studies have confirmed that Salmonella enteritidis and Salmonella typhimurium are the most common serotypes globally, while Salmonella Dublin is considered the most invasive serotype.16,29 There appear to be regional differences in the prevalence of Salmonella serotypes, and differences in the distribution of serotypes in a region may be related to the presence of local animal hosts or food sources.30

Published reports of invasive nontyphoidal Salmonella in Africa suggest that the disease is highly seasonal.31 This is because the ideal temperature range that favours the growth of Salmonella is 35–43°C.32 In summer, a hot and humid climate is conducive to the reproduction of microorganisms, and food is more susceptible to bacterial contamination. Hangzhou is located on the southeast coast of China and has a subtropical monsoon climate, with the summer and fall seasons from June-November. The results of this study showed that 16 cases occurred in summer and fall, which was greater than the 10 cases that occurred in winter and spring. A study in China revealed that the most common causes of outbreaks of Salmonella infections in Zhejiang Province, China, were cross-contamination, inappropriate storage temperatures, and failure to adequately heat food.33 In conclusion, Salmonella is a group of foodborne pathogens that are transmitted primarily via the fecal‒oral route, and exposure to water and food contaminated with animal feces, as well as temperature and humidity, is strongly associated with infection with this pathogen.

Antibiotic-resistant Salmonella strains have emerged globally as a result of widespread antibiotic use.1 However, few studies in China have reported the resistance rates of HIV-infected patients to Salmonella infection. In the present study, the resistance rate of Salmonella isolates to ampicillin and ampicillin/sulbactam was high, similar to the findings of previous studies in China.34 Eight patients with community-acquired infections even developed infections with MDR bacteria, which undoubtedly greatly increased the difficulty of diagnosis and treatment. Thus, resistance to commonly used antimicrobial agents for the treatment of Salmonella bacteremia is a major concern in developing countries with limited health care facilities. Monitoring antimicrobial resistance in Salmonella is important for physicians in order to develop effective treatment plans to minimize complications, and our study also provides valuable information on antibiotic resistance in HIV-infected patients with Salmonella coinfections in China.

Nonetheless, our study has several limitations. First, this was a retrospective study based on data from a single hospital, and our study was limited by this, its small sample size and potential selection bias. We were unable to calculate the incidence of invasive Salmonella infections among HIV-infected patients under ambulatory conditions in Hangzhou. This implies that further large-scale, multicenter studies are necessary. Second, not all the isolates were obtained. Therefore, we suggest that additional molecular typing methods for Salmonella be encouraged in future studies and can be used to study the mechanism of drug resistance. However, our study adds to the limited literature on invasive Salmonella infections in HIV-infected patients in China and emphasizes the need for continuous and improved surveillance of these important cases.

In summary, the clinical presentation of invasive Salmonella infections in HIV patients is nonspecific, and a CD4+ count <100 cells/µL and comorbid intestinal pathology may be important susceptibility factors. Therefore, it is particularly important to actively search for pathogens by culturing or even NGS in suspected patients during treatment.

Conclusion

Salmonella infection is an important but underappreciated burden on HIV-infected patients, and the clinical presentation is easily masked by other mixed infections. Salmonella enteritidis and Salmonella Dublin were the predominant serotypes identified in this study. Antibiotic resistance is also another easily overlooked problem in Chinese patients with HIV infected with invasive Salmonella and warrants further research and surveillance.

Ethics Statement

This study was approved by the Ethics Committee of Hangzhou Xixi Hospital (HangXiMedLunReview 2024 Study No. 007) and was conducted in accordance with the principles of the Declaration of Helsinki. Due to the retrospective nature of this study, the requirement for written informed consent was waived. The data was anonymized or maintained with confidentiality.

Acknowledgments

We thank all the participants in this study.

Disclosure

The authors report no conflicts of interest in this work.

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