Introduction

Vibrio vulnificus is a Gram-negative, halophilic, alkaliphilic marine bacterial pathogen commonly living on plankton and shellfish, especially oysters, which grow in water at temperature between 15 and 27 °C and salinity from 0.7 to 1.6% of the harbor, river, and sea junctions as well as inland salt lakes. The bacterium was reported firstly to cause calf gangrene and endotoxin shock in 1970 [1, 2], and termed V. vulnificus whose opportunistic pathogenesis of infection was reported over the world in 1979 [2, 3]. Humans can be infected after eating seafood contaminated with V. vulnificus or direct contact in a wound. V. vulnificus–associated sepsis is a fatal disease with the mortality rate over 50%, which is more severe in patients with chronic liver disease. It is highly prevalent in some coastal cities in the USA, Japan, and Taiwan.

In this report, we shared a successful diagnosis and treatment case of sepsis shock caused by V. vulnificus infection in our hospital in Shanghai, a coastal city of eastern China, and summarized the related epidemiological characteristics, pathogenetic mechanisms, clinical manifestations, and treatment methods.

Case report

A 72-year-old woman with no significant medical history was admitted to the intensive care unit (ICU) with a diagnosis of severe sepsis shock caused by an accidental sting from a river shrimp on the dorsum of the right foot 2 days before. After the sting, the patient rapidly developed vomiting, unconsciousness, incontinence, with ecchymoses and blisters around the wound on the right lower extremity. The ecchymoses expanded rapidly, and the blisters enlarged and ruptured within 12 h. The patient’s condition deteriorated rapidly, and developed sepsis shock the next day and was immediately admitted to the ICU. Physical examination revealed that the right lower limb was severely inflamed with ecchymosis and several blisters (Fig. 1a). The patient underwent debridement immediately after admission (Fig. 1b). The wound effusion was cultured, and V. vulnificus was detected within 48 h.

Fig. 1
figure 1

Progress of the right lower limb necrotizing fasciitis. a Admission day: leg wound showed inflammation, swelling, and several blisters. b Admission day: leg wound showed redness after debridement on admission day. c Day 7 after admission: skin of right lower limb appeared black and soft tissue began to show necrosis. d Day 15 after admission: skin of right lower limb showed progressive soft tissue necrosis

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Treatment measures, including anti-infection with meropenem and levofloxacin, fluid resuscitation, vasoactive agents, active debridement and dressing change, and continuous renal replacement therapy (CRRT) were applied, and vital signs were gradually improved on day 7. On the same day, magnetic resonance imaging (MRI) was performed and showed extensive swelling in the soft tissue of the right lower limb (Fig. 2a). After a series of treatments, the wound showed no improvement but instead progressed to necrotizing fasciitis (Fig. 1c, d). Computed tomographic angiography (CTA) scan on day 19 revealed stenosis and occlusion of the right posterior tibial and peroneal arteries (Fig. 2b). Finally, right below-knee amputation was carried out on day 20 after admission, and the patient achieved recovery and was discharged from the ICU on day 26.

Fig. 2
figure 2

Results of MRI and CT scan. a MRI results showed extensive swelling in soft tissue of right lower limb. b CT scan showed stenosis and occlusion of right posterior tibial artery and peroneal artery (white arrow)

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Epidemiology

V. vulnificus sepsis overtly has regional and seasonal characteristics, and is sporadic every year. More than 95% of lethal V. vulnificus infections occur in subtropical regions, especially in the western hemisphere and the Atlantic Ocean, including Europe, America, Singapore, Thailand, and Japan. In China, it is mainly prevalent in Taiwan and Hong Kong, and the southeast coastal cities of the mainland [4,5,6].

The elevated incidence of V. vulnificus infection is not limited to the abovementioned countries. Indeed, the geographical area of Vibrio-associated disease is expanding, most likely due to rising ocean temperatures [7, 8]. Some studies have also identified a relationship between Vibrio and salinity [9, 10] while others do not [11, 12], and the relationship between salinity and temperature may be complex [13]. High prevalence of V. vulnificus was found to be associated with a salinity level of 5 to 20‰, with the maximum environmental salinity tolerance of approximately 33–36‰ [14, 15].

The infection rate is higher in males than females (86.1% and 13.9%, respectively), because of higher proportion of exposure to seawater and seafood, as well as an elevated incidence of liver disease due to the higher proportion of drinking in men than women.

Studies found that global warming may have affected marine ecology as well as disease emergence in Israel [16,17,18], which may reflect the direction and path of disease transmission via the warm currents of the global world. Multiple studies have suggested that the environmental temperature is critical for the pathogenic effects of V. vulnificus [19,20,21,22,23,24,25,26]. For example, bacterial richness and virulence are closely related to water temperature. The density of V. vulnificus increases slowly at low temperature, but rapidly at normal temperature (18 to 26 °C), and stop increasing at high temperatures [20]. Cooling shellfish, immediately storing them between 0 and 4° and rationally using antibiotics could reduce the amounts of pathogenic V. vulnificus and critical events.

V. vulnificus infection has an obvious peak in summer, and most cases occur from April to November. According to previous reports, seasonal V. vulnificus infection has slightly shorter durations in Japan (from June to November) and the USA (from May to October) [27, 28]. Farmed fish and shellfish are usually harvested from April to early November with the sea coast temperature above 20 °C, the ideal temperature for V. vulnificus growth, and the tropical warm water lasts longer than that of temperate and subtropical countries or regions. It is not surprising that in warm or harvest months, wound contact with seawater, dealing with seafood, or consumption of raw seafood may lead to increased amounts of V. vulnificus infection. Although the annual average temperature of Taiwan is above 15 °C, the V. vulnificus infection rate is low during the period from December to February because of reduced fishing activities associated with the powerful northeaster waves usually that arrive in Taiwan in winter [4].

Pathogenetic mechanism

The pathogenesis of V. vulnificus sepsis is very complex, and the following factors may be associated.

CadC, cadB, and cadA activation can enhance V. vulnificus tolerance to gastric acid. Meanwhile, capsular polysaccharide (CPS) confers bacterial resistance to phagocytosis, which is related to V. vulnificus survival in vivo.

Excessive serum iron amounts can significantly increase the half-lethal rate and pathogen load of V. vulnificus. Multiple animal experiments and clinical findings show that elevated serum iron increases V. vulnificus infection through various ways of which the specific mechanisms remain unclear. Iron concentration affects V. vulnificus, which through the main ferric uptake regulator (FUR) directly or indirectly inhibits the transcription of the major regulator of quorum-sensing gene, SmcR, and affects the entire iron uptake process to escape the expression of innate immune-related genes. PAJUELO et al. [29] firstly reported FUR inhibition of bacterial metabolic regulators and transmembrane DNA ligation regulatory proteins in Vibrio [30]. It was confirmed that high serum iron levels are prominent features in many V. vulnificus infection patients [31].

Cell injury is another factor in the pathogenesis of V. vulnificus. Virulence factors of V. vulnificus, including cytolysin, repeats-in-toxin A1 (RtxAl), and extracellular protease (ECPase), can directly cause cell injury [32,33,34]. A study found that V. vulnificus enters the body and activates the MD2-TRL4-NF- κB pathway, inducing an inflammatory and anti-inflammatory reaction imbalance, which plays an important role in its pathogenesis.

Outer membrane protein U (OmpU) that binds to fibronectin as a major component of the mammalian extracellular matrix represents a secretory protein of V. vulnificus outer membrane and is involved in bacterial adhesion. In addition to the OmpU protein, V. vulnificus also has immunogenic lipoprotein A (I1pA), which acts as an adhesin and immunogen to activate intracellular TLR1/TLR2, MyD88, MAPKs, NF-κB, and AP-1 pathways by inducing Toll-like receptor 1/2 in human monocytes (THP-1), triggering an inflammatory cascade that releases a large amount of inflammation factors [34].

The cAMP-cAMP receptor protein (CRP) system regulates bacterial virulence factors, including cytolysin, metalloproteinase, and iron uptake systems. Another virulence regulator, AphB, has a wide range of functions which include acid neutralization, motility, adhesion, and pathogenicity. Recent studies have found that AphB also induces intestinal epithelial cells to produce cytokine-8 (interleukin-8, IL-8) [35]. Moreover, hemolysin considered a potential common virulence regulator of bacteria is a major regulator of V. vulnificus toxicity, regulating the repeats-in-toxin A1 (rtxA1), vvhA, and vvpE genes [36].

Clinical characteristics

The trend of V. vulnificus infection increases with climate warming and marine activities, as well as the presence of high-risk factors such as alcohol, liver disease, systemic diseases, and diabetes [29]. V. vulnificus infection mainly manifests the following clinical subtypes, including primary sepsis, traumatic infection, gastroenteritis, and basic diseases.

The pathogen enters the bloodstream through the gastrointestinal tract by eating raw shellfish such as oysters or directly through open wounds, and then induces sepsis. The main disease manifestations include acute fever, chills, shock, skin, and muscle damage. Individuals infected through gastrointestinal tract show symptoms of acute gastroenteritis including diarrhea, nausea, vomiting, abdominal pain, and dyspnea. Typical skin and muscle lesions include local or flaky erythema and ecchymosis, blood blisters with exudation, necrosis and cellulitis, necrotizing fasciitis, and muscle inflammation. After contacting with seawater or infected marine animals, skin and muscle damage rapidly develop into necrosis and lead to severe sepsis, which might result in a life-threatening condition [37, 38]. The calf lesions could progressively worsen within a few hours and quickly spread to the thigh. A definite contact history, rapidly deteriorating systemic state, and local typical bloody bullous lesions are diagnosed as important clues to detect sepsis caused by V. vulnificus infection. Hypotension or shock, rapid progression of symptoms, and multiple organ dysfunction syndrome (MODS) occur within 24–48 h in most patients, with a mortality rate exceeding 50% [39].

V. vulnificus infection more commonly occurs in fishery-processing personnel during the period from April to November [40, 41]. A history of basic diseases, such as long-term alcoholism and chronic liver disease, would increase the risk of V. vulnificus infection [42]. Previous studies have shown that individuals with impaired immune system or chronic liver diseases, such as cirrhosis, are eight times more likely to develop the disease in comparison with healthy people. Another striking observation is that V. vulnificus infection is highly associated with age, and only one death case < 25 years old of the 70 cases was reported, compared with a mortality rate of 49% in 40–60-year-old patients [43].

Treatment

After exact pathogenic diagnosis, appropriate and timely treatment is extremely important. Early susceptibility testing suggested that V. vulnificus is sensitive to various antibiotics. The US Centers for Disease Control (CDC) recommended three-generation cephalosporins combined with tetracyclines as the recommended treatment for V. vulnificus infection. Nevertheless, increasing evidence indicates that V. vulnificus has different degrees of resistance to various antibiotics worldwide and diverse sea areas in recent years [44, 45]. Antibiotic treatment of V. vulnificus–infected patients should be customized in different countries. For example, doxycycline is recommended as the first-line treatment in Italy [46]. Meanwhile, ceftazidime is recommended as the first-line treatment in the USA and India [47]. In some researches, quinolones are considered superior to tetracyclines, and cephalosporin combined with quinolones is more effective [48, 49].

Early debridement and necessary amputation play a vital role in improving prognosis of V. vulnificus–infected patients. Early surgical intervention can improve prognosis, and experienced surgeons should assess whether emergency surgery is needed to treat the infection as soon as possible [50]. In patients with severe hemodynamic instability, low platelet count and severe coagulation disorders, emergency incision, and drainage should be preferred [51]. The skin of the infected limb is incised to bluntly separate the subcutaneous tissue, and fascia is exposed until the sarcolemma under local anesthesia or venous analgesia. The method of incision is determined according to the coagulation function, skin tension, and extent of lesion. After the operation, a gauze soaked with iodophor and sulfamethazine solution is externally applied to facilitate the change of dressing and timely evaluation of the wound. The affected limb should be amputated to save life if muscle necrosis is too severe to mend.

It is necessary to admit the patient to the intensive care unit (ICU) as soon as possible to continue further intensive monitoring and comprehensive treatment. Early continuous renal replacement therapy (CRRT) is helpful in patients with MODS by eliminating endotoxin and inflammatory mediators. Non-invasive or invasive mechanical ventilation should be adopted for patients with acute lung injury or acute respiratory distress syndrome (ARDS).

Prevention

Clinical awareness is critical for the prevention of V. vulnificus infection, especially in patients with low immune function. Individuals may be infected by eating marine products contaminated with the bacteria or directly contacting the bacteria with open wounds. Fifty percent of the patients die from MODS within 48 h of onset [52]. Since V. vulnificus infection is highly lethal, its prevention is extremely important. It is advised that high-risk individuals should avoid eating raw seafood in the summer season, keeping the damaged skin or open wounds away from seawater. In case of recent exposure to seawater or seafood, patients with lower limb infection, fever, hypotension, and other symptoms should seek early diagnosis and treatment of V. vulnificus infection, as it is a critical factor in improving prognosis.

Conclusion

V. vulnificus is a deadly and opportunistic human pathogen which usually infects humans through eating seafood or direct contact with open wounds. V. vulnificus infection could rapidly progress to sepsis shock and even death. Early culture and diagnosis, rational use of antibiotics, timely debridement, and even amputation can save the patient’s life. For patients with low immune function, clinical awareness of prevention is especially important.