Vibrio Infections

The Vibrionaceae family includes the genera Vibrio, Plesiomonas, and Aeromonas. Members of the family Vibrionaceae are natural inhabitants of sea water but can also be found in fresh water. Vibrio species are oxidase-positive, gram-negative bacilli. With the exception of nonhalophilic Vibrio species, such as Vibrio cholerae and Vibrio mimicus, all Vibrio species require saline for growth.

Vibrio species can produce multiple extracellular cytotoxins and enzymes that are associated with extensive tissue damage and that may play a major role in the development of sepsis.

Table 1. Noncholera Vibrio Species and Associated Clinical Presentations (Open Table in a new window)

V vulnificus lives in areas where the temperature exceeds 18°C. In the United States, it is found in the coastal waters of the Gulf of Mexico, ^[10] New England, and the northern Pacific. Low-to-moderate salinity (15-25 parts per thousand) provides the most favorable growing condition for V vulnificus, and, conversely, high salinity (>25 parts per thousand) adversely affects its survival. Similar to the effect of high salinity, low seawater temperature (< 10°C) significantly inhibits the growth of V vulnificus. V vulnificus is ingested by filter-feeding mollusks such as oysters, mussels, clams, and scallops. During the warmer months, the concentration of bacteria can be as high as 1 X 10⁶ bacteria per gram of oyster. ^[11]

It is hypothesized that high salinity supports the proliferation of Bacteriovorax, the predatory bacterium that may infect and kill Vibrio bacteria, particularly V parahaemolyticus and V vulnificus. ^[12]

Several mechanisms contribute to the virulence of V vulnificus. Iron is an important growth factor. However, because free iron is virtually absent in humans, the organism produces siderophores that acquire iron from transferrin or lactoferrin and deliver it to the bacteria. Conversely, the inability to produce siderophores leads to reduction of virulence. Hepcidin, a natural cysteine-rich peptide, has recently been suggested to possess important antibacterial activity. It is possible that inadequate expression of hepcidin in patients with liver disease predisposes them to serious infections, including those caused by Vibrio species. ^{[13, 14]}

Clinical conditions associated with increased free iron, such as hemochromatosis or hemolytic anemia, represent a major risk factor for disseminated Vibrio infections. In addition, V vulnificus produces several other virulence factors, including proteases, hemolysins, and cytolysins. One in particular, a thermolysin-like metalloprotease, activates the bradykinin pathway, causing an increase in vascular permeability. This metalloprotease is far more efficient at activating human enzymes than those of other Vibrio species, possibly explaining why V vulnificus causes severe skin damage and necrotizing fasciitis. ^[15]

A study in mice, however, has shown that metalloprotease is not necessarily fundamental for the virulence of V vulnificus. The absence of protease activity resulted in increased cytolysin activity that may have contributed to the enhanced virulence. ^[16] On animal models, a protease-deficient mutant of V vulnificus was as virulent as the wild-type strain.

The ability of V vulnificus to express a capsular polysaccharide on its cell surface also corresponds to an increased virulence. It allows the bacteria to circumvent the host’s immune system and to cause extensive tissue damage and septicemia. Besides environmental factors such as temperature and aeration, V vulnificus can alter the amount of capsular polysaccharide displayed on its surface. ^[17]

The gene pyrH is essential for in vivo survival and growth of V vulnificus in infected mice and is likely associated with its virulence. Clinical isolates of V vulnificus, but not environmental isolates, caused extensive damage to macrophages in animal models, possibly explaining the lethal effects of this infection. PyrH plays a significant role in catalyzing the phosphorylation of UMP to UDP, which subsequently is used in the synthesis of pyrimidines. The numerous attempts to uncover the biochemical profile of pyrH may lead to a novel set of antimicrobial agents. ^[18] In addition, photodynamic therapy (PDT) with toluidine blue in mice has been found to be curative in otherwise-fatal V vulnificus wound infections. ^[19]

HlyU is a transcriptional regulator required for the activation of various virulence genes in Vibrio species. In V.vulnificus, HlyU regulates the expression of the major pore-forming toxins (PFT), induces the expression of vvhA, rtxA, and plpA encoding hemolysin, multifunctional-autoprocessing repeats-in-toxin (MARTX), and phospholipase A2 by directly binding to the promoter region. A non-toxic small molecule such as f ursultiamine hydrochloride (FTH) or CM14 inhibits HlyU-regulated toxin genes and enhances survival of mices infected with V vulnificus. ^{[20, 21]}

Two major virulence factors in pathogenic V parahaemolyticus strains include a thermostable direct hemolysin (TDH) and a thermostable direct hemolysin-related hemolysin (TRH). TDH induces beta-hemolysis termed the Kanagawa phenomenon on a Wagatsuma blood agar and possesses both enterotoxic and cytotoxic effects, which gives rise to the watery diarrhea associated with V parahaemolyticus infection. ^{[22, 23]}

For additional information on cutaneous V vulnificus infections, see the article Vibrio Vulnificus.

 

Frequency

United States

Between 1998 and 2010, the incidence of Vibrio infections increased by more than 115%. The CDC estimates that 80,000 Vibrio infections (100 V vulnificus, 45,000 V parahaemolyticus) and approximately 100 deaths related to Vibrio infections may occur annually in the United States. ^[24]

Of the 1,252 vibriosis cases reported to CDC in 2014, 325 (26%) were reported from Gulf Coast states, 425 (34%) from Pacific Coast states, 325 (26%) from Atlantic Coast states, and 177 (14%) from non-coastal states. The Vibrio species reported most frequently from Gulf Coast states were V alginolyticus 91 (28%), V vulnificus 64 (21%), and V parahaemolyticus 62 (20%). The Vibrio species reported most frequently from non-Gulf Coast states were V parahaemolyticus 543 (59%), V alginolyticus 148 (16%), and V vulnificus 60 (7%). ^[25]

Vibrio infections are acquired through consumption of contaminated raw or undercooked shellfish such as oysters, clams, mussels, or crabs. Exposure of wounds to contaminated seawater, injury caused by contaminated seashells, and shark and alligator bites are potential alternative sources of infection (see Table 2).

V parahaemolyticus is the leading cause of seafood-associated gastroenteritis in the United States. ^[26] During a large outbreak of gastroenteritis in July 2004 in the Gulf of Alaska, V parahaemolyticus caused illness in almost one third of cruise ship passengers who consumed Vibrio-contaminated oysters. From May to July 2006, health departments of New York City, New York state, Oregon, and Washington state reported a total of 177 cases of V parahaemolyticus gastroenteritis. Of these reported cases, 113 (64%) involved residents of Washington state. ^[27]

The Pacific Northwest (PNW) strain that caused illness in 104 persons from 13 states during May-September 2013 consisted of the V parahaemolyticus serotypes O4:K12 and O4:K(unknown). Illness was associated with consumption of raw shellfish and seafood from harvest areas in Connecticut, Massachusetts, New York, Virginia, Maine, and Washington. ^[26] According to the CDC, the PNW strain is becoming endemic in an expanding area of the Atlantic Ocean, and clinicians, health departments, and fisheries departments should be prepared for this foodborne infection in spring 2014. ^[28]

The CDC reported that as of September 18, 2018, 26 patients with illnesses due to V parahaemolyticus were reported from Colorado, Delaware, the District of Columbia, Louisiana, Maryland, New York City, Pennsylvania, and Virginia. Illnesses in this outbreak started from April 1 to July 19, 2018. Nine patients were hospitalized but no deaths were reported. FDA and regulatory officials in Maryland traced back the source of the crab meat from restaurants and grocery stores and identified potential multiple Venezuelan suppliers of crab meat linked to the outbreak. ^[29]

During June–August 2023, widespread heat waves and above-average sea surface temperatures occurred in the United States. Eleven persons infected with V. vulnificus were reported to health officials in North Carolina (seven), Connecticut (two), and New York (two). Nine out of these cases had at least one underlying condition such as diabetes mellitus, cancer, or heart disease. Waterborne transmission of V. vulnificus resulting from wound exposure to marine or estuarine water along the US Atlantic coast was the route of infection in six cases, or from exposure to a cut on the hand while handling raw seafood in two cases. Four patients had septic shock; five patients died. ^[30]

With around 40 cases reported to the CDC each year since 2000, non-O1 and non-O139 V cholerae are the third most commonly reported group of Vibrio infections. Non-O1 and non-O139 infections are seasonal, with a peak in the late summer and early fall. Diarrhea is the most common presentation. However, non-O1 V cholera has been reported with disseminated infections and high mortality rate due to necrotizing fasciitis and primary sepsis. ^[31]

Based on probable incidence of Vibrio infections and the related costs, V vulnificus ($233 million) and V parahaemolyticus ($20 million) are the first and third most costly marine-borne pathogens. ^[32]

Table 2. Clinical Presentation Rates of Pathogenic Vibrio Infections (Open Table in a new window)

International

Noncholera Vibrio infections are commonly reported in areas such as Japan, Taiwan, China, Hong Kong, Korea, Italy, and Israel. The high prevalence of hepatitis B infections in areas such as China and Taiwan may also contribute to the high incidence of severe noncholera Vibrio infections.

Contrary to epidemiologic patterns of Vibrio infections, only sporadic cases were reported among survivors and injured individuals following the tsunami that devastated Thailand, Indonesia, and India in December 2004.

A 2013 study conducted across 4 Southeast Asian countries (Thailand, Vietnam, Malaysia, Indonesia) found that about half of marketed seafood was contaminated with V parahaemolyticus. The prevalences were 49% in Thailand and Indonesia, 50% in Malaysia, and 70% in Vietnam. V parahaemolyticus markers were found in all types of examined seafood, including fish, shrimp, squid, crab, and molluscan shellfish. Of such, the molluscan shellfish had the highest prevalence of contamination, ranging from 63% (Thailand) to 89% (Vietnam). ^[33]

Asian countries consume seafood at a higher rate than the global average because of their coastal locations and abundant seafood supply, making them more susceptible to V vulnificus infections. ^{[10, 26]} The highest prevalence was reported in Japan, where 47.6% of the seafood samples tested positive for V vulnificus. A meta-analysis of the eligible studies estimated the overall prevalence of seafood-borne V vulnificus in Asia to be 10.47%, with bivalve shellfish, such as oysters, mussels, clams, and cockles being the most contaminated seafood.{ref 68}

Despite a high annual estimated incidence of V vulnificus septicemia in Japan (425 cases), a survey of registered emergency physicians in Japan surprisingly revealed that only 15.7% of responding physicians had a basic knowledge of this frequently fatal infection. ^[34]

In contrast to Asian countries and the USA, non-cholera Vibrio infections are less often reported in Europe. In the UK, only 57cases of V. parahaemolyticus infection were reported between 2004 and 2005, and mostly involved infections obtained via foreign travel to endemic regions. Despite sporadic infections and large outbreaks associated with V parahaemolyticus and V vulnificus have been reported in many European countries in the last several years, both of these pathogens are poorly understood in Europe because of the lack of a systematic surveillance program for non-cholera Vibrio infections together with a lack of standardized, validated methodologies and limited environmental data on the prevalence, distribution, and virulence characteristics. ^[35]  

A multicenter case-series study reported Vibrio infections in 67 patients from 8 hospitals in the Bay of Biscay, France, over a 19-year period (2001-2019). Infections mainly were caused by V alginolyticus (34%), V parahaemolyticus (30%), non-O1/O139 V cholerae (15%), and V vulnificus (10%). Infections were contracted at the beach in 55.3%, 39.5% by handling or eating seafood, and 5.3% while abroad. Most infections (82%) occurred during June–September. ^[36]

According to the European Environment Agency the rise of global sea surface temperature (SST) is one of the major physical impacts of climate change. ^[10] However, SST in coastal European seas has increased 4–7 times faster over the past few decades than in the global oceans. This local increase in SST has been linked to outbreaks of Vibrio-associated human illness caused by Vibrio cholerae non O1-non-O139, V parahaemolyticus, and V. vulnificus in several European countries. ^[35]

Mortality/Morbidity

According to CDC estimates, foodborne diseases cause approximately 48 million illnesses, 128,000 hospitalizations, ^[24]  and 3000 deaths annually in the United States. ^[1]

Foodborne noncholera Vibrio infections may occur at rate of 0.2-0.3 case per 100,000 population. In 2011, CDC estimates 4,500 cases of V parahaemolyticus infection annually, resulting in 129 hospitalizations and 5 deaths. Two hundred and seven cases of V vulnificus infection are estimated to occur annually, resulting in 200 hospitalizations and 77 deaths. ^[24]

Although Vibrio infections are not as common as Campylobacter, Salmonella, or Listeria infections, more patients with Vibrio infections die because of the high mortality rate (35-50%) associated with V vulnificus septicemia.

Among all foodborne diseases, V vulnificus infection is associated with the highest case fatality rate (39%).

Patients with cirrhosis who consumed raw oysters were 80 times more likely to develop V vulnificus infection and 200 times more likely to die of the infection than those without liver disease who consumed raw oysters. ^[37]  A 2017 case study reported V vulnificus cellulitis in a patient with a recent leg tattoo who was infected while swimming in the Gulf of Mexico. The patient had underlying chronic liver disease and died of Vibrio septic shock despite early identification of the infection and aggressive initial empiric treatment with doxycycline and ceftriaxone. ^[38]

A meta-analysis of 12 studies with 1157 patients wih V vulnificus necrotizing skin and soft tissue infections (VNSSTI) revealed a mortality rate of 53.9% in patients with hepatic disease (HD), and 16.1% in non-HD patients. Patients with HD contracted VNSSTIs were more than twice as likely as non-HD patients to die (risk ratio, 2.61). ^[39]

Of the 75 cases of V vulnificus infection reported by the FDA between 2002 and 2007, it appears that the number of oysters consumed (one oyster vs more than 24 oysters) does not relate to the interval before symptom development (0-7 days) or patient outcomes (mortality, 33% vs 25%). ^[40]

A 10-year retrospective study reported that an APACHE II score of 20 or more on the first day of admission is an accurate and reliable predictor of ICU mortality among patients with V vulnificus necrotizing fasciitis (sensitivity, 97%; specificity, 86%; NPV, 98%. ^[41]

In a retrospective study of 34 patients with V vulnificus infection, the initial arterial pH levels obtained upon hospital admission were found to be an important and more accurate prognostic indicator than the APACHE II score. Regardless of whether emergency surgery was performed and appropriate antimicrobial drug therapy administered, all 9 patients with an admission arterial pH < 7.2 died, whereas all 18 patients who had an initial arterial pH ≥7.35 survived. A pH level < 7.35 was an accurate predictor of death (sensitivity, 100%; specificity, 83%; PPV, 84%; NPV, 100%). ^[42]

Regardless of pre-existing conditions, the mortality risk increases in patients with V vulnificus infection who are hospitalized more than 2 days after symptoms develop (odds ratio, 2.9). ^[43]

A delay in performing the first fasciotomy (>24 h) after development of clinical symptoms in patients with V vulnificus necrotizing fasciitis was associated with 5-fold increase in the mortality risk.

Race

Vibrio infections have no racial predilection. Because Vibrio species are natural inhabitants of sea water, Vibrio infections are more commonly reported in states or countries bordered by large bodies of sea water. Persons with underlying medical conditions, such as alcoholism, cirrhosis, or malignancy, and recipients of organ transplants are at increased risk of Vibrio infections and serious complications. Patients with end-stage renal failure who are on continuous ambulatory peritoneal dialysis (CAPD) may develop peritonitis after eating or handling raw sea fish.

Sex

Vibrio infections can occur in all persons, regardless of sex. V vulnificus infections were reported in women who engaged in sexual intercourse in brackish water of the Gulf of Mexico. In general, V vulnificus infections are more common in males (82%), according to most reports.

Age

Persons of any age who consume or are exposed to Vibrio- contaminated food or water are at risk of developing Vibrio infection, especially if they have underlying medical conditions such as advanced liver disease.

Most patients with Vibrio wound infections and septicemia are aged 50-60 years.

The prognosis is excellent in immunocompetent patients who have acute Vibrio gastroenteritis.

In patients with Vibrio wound infection or septicemia, the prognosis is very grave and depends on the following:

• Underlying medical conditions such as cirrhosis or leukemia

• Pathogen (V vulnificus infection is associated with a 50% mortality rate.)

• Prompt initiation of effective antibiotic therapy

• Early fasciotomy and debridement

• Availability of intensive monitoring and medical care for serious complications

• Availability of reconstructive surgery and physical rehabilitation

• Vibrio vulnificus DNA load. Upon admission, patients who later died from V vulnificus sepsis had a significantly higher median DNA copy count of 2,300 copies/mL of blood compared with 316.5 copies/mL of blood in those who survived, as measured by real-time PCR. ^[44]

• Level of the serum tumor necrosis factor-α (TNF-α) measured on admission. The median level of the serum TNF-α in the non-survivor group of patients infected with V vulnificus was 261.0 pg/mL, compared with 69.5 pg/mL in the survivor group. ^[45]

Educate patients with appropriate underlying medical conditions about the serious medical illness that may be associated with the consumption of raw or undercooked seafood.

Educate patients to seek medical attention promptly if fever, nausea, abdominal cramps, diarrhea, myalgia, or severe pain develops in the lower extremities.