Vibrio Infections

Vibrio infections are largely classified into 2 distinct groups: Vibrio cholera infections and noncholera Vibrio infections. Historically, the noncholera Vibrio species are classified as halophilic or nonhalophilic, depending on their requirement of sodium chloride for growth.

Because most Vibrio infections are associated with the consumption of contaminated food, these infections are often considered a foodborne disease. The prevalence of noncholera Vibrio infections in the United States appears to have increased in recent years. The combination of increased water temperature and salinity where shellfish are harvested may contribute to increased contamination rates of shellfish. Although many foodborne diseases are not reportable in the United States, the Centers for Disease Control and Prevention (CDC) estimates that approximately 48 million Americans (or roughly 1 in 6) get sick with foodborne diseases annually. Of these, 128,000 are hospitalized and 3000 die. ^[1]

Since 1988, the CDC has maintained a voluntary surveillance system for culture-confirmed Vibrio infections in the Gulf Coast region (Alabama, Florida, Louisiana, Mississippi, and Texas). In 2007, the surveillance was expanded to national notification of infections caused by any Vibrio species. In 2011, the CDC estimated about 80,000 cases of Vibrio infections in the United States annually, including 45,000 cases of Vibrio parahaemolyticus infection and approximately 100 cases of Vibrio vulnificus infection. However, these figures are likely low owing to underreporting. ^[2]  

While the estimated incidence of infection with Shiga toxin–producing Escherichia coli O157:H7 (STEC O157) and species of Campylobacter, Cryptosporidium, Listeria,Salmonella, and Yersinia significantly decreased from 1998 to 2010, the incidence of Vibrio infections during this period increased 115%. ^[3]

Compared with data from 2016–2018, the incidence in 2019 increased significantly for Cyclospora (1,209%), Yersinia (153%), Vibrio (79%), STEC (34%), and Campylobacter (13%), according to a CDC report. ^[4]

Although V parahaemolyticus is the most common noncholera Vibrio species reported to cause infection, V vulnificus is associated with up to 94% of noncholera Vibrio infection-related deaths. Because clinical laboratories do not routinely use the selective medium thiosulfate-citrate-bile salts-sucrose (TCBS) for stool culture, many cases of Vibriogastroenteritis are not identified. ^[5]

A review of Cholera and Other Vibrio Illness Surveillance (COVIS) data from 1997-2006 reported that of 4754 Vibrio species–related illnesses, 1210 (25%) were nonfoodborne Vibrio infections (NFVIs). ^[6] Of note, the species most frequently isolated in these NFVIs was V vulnificus (35%), followed by Vibrio alginolyticus (29%), and V parahaemolyticus (19%). Not surprisingly, the majority of the reports came from the Gulf Coast region under surveillance (57%), followed by the Atlantic region (24%), the Pacific region (16%), and noncoastal areas (3%). Vibrio was identified in wounds (68%), blood (20%), and “other” (18%).However, a cluster of 5 patients with V. vulnificus necrotizing fasciitis was reported in the summer months of 2017 and 2018 in connection to the Delaware Bay, a previously non-endemic area. The authors postulated that rising sea temperature may lead to more cases of infection in non-endemic areas. ^[7]

In the event of a natural disaster, the disturbance to the environment may increase the risk of infectious diseases such as Vibrio infections. During the 2 weeks following Hurricane Katrina in August 2005, the CDC reported 22 new cases of Vibrio infections in Louisiana and Mississippi. V vulnificus accounted for most (82%) of these wound-associated infections. ^[8] The increased incidence of Vibrio wound infections in the residents of Gulf Coast states was most likely associated with the exposure of skin and soft-tissue injuries to the contaminated floodwaters. ^[8]

A meta-analysis consisted of 19 studies and 2227 total patients with V. vulnificus necrotizing and soft tissue infection (VNSSTI) was done to examine the spatiotemporal distribution of the worldwide reported of this serious infection and its associated mortality rate between 1966 and 2014. Regardless of the publication dates of these studies and their sample sizes, mortality rates varied widely: from 0–68.4%, and followed  a V-shape graph with the vertex located at the lowest 5-year mortality rate of 30% in years 1996-2000. However, according to the current trends of reported VNSSTI cases, the projected 5-year mortality rate might approach 50% in the futures. ^[9]

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, 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. ^[10]

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. ^[11]

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. ^{[12, 13]}

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. ^[14]

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. ^[15] 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 also alter the amount of capsular polysaccharide displayed on its surface. ^[16]

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 is subsequently 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. ^[17] In addition, photodynamic therapy (PDT) with toluidine blue in mice has been found to be curative in otherwise-fatal V vulnificus wound infections. ^[18]

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. ^{[19, 20]}

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. ^{[21, 22]}

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. ^[2]

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%). ^[23]

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. 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. ^[24] .

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. 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. ^[25]

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. ^{[26, 27]}

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. ^[28]

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). ^[29]

Despite a high annual estimated incidence of V vulnificus septicemia in Japan (425 cases; 95% CI, 238-752), 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. ^[30]

Mortality/Morbidity

According to CDC estimates, foodborne diseases cause approximately 48 million illnesses, 128,000 hospitalizations, ^[2]  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. ^[2]

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. ^[31]  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. ^[32]

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). ^[33]

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%). ^[34]

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%. ^[35]

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%). ^[36]

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). ^[37]

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 (12), 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. The median DNA copy measured by real-time PCR upon admission was 2,300 copies/mL of blood (interquartile ratio, 558 to 11,350) in patients who died of V. vulnificus sepsis was significantly higher than 316.5 copies/mL of blood (interquartile ratio, 51 to 705) in those who survived (p = 0.011). ^[38]

• 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, in contrast to 69.5 pg/mL in the survivor group (P = 0.001). ^[39]

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.