Vibrio vulnificus Infection

Etiology

Vibrio vulnificus is a flagellated halophilic motile gram-negative curved rod. It is a resident of marine environments, such as estuaries, rivers, deltas, shorelines as well as deeper ocean surfaces. V. vulnificus enters the food chain by taking up residence in the stomachs of shellfish (primarily oysters) as well as the intestines of fish. The bacilli then infect human hosts either through the ingestion of this contaminated seafood or via direct wound contact with contaminated water or seafood.

There are three distinctive syndromic presentations of V. vulnificus infections; primary septicemia, primary wound infection, and primary (and limited) gastroenteritis.

Ingestion of the bacilli can result in a primary septicemia syndrome, which can rapidly proceed to dramatic extremity involvement. Gastrointestinal symptoms of watery diarrhea, fever, nausea, and vomiting may precede or follow the septicemia or may be completely absent. The exact portal of entry is unknown but is thought to be the small intestine or colon. Primary sepsis accounts for about 60% of all cases seen. The overall death rate for this presentation is 50%.

Wounds created in a marine environment, e.g., lacerations, punctures, abrasions, envenomation, can quickly be colonized by the bacilli, causing an intense skin reaction, and cellulitis with blistering bullae. Untreated, this may proceed rapidly from skin lesion to necrotizing fasciitis with myonecrosis, and finally to overwhelming sepsis. Primary wound presentation is seen in about 25% of all V. vulnificus cases. The overall mortality rate for wound infection approximates 25% but rises to 54% in patients with underlying hepatic disease.[3][4]

A limited gastrointestinal presentation, with sudden onset of fever, chills, watery diarrhea, nausea, and vomiting is seen. Sepsis, severe skin disease, or death in this presentation is minimal. However, since similar GI symptoms can precede the primary septicemic form, caution must be advised in assuming GI symptoms are benign. This limited GI presentation is seen in about 10% to 15% of all V. vulnificus cases seen.

Epidemiology

Though found throughout the world, most Vibrionaceae are found in warmer marine environments. The summer months have higher incidence rates of disease, and areas with subtropical monsoon-type climates are particularly prone to the proliferation of Vibrionaceae. The countries with the most documented cases of V. vulnificus are the United States, South Korea, Taiwan, Japan, and Mexico.  Disease in the southern hemisphere is minimal compared to the northern hemisphere and is thought to be related to the paucity of monsoon climates in that hemisphere. One study found the prevalence of V. vulnificus in shellfish in Mexican coastal seafood markets to be 32%.[5][6]

Host factors are a major determinant of who develops sepsis from the initial infection. Patients with chronic hepatic disease (hepatitis, cirrhosis, hemochromatosis), diabetes, malignancies, renal disease, HIV, or other immunocompromise represent 80% to 90% of all patients presenting with primary sepsis.[4][7]

Males are infected more frequently than females, and patients aged greater than forty are at increased risk. This age and sex disparity may link to the higher prevalence of liver disease in older males.[8]

The effect of global warming has been correlated with the increasing prevalence and virulence of the organism. This is thought to be related to rising sea temperatures and melting of polar ice caps causing increasing salinity of the water.[4][9]

Pathophysiology

The morphology of Vibrionaceae contributes significantly to its virulence. Structurally V. vulnificus is a flagellated motile halophilic bacillus with a capsular polysaccharide (CPS), a lipopolysaccharide (LPS), and specific flagellin homologous proteins (FHPs).

Capsular polysaccharides in the organism’s capsule resist host gastric acid attack, and further trigger the release of host cytokines, such as tumor necrosis factor (TNF) and interleukins-8 and interleukin-6. V. vulnificus infection blocks complement activation as well as inhibits opsonization, both necessary for bacterial eradication. Capsular polysaccharides are also are implicated in neutrophil and macrophage dysfunction. Surface pili facilitate the attachment to host cells. Flagellar elements (FHPs) are required for the development of Vibrio biofilm. Biofilm development is essential for V. vulnificus’s cytotoxicity as well as environmental survival. V. vulnificus lipopolysaccharides mediate septic shock through the release of cytokines and pyrogens.[9][10][11]

Iron uptake during host invasion enhances the cytotoxicity and virulence of V. vulnificus. Specific metabolic pathways can strip host transferrin of iron, triggering sepsis and elevating mortality. At special risk are patients with elevated iron stores, e.g., sickle cell anemia, chronic liver disease, and hemochromatosis.[7][12]

History and Physical

Patients with V. vulnificus infection may present with one of three distinct symptomatologies; 1) primary septicemia, 2) wound infection, or 3) gastroenteritis

In primary sepsis, the patient appears very ill and may even be in shock on hospital arrival. At this point, there may be no history of gastroenteritis or skin problems, though the classic skin and soft tissue findings (v.i.)  may abruptly appear.

Any infected wound sustained in seawater or brackish water raises the possibility of V. vulnificus infection. Swimmers, fishers, scuba divers, snorkelers, beach walkers, coral collectors, surfers with wounds or skin disease must be considered to have V. vulnificus amongst other likely etiologies. Even contaminated seafood contacting skin can be causative.

The patient with V. vulnificus gastroenteritis would commonly have a sudden onset of vomiting, diarrhea, fever, and abdominal pain. This is usually within 24 hours of suspect seafood ingestion. In the limited gastroenteritis presentation of V. vulnificus infection, there would be no sequelae after routine treatment. However, similar GI symptoms may precede the primary septicemic form, so caution is advised.

History of recent shellfish ingestion, especially raw oysters, or exposure to marine water with trauma should elevate suspicion of V. vulnificus infection. Questions about recent dining experiences or seafood purchases, or of recent travel to coastal areas, as well as swimming, diving, snorkeling, should be pursued.

Since chronic underlying disease raises the morbidity and mortality of V. vulnificus infection, a very detailed past medical history must be obtained. History of cirrhosis, hepatitis, hemochromatosis, sickle cell anemia, diabetes, cancers, or HIV or immunocompromise of any type is significant.

Deteriorated mental function is seen in approximately a third to one-half of septic patients on initial hospital evaluation. This may make history taking difficult.

Initial physical findings are related to the manner of presentation.

Septic patients presenting for care will generally, but not always, appear very ill. Vital signs must be determined promptly, and include blood pressure, pulse rate, respiratory rate, pulse-oximetry, core temperature, and pain level. Patients with temperatures exceeding 38 C or below 36 C should immediately initiate screening for sepsis. Similarly, patients with any marked elevation of their heart rate (greater than 90 bpm) or respiratory rate (greater than 20/min) should heighten suspicion of sepsis. Blood pressure should be measured lying, seated, and standing (unless dizziness is induced). Parameters for septic shock in adults are a systolic BP less than 90 mmHg, OR a mean arterial pressure (MAP) less than 60, or a 40 mmHg drop in systolic pressure from the patient’s known prior ‘normal’ systolic pressure. Sepsis is seen on arrival in over 50% of patients presenting with V. vulnificus.

Determination of qSOFA, SIRS, or REMS scores should be part of the initial examination. If scoring is indicative, sepsis protocols must be initiated.[13]

Acute skin findings following V. vulnificus ingestion usually appear within 24 hours of the onset of sepsis. These are usually on the lower extremities, frequently bilateral, and manifest as severe cellulitis with fluid-filled bullae, which then may become hemorrhagic. These may progress rapidly to necrotic ulceration, gangrene, and then to underlying necrotizing fasciitis with myonecrosis.

Patients with primary wound infections present with severe cellulitis, swelling, blister formation, ulceration, hemorrhagic bullae, and abscesses of a wounded area. They may rapidly go on to develop necrotizing fasciitis and myonecrosis. However, these manifestations are localized to the area of initial wounding and therefore are to be differentiated from the bilateral lower extremity pattern of skin findings in the primary septicemic presentation. Additionally, these primary wound patients are at high risk for developing bacteremia, sepsis, and limb loss.[1][13]

In the limited primary gastroenteritis presentation, focal or diffuse abdominal tenderness without peritoneal signs is common. Bowel sounds may be normal or increased. Hepatosplenomegaly is negative unless related to an underlying preexisting disease. Core temperature may be normal or slightly elevated. A rectal exam should be done, stool heme-tested, and appropriate fecal samples sent.

Evaluation

Any suggestion of early-onset sepsis (qSOFA or SIRS criteria) should initiate the acquisition of blood, stool, and wound cultures, as well as samples for complete blood count, comprehensive metabolic panel, lactic acid, coagulation panel, and arterial blood gas. Appropriate fluid resuscitation, vasopressor support, and invasive monitoring should not be delayed pending testing and definitive diagnosis. Multiple organ dysfunction syndrome (MODS) can complicate V. vulnificus infection early. Elevated WBC with a left shift and the presentation of early band forms are indicative of acute infections and may be markers for sepsis. Abnormal clotting studies, decreased platelets, increasing creatinine may presage MODS. Elevated CPK is seen with muscle necrosis. Decreased WBC (<4000) or decreased core temperature (<36 C) may indicate severe sepsis.[14][15]

Clinical suspicion or history of underlying hepatic disease, diabetes, malignancies, AIDS, or other immunosuppressive syndromes should trigger the ordering of targeted lab studies. CT or MRI imaging is useful in identifying underlying necrotizing fasciitis and myonecrosis. These may show swollen tissues, foci of an abscess, or fluid collections. These studies may also be used for guided drainage procedures.

Recently a rapid stool PCR assay was introduced, which can identify all three Vibrionaceae (cholera, parahaemolyticus, and vulnificus) as well as a multitude of other known enteric pathogens. Norovirus, Rotavirus, Astrovirus, Sapovirus, Clostridia difficile, Campylobacter, Salmonella, Shigella, E. coli, including EPEC and ETEC, Yersinia, Cryptosporidium, Giardia lamblia, Entamoeba histolytica, and Cyclospora are all included in this multiplex PCR panel. A recent multicenter evaluation of the QIAstat GIP found a sensitivity of 98% (CI 96% to 99%, p<0.05) in detecting pathogens.

Skin lesions, abscesses, bullae, and necrotic ulcers should be cultured and gram-stained. V. vulnificus will stain as a gram-negative rod.

Real-time PCR testing of blood samples and wound exudate for V. vulnificus has shown almost 100% sensitivity and specificity in detecting the bacillus.  Also, elevated real-time polymerase chain reaction (PCR) for V. vulnificus DNA loads in the blood is predictive of increased mortality. Elevated TNF-alpha levels on admission blood were also correlated with higher mortality.

Treatment / Management

Recognition of septic shock should initiate prompt resuscitative efforts. Facility-based sepsis protocols are essential in guiding management.

Skin cellulitis and blisters should be cultured. Necrotic skin lesions should be debrided. Cutaneous abscesses should be drained. Topicals, such as silver sulfadiazine, should be used to cover infected skin. Underlying necrotizing fasciitis and myonecrosis demand prompt surgical debridement and fasciotomy. This is imperative to prevent limb necrosis and subsequent amputation. As always, adequate fluid resuscitation, an adequate airway, and vasopressors as necessary should precede any septic patient going to the operating room. Patients with necrotizing fasciitis who do not receive surgical debridement promptly have a very high mortality rate.[16](B3)

Correct antibiotic selection and administration should immediately follow cultures. However, delay in obtaining cultures should never hinder the prompt administration of antibiotics. Combination antibiotic therapy is recommended. However, multiple antibiotic resistance has been found in up to 50% of Vibrio infections.[17]

In vitro susceptibility has shown that third-generation cephalosporins, tetracyclines, carbapenems, fluoroquinolones, sulfa-trimethoprim, piperacillin-tazobactam, and aminoglycosides are all effective against V. vulnificus. However, the CDC recommends combination therapy with intravenous ceftazidime with either a quinolone (ciprofloxacin) or a tetracycline (doxycycline). Intravenous ciprofloxacin, in combination with IV doxycycline or IV tigecycline, has also been used with success.  Of note, patients who were septic on arrival and given appropriate antibiotics within 24 hours of admission still had a mortality rate of approximately one-third. Mortality approaches 100% when the administration is delayed past 72 hours.[18][19]

The management of primary, limited gastroenteritis should include fluid replacement, antipyretics, analgesics, and anti-emetics.  Fluids, urine output, electrolytes, as well as renal function should be closely monitored and used to direct replacement therapy.

Current research activity is seeking the development of a vaccine against V. vulnificus.[20]

Differential Diagnosis

The sudden appearance of severe blistering and cellulitis may be seen in pemphigus, pemphigoid, Steven-Johnson syndrome, toxic epidermal necrosis, erythema multiforme; group A streptococcus, pseudomonas, clostridial or Aeromonas infection; radiation exposure, scalding, or UV exposure.

Any appearance of such skin findings, particularly on both lower extremities, following shellfish ingestion, should immediately suggest V. vulnificus infection.

Patients coming in with similar lesions (cellulitis, blistering, bullae, ecchymosis) on an extremity recently wounded in an aquatic environment is V. vulnificus until proven otherwise. Other causes could be skin reaction to applied medicaments (iodine, silver sulfadiazine, chlorhexidine), local hypersensitivity to tape, or concomitant sunburn or applied heat

Acute infectious gastroenteritis may be caused by a multitude of viral, bacterial, parasitic, and protozoan pathogens. Viruses predominate (60%), with noroviruses, rotaviruses, and adenoviruses accounting for many cases. Bacterial etiologies are second, with salmonella, staphylococcus, campylobacteria, E. coli (enteropathogenic E. coli, enterotoxigenic E. coli, enterohemorrhagic E. coli, enteroinvasive E. coli ), Bacillus cereus, Shigella, Yersinia, Vibrionaceae, and Clostridia (C. perfringens and C. difficile). C. difficile is highly suspect in nursing home acquired gastroenteritis. Protozoa Giardia lamblia, Entamoeba histolytica, and Cryptosporidium are responsible for a smaller percentage of cases. Finally, intestinal parasites, such as Enterobius vermicularis, Ancylostoma duodenale, and Necator americanus, are all causative agents.

Non- infectious gastroenteritis is seen much less frequently than infectious and may be related to conditions such as Crohn disease, irritable bowel syndrome, diabetes, lactose intolerance, or medications such as NSAIDs or colchicine are implicated in acute gastroenteritis presentations.

Prognosis

V. vulnificus is a lethal disease. All-case overall mortality is approximately 35%. Mortality rates approaching 50% to 60% are seen in patients who present with underlying hepatic or immunosuppressive disease, as compared to 16% in those without an underlying disease (risk ratio 1.84, 95% CI 1.41-2.85). All patients presenting with sepsis have an overall mortality rate of 50%, but those treated with antibiotics after 72 hours (from arrival) have mortality rates approaching 100%. Delayed surgical debridement of patients manifesting necrotizing fasciitis and myonecrosis have mortality rates approaching 100%. The overall death rate for all patients presenting with wound infection is 25%. Death in patients manifesting primarily limited gastroenteritis is rare.[4]

Though the prevalence of V. vulnificus infection is low, it is the leading cause of all seafood-related deaths in the United States (95% of all cases).[8]

Certain serologic markers are useful not only for diagnosis but in mortality prediction. Tissue necrosis factor (TNF-alpha) level and real-time PCR V. vulnificus DNA load level in blood sampled on arrival are both significantly higher in those dying as opposed to those surviving.

Complications

The major complications of V. vulnificus infection are sepsis, necrotizing fasciitis, myonecrosis, and extremity gangrene. The latter frequently ending in amputation.

Necrotizing fasciitis is a severe life-threatening infection of the soft tissues, involving subcutaneous fat, contiguous fascial sheets, and potentially underlying musculature. The latter is defined as myonecrosis. Necrotizing fasciitis is frequently blamed on ‘flesh-eating bacteria’ in the lay literature. The limbs are the most frequent anatomic location, but occasionally the perineum is involved. Underlying diabetes, hepatic disease, malignancy, intravenous drug abuse, and immunosuppression are all risk factors for its development.[21]

Rarer complications of V. vulnificus include meningoencephalitis, peritonitis, and pneumonitis.