ARTICLE
Auteur(s) : Takaharu Ikeda1,
Shoko Kanehara2, Toshio Ohtani1, Fukumi
Furukawa1
1Department of Dermatology, Wakayama Medical
University, 811-1 Kimiidera, Wakayama 641-0012, JapanFax: (+81)
73 448 1908
2Department of Dermatology, Rinku General Medical
Center, Japan
accepté le 19 Janvier 2006
Vibrio vulnificus is a gram-negative bacterium which is found in
warm seawater. Vibrio vulnificus infection results in 3 clinical
syndromes: primary septicemia, wound infection, and
gastrointestinal diseases. The conditions which predispose to
Vibrio vulnificus are underlying diseases, particularly liver
cirrhosis. The others are liver disorders except liver cirrhosis,
hemochromatosis, diabetes mellitus, or immunocompromised host. Oral
infection after ingesting raw marine products or wound infection in
susceptible individuals such as those with chronic liver disease
can induce fulminant septicemia and a fatal outcome. These
syndromes have a poor prognosis: the mortality rate has been
reported to range from 41% [1] in Taiwan to 69.6% [2] in Japan. We
report here a surviving case of endotoxin shock due to Vibrio
vulnificus infection.
Case report
A 54-year-old man who had been diagnosed with hepatitis C, ingested
some undercooked barbecued mackerel on October 18th,
2001. About 4 hours later he had a fever, stomachache, and
diarrhea. About 12 hours later erythematous skin lesions appeared
on his right and left eyelids, and later on his limbs developed
acute pain, so he consulted the neighboring hospital. He received
corticosteroids equivalent to 1005 mg hydrocortisone with cefotiam
hydrochrolide administrated intravenously, but he fell into a state
of shock. He was conveyed to the intensive care unit of our
hospital on October 19th.
On admission his body temperature was 38.9 °C; blood
pressure 72/40 mmHg; and pulse rate 100/min. Most of the skin
lesions were annular erythema with small vesicles which surrounded
edematous pale maculae or purpura, whereas some lesions were only
purpura ( (figure
1A ) and ( B) ). The main laboratory
findings were as follows: white blood cell count 1,400/μL, red
blood cell count 365 × 104/μL, hemoglobin 12.8 g/dL,
hematocrit 36.7%, platelet count 7.9 × 104/μL,
prothrombin time 54.3%, fibrinogen 266 mg/dL, fibrinogen
degradation product 7.3 μg/mL, C-related protein 9.86 mg/dL, sodium
136 mEq/L, potassium 3.5 mEq/L, chloride 100 mEq/L, calcium 8.1
mg/dL, inorganic phosphate 4.1 mg/dL, creatinine 2.5 mg/dL, urea
nitrogen 32 mg/dL, uric acid 10.6 mg/dL, NH3 68 μg/dL, total
protein 5.2 g/dL, albumin 2.8 g/dL, creatine kinase 1869 IU/L,
lactate dehydrogenase 227 IU/L, glutamic oxaloacetic transaminase
94 IU/L, glutamate pyruvate transaminase 62 IU/L, amylase 51 IU/L.
total bilirubin 1.0 mg/dL. At first anaphylactic shock from the
mackerel with bacterial enterocolitis or necrotizing fasciitis were
suspected. A skin biopsy from the erythema lesions that was rapidly
frozen and stained with haematoxylin and eosin showed edematous
superficial perivascular dermatitis, and was negative for an
immunofluorescent study. Additional drip infusions of 500 mg
methylpredonisolone and cefotiam hydrochloride were performed.
On Day 2, most of the erythematous skin lesions had discolored
or disappeared, leaving purpura, and new skin lesions were not
observed. However, the hypotension, leucopenia, and
thrombocytopenia were exacerbated. Complicated endotoxin shock was
diagnosed according to the results of the serum endotoxin value
which was 293.2 pg/mL (normal range; 0-5 pg/mL). The treatment was
changed to tazobactam sodium/piperacillin sodium (TAZ/PIPC) drip
injections in addition to intravenous immunoglobulin therapy (IVIG)
and hemoperfusion with Polymyxin B immobilized fiber (PMX-F). IVIG
therapy aims to supplement antibodies which bind to and neutralize
toxin and opsonize bacterial cells. Polymyxin B can bind to and
neutralize lipid A which is the active center of endotoxin. PMX-F
is the column for hemoperfusion which is immobilized polymyxin B.
Hemoperfusion with PMX-F can eliminates endotoxin from the
circulation to treat septic patients. Both therapies are used for
severe endotoxin shock and sepsis.
The eruptions enlarged with hemorrhagic bullous lesions, and the
centers of these lesions underwent necrosis. Moreover, the
erythematous lesions which had withdrawn relapsed, and multiple new
erythematous or bullous lesions were identified on Days 3 ( (figure 1C ) and (
D) ) and 4. On
Day 4, the results of skin biopsies taken from the center of the
lesions on Day 2 and from purpura with blisters on the eyelids on
Day 4 revealed that the epidermis, dermis, and subcutaneous tissue
had undergone necrosis, and structures like the coccus, which were
gram-negative, were seen around the dermal vessels and on the
degenerated collagen fibers ( (figure 1E ) and ( F) ).
After Day 5, most of the erythemotous lesions disappeared,
leaving pigmentations, erosions, or ulcers accompanied by a decline
of the serum CK and CRP values. On Day 6, a culture of the biopsied
specimen from the purpura on Day 4 revealed Vibrio vulnificus.
Since the serum CRP value had declined significantly and the
severity of the eruptions was not as bad, the antibiotics were not
changed ( (figure
2A) ). There were no lesions which needed to be
debrided.
Since the serum CK values normalized, the thrombocytopenia
improved gradually, and the ulcers reduced or healed, he was
discharged 1 month after admission. After his discharge he was also
diagnosed with liver cirrhosis.
We measured the proinflammatory cytokines (serum tumor necrosis
factor (TNF) and interleukin-1β (IL-1β)) levels by ELISA and
interleukin-6 (IL-6) levels by chemiluminescent enzyme immunoassay
by SRL, Inc. on admission through to Day 3 and again 1 month after
the discharge. The serum TNF levels were less than normal at all
times (standard value: less than 5.0 pg/mL). The IL-1β level on
admission was 49 pg/ml (standard value: less than 10.0 pg/mL), but
the others were negative. The serum IL-6 values were as follows:
118,000 pg/mL on admission; 26,100 pg/mL and 7,780 pg/ml on Day 2
before and after the first hemoperfusion; 2,280 pg/mL and 2040
pg/ml on Day 3 before and after the second hemoperfusion; and 2.5
pg/mL at 1 month after his discharge (standard value: less than 4.0
pg/mL) ( (figure
2B) ).
Discussion
Several meta-analyses have showed that a short course of high dose
corticosteroid therapy for the suppression of radical septic
inflammation was ineffective in attenuating the mortality, and
increased the incidence of secondary infections [3, 4]. Recently,
however, other meta-analyses reported that a long course of low
dose corticosteroid therapy to improve the adrenal insufficiency
due to septic shock reduced mortality [5] and improved the shock
reversal [6]. This recommended therapy contains 200-300 mg/day of
intravenous hydrocortisone for 7 days [7], and clinical trials have
demonstrated that the initiation of both treatments within 8 hours
[8] and even after 48 hours [9] from the onset of septic shock were
effective. Intraveneous corticosteroid therapy equivalent to 3,505
mg of hydrocortisone was started on Day 1 according to the
suspicion of anaphylactic shock. On Day 2, although his shock state
deteriorated, the surrounding erythema discolored and new lesions
did not appear, and debridement was not needed until discharge.
Even though early comprehensive debridement has been traditionally
thought to be essential, systemic corticosteroid therapy may be
effective in preventing the enlargement of the erythematosus or
necrotic lesions.
It is known that endotoxins induce the production of excessive
cytokines such as tumor necrosis factor α, IL-1, and IL-6, which
aggravate sepsis and cause endotoxin shock. Because polymyxin B can
bind to and neutralize lipid A, which is the active center of
endotoxin, hemoperfusion using PMX-F can eliminate endotoxins from
the circulation to treat septic patients [10] and result in
interrupting the progression of the inflammatory cytokine cascades.
This treatment can prevent the progression to multiple organ
dysfunction, and increase the survival rate by improving the
hemodynamic parameters and respiratory insufficiency [11-13]. In
our case after two hemoperfusion sessions, the serum endotoxin
value decreased from 293.5 pg/mL to 30.2 pg/mL. The serum CK and
CRP levels decreased remarkably after the first and second
hemoperfusion sessions, and resolution of the septic shock was
observed earlier. Therefore for endotoxin shock due to Vibrio
vulnificus infection hemoperfusion using PMX-F was a practical
treatment.
Combination treatments with doxycyclin and ceftazidime [14] or
with cefotaxime and minocycline [15] are recommended as the
antibiotics for severe Vibrio vulnificus infection. After Vibrio
vulnificus was reported to be the pathogen, TAZ/PIPC drip
injections were administrated daily because his serum CRP values
continued to decrease and that showed that PIPC was effective
against this strain. However Oonaka [16] et al. showed that there
were some strains from clinical isolates which were resistant to
both cefotaxime and PIPC, whereas minocycline, ciprofloxacin, and
doxycycline were effective [14, 16]. Many antibiotics are
nevertheless effective against this bacterium, penicillin and
cephem antibiotics should be used according to the results of these
susceptibility tests.
The pathogenicity of Vibrio vulnificus results from its capsular
polysaccharide, cytolysin, lipopolysaccharide and so on. The
radical release of proinflammatory cytokines induced by these
substances plays a pivotal role and results in the harmful systemic
effects. The serum TNF and IL-1β values in septic shock patients
demonstrated a transient peak level at the onset and a rapid
decline to undetectable levels. In contrast the serum IL-6 value
was abnormally high during septic shock [17]. The serum level of
IL-6 has also been reported to increase significantly in Vibrio
vulnificus septicemia patients [18]. The peak IL-6 levels in septic
shock were correlated with the severity of the illness, duration of
survival, and the peak TNF levels [17, 19]. The IL-6 peak level
during septic shock was also significantly higher in non-survivors
and patients with an acute onset [19, 20].
It has been documented that after doxycycline treatment, the
serum TNF and IL-1β levels of septic patients due to Vibrio
vulnificus infection decreased significantly as compared to before
the treatment, whereas the serum IL-6 level did not change [18].
However, penicillin with a β-lactamase inhibitor and cefems are
known to have no effect on IL-1, -6, and TNF levels. Low dose
corticosteroid therapy for septic shock attenuated the inflammatory
responses due to the decreased serum IL-6 and -8 levels [21]
without immunosuppression [22], although high dose corticosteroid
therapy is not known to influence the cytokine profiles. The serum
TNF and IL-6 values have been reported to decrease in survival
patients after hemoperfusion using PMX-F [23, 24]. In addition,
IVIg was indicated a possible cause for the decline in IL-6 [25]
levels. This change in serum IL-6 level showed that hemoperfusion
using PMX-F or IVIg therapy was also useful for modulating radical
proinflammatory cytokines.
In conclusion we experienced a survival case of Vibrio
vulnificus endotoxin shock treated with antibiotics, hemoperfusion,
and immunoglobulin therapies. This case did not receive any
debridement. Although high dose corticosteroid therapy has been
reported to be ineffective or harmful, systemic corticosteroids may
resist the expansion of cutaneous lesions due to Vibrio vulnificus
primary septicemia.
Acknowledgements
This work was supported in part by a Segawa Skin Research Grant.
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