Abstract
Necrotizing fasciitis (NF) is a life-threatening infection. Skin necrosis is an important skin sign of NF. The purposes of this study was to investigate the initial skin conditions of Vibrio NF patients between emergency room (ER) to preoperative status, to compare the clinical and laboratory risk indicators of the skin necrosis group and non-skin necrosis group when they arrived at ER, and to evaluate whether initial cutaneous necrosis related to fulminant course and higher fatalities. From 2015 to 2019, seventy-two Vibrio NF patients with surgical confirmation were enrolled. We identified 25 patients for inclusion in the skin necrosis group and 47 patients for inclusion in the non-skin necrosis group due to the appearance of skin lesion at ER. Seven patients died, resulting in a mortality rate of 9.7%. Six patients of skin necrosis group and one patient of non-skin necrosis group died, which revealed the skin necrosis group had a significantly higher mortality rate than the non-skin necrosis group. All the patients in the skin necrosis group and 30 patients of non-skin necrosis group developed serous or hemorrhagic bullous lesions before operation (pā=ā0.0003). The skin necrosis group had a significantly higher incidence of APACHE score, postoperative intubation, Intensive care unit stay, septic shock, leukopenia, higher counts of banded leukocytes, elevated C-reactive protein (CRP), and lower serum albumin level. Vibrio NF patients presenting skin necrosis at ER were significantly associated with fulminant clinical courses and higher mortality. Physicians should alert the appearance of skin necrosis at ER to early suspect NF and treat aggressively by those clinical and laboratory risk indicators, such as elevated APACHE score, shock, leukopenia, higher banded leukocytes, elevated CRP, and hypoalbuminia.
Similar content being viewed by others
Introduction
Necrotizing fasciitis (NF) is a life-threatening skin and soft tissue infection with rapid and progressive clinical courses which presents a surgical emergency1,2,3. Early stages of NF were difficult to differentiate at initial onset with cellulitis, abscesses and erysipelas because they had similar skin lesions, progressive erythematous change and pain out of proportion in the emergency room (ER), which leads to delayed or missed diagnosis4,5,6,7,8,9. The cutaneous features of NF were defined three stages, and the cutaneous presentations in stage 2 and 3, such as serous-filled bullae and hemorrhagic bullae, played a crucial role in the diagnosis of NF9,10,11,12. Bullae formation indicated critical skin ischemia and was an important diagnostic clue of NF; however, not all NF patients presented bullae formation in clinical settings at ER.
Our previous studies had demonstrated hemorrhagic bullous lesions could be effectively used to differentiate NF from cellulitis at initial onset, and they were significantly associated with the gram-negative bacteria infection and mortality9,12,13,14,15,16. We also found some admitted cellulitis patients with the skin signs of erythema, swelling, warmth and tenderness at ER, revealed progressive edematous pain, hemorrhagic bullous lesions and septic conditions at the time of consultation in the ward; eventually, NF was diagnosed few hours or days after admission9,12,13. Our institution is situated on the western coast of southern Taiwan, and most of the residentsā occupations were fishermen or farmers, and Vibrio species was the leading causative pathogen of NF and related fatality in our institution9,12,13,14,15,16,17,18,19,20. Although Ī²-hemolytic Streptococcus, Staphylococcus aureus and polymicrobial pathogens were most commonly reported to cause NF in the literatures, they did not often present hemorrhagic bullous skin lesion in our previous reports9,12,13,16.
Skin necrosis is a type of tissue death caused by lack of blood supply and subsequent decay ofĀ bodyĀ tissuesĀ caused byĀ infectionĀ or vascular thrombosis; usually, it shows up as a purplish, bluish or black skin coloration, detachment of local skin, and gangrene7,11,21. We had found the gram-negative NF had a significant higher prevalence of hemorrhagic bullous formation than gram-positive NF, and Vibrio species revealed more clinical fulminant course and bullous skin progression than other pathogens did9,12,13,14,15,16,17,18,19,20. Thus, we sought to identify skin lesions in Vibrio patients, characterized by necrotic change, purple skin discoloration, or skin erosion, which could be another alert signs for suspecting NF for physicians at ER.
The purposes of this study was to investigate the initial skin conditions of Vibrio NF patients between ER to preoperative status, to compare the clinical and laboratory risk indicators of the skin necrosis group and non-skin necrosis group when they arrived at ER, and to evaluate whether initial cutaneous necrosis related to fulminant course and higher fatalities.
Method
Patient selection and data extraction
We performed a retrospective cohort study evaluating 299 patients with diagnosis of necrotizing fasciitis of limbs who were admitted to ER and underwent surgical intervention at Chia-Yi Chang Gung Memorial Hospital from January 2015 to December 2019. The retrospective study was conducted in accordance with the ethical standards of the institutional and national research committee and the guidelines of the Declaration of Helsinki, and was approved by the Institutional Review Board (202001656B0 and 201801530B1B0) of Chang Gung Medical Foundation and Chang Gung University. Due to the nature of this retrospective study and the preserved anonymity of patients, a waiver of informed consent was obtained from Chang Gung Medical Foundation/IRB.
Routinely blood cultures and pictures of skin condition were collected at ER. We took pictures of skin lesions before and after surgery, and obtained the wound cultures with sterile cultrate swabs during surgery. The cultured specimens of patients were confirmed by microbiologic evaluation few days after surgery. The inclusion criteria was as followed: (1) NF was confirmed by surgery when necrotic tissue was observed macroscopically and histopathologic confirmation by the presence of necrotic tissues at the time of excisional debridement, fasciotomy, or immediate limb amputation, (2) Vibrio species infection that was detected in wound or blood culture. A total of 72 monomicrobial Vibrio NF patients were included in this study (Fig.Ā 1).
Clinical assessment
Patient characteristics including age, sex, site if infection, antibiotics usage, Acute Physiology and Chronic Health Evaluation (APACHE) II scores upon admission, use of postoperative intubation, ICU stay, length of hospitalization, amputation, as well as mortality rates were documented after reviewing the medical records. Furthermore, laboratory examinations and clinical presentations were collected upon arrival at ER.
The NF patients with skin necrosis mentioned in medical records and pictures taken at ER, such as purplish, bluish or black skin coloration, detachment of local skin, gangrene, skin breakdown, and foul-smelling discharge leaking, were classified into skin necrosis group. Cutaneous manifestations of hemorrhagic or serous bullae formation were also recorded before preoperative status by taking pictures in the operation room (OR). We identified 25 patients for inclusion in the skin necrosis group and 47 patients for inclusion in the non-skin necrosis group who met the criterias.
Statistical analysis
Statistical analyses were performed with the use of SPSS version 18.0 software (SPSS, Inc., Chicago, IL, USA). Continuous data were presented as meansāĀ±āSD and categorical variables were expressed as absolute number or percentages. We used the two-tailed t-test for continuous variables and the Fisher exact test for categorical variables to examine significant relationships between risk factors and outcomes between skin necrosis and non-skin necrosis groups. A value of pā<ā0.05Ā (two tailed) was considered significant.
Ethics approval and consent to participate
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (202001656B0 and 201801530B1B0) of Chang Gung Medical Foundation and Chang Gung University.
Results
Seven patients died, resulting in a mortality rate of 9.7%. Six patients had received amputation with an amputation rate of 8.3%. Forty patients had upper limbs and 32 patients had lower limbs involvement. Six patients of skin necrosis group (24%) and one patients of non-skin necrosis group (2.1%) died, which revealed that the skin necrosis group had a significantly higher mortality rate than the non-skin necrosis group (pā=ā0.005) (Table 1).
Broad-spectrum antibiotics were initially administered to patients with suspecting Vibrio NF at ER: ceftriaxone and doxycycline in 52 cases, ceftriaxone alone in 12 cases, ceftriaxone and vancomycin in 4 case, and ceftriaxone with teicoplanin in 4 case. These antibiotics were continued after surgery under the supervision of infectious doctors. Vibrio vulnificus were the most dominant pathogen, followed by Vibrio cholerae non-O1 and Vibrio parahaemolyticus. All Vibrio isolates were susceptible to ceftazidime, ceftriaxone, levofloxacin, and tetracycline.
Age, sex, seawater and seafood contact, fever, tachycardia, bacteremia, amputation rate and hospital stay did not differ significantly between skin necrosis group and non-skin necrosis group. The skin necrosis group had a significantly higher incidence of elevated APACHE score, postoperative intubation, ICU stay, and systolic blood pressure (SBP)ā<ā90Ā mmHg than non-skin necrosis group. all the patients in the skin necrosis group had revealed progressive skin gangrene change and hemorrhage bullae formation before operation (Fig.Ā 2). Thirty-two patients (68.1%) of non-skin necrosis group developed hemorrhagic or serous bullous skin lesion, and 15 patients showed intact skin without bullous lesion preoperatively in the OR (Figs.Ā 3 and 4). This indicated initial skin necrosis presentation at ER had significantly developed to NF (pā=ā0.0007).
We found that the patients of skin necrosis group had a significantly higher incidence of WBC countsā<ā3500 cells/mm3 (normal ranges, 3500 to 11,000 cells/mm3), higher counts of banded leukocytes, elevated C-reactive protein (CRP), and lower serum albumin level than those patients in non-skin necrosis group (Table 2).
Discussion
NF is a surgical emergency due to its high mortality rate, and the most common early signs of NF are erythema, local warmth, skin sclerosis, and edema1,2,3,4,5,6,7,8,9. Kiat et al. had reviewed that the most reliable cutaneous signs were swelling (79ā80.8%) and erythema (69.6ā70.7%), but they could delay the diagnosis of NF because the skin lesions of involved limbs presented as similar as cellulitis at ER8,9,11. Serous or hemorrhagic bullae formation was considered the key sign to distinguish early and late stages of NF; however, not all patients with NF could demonstrate bullae formation initially9,10,11,12,13,14,15,22,23.
Vibrio species are the most frequent causative organisms of monomicrobial NF, and were proved to occur more rapidly progressive and fulminant clinical courses than other pathogens in our institution12,13,14,15,16,17,18,19,20,22. According to our report, 58 patients (80.6%) with Vibrio infections had a recent history of contact with seawater or raw seafood, which we could early suspect Vibrio NF at ER, and ceftriaxone with/without other appropriate antibiotics under the supervision of infectious doctors appears to have a clinical effectiveness for the treatment of Vibrio NF12,13,14,15,16,17,18,19,20. Hemorrhagic bullous presentation has become an important clinical sign for suspecting NF and surgical indicator; however, most of Vibrio patients had presented the cutaneous signs of erythema, swelling and warmth initially at ER, and then quickly developed to serous or hemorrhagic bullae and sepsis few hours later9,12,13,14,15,23. We found 30 NF patients (63.8%) of non-skin necrosis group developed hemorrhagic or serous bullous skin lesion before emergent surgery, which revealed that the primary pathological site of necrotizing fasciitis affected the deep fascia, and initial cutaneous manifestations did not necessarily reflect the underlying progressive ischemia and destruction7,10,11. So we focused on Vibrio-related NF patients, who could be observed the clinical course in a short time.
The pathological process of NF is that bacteria proliferate within the superficial fascia and produce enzymes and toxins to spread through the fascia which are diffused inside the arteriolar and capillary vascular systems. Finally, the microorganism proliferation leads to rapid obstruction of the vessels by chemical intimal and subintimal lesions, and epidermal-dermal necrosis may rapidly appear at the skin surface which can quickly progress to hemorrhagic bullae24,25,26. Although skin necrosis and crepitus formation were classified as late stage of NF, and they accounted for 23 to 24.1% of reliable cutaneous signs, which may progress to blisters, serous bullae, and hemorrhagic bullae10,11. Vibrio species can produce various extracellular toxic factors, such as lipase, protease, enterotoxin, cytolysin, hyaluronidase, and hemolysin, to cause serious collagenolytic, hemorrhagic or edematous skin damage in the extremities by degrading the vascular basement membrane and the type IV collagen27,28,29. We observed that 34.7% (25/72) of Vibrio patients had revealed skin necrosis at ER before the definite diagnosis of NF. Thus, we used the skin necrosis as the initial skin sign to diagnose NF at ER.
In this study, the skin necrosis group revealed significantly higher incidences of elevated APACHE score, postoperative intubation, ICU stay, shock at ER, leukopenia, higher banded leukocytes, elevated CRP, and hypoalbuminia than non-skin necrosis group, which indicate that NF patients with initial skin necrosis presentation at ER experienced more fulminant clinical courses and higher mortality rate than those NF patients without skin necrosis. Khamnuan et al. reported they had found 26.7% of NF patients (403/1507) presented skin necrosis, and the appearance of skin necrosis at the time of diagnosis had been identified as a significantly predictive factor for amputation, which the causing pathogens did not include Vibrio species in their study7. Therefore, we confirm the cutaneous sign of skin necrosis at ER may act as alternative indicator for suspecting NF and predicting the poor prognosis.
Our study needs to be viewed in light of some limitations. First, we assessed only the initial skin condition of Vibrio NF patients at the emergency department. Our previous study had reported NF patients with gram-negative bacterial infection were significantly associated hemorrhagic bullae13. A further cohort study for investigating the initial skin condition of gram-positive and gram-negative NF may be needed. Second, our study encompassed small sample size and our participants were recruited from only one medical institution. More larger-scale studies are warranted to clarify our viewpoint.
In conclusion, Vibrio NF patients presenting skin necrosis at ER were significantly associated with fulminant clinical courses and higher mortality. Physicians should alert the appearance of skin necrosis at ER to early suspect NF and treat aggressively according to those clinical and laboratory risk indicators, such as elevated APACHE score, shock, leukopenia, higher banded leukocytes, elevated CRP, and hypoalbuminia.
Data availability
All data generated or analysed are included in this published article s. Further information is available from the corresponding author on reasonable request.
Abbreviations
- NF:
-
Necrotizing fasciitis
- ICU:
-
Intensive care unit
- ER:
-
Emergency room
- APACHE:
-
Acute Physiology and Chronic Health Evaluation
- WBC:
-
White blood count
- CRP:
-
C-reactive protein
References
Wong, C. H. et al. Necrotizing fasciitis: Clinical presentation, microbiology, and determinants of mortality. J. Bone Jt. Surg. Am. 85, 1454ā1460 (2003).
Elliott, D., Kufera, J. A. & Myers, R. A. The microbiology of necrotizing soft tissue infections. Am. J. Surg. 179, 361ā366 (2000).
Fontes, R. A. Jr., Ogilvie, C. M. & Miclau, T. Necrotizing soft-tissue infections. J. Am. Acad. Orthop. Surg. 8, 151ā158 (2000).
Borschitz, T., Schlicht, S., Siegel, E., Hanke, E. & von Stebut, E. Improvement of a clinical score for necrotizing fasciitis: āPain out of proportionā and high CRP Levels aid the diagnosis. PLoS ONE 10, e0132775 (2015).
Chang, C. P., Fann, W. C., Wu, S. R., Lin, C. N. & Hsiao, C. T. Lactate on emergency department arrival as a predictor of in-hospital mortality in necrotizing fasciitis: A retrospective study. J. Orthop. Surg. Res. 14, 73 (2019).
Cohen, L. et al. Differentiating upper extremity necrotizing soft tissue infection frome serious cellulitis and abscess. Cureus 13, e17806 (2021).
Khamnuan, P., Chongruksut, W., Jearwattanakanok, K., Patumanond, J. & Tantraworasin, A. Necrotizing fasciitis: Epidemiology and clinical predictors for amputation. Int. J. Gen. Med. 8, 195ā202 (2015).
Misiakos, E. P. et al. Current concepts in the management of necrotizing fasciitis. Front. Surg. 1, 36 (2014).
Tsai, Y. H. et al. Bullous skin signs and laboratory surgical indicators can quickly and effectively differentiate necrotizing fasciitis from cellulitis. Int. J. Infect. Dis. 128, 41ā50 (2023).
Wang, Y., Wong, C. & Tay, Y. Staging of necrotising fasciitis based on the evolving cutaneous features. Int. J. Dermatol. 46, 1036ā1041 (2007).
Kiat, H. J., En Natalie, Y. H. & Fatimah, L. Necrotizing fasciitis: How reliable are the cutaneous signs?. J. Emerg. Trauma Shock 10, 205ā210 (2017).
Huang, T. Y. et al. Different types of bullae of limbs with necrotizing fasciitis predict different outcome: A prospective study. Infection 49, 135ā144 (2021).
Chen, H. Y. et al. Rational use of ceftriaxone in necrotizing fasciitis and mortality associated with bloodstream infection and hemorrhagic bullous lesions. Antibiot. Basel 11, 1454 (2022).
Hsiao, C. T., Lin, L. J., Shiao, C. J., Hsiao, K. Y. & Chen, I. C. Hemorrhagic bullae are not only skin deep. Am. J. Emerg. Med. 26, 316ā319 (2008).
Hsiao, C. T., Weng, H. H., Yuan, Y. D., Chen, C. T. & Chen, I. C. Predictors of mortality in patients with necrotizing fasciitis. Am. J. Emerg. Med. 26, 170ā175 (2008).
Huang, T. U. et al. Predictors for gram-negative monomicrobial necrotizing fasciitis in southern Taiwan. BMC Infect. Dis. 20, 60 (2020).
Tsai, Y. H., Hsu, R. W., Huang, K. C. & Huang, T. J. Laboratory indicators for early detection and surgical treatment of Vibrio necrotizing fasciitis. Clin. Orthop. Relat. Res. 468, 2230ā2237 (2010).
Tsai, Y. H. et al. Microbiology and surgical indicators of necrotizing fasciitis in a tertiary hospital of southwest Taiwan. Int. J. Infect. Dis. 16, e159āe165 (2012).
Tsai, Y. H. et al. Bacteriology and mortality of necrotizing fasciitis in a tertiary coastal hospital with comparing risk indicators of methicillin-resistant Staphylococcus aureus and Vibrio vulnifcus infections: A prospective study. BMC Infect. Dis. 21, 771 (2021).
Tsai, Y. H. et al. Comparison of surgical outcomes and predictors in patients with monomicrobial necrotizing fasciitis caused by Vibrio vulnificus, Aeromonas hydrophila and Aeromonas sobria. Surg. Infect. 23, 288ā297 (2022).
Tottoli, E. M. et al. Skin wound healing process and new emerging technologies for skin wound care and regeneration. Pharmaceutics 12, 735 (2020).
Chang, C. Y. et al. In-hospital mortality associated with necrotizing soft tissue infection due to Vibrio vulnificus: A matched-pair cohort study. World J. Emerg. Surg. 17, 28 (2022).
Chang, C. P., Hsiao, C. T., Lin, C. N. & Fann, W. C. Risk factors for mortality in the late amputation of necrotizing fasciitis: A retrospective study. World J. Emerg. Surg. 13, 45 (2018).
Wong, C. & Wang, Y. The diagnosis of necrotizing fasciitis. Curr. Opin. Infect. Dis. 18, 101ā106 (2005).
Morgan, M. S. Diagnosis and management of necrotizing fasciitis: A multiparametric approach. J. Hosp. Infect. 75, 249ā257 (2010).
Shimizu, T. & Tokuda, Y. Necrotizing fasciitis. Intern. Med. 49, 1051ā1057 (2010).
Morris, J. G. Jr. Cholera and other types of vibriosis: A story of human pandemics and oysters of half shell. Clin. Infect. Dis. 37, 272ā280 (2003).
Zhang, X. H. & Austin, B. Haemolysins in Vibrio species. J. Appl. Microbiol. 98, 1011ā1019 (2005).
Elgaml, A. & Miyoshi, S. I. Regulation systems of protease and hemolysin production in Vibrio vulnificus. Microbiol. Immunol. 61, 1ā11 (2017).
Acknowledgements
The authors thank all the participants who participated in this study.
Funding
This work was supported by grants from the Chang Gung Memorial Hospital in Taiwan (Grant No. CMRPG6L0071 and CMRPG6H0641 to Tsung-Yu Huang).
Author information
Authors and Affiliations
Contributions
H.C.Y.: contributed the conception and design of the study and drafting the article. C.H.Y.: contributed acquisition of data. T.L.Y.: contributed analysis and interpretation of data. C.H.Y. & K.S.F.: contributed analysis and interpretation of data. H.T.Y.: contributed final approval of the version to be submitted. T.Y.H.: participated in its design and coordination. H.C.T.: contributed revising it critically for important intellectual content. All authors read and approved the final manuscript. Due to the nature of this retrospective study and the preserved anonymity of patients, a waiver of informed consent was obtained form Chang Gung Medical Foundation/IRB.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Hsiao, CY., Huang, TY., Teng, LY. et al. Initial skin necrosis presentation at emergency room was associated with fulminant clinical course and mortality in patients with Vibrio necrotizing fasciitis. Sci Rep 13, 18410 (2023). https://doi.org/10.1038/s41598-023-45854-1
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-023-45854-1
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.