The key to life-saving is early clinical DX & STAT treatment which is possible by sharp alertness to early lesion signs of pain-intensity out of proportion to early lesion apparences...skip to below5! There are at least 1000-2000 deaths per year in the USA9 (the NNFS estimates 2000-10,00012). Within 3 hours of suspecting sepsis, (1) obtain pre-antibiotic blood or other cultures, (2) obtain serum lactate levels, (3) administer broad-spectrum antibiotic therapy, and (4) institute fluid and/or pressor therapy against hypotension13.
URGENT, EMERGENCY (head for the ER) SIGNS:14 (1) severe pain in the abnormal area that seems disproportionate (way worse) than you'd expect from the other ways the area looks (and tends to extend beyond any abnormal looking skin). (2) a classical erythematous skin color...in white skin...somewhere between pink and violet. And (3) 75% have swelling in the area.You need not see the patient looking ill or febrile in early stage. Hard signs (positive X-ray imaging or crepitation) are late signs!
Some 10%14 of USA hospital admissions involve a skin infection problem due to anything that can disrupt skin (from yellow jacket & other stings to blisters, to cuts, to burns, to scarpes). Such problems can be either primary or secondary. Another classification is uncomplicated or complicated. CELLULITIS of skin and subdermal tissue can be non-necrotizing. If it developes necrosis within the process, it achieves complicated status. And, if the necrosis advances and grows, it is a necrotizing process.
AXIOM: Optimal TISSUE SAMPLE lab/pathology assessment of a possible infectious disease lesion happens when the pathologist/we can promptly work with FRESH-specimen (NO preservative!) tissue...especially if there is a clinical attempt at (1) early incisional BX or (2) early lesion resection. Our lab is staffed 24/7/365 with certified MT provision of STAT Gram stains from such as intra-operative glass-slide touch preps which are then quickly air dried by hand waving. These can be used for STAT Gram stain for generic bacterial classification as to rods, cocci or mixed & whether positive or negative stain. This avoids the hour or longer after-hours wait for a pathologist to drive in for & perform frozen section after hours. When subsequent resected tissue is submitted without fixative, it allows pathologist to make intact-edges & specimen-cut-surface touch preps for Gram (or other organism rapid stains, as well as stains for leukocytes) as suppliments or initial non-FS diagnosis efforts if handled during off hours & frozen section less easily accomplished (all FS/STAT pathology in this situation likely has a significant false negative rate). (3) ON THE OTHER HAND10: the patient is likely already on broad spectrum coverage which will probably not de-escalate until cultures identify the pathogen(s). STAT/ASAP fungal (as one would do in situations needing rule out of angioinvasive fungal infection11) & AFB stains may save the day when any suspicion by touch prep or FS to help disposition the unfixed tissue. THEN, on the fixed blocks, ASAP fungal & AFB stains on a "most supicious" block...(1) if negative...help to remove those pathogens as complicating features in that case & (2) if positive..allow a modification in the empiric therapy.
STAT DX: Direct team-like communication between the clinicians & the involved pathologists can be crucial to correct & rapid diagnosis. It could be that touch preps from an excised tissue piece selectively and carefully removed from a deep, questionably involved zone, made by the surgeon & sent urgently for the microbiology techs (and/ or pathologist) to do STAT Gram stain (on which one could also discern polys) to quickly help to establish the basic bacterial type (Gram pos. or neg.; cocci vs. rods vs. mixed) in the manner of STAT Gram stains on CSF. [Gram stain morphologies] Otherwise & PREDOMINANTLY, these dramatic situations are handled using clinico-surgical findings for surgical decisions. A pathologiist can expedite correct handling of materials with direct interplay with the microbiology lab. Whether designated as necrotizing fasciitis (NF) or necrotizing soft tissue infection (NSTI), there are some things worth noting:
Non-epidemic, often-lethal acute infectious disease: In our autopsy service involving the Lexington County Coroner cases, we regularly encounter people dying suddenly of non-glamorous but tragic infectious processes that did not get to medical treatment...the deaths often being "sudden" and apparently with symptoms not that alarming to themselves, friends or family. My guess is that, out of those cases, less than one in 10 will be due to necrotizing fasciitis. SO, I (EBS) believe that non-epidemic, rapidly lethal infectious disease cases arising sporadically from extremely common minor injuries or situations are publicly under-appreciated & highly under-reported (but, in May of 2012, the news media have been giving reports of a number of cases of NF in the Southeastern USA). And, then, our surgical pathology service brings other cases to light with specimens before a lethal event.
DDX: Precise skin-infection-diseases classification is hugely dependant on depth of involvement. The soft tissue elements are the dermis, subcutaneous tissue, superficial fascia, deep fascia, and muscle. There are several entities caused by bacteria which result in local,
spreading skin & deep tissue necrosis; and they go by various names, variously called (or having been called in the past): acute nonclostridial crepitant cellulitis, non-clostridial gas gangrene, necrotizing cellulitis, bacterial synergistic gangrene, gangrenous erysipelas, necrotizing erysipelas, hemolytic streptococcal gangrene, Meleney ulcer or Meleney synergistic gangrene, acute dermal gangrene, hospital gangrene, suppurative fascitis, synergistic necrotizing cellulitis, necrotizing soft tissue infection (NSTI), and necrotizing fasciitis (NF). Differential diagnosis hinges on (1) clinical presentation details, (2) Gram stain findings (select away from open wound possibly over-run with saprophytes), and (3) operative inspection (the life-threatening process need not truly involve fascia or muscle deep to fascia)1. There are comparable non-skin, deep & internal comparable infections of all the various anatomical structures having an opening to the outside [FA11-7; FA12-46]. And, there are deep infections introduced through gross or nearly invisible punctures of skin or various linings. Finally, there are comparable, even apparently spontaneously originating, deep infections [FA11-207].
These necrotizing soft tissue infections (NSTI) are extremely
life threatening and, though often seeming de novo, are usually complications of a surgical or other type of break in the skin (even an insect sting [about 1980, a yellow-jacket sting to a young man's calf who came to our ER] or dog bite)! [FA95-12]). We have seen a number of these cases in my (EBS) career
at one community hospital since 1975 (to even include a coroner case of sudden unexpected death in a 36 y/o due to an internal NSTI [FA11-207]). Some other cases: [L12:8998]. When a lesion has "gas",
the clinical implication should be that it is an anaerobic infection...but one
should not automatically presume that it is a clostridial infection. Bacteria
can be morphologically demonstrated on excellently processed, permanent sections in a significant percentage of
these cases...but not in all cases (we have had at least one case
in which we were unable to identify any bacteria on slide sections...although cultures
Other related: there are other serious bacterial cellulitis case types that some
surgeons say do not to appear to need drastic surgical intervention (erysipelas ?[usually Staph. &
Strep. can seem this way even when very superficial4]; gets deeper = SSTI or "cellulitis"4; "necrotizing cellulitis" is similar to NF but without subcutaneous extension, though it may herald NF4; "hemorrhagic
cellulitis", usually is Gram positive or negative non-cutaneous bacteria4; subacute NF/NSTI ?). Seawater contamination of a minor superficial wound can be infected with Vibrio vulnificus or other vibrio and cause inflammatory skin plaques that undergo central necrosis; deeper puncture wounds can deposit vibrio deeper and give NF/NTSI; Vibio is Gram negative curved rod5. I have been involved in two cases of post-dog-bite bacterial sepsis: one lived & the other died (FA95-12 [a 38 y/o truck driver with normal spleen]...by a bacterium peculiar to the oral cavity of dogs). And, in immunocompromised patients (especially) with neutropenia and FUO, pathologists may have urgent cases needing very rapid ruling out of invasive fungal infection (as in sinus contents) or need to come in after hours for frozen section on skin or mucosal lesion biopsies in search of primary invasive fungi or disseminated angioinvasive fungal lesions11...critical cases with high mortality, even if diagnosis is NOT delayed.
DDX Warning: especially on the lower legs, be careful to not mistake easily treatable by steroid therapy (dramatically steroid-responsive), pyoderma gangrenosum (PG) (usually no deeper than dermal) as NF/NSTI. PG is a rapidly ulcerating lesion without prior trauma or inciting event. We have seen a case where PG dramatically involved the breast skin (LCH-83-1210, 37 y/o with necrotizing dermatitis due to staph. &/or micrococcus). [PG DDX] There have also previously been some medications (promethazine) which had to be taken off the market because of soft-tissue damage/gangrene at injection sites. MRSA skin infection may come to us in a skin biopsy (S11-4968 [MRSA pos. on culture]) and may be antibiotic resistant but is not as concerning for dramatic NF/NSTI. We have had a case of probable vasospastic (cocaine?) small areas of secondarily infected (Staph. aureus) skin excised for rapid diagnosis (L12-15636). Again, exact clinical history is critically important to pathology interpretations which help clinicians to help the patient.
- early: not severely ill, afebrile, without leukocytosis (CRP ?).
- early: severe lesion pain disproportionate to physical "look" pink/violet erythema of the lesional skin (the infection is deep)
- lesion warmth noted early in 97-100% of cases
- early: tenderness notably (!!) beyond the visible skin lesion
Gross/Macroscopic/ Surgical Findings:
- grayish-discolored, lifeless, necrotic tissues
- positive (lack of resistance) dissection "finger test"
- non-bleeding dissection
- thrombosed vessels
- foul smelling "dishwater" pus/weepage
- non-contracting muscle on electrocautery stimulation
- necrosis within compromised area
- PMN (polys) infiltration
- vascular fibrinous thrombi
- vascular angiitis (mural fibrinoid necrosis)
- microorganisms present within compromised area
"Simple contamination": This denotes
growth of clostridia in an untidy wound, negative for true
tissue invasion...connoting the saprophytic growth of clostridia
in already-devitalized tissues.
Clostridial cellulitis/gas abscess/local gas
gangrene/brown form of gas gangrene/epifascial gas gangrene:
A heavier infection primarily involving already-necrotic
tissue and usually not "invasive". Little
or no local pain, edema (structural swelling), or toxemia.
Clostridial anaerobic myonecrosis: includes very deep necrosis.
the most common single-agent offender is group A Streptococcus (a facultative anaerobe), the cause of a number of types of group A Streptococcal (GAS) diseases (11,000-13,000 cases per year in the USA & is reported as the single-agent cause of NF/NSTI [L11-2109; L12-8998] with some frequency (other bacteria vary from single-agent to as many as 11 bacterial types [polymicrobial5], some likely saprophytic 1). Some organisms that are usually aerobic (facultative aerobic) can switch to anaerobic metabolism (Aeromonas hydrophilia) and result in deep, anaerobic infections.
Necrotizing fasciitis: a rapidly spreading skin and soft-tissue necrosis which must be emergency-style
surgically treated...plus antibiotics, etc. The NF foundation has numerous survivor stories, some with dramatic photos.
Fournier's scrotal gangrene: The above, when
a disease of the male scrotum...though it commonly begins
as a perirectal abscess which spreads through the perineum
to the scrotum (L07-5263).
Balanitis gangrenosa (Corbus' disease): A mixed
and necrosing process of the penile glans and foreskin involving
a mixed growth of anaerobes, spirochetes, and fusobacteria (Gram neg. needle-crystal like rod).
- Stagnant water infections (sustained water temp. 80 degrees or higher):
- brain-eating ameba (Naegleria fowleri - Primary Amebic Meningoencephalitis [PAM]): the organisms enter through the roof of the interior of the nose through a thin zone into the brain-containg skull cavity.There are a few disastrous USA cases per year.
- Vibrio vulnificus: a bacterial skin infection (after being in stagnant water) causing dramatic skin lesions.
- leptospirosis: a bacterial infection (after being in stagnant water, especially if around cows who may carry the bacteria in their urine) after which one comes down with a flu-like illness followed later by jaundice.
- Some of our other-type acute infectious death cases: LCH-83-4375 (post-C-section site, specimen date 12/28/83, 19 y/o & survived); FA85-157 a 12 y/o went to sleep with a sore throat and was dead in bed and autopsy negative but blood culture positive for strep.; in 2000, a 62 y/o injured her hand working in the yard & was dead within 10 days & family remembers another patient in hospital at same time severely sick from a paper-cut; L07-5263; FA09-9 a 6 month-old appeared to be a SIDS death & slides showed lymphoid follicular (viral) laryngo-tracheo-bronchitis with pericardial effusion; L11-2109 (Strep. NSTI of triceps [36 y/o, died]); FA11-207 (retroperitoneal lesion & sudden septic death); (GW) died in his 30s about 18 months after losing spleen in a car wreck & prior to ready availability of pneumococcal vaccination; FA11-7 a 36 y/o with headache 2-3 days had a multi-organism infected cholesteatoma that produced a brain abscess & fatal sepsis & died at home. A man in his 40s has thigh pain & goes to the ER where an MRI finds an abcess (Staph.) in the underlying muscle without history of preceeding injury (L12-7489). And, throughout the USA, there are some 30,000 deaths per year from post-antibiotic Clostridium difficile colitis (rivaling 32,000 deaths per year in traffic accidents!). On top of the lethal C. diff. cases are additional large numbers of nonlethal C. diff. cases, sometimes even triggering life-saving colectomy for toxic megacolon (about 500,000 cases per year
), maybe even perforated [pseudomembraneous colitis: a dramatic case in a 67 y/o with pneumoperitoneum, L12-9760].
- Some of our mutilating (nonlethal?) acute infectious cases: CP12-19 was a winter-time, nonspecific bronchitis case that began to "go sour" with cocci in sputum and was caught early & cured without hospitalization. And, dying without medical care was a young women with group A Strep. laryngitis moving so fast into pneumonia/sepsis that she never sought medical care (FA12-46). A streptococcal toxic shock syndrome case (a type of GAS, above) with systemic shock requiring dramatic pressor therapy & then multisystems failure and subsequent amputations (L12-6661) was encountered. Here is a link to the somewhat similar story of a Michigan man who contracted Strep of the peritoneal cavity & survived but lost his hands and feet due to ischemic necrosis from the septic vascular collapse, HERE.
(posted 25 March 2004; updated July 2012; latest addition 12 August 2017)
Dellinger EP, "State of the Art: Severe necrotizing soft-tissue
infections. Multiple disease entities requiring a common
approach", JAMA, 246(15):1717-21, 9 October 1981. [AMA members on-line PDF file]
- Chowsidow O, et. al., [Subacute forms of necrotizing fasciitis and necrotizing cellulitis: diagnosis criteria and surgical decision-making], Ann Dermatol Venereol., 128(3 Pt 2):390-3, March 2001 [here].
- Medscape web site file [HERE].
- McKee, Calonje, & Granter, Pathology of The Skin... Two volumes, 3rd Ed. 2005; vol. 1, pages 874-878 [EBS's office].
- Wolf R, et. al., Emergency Dermatology, 2010, 363 pages. [book in EBS's office]
- USC School of Med. on-line Infectious Disease, Dr. Charles Bryan, HERE.
- The National NF Foundation web site HERE.
- A local story of a church-comember (of years gone by) of one of our pathologists (EBS) around 2002-4 of a recurring NF case HERE.
- CDC web site about GAS as to NF/NSTI HERE.
- points of commentary/advice by some of our local specialists, such as Dr. Emilio Perez-Jorge.
- Micheletti R and Rosenbach M, JAMA Clinical Challenge CLINICIAN'S CORNER,
"A Violaceous Plaque in an Immunosuppressed Patient", JAMA,307(24):2635-2636. June 27, 2012, HERE.
- National Necrotizing Fasciitis Syndrome web site, HERE.
- Dellinger RP, et. al. "Surviving Sepsis Campaign: International Guidelines..." HERE, reported in JAMA 309(1):969-970, 13 March 2013 HERE.
- Wolf R, et. al., Emergency Dermatology 2010.