The Rapid Killer – Clostridium Septicum and Cancer

I am a fan of world war I. The biggest cluster in history (where two cousins were basically texting each other prior to the breakout of the war) led to the demise of several monarchies, the rise of new superpowers, and the grim reality of how modern warfare was going to play out going forward. The trench warfare that was waged in the western front was some of the worst conditions people have faced, with the goal of gaining a bit of territory in “no man’s land” being juxtaposed with the terrible conditions soldiers tolerated during battle. Trench fever, a disease called by Bartonella Quintana, was first described in the trenches of WW1. Other conditions associated with this war included necrotizing fasciitis and gas gangrene, surgical emergencies that require prompt debridement and source control if there is any hope of survival. Necrotizing fasciitis and its many iterations, which include fournier’s gangrene, is a topic of another post. Trauma has been traditionally associated with the development of gas gangrene, a fact that was noted during the American civil war (1), and a lot of people know the link between cirrhosis, sea water, and vibrio vulnificus. What if I told you there exists a gas gangrene that shows up without trauma, the classic symptoms of necrotizing fasciitis, and kills fairly rapidly?

Unfortunately, this entity exists and is caused by the organism clostridium septicum. This organism is an anaerobic gram positive rod that forms endospores (2) and is part of the clostridial family of gram positives. These are present in the intestinal and vaginal flora, as well as soil and are typically acquired via traumatic injury that breaches the skin after being contaminated with soil, unsanitary water, or fecal material. The classic clostridia that is often associated with gas gangrene is C. perfringens, which generates the alpha-toxin, a lecithinase that causes damage to cell membranes (2).  An animal study found that C.perfringens supernatant was associated increased rate in cell death as well as a rapid reduction in functional capillary density (3):

Indeed, when testing supernatants who had either an absent alpha-toxin or perfringolysin O-deficient strain, their functional capillary density increased when compared to a wild-type strain suggesting both of these toxins induce microvascular perfusion collapse within 60 minutes:

Clostridium septicum, which is related to C. perfringens, has similar pathophysiology when it comes to gas gangrene, despite the former being found to cause “spontaneous” myonecrosis, that is, in the absence of any trauma.  Clostridia tend to do well in areas of low oxygen tension (4). Upon tissue injury, vascular supplies to tissues are compromised which allow clostridia to multiply. Exotoxins are released, which allow edema to develop around the area of necrosis. Further edema compromised blood supply, which reduces the availability of leukocytes to the area, thus leading to reduction of oxygen tension in surrounding tissues. This mechanism allows the rapid spread of the necrotizing process. The major driving force here is the alpha toxin which causes hemolysis and necrosis, remaining active despite exposure to hyperbaric oxygen (4). This pathophysiology makes sense for traumatic gas gangrene, however in spontaneous gas gangrene it tends to be a bit more complicated. One review noted that perhaps a compromised intestinal wall allows C. septicum to gain access to the rest of the body, and therefore causes a “metastatic” or “distant” infection (5). Presence of IgG may play a role in pathogenesis. In a case series of 7 patients who survived C. septicum, the development of IgG against the alpha toxin was more likely in those who got myonecrosis compared to those who only had bacteremia or typhlitis (16), suggest immune dysfunction  may play a role here. 

How does it show up? Typically, patients present with significant extremity pain which is followed by edema and a rapid, progressive bronze discoloration and swelling of the soft tissues with hemorrhagic bullae being seen as a fairly late finding (6, 7). 

A typical presentation consists of significant pain, usually in an extremity, followed by rapid progressive discoloration and swelling of soft tissues, with bronze discoloration and hemorrhagic bullae seen in the affected area. Others will show up frankly septic, with deterioration being rapid once systemic toxicity manifests itself, leading to death due to septic shock (5). The disease spreads rapidly, with one pathological description noting the pathogenesis and necrosis had started within 3 and a half hours of specimen receipt and death occurring within 12 hours in another case (8). One paper describes the drainage as having a “sweet odor.” (9). A review of 93 cases (5) of spontaneous gas gangrene found that the most common signs and symptoms include pain and swelling at the affected area, with erythema/discoloration only occurring in 35% of patients at presentation, but increasing to 79% in those who did not survive:

One of the fascinating aspects of the illness is its relationship with malignancy. One cohort found that 23/27 cases of spontaneous myonecrosis were associated with some malignancy (10). Similarly, a larger review of 131 cases found that 34% of these were associated with colorectal carcinoma with 47% having cecal carcinoma (11). Further, 40% were found to have some sort of hematological malignancy:

Distant myonecrosis was more common in those who had colon or occult cancer:

A more recent case series of 231 patients found a similar breakdown, with GI or heme malignancies being found in 72% of patients (12). The most common presentation was skin and soft tissue infections, followed by bacteremia:

In all cases, no preceding trauma was mentioned. Notably, patients who did not have cancer were more likely to present with SSTI (72% vs 47%), a relationship that was reversed in those who had diabetes (77% SSTI in diabetes, vs 45%). A review of 23 cases found that patients who had spontaneous myonecrosis tended to have primary neoplasm at the colon, with the area of necrosis being distal to the malignancy, usually in an extremity (13).

What are the outcomes here? As one could gather, not great. Multivariate analysis showed that only surgery was associated with higher likelihood of survival (5):

A review of 139 cases (4) found that overall mortality for gas gangrene was 19%, with the highest being found in spontaneous myonecrosis in the head and neck (46%).Three factors associated with higher mortality included shock, incubation period greater than 30 hours, and intercurrent disease:

In many case series, surgical intervention was the main modality of therapy.  Penicillin (15) is the usual antibiotic of choice, but given its mainly a toxin-driven disease, the addition of clindamycin is a reasonable choice. An older study of 22 isolates found that early penicillins tended to have lower MICs, with older generation cephalosporins and aminoglycosides having higher susceptibilities (15):

So what is the take-home here? In an elderly person, who presents with significant pain at a site that then progresses to bronze discoloration and bullae, take them to the OR and, if they survive, look for a cancer.

References:

1. Trombold JM. Gangrene therapy and antisepsis before lister: the civil war contributions of Middleton Goldsmith of Louisville. Am Surg. 2011 Sep;77(9):1138-43. PMID: 21944621.
2. [edited by] John E. Bennett, Raphael Dolin, Martin J. Blaser. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Philadelphia, PA :Elsevier/Saunders, 2015.\
3. Hickey MJ, Kwan RY, Awad MM, Kennedy CL, Young LF, Hall P, Cordner LM, Lyras D, Emmins JJ, Rood JI. Molecular and cellular basis of microvascular perfusion deficits induced by Clostridium perfringens and Clostridium septicum. PLoS Pathog. 2008 Apr 11;4(4):e1000045. doi: 10.1371/journal.ppat.1000045. PMID: 18404211; PMCID: PMC2275794.
4. Hart GB, Lamb RC, Strauss MB. Gas gangrene. J Trauma. 1983 Nov;23(11):991-1000. doi: 10.1097/00005373-198311000-00006. PMID: 6355502.
5. Srivastava I, Aldape MJ, Bryant AE, Stevens DL. Spontaneous C. septicum gas gangrene: A literature review. Anaerobe. 2017 Dec;48:165-171. doi: 10.1016/j.anaerobe.2017.07.008. Epub 2017 Aug 2. PMID: 28780428.
6. Leung FW, Serota AI, Mulligan ME, George WL, Finegold SM. Nontraumatic clostridial myonecrosis: an infectious disease emergency. Ann Emerg Med. 1981 Jun;10(6):312-4. doi: 10.1016/s0196-0644(81)80122-9. PMID: 7235341.
7. Johnson S, Driks MR, Tweten RK, Ballard J, Stevens DL, Anderson DJ, Janoff EN. Clinical courses of seven survivors of Clostridium septicum infection and their immunologic responses to alpha toxin. Clin Infect Dis. 1994 Oct;19(4):761-4. doi: 10.1093/clinids/19.4.761. PMID: 7803645.
8. Yildiz T, Gündeş S, Willke A, Solak M, Toker K. Spontaneous, nontraumatic gas gangrene due to Clostridium perfringens. Int J Infect Dis. 2006 Jan;10(1):83-5. doi: 10.1016/j.ijid.2005.02.005. Epub 2005 Nov 28. PMID: 16310394
9. Zelić M, Vukas D, Vukas D Jr, Valković P, Kovac D, Sustić A, Rukavina T. Fulminant endogene gas gangrene in a previously healthy male. Scand J Infect Dis. 2004;36(5):388-9. doi: 10.1080/00365540410020307. PMID: 15287388.
10. Alpern RJ, Dowell VR Jr. Clostridium septicum infections and malignancy. JAMA. 1969 Jul 21;209(3):385-8. PMID: 5819436.
11. Kornbluth AA, Danzig JB, Bernstein LH. Clostridium septicum infection and associated malignancy. Report of 2 cases and review of the literature. Medicine (Baltimore). 1989 Jan;68(1):30-7. doi: 10.1097/00005792-198901000-00002. PMID: 2642585.
12. Hermsen JL, Schurr MJ, Kudsk KA, Faucher LD. Phenotyping Clostridium septicum infection: a surgeon’s infectious disease. J Surg Res. 2008 Jul;148(1):67-76. doi: 10.1016/j.jss.2008.02.027. Epub 2008 Apr 7. PMID: 18570933.
13. Kaiser CW, Milgrom ML, Lynch JA. Distant nontraumatic clostridial myonecrosis and malignancy. Cancer. 1986 Feb 15;57(4):885-9. doi: 10.1002/1097-0142(19860215)57:4<885::aid-cncr2820570433>3.0.co;2-u. PMID: 3943020.
14. Kaiser CW, Milgrom ML, Lynch JA. Distant nontraumatic clostridial myonecrosis and malignancy. Cancer. 1986 Feb 15;57(4):885-9. doi: 10.1002/1097-0142(19860215)57:4<885::aid-cncr2820570433>3.0.co;2-u. PMID: 3943020.
15. Gabay EL, Rolfe RD, Finegold SM. Susceptibility of Clostridium septicum to 23 antimicrobial agents. Antimicrob Agents Chemother. 1981 Dec;20(6):852-3. doi: 10.1128/AAC.20.6.852. PMID: 7325648; PMCID: PMC181814.
16. Johnson S, Driks MR, Tweten RK, Ballard J, Stevens DL, Anderson DJ, Janoff EN. Clinical courses of seven survivors of Clostridium septicum infection and their immunologic responses to alpha toxin. Clin Infect Dis. 1994 Oct;19(4):761-4. doi: 10.1093/clinids/19.4.761. PMID: 7803645.