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Review

Clinical and Microbiological Features of Fulminant Haemolysis Caused by Clostridium perfringens Bacteraemia: Unknown Pathogenesis

by
Ai Suzaki
and
Satoshi Hayakawa
*
Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Ohyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
*
Author to whom correspondence should be addressed.
Microorganisms 2023, 11(4), 824; https://doi.org/10.3390/microorganisms11040824
Submission received: 6 February 2023 / Revised: 16 March 2023 / Accepted: 16 March 2023 / Published: 23 March 2023
(This article belongs to the Special Issue Bacterial Pathogens Associated with Bacteremia)
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Abstract

:
Bacteraemia brought on by Clostridium perfringens has a very low incidence but is severe and fatal in fifty per cent of cases. C. perfringens is a commensal anaerobic bacterium found in the environment and in the intestinal tracts of animals; it is known to produce six major toxins: α-toxin, β-toxin, ε-toxin, and others. C. perfringens is classified into seven types, A, B, C, D, E, F and G, according to its ability to produce α-toxin, enterotoxin, and necrotising enterotoxin. The bacterial isolates from humans include types A and F, which cause gas gangrene, hepatobiliary infection, and sepsis; massive intravascular haemolysis (MIH) occurs in 7–15% of C. perfringens bacteraemia cases, resulting in a rapid progression to death. We treated six patients with MIH at a single centre in Japan; however, unfortunately, they all passed away. From a clinical perspective, MIH patients tended to be younger and were more frequently male; however, there was no difference in the toxin type or genes of the bacterial isolates. In MIH cases, the level of θ-toxin in the culture supernatant of clinical isolates was proportional to the production of inflammatory cytokines in the peripheral blood, suggesting the occurrence of an intense cytokine storm. Severe and systemic haemolysis is considered an evolutionary maladaptation as it leads to the host’s death before the bacterium obtains the benefit of iron utilisation from erythrocytes. The disease’s extraordinarily quick progression and dismal prognosis necessitate a straightforward and expedient diagnosis and treatment. However, a reliable standard of diagnosis and treatment has yet to be put forward due to the lack of sufficient case analysis.

1. Introduction

The anaerobic bacterium Clostridium perfringens, widespread in the environment and gastrointestinal tract, infrequently produces bacteraemia. However, when it does occur, the fatality rate can exceed 52 per cent, making it one of the most severe types of bacteraemia [1]. C. perfringens infection is more lethal when massive intravascular haemolysis (MIH) develops, with fatality rates ranging from 70 to 100 per cent [2,3,4,5,6]. At Nihon University Hospital in Tokyo, we observed six cases of C. perfringens-related MIH.
To clarify the clinical and bacteriological profiles of MIH caused by C. perfringens bacteraemia, a systematic search of Pubmed over the past seven decades was conducted in this study. We searched for every English-language case report with C. perfringens and hemolysis (haemolysis) in the title, abstract, or main body. Then, we compared our findings to those of earlier studies.
Recent advancements in highly sensitive molecular detection techniques, such as polymerase chain reaction (PCR), have permitted the detection of bacterial genes in peripheral blood samples. After brushing or dental treatment, susceptible bacteria, such as Polyphylomonas gingivalis, are often detected. Nevertheless, culture tests are essential for accurately diagnosing bacteraemia, in which living bacteria are discovered in the blood. Even in developed countries, 30-day death rates range from 3 to 47% when a definitive diagnosis of clinically significant bacteraemia caused by Staphylococcus aureus, Escherichia coli, Klebsiella spp., and Pseudomonas spp. is made [7,8]. In most cases of bacteraemia, the bacteria are rapidly eliminated from the bloodstream; however, patients with sepsis have a poor prognosis due to systemic infection and damage to several organs. Understanding sepsis’s pathophysiology is essential, and we must investigate the specific features of relevant bacteria and host immune response.

2. Clostridium Perfringens

C. perfringens is a Gram-positive anaerobic spore-forming bacterium frequently isolated from soil and human and animal intestinal tracts. Interestingly, C. perfringens is also a component of the normal genital flora of 1–10% of healthy women [9]. C. perfringens is classified into seven types, A, B, C, D, E, F and G, according to the production of six major toxins: α-toxin, β-toxin, ε-toxin, ι-toxin, enterotoxin, and necrotising enterotoxin. All seven types produce α-toxin [10,11]. In addition to these toxins, C. perfringens secretes more than 20 pathogenic substances. The C. perfringens subtypes usually isolated from humans are type A and type F. Type A organisms only produce α-toxin (phospholipase C, CPA), which causes gas gangrene, hepatobiliary infections, sepsis [10,11], and foodborne diarrhoea [10]. Type F organisms produce CPA and enterotoxins, which cause food poisoning and nonfoodborne diarrhoea [10]. In clinical practice, bacteraemia occurs much less often than food poisoning or gas gangrene. Only approximately 0.12–0.16% of blood culture-positive samples in clinical laboratories show Clostridium spp., with C. perfringens found in 22–42% of them [12,13,14]. Clinically relevant is the fact that 7–15% of patients with C. perfringens bacteraemia suffer massive intravascular haemolysis (MIH) [6,15], which is characterised by the severe and systemic destruction of red blood cells. MIH is brought on by many pathogeneses [16], including immune-mediated and microangiopathic illnesses, malaria, and babesiosis [17,18]. MIH is characterised by bright red serum (Figure 1) [5,19].
Though the laboratory criteria for MIH have yet to be established, the clinical diagnosis is simple: due to the release of large amounts of haemoglobin from red blood cells into plasma, the serum of patients with MIH becomes very bright red in appearance. Among various infections that cause MIH, C. perfringens is one of the most critical causative organisms [1,2].

3. C. perfringens Infection with MIH

Epidemiology

The median age of patients with C. perfringens bacteraemia is reported to be relatively old, ranging from 70.7 to 75.6 years [5,20,21,22]. Therefore, older age has been reported to be a risk factor for bacteraemia [1,14]. Interestingly, in our clinical cohort, the median age of bacteraemia patients with MIH was 61–66.5 years. As reported by us and others, MIH patients are suggested to be significantly younger than non-MIH patients [2,3,5]. In addition, it appears to be more prevalent in men; as reported previously, 60% [13] and 58.1% [20] were males, while the molecular basis of these gender differences is so far unknown.
C. perfringens bacteraemia is more prevalent in patients with diabetes, malignant neoplasms, biliary tract illness, renal failure, cirrhosis, and/or those being treated with immunosuppressive formulas [5,13,20,21]. Community-acquired infections are considered to be more common than hospital-based infections [5,13,20]. C. perfringens-related MIH is typically accompanied by intra-abdominal infections, liver and biliary tract infections, and lower respiratory tract infections. However, 20–30% of cases have an unknown focus [5,13,20], with no significant difference between MIH and non-MIH groups [5].

4. Pathogenic Factors

There have been approximately 100 case reports of C. perfringens bacteraemia with MIH over the past 60 years, and the number of cases has been increasing in recent years (Table 1 and Table 2). Nevertheless, because most of these cases are found in single case reports, there has been little research on causative organisms. In six cases, multiplex PCR was applied for typing toxins produced by the causative organism, all of which were type A bacteria that produce only CPA [6,21,23,24,25]. Type A C. perfringens bacteria, on the other hand, are common and have been linked to hepatobiliary infections, gas gangrene, and sepsis in humans. Furthermore, CPA produced by type A bacteria is produced by all types of C. perfringens [10]; assuming that the alpha toxin is the main pathogenic toxin in MIH is unreasonable. We typed eleven C. perfringens bacteraemia blood-derived clinical isolates (five from the MIH group and six from the non-MIH group) [26]. Four of the five C. perfringens strains that caused MIH were type A, one was type F, four of the six non-MIH strains were type A, and two were type F. Involvement of type A and F strains suggests that both may be responsible for MIH. There was no difference in the type of bacteria between the two groups.
Next, we examined the virulence factors other than the six toxins used in A-G typing for MIH. We extracted chromosomal DNA from eleven clinical isolates and compared the repertoire of known virulence-related genes between five MIH and six non-MIH groups [27]. However, there were no differences in the variation of genes considered to encode virulence factors between the groups [26].
We then compared the biological characteristics of isolates between MIH and non-MIH groups, and the growth rate of the isolates and the production of CPA did not differ [26]. In vitro human erythrocyte haemolysis experiments showed that erythrocyte haemolytic elements were present in the culture supernatants of the MIH group bacteria, with significant differences. A significant correlation was found between the erythrocyte haemolytic effect of the culture supernatant of the bacteria and the amount of θ toxin (perfringolysin O, PFO) in the culture supernatant. The amount of PFO in the culture supernatant of this clinical isolate also correlated with cytotoxicity towards human peripheral blood mononuclear cells (PBMCs) and production of interleukin-6 (IL-6) and interleukin-8 (IL-8) by human PBMCs [26]. However, there was no correlation between CPA in culture supernatants and erythrocyte haemolytic effects, cytotoxicity towards human PBMCs, or production of IL-6 and IL-8 by human PBMCs. These findings suggest that PFO is one of the most important virulence factors in C. perfringens bacteraemia with MIH [26].
PFO and CPA produced by C. perfringens have potent cytotoxic and proinflammatory cytokine-inducing effects on human blood cells [26]. PFO is produced from human PBMCs via induction of tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, and macrophage inflammatory protein-1β (MIP-1β), inducing human erythrocyte haemolysis. PFO induces TNF-α, IL-5, IL-6, and IL-8 production more strongly than CPA. CPA induces production of IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, granulocyte macrophage colony-stimulating factor (GM-CSF), and MIP-1β [26]. PFO, which induces a potent haemolytic and acute inflammatory response, plus the proinflammatory cytokine-producing effect of the CPA produced by all C. perfringens strains, may lead to a rapid and lethal course.
PFO is a cholesterol-dependent cytolysin (CDC) toxin family member that forms pores in membranes containing cholesterol [28]. PFO has been demonstrated to promote the development of human gas gangrene by synergistically enhancing the action of the main toxin CPA [11,29,30,31]. In animal studies, it has been documented that PFO synergistically amplifies the effects of other toxins and contributes to disease progression, such as in bovine necrohemorrhagic enteritis in combination with CPA [32] and in enterotoxaemia of sheep and goats in cooperation with ε-toxin [31]. Despite the ubiquitous occurrence of C. perfringens strains that produce PFO, no illnesses in which PFO has been identified as a major virulence factor have been reported [10,33,34]. More case series and research are required to establish that PFO is the primary virulence factor for MIH in C. perfringens bacteraemia.

5. Symptoms and Laboratory Findings

In MIH patients, severe primary symptoms such as altered consciousness, severe pain, shock, haematuria, and gas formation occur more frequently than in those without MIH [5]. Sudden onset of severe pain is also characteristic [5,21,23,35,36], which is difficult to distinguish from myocardial infarction or aortic dissection [35,36]. Due to the high incidence of intra-abdominal, hepatic, and biliary tract infections, significant abdominal pain is frequently observed. However, the pain may involve the entire abdomen, not just the pericardium, the right upper abdomen, the lower abdomen, or the suprapubic region. In cases of unknown aetiology, abdominal pain, chest pain, back pain, and headache could be present. Serum ALT levels are higher in those with MIH than those without MIH, despite no difference in underlying disease, foci of infection, or total bilirubin levels [5]; this may reflect a severe inflammatory response and progressive shock [37,38]. MIH patients present with tachypnoea and subsequent rapid respiratory failure, although the focus is not a respiratory infection. Initial blood gas analysis reveals acidaemia due to metabolic acidosis, followed by further hypoxaemia and respiratory acidosis, often resulting in death from acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) despite ventilatory management. MIH patients may present with metabolic acidosis at an early stage, even in the absence of hypoxemia or chest X-ray abnormalities [15,23,24,35,36,39,40,41,42], and some documented patients were acidotic before the onset of intravascular haemolysis [39]. A comparison of the symptoms of C. perfringens sepsis with/without MIH is listed in Table 3.
High cytokine levels in the blood have been reported to rapidly cause metabolic acidosis and multiorgan failure with ARDS, acute liver failure, and acute renal failure [43]. Cytokines are also known to be induced by exotoxins of pathogenic microorganisms, such as Streptococcus pyrogenic exotoxins (SPE) [44] and Staphylococcus aureus toxic shock syndrome toxin [45]. Autopsy findings in reported MIH patients show simple oedema; however, without pathological findings suggestive of so-called bacterial pneumonia, such as inflammatory reactions or massive bacterial growth in the alveoli of the lungs [35,46]. These findings suggest that inflammatory cytokine levels are strongly related to the rapid progression of C. perfringens bacteraemia with MIH. The significantly higher age group among non-MIH patients with C. perfringens bacteraemia [5] may be because the production of inflammatory cytokines decreases with age [15,47]. The induction of cytokines may be related to PFO and CPA produced by C. perfringens. In particular, TNF-α and IL-6, which PFO strongly induces, produce pathological pain as well as fever [48], which may explain the characteristic severe pain, and it has been reported that ALI/ARDS is induced by IL-6, IL-8, and IL-10 [49,50]. However, because the sera from patients with MIH were strongly haemolytic, it was difficult to measure cytokine levels or C. perfringens-produced toxins in serum samples using ELISA or other laboratory methods. This was also the case at other centres, which may have hindered pathophysiologic analysis.

6. Diagnosis with/without Bacterial Culture

Among patients with C. perfringens bacteraemia, 40–55% have polymicrobial bacteraemia [5,20], with no difference between the MIH and non-MIH groups. Regarding susceptibility to antimicrobial agents, both groups were found to be sensitive to penicillin and carbapenem, while susceptibility to clindamycin tended to be lower in the MIH group [5]. Blood culture tests for C. perfringens provide positive results in an average of 16.9 hours, which is faster than those for other Clostridium species [13]. This is owing to a doubling period of around 7 minutes, which is significantly faster than other bacteria. Due to the rapid progression of MIH, however, patients cannot be treated based on culture results, and many perish by the time the results are acquired. Gram staining of the buffy coat and the presence of Gram-positive rods will lead to an early diagnosis if MIH is suspected based on patient serum results (Figure 2) [5,51].

7. State-of-the-Art Treatment and Prognosis

C. perfringens bacteraemia with MIH has a poor prognosis. Because reported cases suggested that life expectancy was significantly lower among MIH patients, with attributed mortality of 6/6, or 100%, compared to 13/54, or 24.1%, among non-MIH patients (p 0.001), the mean time between bacteraemia and death was 0.18 days (range: 0.04–1.08 days) in MIH versus 32 days (5–73 days) in controls (p 0.001).
Therefore, it is strongly recommended that a clinician who encounters such cases begin potent systemic antibacterial therapy as soon as it is suspected. Although there are few reports, some suggest that penicillin plus clindamycin lowers the risk of death compared to penicillin alone or other antimicrobial agents [15]. In association with antimicrobial therapy, surgical resection of infected lesions has been reported to improve survival [3] significantly. However, patients with C. perfringens bacteraemia with MIH are already in a state of shock when the disease is suspected. Many patients die before they can benefit from treatment [2,33], making the choice of surgical intervention difficult. Patients who can undergo surgery may have MIH but are relatively haemodynamically stable and have a high chance of survival [3]. Blood purification [4] and hyperbaric oxygen therapy (HBOT) [3] have also been attempted. However, the prognosis for C. perfringens bacteraemia with MIH is extremely poor, with a median time from admission to death of only 10 hours, despite intensive care [2,3,5]. Even when apparently susceptible antimicrobial agents are used, mortality rates range from 70 to 100% [2,3,4,5,6], and there has been no decrease in mortality over the past 30 years. So far, antimicrobials have been used to treat cases of other Clostridium pathogens, including C. difficile infection (CDI), while C. tetani and C. botulinum infections are already effectively treated with antitoxins. [52]. Antitoxin therapy has also been utilised to treat gas gangrene induced by C. perfringens [53]. In newborn piglets infected with C. perfringens type C, commercial swine anti-beta toxoid vaccinations have also been reported to be efficacious against necrotising enterocolitis [54]. To treat C. perfringens bacteremia with MIH, we suggest using anti-PFO toxin therapy and establishing cytokine-targeted treatment with anti-IL-6 antibodies [34]. We suggest this because anti-IL-6 monoclonal antibody medicines were initially developed to treat persistent inflammation, such as that caused by autoimmune disorders. Furthermore, multiple data suggest that they are efficacious for COVID-19-induced cytokine storms.

8. Inflammatory Foci or Bacterial Translocation Preceding C. pefringens Invasion Pathways

Bacterial translocation or inflammatory foci can come before C. pefringens invasion routes. Numerous anaerobic bacteria are present in the commensal flora on the skin, oral cavity, gastrointestinal tract, and vagina. Anaerobic bacteria can infect wounded tissues even in the presence of a normally functioning host immune system. In some instances, the illness is caused by a combination of aerobic and anaerobic bacteria, as opposed to anaerobic bacteria alone. The main focus of mixed infection is necrotic tissue resulting from trauma, ischaemia, or malignancies. Neoangiogenesis is induced by inflamed tissue, which boosts blood flow and makes it possible for aerobic or anaerobic bacteria to enter the bloodstream and cause bacteremia. As a result, after an infection has established itself at the primary site, it may spread to other areas through the bloodstream and induce systemic effects, such as disseminated intravascular coagulation (DIC), cytokine storms, and MIH. Most anaerobic infections do not result in DIC when bacteraemia occurs. However, clostridial infections can infrequently result in coagulopathy related to sepsis. In 20–30% of the 60 cases of C. perfringens bacteraemia we documented, the main inflammatory lesion of the bacterial entrance was difficult to identify. This result is reflected in reports from other centres.
This means that C. perfringens can enter the bloodstream without necessitating the formation of inflammatory foci anywhere in the body, which could have catastrophic effects. In such circumstances, the most likely entrance route is bacterial translocation from the gastrointestinal system. Small amounts of enteric bacteria can enter the bloodstream even in healthy people; however, they have been detoxified in the liver via the portal vein. The reticuloendothelial system also processes them at the spleen. However, for unknown reasons, such as an abnormality in the intestinal microbiota or a disruption in the intestinal mucosal barrier, more bacteria are allowed to enter into circulation. Inadequate processing of blood bacteria causes systemic bacteraemia. Furthermore, as previously reported, C. perfringens-produced cholesterol-dependent cytolysin (CDC) is another candidate mucosal disruptor [55]. This bacterial species damages the mucosal function to prevent bacterial entry into the systemic circulation by silencing mucosal macrophages that protect the intestinal barrier function.

9. Evolutionary Significance of Bacterial Haemolysis

Haemolysis is the breakdown of red blood cells and derives from the Greek word αιμόλυση, meaning “destruction of blood.” It emerged in evolution because of the use of host animals with red blood cells as a source of nutrients. Iron is an essential component for bacterial growth, and it is believed that the breakdown of erythrocytes, which contain large amounts of iron, promotes bacterial growth. Many human infections, particularly Gram-positive cocci, produce haemolysin, a substance that induces haemolysis. In clinical bacteriology, bacteria can also be categorised based on their haemolysis pattern. The haemolytic pattern of bacterial colonies grown on blood agar media determines whether they cause alpha- or beta-haemolysis. Alpha-haemolysis, in which hydrogen peroxide produced by the bacteria oxidises haemoglobin to become methaemoglobin, a green oxidised derivative, is indicative of Streptococcus pneumoniae and Streptococcus viridans. Group A streptococci (GAS) and Streptococcus dysgalactae produce beta-haemolysis (complete haemolysis), a condition in which red blood cells in the medium around and under the colony fully decompose and become transparent. Streptolysin O (SLO) and streptolysin S (SLS), both of which are generated by bacteria, are responsible. SLS specifically damages immunological cells, including polymorphonuclear leukocytes and lymphocytes. For convenience, bacteria that do not cause haemolysis are referred to as “gamma-haemolytic”, which include Enterococcus faecalis and Staphylococcus epidermidis, commensal bacteria of the gastrointestinal system and skin that have no direct contact with red blood cells. C. perfringens is a common bacterium in the gastrointestinal tract and on the skin. As mentioned previously, C. perfringens is found in the environment, intestines, and vagina. It rarely interacts with erythrocytes. Therefore, it is unlikely that C. perfringens actively uses the iron in erythrocytes released by haemolysis, and the damaging haemolysis that occurs with bacteraemia is either incidental or an overreaction by the host. We believe that the haemolysis associated with bacteraemia is either an evolutionary accident or an overreaction by the host, as killing the host would render the parasite bacteria unable to thrive.

10. Involvement of Haemolysis in Pathophysiology of C. Perfringens MIH and Potential for Iron/Haem Scavenging Therapy

Haemolysis is caused by various factors; however, there is growing evidence that free haem and iron can harm the body by activating endothelial and immune cells [56]. The haem and iron released from erythrocytes as a result of haemolysis promote leukocyte adhesion to endothelial cells, causing damage not only to blood vessels but also to the various functions of systemic organs. Increased circulating free Hb concentrations reduce the Hb scavenger haptoglobin (Hp), part of a critical detoxification system in mammals, scavenging haemolytic by-products in the blood and maintaining normal intracellular metabolism [57,58]. Furthermore, the haemopexin (Hx) scavenger and the intracellular enzymes haem oxygenase (HO-1 and -2) are involved [59]. Hp and Hx bind to Hb and haem with high affinity and transport Hb to macrophages and haem to hepatocytes, respectively, preventing oxidative enhancement in the circulation and non-specific uptake in non-target cells; HO degrades haemo porphyrins to iron-carbon monoxide and biliverdin, which have anti-inflammatory, anti-oxidative, and anti-apoptotic effects. Released iron, on the other hand, forms ferritin-heavy chains (H-ferritin). It is oxidised to ferrous iron (Fe2+) by ferroxidase activity; if the haem detoxification system is saturated with high levels of haemolysis, these systems fail [60]. Increased oxidative stress and elevated levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble endothelial selectin (sE-selectin), tumour necrosis factor (TNF), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) result from scavenger depletion [61]. Soluble haem is a potent inducer of type I IFN, which causes haemophagocytic syndrome and worsens the patient’s prognosis. These findings suggest that C. perfringens-caused severe haemolysis has a common aetiology, with non-infectious haemolysis as a cause of death in patients. In this context, we advocate for early iron/haem scavenging therapy in non-infectious haemolytic diseases.

11. Local or Systemic Modulation of Immune Function by Genus Clostridium and How to Control Them

Bacteria of the genus Clostridium are known for their strong immunoregulatory effects. Regulatory T cells, essential for maintaining pregnancy and preventing the onset of autoimmune diseases, are induced by bacteria of the genus Clostridium living in the intestinal tract [62]. The number of Treg cells in the large intestines of mice raised in a normal environment is drastically higher than in the intestines of mice raised in a sterile environment (aseptic mice). When sterile mice are inoculated with various intestinal bacteria, Clostridium spp. markedly increase the number of Treg cells in the colon. It has long been known that mice with high levels of Clostridium spp. are less prone to develop enteritis and allergic reactions; however, when the intestinal bacteria are eradicated with antimicrobial agents, the incidence of these reactions increases. Similarly, in humans, Clostridia in the intestinal tract are supposed to induce regulatory T cells. In our study of the intestinal microbiota in children, we reported that intestinal Clostridia are closely related to the development of orthostatic dysregulation and allergic diseases [63]. It is thought that there are two types of clostridia: so-called “good” clostridia, which are useful for our intestinal environment and immune function, and “bad” clostridia, which are the focus of inflammation and induce excessive immunosuppression. It is difficult to speculate whether the bias in the intestinal microflora can be corrected simply by the administration of probiotics or antibiotics. The most probable candidate is breastfeeding during the neonatal period. This is because C. perfringens colonisation occurs early after birth and persists for an extended period of time throughout life but is reported to be more frequent in children born by caesarean section [64]. Breastfeeding is strongly recommended to maintain a healthy gut microbiota throughout life [65] because it effectively prevents necrotising enterocolitis caused by C. perfringens in infants born by either vaginal delivery or caesarean section.

12. Conclusions

Bacteraemia associated with MIH advances rapidly, and patients with suspected cases frequently die before blood cultures can be completed because they are in serious shock condition when they arrive at the hospital. The clinical features of C. perfringens bacteraemia are severe pain at onset, impaired consciousness, shock, haematuria, metabolic acidosis, and gas formation. When a blood sample from a person with these symptoms shows intravascular haemolysis, the physician should be ready for a very fulminant case outcome. Future multicentre, case-intensive clinical studies using, if possible, the prospective approach is desirable to elucidate the pathophysiology of this rare but fatal disease and to establish treatment for it.
In addition, the identification of the molecular backgrounds of the MIH-causing C. perfringens substrains is required.
There have been numerous instances of various Clostridium species causing haemolysis [3]. However, this is uncommon, indicating that MIH-related C. perfringens may have a particular mechanism. Moreover, C. perfringens occasionally inhabits the digestive and vaginal tracts. While the number of clinical cases in humans is exceedingly low, it may be possible to clarify the aetiology of MIH by using animal models to identify the strains prone to cause MIH, the relevant genes, and the host immune response and cytokine patterns.

Author Contributions

Conceptualization, S.H. and A.S.; Analysis of clinical data: A.S.; Collection of published materials and analysis A.S.; writing—original draft preparation, A.S.; writing—review and editing, S.H. project administration, S.H.; funding acquisition, S.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Nihon University Research Grant for emerging infectious diseases (Satoshi Hayakawa 2022–23).

Acknowledgments

The Nihon University research grant for Emerging Infectious Diseases partially supported this study (Satoshi Hayakawa).

Conflicts of Interest

The authors declare no conflict of interest.

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Microorganisms 11 00824 g001 550
Figure 1. Macroscopic appearance of massive haemolysis caused by C. perfringens bacteraemia. Bright red appearance of the serum (arrow).
Figure 1. Macroscopic appearance of massive haemolysis caused by C. perfringens bacteraemia. Bright red appearance of the serum (arrow).
Microorganisms 11 00824 g001
Microorganisms 11 00824 g002 550
Figure 2. Microscopic appearance of C. perfringens prepared from the buffy coat of a patient’s peripheral blood and Gram staining (×1000).
Figure 2. Microscopic appearance of C. perfringens prepared from the buffy coat of a patient’s peripheral blood and Gram staining (×1000).
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Table
Table 1. Reported case numbers of C. perfringens bacteraemia with MIH from 1951 to 2022.
Table 1. Reported case numbers of C. perfringens bacteraemia with MIH from 1951 to 2022.
By DecadeReported Cases
1951–19603
1961–19702
1971–19802
1981–19908
1991–200015
2001–201030
2011–202037
2021–202218
Total115
Table
Table 2. All reported cases of C. perfringens bacteraemia with MIH from 1991 to 2022.
Table 2. All reported cases of C. perfringens bacteraemia with MIH from 1991 to 2022.
AuthorYearAgeSexOrigin InfectionPositive CultureSurvivalToxinToxinotype
CPACPE
1Bätge 1992 61 M Liver ab-scess Blood Yes NRNR
2 Ifthikaruddin 1992 54 F Unknown Blood No NRNR
3 Hübl 1993 84F Intestinal BloodNo + NR
4 Rogstad 1993 61 M Micro liver abscessBlood, liverNoNRNR
5 Clarke 1994 53 F Necrotising enteritis Blood, peritoneal fluidYesNRNR
6 Meyerhoff1995 66 F Unknown Blood No NR NR
7Gutiérrez 1995 74 M Micro liver abscessBlood No NRNR
8 Singh 1996 73 F Unknown Blood No NR NR
9Bush 1996 58 F BiliaryBlood YesNRNR
10Jones 1996 66 F Liver abscess Blood, liver abscessNoNR NR
11Pun 1996 47 M Cholangitis Blood No NRNR
12 Singer 1997 55 F Unknown Blood No NRNR
13 Alvarez 1999 77 F Abdominal Blood No NRNR
14 Thomas 1999 73 M Cholecystitis BloodYes NRNR
15 Eckel 2000 65 F Liver abscess BloodYes NRNR
16 Kreidl2002 80 M Liver abscess Blood, liver abscessNoNRNR
17Barrett 2002 NR F Septic abortionBlood No NRNR
18 Jimenez 2002 79 M Unknown Blood No NRNR
19Halpin 2002 29 F Post-caesarean endometritisBlood YesNRNR
20Hamoda 2002 39 F Post-amniocentesis endometritisBlood YesNRNR
21Ikegami 2004 67 M Acute pancreatitis Pancreas Yes NRNR
22 Vaiopoulos 2004 74 M Intestinal and biliary Blood No NRNR
23Solis 2004 50 M Hepatic gas gangreneDonor liverNoNRNR
24 Rodriguez 2005 57 M Biliary Blood No NRNR
25 Pirrotta 2005 50 M Unknown Blood, stool No NRNR
26 Au 2005 65 M Liver abscess NR No NRNR
27 McArthur 2006 49 M Abdominal Blood No NRNR
28Daly 2006 80 M Liver abscess Blood No NRNR
29Kwon 2006 71 F Unknown BloodNo NRNR
30Loran 2006 69 F Liver abscess NR No NRNR
31Ohtani 2006 78 M Liver abscess Blood, liver abscessNoNRNR
32Eigneberger 2006 60 M Liver abscess Liver (Gram stain)NoNRNR
33Poulou 2007 74 M Unknown Blood No LecithinaseNR
34Kapoor 2007 58 M Unknown Blood No NRNR
35Poon 2007 64 F HepatobiliaryBloodNo NRNR
36 Nadisauskiene 2008 31 F Post-caesarean endometritisBlood NoNRNR
37Egyed 2008 39 F Unknown Blood Yes NRNR
38Hess 2008 81 M Diverticulitis Blood, brain, heart, spleenNoNRNR
39Boyd 2009 46 M CholecystitisBlood NoNRNR
40Uppal 2009 61 M Unknown Blood No NRNR
41 Merino 2010 83 F Liver abscess Blood No NRNR
42Ng 2010 61 F Liver abscess BloodYesNRNR
43Rajendran 2010 58 M Liver abscess Blood, liver abscess, gall bladderYesNRNR
44 Bunderen 2010 74 M Cholangitis Blood Yes NRNR
45Bryant 2010 60 F Uterus Blood, intrauterineYesNRNR
46Stroumsa 2011 41 F Uterine myoma BloodYesNRNR
47 Qandeel 2012 59 M Liver abscess (post-laparoscopic cholecystectomy)Blood YesNRNR
48Watt 2012 52 M Pan-enteritis Blood Yes NRNR
49Law 2012 50 F Liver abscess Blood No NRNR
50 Okon 2013 71 M Unknown Blood, CSF No NRNR
51Cécilia 2013 64M Unknown Blood No NRNR
52 Dutton 2013 66 M NR Blood No NRNR
53 Kitterer 2014 71 M Liver abscess Blood No NRNR
54 Kurasawa 2014 65 M Liver abscess Blood No NRNR
55 Renaudon-Smith 2014 37 M Liver abscess Blood Yes NRNR
56 Simon 2014 79 F Unknown Blood No NRNR
57 Shindo 2015 73 F Liver abscess Liver abscessNo+ −A
58 Khan 2015 77 M Cholecystitis, liver abscessLiver (Gram stain)NoNRNR
59Cochrane 2015 65 F Emphysematous cholecystitisBlood YesNRNR
60Yamaguchi 2015 80–89 F Unknown Bile, pleural effusionsNoNRNR
61Li 2015 71 M Liver abscess (post-TACE)Blood YesNRNR
62Medrano-Juarez 2016 32 M Unknown BloodYesNRNR
63Lim 2016 58 M Liver abscess Blood No NRNR
64Hashiba 2016 82 MLiver abscess, emphysematous cholecystitisBlood No+ −A
65Sarvari 2016 76 F Emphysematous gastritisIntestine subcutaneous tissueNoNR NR
66Carretero 2016 65 M Liver abscess Blood, liver abscessYesNRNR
67 Kent 2017 74 F EnteritisBlood NoNRNR
68 Kukul 2017 17 M Gastrointestinal tract Quadratus muscle NoNRNR
69Balan 2017 71 F Unknown Blood No NRNR
70Ewing 2017 53 F Necrotising fasciitisWound No NRNR
71Shibazaki 2018 68 F Liver abscess Blood No NRNR
72Wild 2018 81 F Unknown Blood No+−A
73Gelonch 2018 66 M Liver abscess NR No NRNR
74Gelonch 2018 63 M Liver abscess NR No NRNR
75 Uojima 2019 83 M Liver abscess (post-TACE)Liver abscess NoNRNR
76Sakaue 2019 76 M Liver abscess Blood No+ −A
77Kawakami 2020 83 M Pelvic abscess Blood, intraabdominal samplesNoNRNR
78 Fujikawa 2020 77 F Liver abscess Blood No NRNR
79Chinen 2020 80 F Liver abscess Blood, liver abscessNoNRNR
80Smit 2020 61 M Liver abscess Blood No NRNR
81Smit 2020 71 F Unknown BloodNoNRNR
82Koubaissi 2020 50 M AbdominalBlood No NRNR
83Poletti202164FUnknown BloodNoNRNR
84Liu202121MIntestineBloodYesNRNR
85Liu202142MIntestineBloodNoNRNR
86Fukui202169MUnknown BloodNo+−A
87Olds 2021 85 F Liver abscess Blood No NRNR
88Bibi202177MCholecystitis (Post ERCP)BloodNoNRNR
89Guo202162MHepatoma (post-microwave ablation)Blood NoNRNR
90Woittiez 2021 65 M Gangrenous cholecystitisBlood, liver abscessNo+−A
91Woittiez 2021 69 M Liver meta? (post-microwave ablation)BloodNo +−A
92Takahashi202270MLiver abscess Blood, liver abscessYesNRNR
93Wong202280MLiver abscess BloodYesNRNR
94Kohya202260MPerforation in ascending colon cancerBloodNo++F
95Suzaki202269MEnteritisBloodNo+ −A
96 Suzaki202265FCholecystitisBloodNo+−A
97 Suzaki202268FOvarian tumourBloodNo+−A
98 Suzaki202246MTraumaBloodNo++F
99 Suzaki202272MUnknownBloodNo+−A
100Suzaki202258MUnknown BloodNo+−A
CPA: phospholipase C; CPE: Clostridium perfringens enterotoxin; NR: not reported; CSF: cerebrospinal fluid; TACE: transarterial chemo-embolisation; ERCP: endoscopic retrograde cholangiopancreatography.
Table
Table 3. Clinical profiles of C.perfringens infection with/without MIH.
Table 3. Clinical profiles of C.perfringens infection with/without MIH.
MIH (n = 6)w/o MIH (n = 54)
Median age66.5 (46–72 years)77.0 (46–72 years)p = 0.017
Loss of consciousness6/6 (100%)19/54 (35.2%)p = 0.004
Severe pain at the onset4/6 (66.7%)10/54 (18.5%)p = 0.008
Shock at onset3/6 (50%)3/54 (5.6%)p = 0.010
Haematuria2/6 (33.3%)1/54 (1.9%)p = 0.024
GAS formation3/6 (50%)4/54 (7.4%)p = 0.017
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Suzaki, A.; Hayakawa, S. Clinical and Microbiological Features of Fulminant Haemolysis Caused by Clostridium perfringens Bacteraemia: Unknown Pathogenesis. Microorganisms 2023, 11, 824. https://doi.org/10.3390/microorganisms11040824

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Suzaki A, Hayakawa S. Clinical and Microbiological Features of Fulminant Haemolysis Caused by Clostridium perfringens Bacteraemia: Unknown Pathogenesis. Microorganisms. 2023; 11(4):824. https://doi.org/10.3390/microorganisms11040824

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Suzaki, Ai, and Satoshi Hayakawa. 2023. "Clinical and Microbiological Features of Fulminant Haemolysis Caused by Clostridium perfringens Bacteraemia: Unknown Pathogenesis" Microorganisms 11, no. 4: 824. https://doi.org/10.3390/microorganisms11040824

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