JACOBS, AVRUM; BARNARD, KATHRYN M.D.; FISHEL, RHONDA M.D.; GRADON, JEREMY D. M.D.

Introduction

Infection with Clostridium difficile is a common complication of antibiotic therapy. The usual clinical scenario is of pseudomembranous colitis manifesting as fever and diarrhea, usually within 4–9 days of starting antibiotic therapy. This is occasionally complicated by the development of toxic megacolon, necessitating urgent surgical intervention. All antibiotics have the potential to cause pseudomembranous colitis, and while clindamycin is the antimicrobial best known for it, broad-spectrum cephalosporins are now the most commonly implicated agents.

Not well appreciated by many clinicians, though, is the ability of C. difficile to cause disease at sites other than the colon. We recently encountered 2 such extracolonic manifestations of C. difficile infection in 1 week (reactive arthritis and small bowel involvement) which prompted a review of the available literature. Since we could not find a comprehensive review in the general medical literature (using MEDLINE [National Library of Medicine, Bethesda, MD] from 1966 to October 2000), we undertook the writing of this article to aid clinicians dealing with noncolonic problems in patients known to be infected with C. difficile.

In the original report of C. difficile, published by Hall and O’Toole ⁽²⁴⁾ in 1935, the bacterium was named “the difficult clostridium” because it grew slowly in culture and early attempts at isolation were unsuccessful. This Gram-positive, spore-forming, obligate anaerobic bacillus is now recognized as the major cause of pseudomembranous colitis ^(6,33). Once present in the colon, C. difficile produces both an enterotoxin (toxin A) and a cytotoxin (toxin B) ⁽⁷¹⁾. While toxin A has been implicated as the cause of C. difficile-associated diarrhea and pseudomembranous colitis ⁽²⁹⁾, the contributions of these toxins to the extracolonic manifestations of C. difficile infection are unknown.

When initially isolated from extraintestinal sites, C. difficile was considered to be of questionable pathologic significance ⁽⁶⁴⁾. However, it is now clear that such isolates are indeed clinically significant. Knowledge of the clinical presentation of these extracolonic manifestations of infection will help in patient care and disease management. Topics to be discussed include small bowel involvement, bacteremia, visceral abscess formation, infection of implanted prosthetic devices, encephalopathy, reactive arthritis, and osteomyelitis. Where possible, the clinical presentation, proposed mechanisms of pathogenesis, and treatment options are summarized for each of the clinical conditions discussed.

Case Reports

Both patients were seen at Sinai Hospital of Baltimore in June 2000.

Small bowel involvement

An 83-year-old woman was admitted to the medical service for confusion and an Escherichia coli urinary tract infection. Further evaluation of her mental status change revealed evidence of late-latent syphilis but no evidence of neurosyphilis. The urinary tract infection was treated with oral trimethoprim-sulfamethoxazole, and intramuscular penicillin was administered weekly as syphilis treatment. The patient acutely decompensated on hospital day 8 and was found to have an acute abdomen. Computed tomography (CT) scanning (Figure 1) revealed abnormalities of both the colon and distal small intestine. At laparotomy, an inflammatory process was found throughout the colon as well as the distal and middle thirds of the small intestine. All the involved areas of bowel had pseudomembranes, were judged clinically to be nonviable, and were resected. Histopathologic examination of the excised small and large bowel demonstrated changes consistent with C. difficile-related infection, and the stool C. difficile toxin assay was positive. Postoperatively, the patient had a complicated course, could not be weaned from ventilatory support, and ultimately was discharged to a chronic-care facility.

Fig. 1

Clostridium difficile -related reactive arthritis

A 36-year-old man with newly diagnosed acute myelogenous leukemia was admitted for induction chemotherapy. He became profoundly neutropenic and then febrile. Empiric therapy with imipenem-cilastatin was initiated. Five days later diarrhea developed together with severe right lower quadrant pain. A CT scan of the abdomen demonstrated right-sided colitis. Stool was positive for C. difficile toxin A. Therapy with oral metronidazole was started. On day 5 of metronidazole therapy, left knee pain, swelling, and tenderness developed. The knee joint effusion was drained and revealed cloudy fluid with a white cell count of 67,000/mm³. There were no crystals found on fluid microscopy, serum uric acid had been normal throughout, and fluid and blood cultures remained negative. A diagnosis of C. difficile related reactive arthritis was made. The patient was managed with nonsteroidal antiinflammatory drugs and physical therapy. Fourteen days later the swelling had subsided and the patient was able to bear weight on the affected knee again.

Small Intestinal Involvement

The normal flora of the small intestine changes dramatically as it approaches the connection with the colon. The distal third of the small intestine provides an environment hospitable to anaerobic bacteria. Despite this, involvement of the small intestine in infections with C. difficile is rare even when there is infection of the immediately adjacent right colon.

Previously reported cases of small bowel involvement are summarized in Table 1. It is noteworthy that most of the reported patients had surgically altered intestinal anatomies. This, then, may be a predisposing factor to small bowel susceptibility to pseudomembranous enteritis. It has been reported that after an ileostomy, ileal flora may change to resemble fecal flora ⁽⁷⁷⁾. This leads to the hypothesis that surgical alteration of the small bowel could lead to bacterial colonization resembling the colon, resulting in the increased susceptibility to C. difficile infection. Kralovich et al ⁽³⁵⁾ postulate that the constant peristaltic activity of the small bowel and mechanical action of the ileocecal valve prevent C. difficile from colonizing the small bowel. They reported a patient with C. difficile infection of a bypassed segment of ileum created during a jejunal-ileal bypass performed 30 years earlier. The authors propose that ileal hypomotility may have contributed to its becoming colonized and infected with C. difficile.

Table 1

Table 1

Apel et al ⁽⁴⁾ report that there are histologic changes in the small intestine epithelium when fecal flow is altered, and Yee et al ⁽⁸¹⁾ note that the patient they reported demonstrated abnormal epithelium of the ileorectal anastomosis with histologic features similar to colonic epithelium. These changes may have made the local milieu more conducive to this infection. The cases discussed by Shortland et al ⁽⁶¹⁾ and Kralovich et al ⁽³⁵⁾ are fascinating in that the only parts of the small bowel that developed pseudomembranous colitis were the segments used as a conduit from the ureters following cystoscopy, and the bypassed and defunctionalized small bowel, respectively. The colitis affecting the colon in both cases stopped abruptly at the ileocecal valve—that is, there were no plaques at the terminal ileum. This appears to indicate that the normal small bowel is not usually susceptible to developing infection with C. difficile; however, as in the case we presented, such infections may occasionally occur even in the absence of apparent predisposing factors. Overall, when the small bowel is involved with infection with C. difficile, the mortality rate is high, with 4 of 7 reported patients dying.

Cellulitis and Soft Tissue Involvement

Cases in adults

Smith and King ⁽⁶⁴⁾ reported the first 2 cases of C. difficile-related cellulitis in adult patients, and in each case the development of cellulitis followed local trauma. The first case was of a soldier in 1943 hit with a shell fragment in the thigh. The patient died, and C. sporogenes, C. sphenoides, and C. difficile were isolated from the patient’s wound. The second case was described in 1957 involving a patient who fractured his femur in an airplane accident. An anaerobic streptococcus was isolated along with C. difficile. The same authors reported a case of an abscess in the vaginal vault of a 45-year-old woman. C. difficile was isolated in addition to anaerobic streptococci and a non-spore-forming obligate anaerobic bacterium.

Eastwood ⁽¹⁹⁾ reported a case of a 28-year-old man who developed a perianal abscess about 3 months after beginning antituberculous therapy. Pus drained from the abscess grew E. coli, Citrobacter freundii, Streptococcus viridans, and a Clostridium species later identified as C. difficile. Eastwood noted that this case of C. difficile infection was not accompanied or preceded by diarrhea.

Recently, a case of C. difficile-induced necrotizing fasciitis of the thigh following multiple trauma due to a motor vehicle accident has been reported ⁽⁷⁾. The patient, a 59-year-old woman, had negative blood cultures, with a pure growth of C. difficile being cultured from the involved thigh. The patient survived with intensive surgical and medical management.

Pediatric cases

Katner, Pankey, and colleagues ⁽³⁰⁾ described the first case of cellulitis in an infant due to C. difficile with neurologic complications that eventually lead to death. A 3-month-old female developed a 5-cm tender brownish blue macular lesion over her left hip. The lesion was aspirated and grew a pure growth of C. difficile. The baby began jerking her right upper extremity and twitching at the mouth. She then rapidly deteriorated and died. Danielsson et al ⁽¹⁷⁾ also reported a case of a perirectal abscess, this in a 15-year-old girl with Crohn disease. C. difficile was isolated, along with Bacteroides fragilis ss fragilis, S. epidermidis, E. coli, and Propionibacterium acnes.

Because C. difficile is a spore-forming bacterium found in the environment, it would seem likely that it could cause cellulitis following a traumatic event such as a war wound or a motor vehicle accident. Furthermore, because approximately 4% of individuals are asymptomatic colonic carriers of C. difficile, a lower extremity wound could readily become infected with the C. difficile spores shed from the anus. Thus, Smith and King ⁽⁶⁴⁾ proposed that the wounds in the patients’ thighs may have been con-taminated with fecal matter resulting in these infections. Similarly, Katner, Pankey, and colleagues ⁽³⁰⁾ proposed that C. difficile may have infected the skin of the patient they presented via contaminated diaper pins, especially considering the high carriage rate of C. difficile in the stool of infants ⁽¹⁴⁾. They did not believe the infection spread hematogenously, as blood cultures demonstrated no growth, and there was no other identifiable source of infection found. It is likely that the local in vivo production of toxins A and B contributes to the soft tissue infections.

Bacteremia and Sepsis Syndrome

Bacteremia

There have been 9 cases of C. difficile bacteremia reported. The first was by Smith and King ⁽⁶⁴⁾ who reported C. difficile bacteremia in a 5-month-old baby boy with a 3-week history of coryza, cough, and anorexia. They assumed at the time that the source of infection was the respiratory tract, and were unsure of the pathologic significance of the positive blood culture. Spencer et al ⁽⁶⁷⁾ reported a case of polymicrobial bacteremia in 1984. The 2 organisms that grew on culture were C. difficile and Bacteroides fragilis. Five years later, Gerard et al ⁽²³⁾ presented a case of polymicrobial bacteremia with C. difficile during an attack of acute diverticulitis. The other organisms isolated were E. coli, Enterococcus faecalis, and Bacteroides vulgatus.

The reported cases are summarized in Table 2. Of note, the majority of cases are of polymicrobial bacteremia, with C. difficile being just 1 isolate among other usual bowel flora. The mortality rate is low, with 2 of 10 reported patients dying. The prevailing theory explaining the pathophysiology of these events is that in the setting of pseudomembranous colitis, colonic inflammation permits transient bacteremia to develop.

Table 2

Sepsis syndrome

Chatila and Manthous ⁽¹²⁾ reported the first cases of C. difficile-related sepsis syndrome in 1995. They reported 4 patients with C. difficile infection who presented with acute abdomens and sepsis syndrome. One patient underwent surgical intervention while the others were managed medically. The sepsis syndrome resolved in all 4 cases. Lowenkron et al ⁽⁴⁰⁾ reported 3 cases of sepsis syndrome following large intestinal C. difficile infection. Two of the 3 patients were treated surgically, and all 3 patients died.

With regard to the proposed pathophysiology of blood culture-negative sepsis syndrome in the setting of acute pseudomembranous colitis, there is discussion in the literature regarding possible mechanisms of pathogenesis. Chatila and Manthous ⁽¹²⁾ suggest that sepsis can be stimulated by the cellular inflammatory response of severe enterocolitis alone. The same authors also note that severe enterocolitis is due, at least in part, to activation of host monocytes by both C. difficile toxins A and B, as well as the neutrophilic chemoattractant response to toxin A ⁽⁷¹⁾. The toxins can then enter the bloodstream via the pervious gut epithelium, ultimately leading to the release of cytokines and interleukins mediating the development of sepsis syndrome. Normally the gastrointestinal tract serves as a barrier, preventing systemic absorption of toxins and microbes ⁽¹⁸⁾. When this barrier is compromised, for example, in the setting of pseudomembranous colitis, it can no longer offer such protection.

Visceral Organ Involvement

Splenic abscess

The first report of C. difficile causing splenic abscess was by Saginur and colleagues ⁽⁵⁸⁾ in 1983. In that patient, cultures of blood and ascitic fluid grew C. difficile, but there was no suggestion of intraabdominal abscess on CT scanning. At autopsy, however, a 6 × 5-cm, well-encapsulated abscess was located in the upper pole of the spleen. Postmortem cultures of the abscess grew C. difficile.

In 1987, Studemeister et al ⁽⁷⁰⁾ reported a case of C. difficile bacteremia associated with a polymicrobial splenic abscess. Five months before presentation, the patient had positive cultures for 4 species of Clostridium (difficile, fallax, perfringens, ramosum), with a normal abdominal CT scan. On the second hospital admission, blood cultures were positive for C. difficile alone. A CT scan revealed a 4-cm area of decreased attenuation in the spleen. A splenectomy was successfully performed, and a splenic abscess was found containing 100 ml of foul-smelling pus. Cultures of the pus grew out C. difficile and Pseudomonas paucimobilis. The patient did well on cefoxitin and metronidazole postoperatively.

Stieglbauer et al ⁽⁶⁸⁾ reported a patient who developed abdominal symptoms 2 weeks after being admitted for atrial fibrillation with rapid ventricular response and congestive heart failure. Along with a 135-cm segment of ischemic small bowel, a 12 × 10 × 5-cm³ purulent splenic abscess was resected, and C. difficile was isolated in culture. Cultures of ascitic fluid were negative. The authors believed that abscess formation followed splenic infarct due to thromboembolism as a complication of atrial fibrillation.

Kumar and colleagues ⁽³⁶⁾ reported a case of a patient who was admitted to the intensive care unit because of pneumonia complicating a laminectomy. Three weeks into the admission, the patient developed diarrhea and new fever. He had been treated with amphotericin B, cefotaxime, and amoxicillin/clavulanic acid. Ultrasound revealed a 16 × 13-cm splenic abscess, confirmed by CT scan. Percutaneously drained splenic pus grew C. difficile and coagulase-negative Staphylococci. Intravenous vancomycin was used to treat the infection. A repeat CT scan 4 weeks later demonstrated that the abscess was adequately drained and the patient improved, but he died 2 months later from respiratory failure. Shedda et al ⁽⁶⁰⁾ also reported a case of a patient treated without splenectomy. The abscess was localized by ultrasound, and the cavity was drained transdiaphragmatically. C. difficile toxin B was detected from cultured splenic fluid.

Thus, splenic abscess may result from bacteremia, trauma, or other events such as thromboembolism. Pickleman et al ⁽⁴⁸⁾ noted that patients with a recent history of bacteremia are at risk for developing splenic abscesses. In several cases, C. difficile bacteremia was documented from weeks ⁽⁵⁸⁾ to months ⁽⁷⁰⁾ before the manifestations of the abscess formation. These cases demonstrate that C. difficile should be considered in the differential diagnosis of the cause of a splenic abscess even at a time remote from a previous bout of pseudomembranous colitis and/or bacteremia.

Pancreatic abscess

Sofianou ⁽⁶⁶⁾ reported the only known case of C. difficile pancreatic abscess in a patient with no previous antibiotic therapy or history of diarrhea. A 68-year-old man had fluid from a pancreatic cyst drained during surgery and was demonstrated to have C. difficile. Culture of the ascitic fluid was negative and blood cultures were not taken, but the author believed that the bacteria got to the pancreas via the bloodstream. The patient was treated with metro-nidazole and ceftriaxone and recovered completely.

The reported cases of visceral abscess formation are summarized in Table 3. From the available reported cases, it can be seen that frequently, such visceral abscesses are only detected clinically weeks to months after the initial colonic process.

Table 3

Pleural Involvement (Effusion/Empyema)

The first 2 reports of C. difficile isolated from pleural fluid were by Smith and King ⁽⁶⁴⁾. They both occurred in 1959, the first in a 65-year-old man with severe acute and chronic pleuritis, and the second in a 58-year-old man with a pneumothorax and pleural effusion. The authors believed that the likely source of infection was the respiratory tract. Again, they were unsure at that time of the pathologic significance of these isolates.

Simpson et al ⁽⁶²⁾ reported a case of nosocomial empyema following chest drain insertion in a 46-year-old man. C. difficile was the only organism grown following thoracentesis and pleural biopsy after several previous taps and biopsies yielded no growth of any organism. They believed that the patient probably acquired the organism nosocomially, resulting in an empyema secondary to multiple previous attempts at drainage of the pleural effusion. The patient responded to treatment with metronidazole.

Stolk-Engelaar et al ⁽⁶⁹⁾ reported a case of a 33-year-old man who developed a left-sided pleural effusion several days after surgical removal of a bronchogenic cyst from the upper lobe of the left lung. Isolates of the effusion were identified as C. difficile and C. cadaveris. The strain of C. difficile was noted to produce cytotoxin B.

Reactive Arthritis/Reiter Syndrome

Reactive arthritis is defined as the occurrence of an acute aseptic, inflammatory arthropathy following an infectious process, at a site removed from the primary infectious source ⁽³⁾. A subgroup of patients with reactive arthritis demonstrate a triad of symptoms—arthritis, conjunctivitis, and urethritis—referred as Reiter syndrome ⁽³¹⁾. Interestingly, Reiter ⁽⁵³⁾ first described this triad in a World War I soldier after an episode of bloody diarrhea. The leading bacterial causes of reactive arthritis following enteric infections are Yersinia, Salmonella, Shigella, and Campylobacter. In 1976, Rollins and Moeller ⁽⁵⁶⁾ described the first case of antibiotic-associated pseudomembranous colitis associated with arthritis, though at that time it had not yet been realized that C. difficile caused the colitis. There are now 36 reported cases of reactive arthritis secondary to C. difficile infection. In 1993, Putterman and Rubinow ⁽⁵¹⁾ established the following diagnostic criteria for C. difficile-induced reactive arthritis:

1) appearance of arthritis together with or following the onset of diarrhea and/or colitis

2) diarrhea appearing some time after a course of systemic antimicrobial therapy

3) microbiologic proof of C. difficile involvement (either positive stool culture or assay for toxin)

4) no reasonable alternative diagnosis for the arthritis or diarrhea (that is, no other identified infectious agents).

The cases reported in the literature are summarized in Table 4. From the reported cases it can be seen that the most commonly involved joints are the knee and the wrist (18 of 36 cases). The onset of reactive arthritis appears to occur, on average, 11.3 days after the onset of colonic symptoms (range, 1–35 d). The illness is frequently prolonged with recovery taking an average of 68 days (range, 5–300 d). Fever is not universally present. Both patients positive for HLA-B27 antigen and those not possessing this antigen may develop reactive arthritis.

Table 4

Table 4

Table 4

Pathophysiology

Although the pathogenesis of this process is unclear, various hypotheses have been proposed in an attempt to explain reactive arthritis following C. difficile enteric infection. Fairweather et al ⁽²⁰⁾ and McCluskey et al ⁽⁴²⁾ found an antitoxin (Fairweather discovered it to be immunoglobulin A) directed against C. difficile toxin A in their patients, that was not found in 11 controls with C. difficile colitis without arthritis. The patients’ symptoms of arthritis correlated with fluctuations of this antitoxin titer. It was thus postulated that arthritis in this setting resulted from a systemic immunologic reaction to intestinal bacterial antigens.

The pathogenesis of reactive arthritis associated with C. difficile also may be analogous to that proposed for intestinal bypass syndrome ⁽²⁸⁾. Wands et al ⁽⁷⁸⁾ found cryoglobulins containing immunoglobulin and complement during arthritic flares following jejunocolic or jejunoileal bypass. IgG antibodies to intestinal bacteria were also identified, implicating bacterial antigens in the pathogenesis. Furthermore, there were 2 cases of urticaria ^(47,56) that preceded the arthritic symptoms that may support an etiology of circulating immune-complex deposition.

Putterman and Rubinow ⁽⁵¹⁾ suggest that intestinal bacterial antigens could gain access to the systemic circulation via increased gut epithelial permeability that could result in a systemic inflammatory response. They propose that C. difficile enterotoxin, toxin A, and the presence of the HLA-B27 antigen both independently predispose the bowel to become more permeable, allowing bacterial antigens to gain access to the systemic circulation. In support of this, Mermel and Osborn ⁽⁴³⁾ state that patients with ankylosing spondylitis have abnormally increased bowel permeability, and that when a patient who is HLA-B27 positive acquires an intestinal infection, the toxin-induced, augmented bowel permeability allows some bacterial antigens to cross into the systemic circulation.

Various studies support this idea that joint inflammation can be induced by increased intestinal permeability in patients who are HLA-B27 positive ^(44,45,63). Given the absence of bacteremia or the isolation of C. difficile in blood or joint fluid cultures, direct septic involvement of the joints is excluded as a possible pathogenic mechanism.

Management of this form of reactive arthritis is unclear. Rheumatologists have employed a wide variety of strategies, including joint fluid drainage, intraarticular steroid administration, and nonsteroidal antiinflammatory therapy. No single therapeutic modality has emerged as being clearly superior. As with all forms of “reactive” processes, the primary objective of therapy is to control the underlying causative problem, namely, in these cases, the colitis.

Osteomyelitis

Riley and Khartigasu ⁽⁵⁴⁾ described the first case of osteomyelitis caused by C. difficile in 1982. A 21-year-old man developed chronic osteomyelitis around a Kirschner intramedullary nail that had been placed following a femur fracture in a motorcycle accident. Cultures were repeatedly positive for C. difficile. After therapy was changed to metronidazole, the patient recovered.

A 30-year-old woman with sickle cell anemia who presented with 2 areas of frontal bone osteomyelitis was reported by Towns et al ⁽⁷⁴⁾ in 1996. Cultures of the frontal bone yielded C. difficile. The patient was treated with bifrontal craniectomy and chloramphenicol and recovered. Incavo et al ⁽²⁷⁾ described a case of vertebral osteomyelitis, probably secondary to bacteremia with hematogenous osseous seeding. In 1996, Gaglani et al ⁽²²⁾ described a case of a patient with sickle cell anemia who developed C. difficile osteomyelitis of the tibia.

Infection of Prosthetic Devices

Infections of implanted prosthetic devices are frequently devastating, requiring combined surgical and medical management. When C. difficile involves prosthetic devices, the outcome appears to be grim. McCarthy et al ⁽⁴¹⁾ reported the case of a patient who developed culture-positive C. difficile-associated diarrhea following pneumonia and a total hip replacement. The patient was successfully treated with oral metronidazole. Twelve months later she was readmitted for revision of the hip prosthesis because of increasing pain. An abscess associated with the prosthesis was cultured and grew C. difficile. It was demonstrated to be the same strain as that from 12 months earlier.

Pron et al ⁽⁴⁹⁾ reported a 16-year-old patient who had a complete transarticular resection of a femoral osteosarcoma with subsequent implantation of a total knee prosthesis and allogenic osseous transplant. Sixteen months later the patient was readmitted with traumatic fracture of his patella. An external arthrotomy with drainage was performed and anaerobic culture yielded pure growth of a “Clostridium strain.” The patient was treated with amoxicillin and ornidazole, but when the antibiotics were stopped 4 months later, the inflammation grew more severe and a sinus formed discharging pus. The pus was cultured and showed the same Clostridium species as that isolated 5 months earlier, and was identified as C. difficile. The patient eventually underwent limb amputation.

Achong et al ⁽²⁾ describe a 31-year-old woman with a history of bilateral hip replacements due to avascular necrosis of the femoral heads who was admitted to the hospital for management of a sickle cell crisis. Two months after she was admitted, she noted pain in her left hip and thigh. Radionuclear medicine scanning using Indium-¹¹¹ labeled white blood cell scintography supplemented by technetium^99m bone marrow imaging showed abnormal white blood cell accumulation surrounding the left greater trochanter. Pus was drained and culture yielded C. difficile. Blood cultures were negative, but a stool sample was positive for C. difficile toxin. The patient eventually died weeks later of cardiorespiratory failure.

The authors of the first case ⁽⁴¹⁾ postulated that following treatment for pneumonia with ceftriaxone and clindamycin, the patient developed subclinical C. difficile-associated diarrhea. The diarrhea may have contaminated the skin of the pelvis and perineum with spores of C. difficile. (This idea is similar to that proposed earlier for the explanation of cellulitis caused by C. difficile). During the operation of the patient’s fractured femur, the wound could have become contaminated with the spores or vegetative forms of C. difficile that were not eradicated by preoperative surgical prophylaxis (flucloxacillin and gentamicin).

Achong et al ⁽²⁾ offered 2 possible mechanisms of infection: as others considered, C. difficile may have spread from the gastrointestinal tract hematogenously to the prosthesis, with subsequent abscess formation. Of note, their patient incidentally demonstrated “functional asplenia” by the absence of technetium and indium uptake by an anatomically present spleen. The authors proposed that this may have led to poor clearance of bacteremia, and subsequent hematogenous spread. An alternate mechanism is that the bacteria may have directly seeded the hip joint via an unrecognized enteric-hip fistula ⁽³⁸⁾.

Encephalopathy

Clinicians experienced in the management of patients with C. difficile infections have noted the occasional occurrence of cases of encephalopathy in this population. This has been ascribed anecdotally to the neurotoxic effects of high titers of circulating C. difficile toxins.

In light of this, the development of mental status changes in patients with C. difficile colitis should prompt aggressive therapy of the known colonic infection. However, firm proof of the role of C. difficile in diseases of the central nervous system is lacking in the literature.

Miscellaneous Conditions

Cases of C. difficile colitis have been proposed to be related to the sudden infant death syndrome. Cooperstock et al ⁽¹⁴⁾ reported 2 cases of sudden infant death syndrome with concurrent “high levels” of C. difficile toxin in the patients’ stool. Katner, Pankey, and colleagues ⁽³⁰⁾ considered the death of the 3-month-old patient in their report to be possibly related to the “neurotoxic effects” of C. difficile toxin.

Summary

Clostridium difficile is most commonly associated with colonic infection. It may, however, also cause disease in a variety of other organ systems. Small bowel involvement is often associated with previous surgical procedures on the small intestine and is associated with a significant mortality rate (4 of 7 patients). When associated with bacteremia, the infection is, as expected, frequently polymicrobial in association with usual colonic flora. The mortality rate among patients with C. difficile bacteremia is 2 of 10 reported patients. Visceral abscess formation involves mainly the spleen, with 1 reported case of pancreatic abscess formation. Frequently these abscesses are only recognized weeks to months after the onset of diarrhea or other colonic symptoms. C. difficile-related reactive arthritis is frequently poly-articular in nature and is not related to the patient’s underlying HLA-B27 status. Fever is not universally present. The most commonly involved joints are the knee and wrist (involved in 18 of 36 cases). Reactive arthritis begins an average of 11.3 days after the onset of diarrhea and is a prolonged illness, taking an average of 68 days to resolve. Other entities, such as cellulitis, necrotizing fasciitis, osteomyelitis, and prosthetic device infections, can also occur. Localized skin and bone infections frequently follow traumatic injury, implying the implantation of either environmental or the patient’s own C. difficile spores with the subsequent development of clinical infection.

It is noteworthy that except for cases involving the small intestine and reactive arthritis, most of the cases of extracolonic C. difficile disease do not appear to be strongly related to previous antibiotic exposure. The reason for this is unclear.

We hope that clinicians will become more aware of these extracolonic manifestations of infection, so that they may be recognized and treated promptly and appropriately. Such early diagnosis may also serve to prevent extensive and perhaps unnecessary patient evaluations, thus improving resource utilization and shortening length of hospital stay.

References