Apoorv Broor, MD

Clostridium difficile colitis (CDC) is the most common cause of hospital‐acquired diarrhea.1 The incidence of CDC has sharply increased over the past decade despite increasing awareness among health care professionals.24 C. difficile pathogenic strains induce diarrhea through the elaboration and secretion of 2 exotoxins: toxin A and toxin B. Toxin A is an inflammatory toxin, leading to fluid secretion, increased mucosal permeability, and marked enteritis and colitis.5 Toxin B is cytotoxic, leading to cell injury and apoptosis.5 Combined, toxin A and toxin B can cause a wide spectrum of clinical presentations, ranging from mild diarrhea that resolves with the discontinuation of antibiotics to a fulminant colitis requiring surgical intervention.

The severity of clinical manifestations has been shown to be inversely proportional to the host anti‐toxin A antibody level in response to toxin exposure. Kyne et al.6 demonstrated that asymptomatic C. difficile carriers produced significantly higher anti‐toxin A immunoglobulin G (IgG) levels compared to symptomatic patients. Among the latter group, patients with mild disease had a higher antibody level compared to those with severe colitis.6, 7 Additional risk factors predisposing to severe colitis are advanced age, severe underlying illness,8 and immunocompromised state.9

Recently, a new C. difficile strain (BI/NAP1) with a mutated toxin A and toxin B promoter silencer, a binary toxin gene, and fluoroquinolone resistance has been described in Canada and the United States.3, 10 This strain has been associated with an increased incidence of CDC among hospitalized patients, especially the incidence of severe disease requiring colectomy. At the same time, several reports describing metronidazole treatment failure have been published.1114 These recent findings emphasize the importance of finding alternative treatments for CDC.

Intravenous immunoglobulin (IVIG) was used to treat CDC for the first time in 1991.15 Since then, 12 case reports and small case series, along with 1 case‐control study have been published documenting IVIG treatment outcomes.1527 However, only 5 reports to date examined patients with severe CDC.2125 In the present study, we report the largest series of patients with severe CDC treated with IVIG in the literature to our knowledge.

Patients and Methods

Results

Discussion

To our knowledge, the present study is the largest series published in the literature to date on the use of IVIG for severe CDC. It is also the first study to report a high mortality rate compared to the 5 previous smaller studies on this topic. In the first report on IVIG use for CDC, Leung et al.15 used IVIG to treat 5 pediatric patients suffering from chronic relapsing CDC. It was not until 7 years later, in 1997, that the first IVIG use for severe CDC was reported.22 Since then, a total of 13 works have been published on IVIG for CDC treatment, and only in 5 of these was IVIG administered for severe CDC treatment:2125 3 case reports, 1 case series, and 1 case‐control study. Although the 4 uncontrolled reports concluded that IVIG is beneficial for severe CDC, the only controlled study reported no significant difference between cases and controls for all‐cause mortality, length of stay, and colectomy rate.25

The definition of severe CDC varied between reports, making comparison difficult. McPherson et al.21 and Hassoun and Ibrahim24 defined severe disease as one causing pancolitis on CT scan either with or without megacolon. In the study by Juang et al.,25 disease severity was assessed using the modified criteria of Rubin et al.9 Salcedo et al.22 defined severe CDC as one causing pancolitis in one patient and thumbprinting on CT scan in another, whereas Chandrasekar et al.23 defined it as one causing shock requiring inotropic support and presence of pseudomembranes on colonoscopy.

The present report is unique in that it provided 2 scales to characterize disease in each patient. The first scale measured colonic involvement anatomically and physiologically using a combination of computerized axial tomography (CAT) scan findings, presence or absence of ileus or referral for possible colectomy. This is not a prognostic scale, however, since CAT scan findings have been previously shown to be poor predictors of treatment outcome.29 The second scale measured the severity of systemic involvement using a well‐validated and standardized scale, the APACHE II score. We have shown in this report that it is associated with prognosis in the context of IVIG use.

Our study reports a higher mortality rate than previously described, and suggests that risk stratification and patient selection are important before IVIG administration, since not all patients seem to benefit from this treatment as previously suggested by smaller case series. Previously, several physical findings and laboratory values were found to be associated with worse outcome in CDC. These were increasing age, immunosuppression, shock requiring vasopressors, peak white blood cell count, peak serum lactate level, hypoalbuminemia, a fall in serum albumin level of >1.1 g/dL at the onset of CDC symptoms, use of 3 or more antibiotics, comorbid disease, previous history of CDC, acute renal failure and hypotension, underlying altered or depressed mental status, abdominal pain or distention, white blood cell count over 20,000/mm³ or <1500/mm³ and/or a >10% band forms on the white blood cell differential count, and ascites or pneumatosis coli by abdominal imaging.9, 3033 Using the APACHE II scale for the same purpose has the advantage of utilizing a well‐validated and objective scale that is expected to measure the degree of systemic involvement more reliably compared to the clinical and laboratory values above.

Timing of IVIG infusion remains controversial. Due to the lack of randomized controlled trials, the current practice is guided by expert opinion, leading to wide variations between reports. Since the APACHE II score was positively associated with mortality in the setting of IVIG treatment, the same scale could be used to guide decisions regarding timing of IVIG infusion. Our results suggest that IVIG should be preferentially used while the APACHE II score is still relatively low. This association and the specific APACHE II score at which to initiate or hold treatment need to be validated in the setting of a randomized controlled study before being used in clinical practice.

Although the current study was not designed to test this theory, IVIG could be associated conceptually with treatment success for patients with severe disease that is still restricted to the colon (without other organ dysfunction or at least at an early stage of extracolonic organ failure and thus associated with a low APACHE II score) but not for severe colonic disease with secondary multiple organ failure (high APACHE II score). This may be because colonic disease is toxin‐mediated whereas secondary systemic involvement is mediated through toxin‐induced inflammatory mediators (interleukin‐8, macrophage‐inflammatory protein‐2, substance P, tumor necrosis factor‐alpha) released locally in the colon,3436 triggering a SIRS and hematogenous translocation of colonic bacteria,37 both of which are poorly responsive to immunoglobulin infusion. Along the same lines, waiting for failure of conventional therapy before IVIG use might result in IVIG treatment failure because of disease progression and secondary sepsis, at which point no treatment may be effective. No study thus far has addressed this issue specifically.

Overall, the combined cohort of patients with severe CDC treated with IVIG in the literature includes 51 patients (Table 4). The current report contributes 41% of these patients. The patients' average age was 68 years, with a 2 to 1 female‐male ratio. The dose of IVIG used varied largely also, with 400 mg/kg being the mode (range, 75400 mg/kg from 1 to 5 doses). This dose is significantly below the doses used in the treatment of other diseases, like Guillain‐Barr syndrome, myasthenia gravis, Kawasaki disease, autoimmune hemolytic anemia, agammaglobulinemia, and hypogammaglobulinemia, where the usual dose is 400 mg/kg for 5 days. The resolution of diarrhea in these cases occurred after an average of 9 (range, 142) days. The index hospitalization survival rate varied from 43% to 100%. Patients received standard treatment for an average of 13 (range, 065) days before IVIG infusion. Thirty‐two of 51 patients survived their illness (63%). Neither total IgG nor anti‐toxin A IgG levels were measured in any of the reports. Of the 32 patients who had clinical resolution, 3 (10%) experienced symptoms recurrence in a follow‐up period of 1 to 13 months. This number is most probably an underestimation of the true recurrence rate resulting from an incomplete reporting because there was no uniform or active recurrence ascertainment mechanism in any of the studies. The recurrences were at 10, 14, and 30 days posttreatment. Since standard treatment was not discontinued in any of the reports once IVIG was given, the relative contribution and the ideal timing for IVIG infusion are still unclear.

The mechanism of action of IVIG is passive immunization (with anti‐toxin A and anti‐toxin B antibodies present in the pooled immunoglobulin) of a host who is usually unable to mount an adequate protective immune response.15, 22 IVIG is formed from pooling immunoglobulin from several random donors. It has been shown that many such donors express high anti‐toxin A and anti‐toxin B antibody serum titers.38, 39 In addition, high levels of anti‐toxin A and anti‐toxin B antibodies were present in the IVIG preparations and the recipients after infusion.1517, 22 Although constituting only a small fraction of the total IVIG administered, these antitoxin antibodies are believed to neutralize toxin A and B and help the host recover from the disease. In fact, Babcock et al.40 used an experimental hamster model of CDC to demonstrate a mortality reduction from 100% to 55% postinfusion of combined anti‐toxin A and anti‐toxin B antibodies. While some early reports indicated that anti‐toxin B antibodies were the major determinants of protection against colitis,41 later reports correlated disease severity pathologically42 and clinically43, 44 with anti‐toxin A levels. Anti‐toxin B antibodies were later shown to play an adjunctive role in conferring immunity against CDC40, 45, 46 when added to anti‐toxin A antibodies, but not to have any significant role on their own.

However, IVIG has been shown to contain IgG, but not IgA, anti‐toxin A and anti‐toxin B antibodies while it is only the IgA class of anti‐toxin A antibodies, and not the IgG class, that could neutralize toxin A in vitro and in vivo.47, 48 Babcock et al.40 solved this apparent dilemma by showing that a combination of 3 different monoclonal IgG anti‐toxin A antibodies could neutralize toxin A activity in vitro and prevent disease in the hamster model in vivo. Each of the 3 antibodies recognized a different toxin A domain: the first neutralized toxin A enzymatic activity, while the second prevented toxin A binding to its receptor on enterocytes, and the third prevented toxin internalization after binding to the receptor.

Thus, the mechanism of action of IVIG is most likely through the transfer of IgG anti‐toxin A antibodies that gain access to the intestinal lumen presumably secondary to inflammation‐induced mucosal damage and neutralize toxin A. Transfer of yet undetected IgA anti‐toxin A antibodies that prevent toxin A from binding to its receptor is much less likely, although possible.

The present study has limitations. As in all retrospective studies, selection bias was unavoidable. In addition, the decision to initiate IVIG administration was dependent on the attending physician, who also decided the dose, leading to heterogeneity in the total dose of IVIG infused. Such heterogeneity, however, is primarily the result of a lack of a standard dose for IVIG infusion for CDC in the published literature, as reported above. In addition, since IVIG is not yet approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe CDC, standard treatment was not discontinued in any of the reports to date, including ours.

Choosing appropriate controls for patients suffering from severe CDC is challenging. This patient population is usually frail, with severe and multiple underlying diseases. The deteriorating clinical condition (and subsequently the need for multiple antibiotics) may be either the result of or the cause of CDC. Furthermore, IVIG has been in short supply for several years and therefore it has been expensive, making its administration to the number of patients needed to design adequately‐powered controlled studies difficult. These are mainly the reasons no randomized, multicenter, placebo‐controlled trial on IVIG use in severe CDC has been conducted to date.

Conclusions

In the present study, we report the results of IVIG use for the treatment of 21 patients with severe CDC. This is the largest cohort to our knowledge in the literature. Unlike previous studies on the subject, the present report provided 2 scales for disease assessment: the first based on the extent of colonic involvement and the second measuring the severity of systemic involvement using the APACHE II score. The latter was positively associated with mortality in this context. Of the 21 study patients treated with IVIG, only 9 patients (43%) survived their illness. This is the highest reported mortality rate among all studies on this subject so far. Further studies on the ideal timing of IVIG infusion, dose, and patient selection are needed before accepting IVIG as a standard of care for severe CDC treatment. The role of APACHE II score in the decision to use IVIG is promising and should be validated in randomized controlled trials.

Clostridium difficile colitis (CDC) is the most common cause of hospital‐acquired diarrhea.1 The incidence of CDC has sharply increased over the past decade despite increasing awareness among health care professionals.24 C. difficile pathogenic strains induce diarrhea through the elaboration and secretion of 2 exotoxins: toxin A and toxin B. Toxin A is an inflammatory toxin, leading to fluid secretion, increased mucosal permeability, and marked enteritis and colitis.5 Toxin B is cytotoxic, leading to cell injury and apoptosis.5 Combined, toxin A and toxin B can cause a wide spectrum of clinical presentations, ranging from mild diarrhea that resolves with the discontinuation of antibiotics to a fulminant colitis requiring surgical intervention.

The severity of clinical manifestations has been shown to be inversely proportional to the host anti‐toxin A antibody level in response to toxin exposure. Kyne et al.6 demonstrated that asymptomatic C. difficile carriers produced significantly higher anti‐toxin A immunoglobulin G (IgG) levels compared to symptomatic patients. Among the latter group, patients with mild disease had a higher antibody level compared to those with severe colitis.6, 7 Additional risk factors predisposing to severe colitis are advanced age, severe underlying illness,8 and immunocompromised state.9

Recently, a new C. difficile strain (BI/NAP1) with a mutated toxin A and toxin B promoter silencer, a binary toxin gene, and fluoroquinolone resistance has been described in Canada and the United States.3, 10 This strain has been associated with an increased incidence of CDC among hospitalized patients, especially the incidence of severe disease requiring colectomy. At the same time, several reports describing metronidazole treatment failure have been published.1114 These recent findings emphasize the importance of finding alternative treatments for CDC.

Intravenous immunoglobulin (IVIG) was used to treat CDC for the first time in 1991.15 Since then, 12 case reports and small case series, along with 1 case‐control study have been published documenting IVIG treatment outcomes.1527 However, only 5 reports to date examined patients with severe CDC.2125 In the present study, we report the largest series of patients with severe CDC treated with IVIG in the literature to our knowledge.

Patients and Methods

Results

Discussion

To our knowledge, the present study is the largest series published in the literature to date on the use of IVIG for severe CDC. It is also the first study to report a high mortality rate compared to the 5 previous smaller studies on this topic. In the first report on IVIG use for CDC, Leung et al.15 used IVIG to treat 5 pediatric patients suffering from chronic relapsing CDC. It was not until 7 years later, in 1997, that the first IVIG use for severe CDC was reported.22 Since then, a total of 13 works have been published on IVIG for CDC treatment, and only in 5 of these was IVIG administered for severe CDC treatment:2125 3 case reports, 1 case series, and 1 case‐control study. Although the 4 uncontrolled reports concluded that IVIG is beneficial for severe CDC, the only controlled study reported no significant difference between cases and controls for all‐cause mortality, length of stay, and colectomy rate.25

The definition of severe CDC varied between reports, making comparison difficult. McPherson et al.21 and Hassoun and Ibrahim24 defined severe disease as one causing pancolitis on CT scan either with or without megacolon. In the study by Juang et al.,25 disease severity was assessed using the modified criteria of Rubin et al.9 Salcedo et al.22 defined severe CDC as one causing pancolitis in one patient and thumbprinting on CT scan in another, whereas Chandrasekar et al.23 defined it as one causing shock requiring inotropic support and presence of pseudomembranes on colonoscopy.

The present report is unique in that it provided 2 scales to characterize disease in each patient. The first scale measured colonic involvement anatomically and physiologically using a combination of computerized axial tomography (CAT) scan findings, presence or absence of ileus or referral for possible colectomy. This is not a prognostic scale, however, since CAT scan findings have been previously shown to be poor predictors of treatment outcome.29 The second scale measured the severity of systemic involvement using a well‐validated and standardized scale, the APACHE II score. We have shown in this report that it is associated with prognosis in the context of IVIG use.

Our study reports a higher mortality rate than previously described, and suggests that risk stratification and patient selection are important before IVIG administration, since not all patients seem to benefit from this treatment as previously suggested by smaller case series. Previously, several physical findings and laboratory values were found to be associated with worse outcome in CDC. These were increasing age, immunosuppression, shock requiring vasopressors, peak white blood cell count, peak serum lactate level, hypoalbuminemia, a fall in serum albumin level of >1.1 g/dL at the onset of CDC symptoms, use of 3 or more antibiotics, comorbid disease, previous history of CDC, acute renal failure and hypotension, underlying altered or depressed mental status, abdominal pain or distention, white blood cell count over 20,000/mm³ or <1500/mm³ and/or a >10% band forms on the white blood cell differential count, and ascites or pneumatosis coli by abdominal imaging.9, 3033 Using the APACHE II scale for the same purpose has the advantage of utilizing a well‐validated and objective scale that is expected to measure the degree of systemic involvement more reliably compared to the clinical and laboratory values above.

Timing of IVIG infusion remains controversial. Due to the lack of randomized controlled trials, the current practice is guided by expert opinion, leading to wide variations between reports. Since the APACHE II score was positively associated with mortality in the setting of IVIG treatment, the same scale could be used to guide decisions regarding timing of IVIG infusion. Our results suggest that IVIG should be preferentially used while the APACHE II score is still relatively low. This association and the specific APACHE II score at which to initiate or hold treatment need to be validated in the setting of a randomized controlled study before being used in clinical practice.

Although the current study was not designed to test this theory, IVIG could be associated conceptually with treatment success for patients with severe disease that is still restricted to the colon (without other organ dysfunction or at least at an early stage of extracolonic organ failure and thus associated with a low APACHE II score) but not for severe colonic disease with secondary multiple organ failure (high APACHE II score). This may be because colonic disease is toxin‐mediated whereas secondary systemic involvement is mediated through toxin‐induced inflammatory mediators (interleukin‐8, macrophage‐inflammatory protein‐2, substance P, tumor necrosis factor‐alpha) released locally in the colon,3436 triggering a SIRS and hematogenous translocation of colonic bacteria,37 both of which are poorly responsive to immunoglobulin infusion. Along the same lines, waiting for failure of conventional therapy before IVIG use might result in IVIG treatment failure because of disease progression and secondary sepsis, at which point no treatment may be effective. No study thus far has addressed this issue specifically.

Overall, the combined cohort of patients with severe CDC treated with IVIG in the literature includes 51 patients (Table 4). The current report contributes 41% of these patients. The patients' average age was 68 years, with a 2 to 1 female‐male ratio. The dose of IVIG used varied largely also, with 400 mg/kg being the mode (range, 75400 mg/kg from 1 to 5 doses). This dose is significantly below the doses used in the treatment of other diseases, like Guillain‐Barr syndrome, myasthenia gravis, Kawasaki disease, autoimmune hemolytic anemia, agammaglobulinemia, and hypogammaglobulinemia, where the usual dose is 400 mg/kg for 5 days. The resolution of diarrhea in these cases occurred after an average of 9 (range, 142) days. The index hospitalization survival rate varied from 43% to 100%. Patients received standard treatment for an average of 13 (range, 065) days before IVIG infusion. Thirty‐two of 51 patients survived their illness (63%). Neither total IgG nor anti‐toxin A IgG levels were measured in any of the reports. Of the 32 patients who had clinical resolution, 3 (10%) experienced symptoms recurrence in a follow‐up period of 1 to 13 months. This number is most probably an underestimation of the true recurrence rate resulting from an incomplete reporting because there was no uniform or active recurrence ascertainment mechanism in any of the studies. The recurrences were at 10, 14, and 30 days posttreatment. Since standard treatment was not discontinued in any of the reports once IVIG was given, the relative contribution and the ideal timing for IVIG infusion are still unclear.

The mechanism of action of IVIG is passive immunization (with anti‐toxin A and anti‐toxin B antibodies present in the pooled immunoglobulin) of a host who is usually unable to mount an adequate protective immune response.15, 22 IVIG is formed from pooling immunoglobulin from several random donors. It has been shown that many such donors express high anti‐toxin A and anti‐toxin B antibody serum titers.38, 39 In addition, high levels of anti‐toxin A and anti‐toxin B antibodies were present in the IVIG preparations and the recipients after infusion.1517, 22 Although constituting only a small fraction of the total IVIG administered, these antitoxin antibodies are believed to neutralize toxin A and B and help the host recover from the disease. In fact, Babcock et al.40 used an experimental hamster model of CDC to demonstrate a mortality reduction from 100% to 55% postinfusion of combined anti‐toxin A and anti‐toxin B antibodies. While some early reports indicated that anti‐toxin B antibodies were the major determinants of protection against colitis,41 later reports correlated disease severity pathologically42 and clinically43, 44 with anti‐toxin A levels. Anti‐toxin B antibodies were later shown to play an adjunctive role in conferring immunity against CDC40, 45, 46 when added to anti‐toxin A antibodies, but not to have any significant role on their own.

However, IVIG has been shown to contain IgG, but not IgA, anti‐toxin A and anti‐toxin B antibodies while it is only the IgA class of anti‐toxin A antibodies, and not the IgG class, that could neutralize toxin A in vitro and in vivo.47, 48 Babcock et al.40 solved this apparent dilemma by showing that a combination of 3 different monoclonal IgG anti‐toxin A antibodies could neutralize toxin A activity in vitro and prevent disease in the hamster model in vivo. Each of the 3 antibodies recognized a different toxin A domain: the first neutralized toxin A enzymatic activity, while the second prevented toxin A binding to its receptor on enterocytes, and the third prevented toxin internalization after binding to the receptor.

Thus, the mechanism of action of IVIG is most likely through the transfer of IgG anti‐toxin A antibodies that gain access to the intestinal lumen presumably secondary to inflammation‐induced mucosal damage and neutralize toxin A. Transfer of yet undetected IgA anti‐toxin A antibodies that prevent toxin A from binding to its receptor is much less likely, although possible.

The present study has limitations. As in all retrospective studies, selection bias was unavoidable. In addition, the decision to initiate IVIG administration was dependent on the attending physician, who also decided the dose, leading to heterogeneity in the total dose of IVIG infused. Such heterogeneity, however, is primarily the result of a lack of a standard dose for IVIG infusion for CDC in the published literature, as reported above. In addition, since IVIG is not yet approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe CDC, standard treatment was not discontinued in any of the reports to date, including ours.

Choosing appropriate controls for patients suffering from severe CDC is challenging. This patient population is usually frail, with severe and multiple underlying diseases. The deteriorating clinical condition (and subsequently the need for multiple antibiotics) may be either the result of or the cause of CDC. Furthermore, IVIG has been in short supply for several years and therefore it has been expensive, making its administration to the number of patients needed to design adequately‐powered controlled studies difficult. These are mainly the reasons no randomized, multicenter, placebo‐controlled trial on IVIG use in severe CDC has been conducted to date.

Conclusions

In the present study, we report the results of IVIG use for the treatment of 21 patients with severe CDC. This is the largest cohort to our knowledge in the literature. Unlike previous studies on the subject, the present report provided 2 scales for disease assessment: the first based on the extent of colonic involvement and the second measuring the severity of systemic involvement using the APACHE II score. The latter was positively associated with mortality in this context. Of the 21 study patients treated with IVIG, only 9 patients (43%) survived their illness. This is the highest reported mortality rate among all studies on this subject so far. Further studies on the ideal timing of IVIG infusion, dose, and patient selection are needed before accepting IVIG as a standard of care for severe CDC treatment. The role of APACHE II score in the decision to use IVIG is promising and should be validated in randomized controlled trials.

Clostridium difficile colitis (CDC) is the most common cause of hospital‐acquired diarrhea.1 The incidence of CDC has sharply increased over the past decade despite increasing awareness among health care professionals.24 C. difficile pathogenic strains induce diarrhea through the elaboration and secretion of 2 exotoxins: toxin A and toxin B. Toxin A is an inflammatory toxin, leading to fluid secretion, increased mucosal permeability, and marked enteritis and colitis.5 Toxin B is cytotoxic, leading to cell injury and apoptosis.5 Combined, toxin A and toxin B can cause a wide spectrum of clinical presentations, ranging from mild diarrhea that resolves with the discontinuation of antibiotics to a fulminant colitis requiring surgical intervention.

The severity of clinical manifestations has been shown to be inversely proportional to the host anti‐toxin A antibody level in response to toxin exposure. Kyne et al.6 demonstrated that asymptomatic C. difficile carriers produced significantly higher anti‐toxin A immunoglobulin G (IgG) levels compared to symptomatic patients. Among the latter group, patients with mild disease had a higher antibody level compared to those with severe colitis.6, 7 Additional risk factors predisposing to severe colitis are advanced age, severe underlying illness,8 and immunocompromised state.9

Recently, a new C. difficile strain (BI/NAP1) with a mutated toxin A and toxin B promoter silencer, a binary toxin gene, and fluoroquinolone resistance has been described in Canada and the United States.3, 10 This strain has been associated with an increased incidence of CDC among hospitalized patients, especially the incidence of severe disease requiring colectomy. At the same time, several reports describing metronidazole treatment failure have been published.1114 These recent findings emphasize the importance of finding alternative treatments for CDC.

Intravenous immunoglobulin (IVIG) was used to treat CDC for the first time in 1991.15 Since then, 12 case reports and small case series, along with 1 case‐control study have been published documenting IVIG treatment outcomes.1527 However, only 5 reports to date examined patients with severe CDC.2125 In the present study, we report the largest series of patients with severe CDC treated with IVIG in the literature to our knowledge.

Patients and Methods

Results

Discussion

To our knowledge, the present study is the largest series published in the literature to date on the use of IVIG for severe CDC. It is also the first study to report a high mortality rate compared to the 5 previous smaller studies on this topic. In the first report on IVIG use for CDC, Leung et al.15 used IVIG to treat 5 pediatric patients suffering from chronic relapsing CDC. It was not until 7 years later, in 1997, that the first IVIG use for severe CDC was reported.22 Since then, a total of 13 works have been published on IVIG for CDC treatment, and only in 5 of these was IVIG administered for severe CDC treatment:2125 3 case reports, 1 case series, and 1 case‐control study. Although the 4 uncontrolled reports concluded that IVIG is beneficial for severe CDC, the only controlled study reported no significant difference between cases and controls for all‐cause mortality, length of stay, and colectomy rate.25

The definition of severe CDC varied between reports, making comparison difficult. McPherson et al.21 and Hassoun and Ibrahim24 defined severe disease as one causing pancolitis on CT scan either with or without megacolon. In the study by Juang et al.,25 disease severity was assessed using the modified criteria of Rubin et al.9 Salcedo et al.22 defined severe CDC as one causing pancolitis in one patient and thumbprinting on CT scan in another, whereas Chandrasekar et al.23 defined it as one causing shock requiring inotropic support and presence of pseudomembranes on colonoscopy.

The present report is unique in that it provided 2 scales to characterize disease in each patient. The first scale measured colonic involvement anatomically and physiologically using a combination of computerized axial tomography (CAT) scan findings, presence or absence of ileus or referral for possible colectomy. This is not a prognostic scale, however, since CAT scan findings have been previously shown to be poor predictors of treatment outcome.29 The second scale measured the severity of systemic involvement using a well‐validated and standardized scale, the APACHE II score. We have shown in this report that it is associated with prognosis in the context of IVIG use.

Our study reports a higher mortality rate than previously described, and suggests that risk stratification and patient selection are important before IVIG administration, since not all patients seem to benefit from this treatment as previously suggested by smaller case series. Previously, several physical findings and laboratory values were found to be associated with worse outcome in CDC. These were increasing age, immunosuppression, shock requiring vasopressors, peak white blood cell count, peak serum lactate level, hypoalbuminemia, a fall in serum albumin level of >1.1 g/dL at the onset of CDC symptoms, use of 3 or more antibiotics, comorbid disease, previous history of CDC, acute renal failure and hypotension, underlying altered or depressed mental status, abdominal pain or distention, white blood cell count over 20,000/mm³ or <1500/mm³ and/or a >10% band forms on the white blood cell differential count, and ascites or pneumatosis coli by abdominal imaging.9, 3033 Using the APACHE II scale for the same purpose has the advantage of utilizing a well‐validated and objective scale that is expected to measure the degree of systemic involvement more reliably compared to the clinical and laboratory values above.

Timing of IVIG infusion remains controversial. Due to the lack of randomized controlled trials, the current practice is guided by expert opinion, leading to wide variations between reports. Since the APACHE II score was positively associated with mortality in the setting of IVIG treatment, the same scale could be used to guide decisions regarding timing of IVIG infusion. Our results suggest that IVIG should be preferentially used while the APACHE II score is still relatively low. This association and the specific APACHE II score at which to initiate or hold treatment need to be validated in the setting of a randomized controlled study before being used in clinical practice.

Although the current study was not designed to test this theory, IVIG could be associated conceptually with treatment success for patients with severe disease that is still restricted to the colon (without other organ dysfunction or at least at an early stage of extracolonic organ failure and thus associated with a low APACHE II score) but not for severe colonic disease with secondary multiple organ failure (high APACHE II score). This may be because colonic disease is toxin‐mediated whereas secondary systemic involvement is mediated through toxin‐induced inflammatory mediators (interleukin‐8, macrophage‐inflammatory protein‐2, substance P, tumor necrosis factor‐alpha) released locally in the colon,3436 triggering a SIRS and hematogenous translocation of colonic bacteria,37 both of which are poorly responsive to immunoglobulin infusion. Along the same lines, waiting for failure of conventional therapy before IVIG use might result in IVIG treatment failure because of disease progression and secondary sepsis, at which point no treatment may be effective. No study thus far has addressed this issue specifically.

Overall, the combined cohort of patients with severe CDC treated with IVIG in the literature includes 51 patients (Table 4). The current report contributes 41% of these patients. The patients' average age was 68 years, with a 2 to 1 female‐male ratio. The dose of IVIG used varied largely also, with 400 mg/kg being the mode (range, 75400 mg/kg from 1 to 5 doses). This dose is significantly below the doses used in the treatment of other diseases, like Guillain‐Barr syndrome, myasthenia gravis, Kawasaki disease, autoimmune hemolytic anemia, agammaglobulinemia, and hypogammaglobulinemia, where the usual dose is 400 mg/kg for 5 days. The resolution of diarrhea in these cases occurred after an average of 9 (range, 142) days. The index hospitalization survival rate varied from 43% to 100%. Patients received standard treatment for an average of 13 (range, 065) days before IVIG infusion. Thirty‐two of 51 patients survived their illness (63%). Neither total IgG nor anti‐toxin A IgG levels were measured in any of the reports. Of the 32 patients who had clinical resolution, 3 (10%) experienced symptoms recurrence in a follow‐up period of 1 to 13 months. This number is most probably an underestimation of the true recurrence rate resulting from an incomplete reporting because there was no uniform or active recurrence ascertainment mechanism in any of the studies. The recurrences were at 10, 14, and 30 days posttreatment. Since standard treatment was not discontinued in any of the reports once IVIG was given, the relative contribution and the ideal timing for IVIG infusion are still unclear.

The mechanism of action of IVIG is passive immunization (with anti‐toxin A and anti‐toxin B antibodies present in the pooled immunoglobulin) of a host who is usually unable to mount an adequate protective immune response.15, 22 IVIG is formed from pooling immunoglobulin from several random donors. It has been shown that many such donors express high anti‐toxin A and anti‐toxin B antibody serum titers.38, 39 In addition, high levels of anti‐toxin A and anti‐toxin B antibodies were present in the IVIG preparations and the recipients after infusion.1517, 22 Although constituting only a small fraction of the total IVIG administered, these antitoxin antibodies are believed to neutralize toxin A and B and help the host recover from the disease. In fact, Babcock et al.40 used an experimental hamster model of CDC to demonstrate a mortality reduction from 100% to 55% postinfusion of combined anti‐toxin A and anti‐toxin B antibodies. While some early reports indicated that anti‐toxin B antibodies were the major determinants of protection against colitis,41 later reports correlated disease severity pathologically42 and clinically43, 44 with anti‐toxin A levels. Anti‐toxin B antibodies were later shown to play an adjunctive role in conferring immunity against CDC40, 45, 46 when added to anti‐toxin A antibodies, but not to have any significant role on their own.

However, IVIG has been shown to contain IgG, but not IgA, anti‐toxin A and anti‐toxin B antibodies while it is only the IgA class of anti‐toxin A antibodies, and not the IgG class, that could neutralize toxin A in vitro and in vivo.47, 48 Babcock et al.40 solved this apparent dilemma by showing that a combination of 3 different monoclonal IgG anti‐toxin A antibodies could neutralize toxin A activity in vitro and prevent disease in the hamster model in vivo. Each of the 3 antibodies recognized a different toxin A domain: the first neutralized toxin A enzymatic activity, while the second prevented toxin A binding to its receptor on enterocytes, and the third prevented toxin internalization after binding to the receptor.

Thus, the mechanism of action of IVIG is most likely through the transfer of IgG anti‐toxin A antibodies that gain access to the intestinal lumen presumably secondary to inflammation‐induced mucosal damage and neutralize toxin A. Transfer of yet undetected IgA anti‐toxin A antibodies that prevent toxin A from binding to its receptor is much less likely, although possible.

The present study has limitations. As in all retrospective studies, selection bias was unavoidable. In addition, the decision to initiate IVIG administration was dependent on the attending physician, who also decided the dose, leading to heterogeneity in the total dose of IVIG infused. Such heterogeneity, however, is primarily the result of a lack of a standard dose for IVIG infusion for CDC in the published literature, as reported above. In addition, since IVIG is not yet approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe CDC, standard treatment was not discontinued in any of the reports to date, including ours.

Choosing appropriate controls for patients suffering from severe CDC is challenging. This patient population is usually frail, with severe and multiple underlying diseases. The deteriorating clinical condition (and subsequently the need for multiple antibiotics) may be either the result of or the cause of CDC. Furthermore, IVIG has been in short supply for several years and therefore it has been expensive, making its administration to the number of patients needed to design adequately‐powered controlled studies difficult. These are mainly the reasons no randomized, multicenter, placebo‐controlled trial on IVIG use in severe CDC has been conducted to date.

Conclusions

In the present study, we report the results of IVIG use for the treatment of 21 patients with severe CDC. This is the largest cohort to our knowledge in the literature. Unlike previous studies on the subject, the present report provided 2 scales for disease assessment: the first based on the extent of colonic involvement and the second measuring the severity of systemic involvement using the APACHE II score. The latter was positively associated with mortality in this context. Of the 21 study patients treated with IVIG, only 9 patients (43%) survived their illness. This is the highest reported mortality rate among all studies on this subject so far. Further studies on the ideal timing of IVIG infusion, dose, and patient selection are needed before accepting IVIG as a standard of care for severe CDC treatment. The role of APACHE II score in the decision to use IVIG is promising and should be validated in randomized controlled trials.