Polyclonal Immunoglobulins and Hyperimmune Globulins in Prevention and
Management of Infectious Diseases
Jennifer L. Hsu, MDa, Nasia Safdar, MD, PhDb,*
Infect Dis Clin N Am 25 (2011) 773–788
感染における免疫グロブリンのメカニズム
Immunomodulatory Actions
Neutralization of circulating superantigens
Blockade of Fc receptor-mediated events
Modulation of cytokines
Regulation of T-cell production
Antiinflammatory Actions
Reduction of complement-mediated damage
Neutralization of microbial toxins
Activation of leukocytes
Infectious Diseases Society of America: US public health service grading system for ranking recommendations in clinical guidelines
Category, Grade Definition
Strength of Recommendation
A Good evidence to support a recommendation for use
B Moderate evidence to support a recommendation for use
C Poor evidence to support a recommendation
D Moderate evidence to support a recommendation against use
E Good evidence to support a recommendation against use
Quality of evidence
I Evidence from 1 properly randomized controlled trial
II Evidence from 1 well-designed clinical trial, without randomization;
from cohort or case-controlled analytic studies (preferably from >1
center); from multiple time series; or from dramatic results from
uncontrolled experiments
III Evidence from opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert committees
Indication Level of Evidence Plain Language
Sepsis IIC May be beneficial
Streptococcal TSS IIC May be beneficial
Staphylococcal TSS IIIC May be beneficial
C difficile IIIC May be beneficial
C tetani IIIB Standard of care
C botulinum IIIB Standard of care
C diphtheriae IIIB Likely beneficial
CMV prophylaxis in SOT IID Likely not beneficial
CMV prophylaxis in HSCT IIE Not beneficial
CMV treatment in SOT IIIC May be beneficial
CMV treatment in HSCT IIE Not beneficial
Hepatitis A IIB Beneficial
Hepatitis B IIB Beneficial
Varicella IIIC Beneficial
Rabies IIIB Beneficial
RSV IIB May be beneficial
BACTERIAL INFECTIONS
Sepsis
In 2007, 3 systematic reviews were published showing a mortality benefit when IVIG was compared with placebo, with relative risk (RR) ratios of 0.74 and 0.79 in 2 of the reviews。Similarly, Laupland, and colleagues11 reported a significant reduction in mortality associated with IVIG treatment with a pooled odds ratio of 0.66 (95% confidence interval [CI] 0.53–0.83, P<.0005).
→３つのsystemic reviewsで有効性を指摘、同様にLauplandらも有効性を指摘、一方で質の高い研究が必要であると提言。
Cochrane review, which included 42 studies comparing IVIG (polyclonal and
monoclonal) to placebo or no intervention in patients with bacterial sepsis or septic
shock. There was a significant mortality benefit when IVIG was compared with
placebo (RR 0.81; 95% CI 0.70–0.93). However, analysis of trials with a low risk of
bias yielded no reduction in mortality (RR 0.97; 95% CI 0.81–1.15).
→有効性を指摘も軽症例では差が無し。
現時点ではルーチンでは推奨されない。
Toxic Shock Syndrome
In the first randomized, double-blind, placebo-controlled trial evaluating IVIG as an
adjunctive therapy, a 3.6-fold higher mortality was identified in the placebo group,
and a significant decrease in sepsis-related organ failure was seen in the IVIG group
→早期に終了され統計的有意差は認められていない研究ではあるが有効性を指摘
Similar results were seen in a pediatric population in which IVIG increased cost, but did not show an association with improved outcome
→小児では有効性が示せず
→Streptococcus TSSでは推奨はなし、同様にStaphylococcus TSSも推奨はしない
Clostridium Difficile Infection
More recently, attention has turned to the treatment of CDI with human monoclonal
antibodies directed against C difficile toxins A and B, which has the advantage of targeting therapy and avoiding the increased use of pooled IVIG. In a phase II trial, 200 patients receiving either metronidazole or vancomycin for CDI treatment were
randomized to antibody and placebo. Among the antibody group, the rate of CDI
recurrence was decreased compared with placebo (7% vs 25%; 95% CI 7–29;
P<.001). No increase in adverse events was seen
→多価抗体については賛否両論。モノクローナル抗体に今後の期待。
VIRAL INFECTIONS
Cytomegalovirus Infection in Solid Organ Transplant
A subsequent systematic review of 37 trials (2185 participants) evaluating
IVIG and CMV-Ig for prophylaxis in SOT recipients showed decreased risk of
mortality from CMV disease
→死亡率は減少も発生率は低下させず。
CMV pneumonitis and possibly other severe or treatment-refractory forms of disease.
→CMV肺炎や再発性で考慮
Hematopoietic Stem Cell Transplantも同様。
Hepatitis A
Preexposure IVIG is only recommended for high-risk persons who could not be vaccinated, including infants aged younger than 12 months, individuals with an allergy to vaccine components, or travelers declining vaccination.60 More recently, HAV vaccination also became an acceptable option for postexposure prophylaxis based on data showing equivalent protection to IVIG when administered within 2 weeks of HAV exposure in persons aged 2 to 40 years
→暴露後ワクチンのみでも十分な予防効果があるためワクチン接種ができない12か月未満やアレルギー患者のみ。
Hepatitis B
The combination of HBIG and vaccine are highly effective in preventing the transmission of HBV, with studies in health care workers and sexual contacts of HBV-infected persons showing 80% to 90% efficacy when treatment is completed within 7 days for needlesticks and 14 days for sexual contact
→針刺し後HBIGとワクチンで80-90%を予防
Varicella
VZIG can be considered in susceptible patients (no history of varicella disease or
vaccination), if the exposure is likely to result in infection and the patient is at a greater
risk for complications than the general population, including immunocompromised
adults and pregnant women
→感受性のある人が暴露した場合、免疫不全者、妊娠者では行う。
Rabies
CDC recommends the administration of HRIG 20 IU/kg body weight once at
the beginning of rabies prophylaxis. If not begun at the time of initial vaccination, HRIG can be administered up to and including day 7 of the postexposure prophylaxis
series. If anatomically feasible, HRIG should be fully administered in and around
the wound, and the first vaccine dose should be given at an anatomically distant location to prevent neutralization by HRIG
→暴露後の予防はIVIG＋ワクチン
Respiratory Syncytial Virus Infection
Uncontrolled studyのみ
副作用：
1000例中440例で認められ特に1/3で初回に多いとの報告あり注意
Management of Infectious Diseases
Jennifer L. Hsu, MDa, Nasia Safdar, MD, PhDb,*
Infect Dis Clin N Am 25 (2011) 773–788
感染における免疫グロブリンのメカニズム
Immunomodulatory Actions
Neutralization of circulating superantigens
Blockade of Fc receptor-mediated events
Modulation of cytokines
Regulation of T-cell production
Antiinflammatory Actions
Reduction of complement-mediated damage
Neutralization of microbial toxins
Activation of leukocytes
Infectious Diseases Society of America: US public health service grading system for ranking recommendations in clinical guidelines
Category, Grade Definition
Strength of Recommendation
A Good evidence to support a recommendation for use
B Moderate evidence to support a recommendation for use
C Poor evidence to support a recommendation
D Moderate evidence to support a recommendation against use
E Good evidence to support a recommendation against use
Quality of evidence
I Evidence from 1 properly randomized controlled trial
II Evidence from 1 well-designed clinical trial, without randomization;
from cohort or case-controlled analytic studies (preferably from >1
center); from multiple time series; or from dramatic results from
uncontrolled experiments
III Evidence from opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert committees
Indication Level of Evidence Plain Language
Sepsis IIC May be beneficial
Streptococcal TSS IIC May be beneficial
Staphylococcal TSS IIIC May be beneficial
C difficile IIIC May be beneficial
C tetani IIIB Standard of care
C botulinum IIIB Standard of care
C diphtheriae IIIB Likely beneficial
CMV prophylaxis in SOT IID Likely not beneficial
CMV prophylaxis in HSCT IIE Not beneficial
CMV treatment in SOT IIIC May be beneficial
CMV treatment in HSCT IIE Not beneficial
Hepatitis A IIB Beneficial
Hepatitis B IIB Beneficial
Varicella IIIC Beneficial
Rabies IIIB Beneficial
RSV IIB May be beneficial
BACTERIAL INFECTIONS
Sepsis
In 2007, 3 systematic reviews were published showing a mortality benefit when IVIG was compared with placebo, with relative risk (RR) ratios of 0.74 and 0.79 in 2 of the reviews。Similarly, Laupland, and colleagues11 reported a significant reduction in mortality associated with IVIG treatment with a pooled odds ratio of 0.66 (95% confidence interval [CI] 0.53–0.83, P<.0005).
→３つのsystemic reviewsで有効性を指摘、同様にLauplandらも有効性を指摘、一方で質の高い研究が必要であると提言。
Cochrane review, which included 42 studies comparing IVIG (polyclonal and
monoclonal) to placebo or no intervention in patients with bacterial sepsis or septic
shock. There was a significant mortality benefit when IVIG was compared with
placebo (RR 0.81; 95% CI 0.70–0.93). However, analysis of trials with a low risk of
bias yielded no reduction in mortality (RR 0.97; 95% CI 0.81–1.15).
→有効性を指摘も軽症例では差が無し。
現時点ではルーチンでは推奨されない。
Toxic Shock Syndrome
In the first randomized, double-blind, placebo-controlled trial evaluating IVIG as an
adjunctive therapy, a 3.6-fold higher mortality was identified in the placebo group,
and a significant decrease in sepsis-related organ failure was seen in the IVIG group
→早期に終了され統計的有意差は認められていない研究ではあるが有効性を指摘
Similar results were seen in a pediatric population in which IVIG increased cost, but did not show an association with improved outcome
→小児では有効性が示せず
→Streptococcus TSSでは推奨はなし、同様にStaphylococcus TSSも推奨はしない
Clostridium Difficile Infection
More recently, attention has turned to the treatment of CDI with human monoclonal
antibodies directed against C difficile toxins A and B, which has the advantage of targeting therapy and avoiding the increased use of pooled IVIG. In a phase II trial, 200 patients receiving either metronidazole or vancomycin for CDI treatment were
randomized to antibody and placebo. Among the antibody group, the rate of CDI
recurrence was decreased compared with placebo (7% vs 25%; 95% CI 7–29;
P<.001). No increase in adverse events was seen
→多価抗体については賛否両論。モノクローナル抗体に今後の期待。
VIRAL INFECTIONS
Cytomegalovirus Infection in Solid Organ Transplant
A subsequent systematic review of 37 trials (2185 participants) evaluating
IVIG and CMV-Ig for prophylaxis in SOT recipients showed decreased risk of
mortality from CMV disease
→死亡率は減少も発生率は低下させず。
CMV pneumonitis and possibly other severe or treatment-refractory forms of disease.
→CMV肺炎や再発性で考慮
Hematopoietic Stem Cell Transplantも同様。
Hepatitis A
Preexposure IVIG is only recommended for high-risk persons who could not be vaccinated, including infants aged younger than 12 months, individuals with an allergy to vaccine components, or travelers declining vaccination.60 More recently, HAV vaccination also became an acceptable option for postexposure prophylaxis based on data showing equivalent protection to IVIG when administered within 2 weeks of HAV exposure in persons aged 2 to 40 years
→暴露後ワクチンのみでも十分な予防効果があるためワクチン接種ができない12か月未満やアレルギー患者のみ。
Hepatitis B
The combination of HBIG and vaccine are highly effective in preventing the transmission of HBV, with studies in health care workers and sexual contacts of HBV-infected persons showing 80% to 90% efficacy when treatment is completed within 7 days for needlesticks and 14 days for sexual contact
→針刺し後HBIGとワクチンで80-90%を予防
Varicella
VZIG can be considered in susceptible patients (no history of varicella disease or
vaccination), if the exposure is likely to result in infection and the patient is at a greater
risk for complications than the general population, including immunocompromised
adults and pregnant women
→感受性のある人が暴露した場合、免疫不全者、妊娠者では行う。
Rabies
CDC recommends the administration of HRIG 20 IU/kg body weight once at
the beginning of rabies prophylaxis. If not begun at the time of initial vaccination, HRIG can be administered up to and including day 7 of the postexposure prophylaxis
series. If anatomically feasible, HRIG should be fully administered in and around
the wound, and the first vaccine dose should be given at an anatomically distant location to prevent neutralization by HRIG
→暴露後の予防はIVIG＋ワクチン
Respiratory Syncytial Virus Infection
Uncontrolled studyのみ
副作用：
1000例中440例で認められ特に1/3で初回に多いとの報告あり注意
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