March 2018 FAQs
March 2018 FAQs
Is one type of influenza vaccine more effective than another?
Is one type of influenza vaccine more effective than another?
Each year, seasonal influenza affects millions of people in the United States.1 Flu season typically begins around October, and peak influenza activity is generally seen between December and February.2 Annual influenza vaccination is recommended for all patients older than 6 months of age who do not have contraindications to the vaccine.3 In the 2015-16 flu season, it is estimated that influenza vaccination prevented about 5.1 million illnesses, 2.5 million medical visits, and 71,000 hospitalizations.1
The 2017-18 flu season has been particularly severe; according to data from the Centers for Disease Control and Prevention (CDC), the proportion of medical visits related to influenza-like illness reached 7.7% on February 3, 2018, the highest proportion since the H1N1 pandemic in 2009.4 The rate of hospitalization due to influenza has reached 59.9 hospitalizations per 100,000 people. There has been concern that the effectiveness of the flu vaccine may be lower than usual in the 2017-18 season; a recent CDC study estimated the vaccine effectiveness to be 36% overall, and only 25% for a common viral subtype, H3N2.5 This article will discuss the factors that may impact flu vaccine effectiveness and examine the question of whether or not the available flu vaccine types differ in their effectiveness.
Determinants of Flu Vaccine Effectiveness
The effectiveness of the flu vaccine varies from year to year, and the effectiveness of the vaccine in any given flu season depends on several factors.6 Influenza viruses are divided into two major types, influenza A and influenza B; within these major types, viruses are classified into different subtypes (influenza A) or lineages (influenza B).7,8 The major disease-causing subtypes of influenza A are H1N1 and H3N2, and the major disease-causing lineages of influenza B are the Victoria and Yamagata lineages.7,9 Each year, the viral strains contained in the flu vaccine are selected based on the viral subtypes that are anticipated to be the most common in circulation that year.6 When the vaccine viruses are well-matched with the circulating virus types, overall effectiveness of the flu vaccine usually ranges from 40 to 60%. However, if the vaccine is not well-matched to the circulating flu viruses, it may not confer any benefit in the prevention of flu illness.
Even when the vaccine is well-matched to the circulating virus types, there are other factors that may impact its effectiveness.6 In general, the vaccine is less effective against the H3N2 viral subtype; there are several reasons why this may be the case. The H3N2 subtype undergoes genetic change more frequently than other subtypes, and may change in the time interval between vaccine composition determination and vaccine delivery. The decreased effectiveness against H3N2 subtypes may also be linked to the production methods used to propagate flu vaccine viruses, as is further discussed below. Therefore, if H3N2 is the predominant subtype in circulation, the vaccine may be less effective than usual. Individual patient characteristics, such as age, previous infection/vaccination history, and health status, may also impact effectiveness.5,6 In general, elderly patients have decreased immune responses to flu vaccination; therefore, decreased vaccine effectiveness may be seen in this population.6
Characteristics of Available Influenza Vaccines
Typically, flu vaccines will contain either 3 (trivalent) or 4 (quadrivalent) viral strains.3,8 The Food and Drug Administration (FDA) regulates the selection of strains for vaccine production. The exact strains may change yearly to match the strains that are anticipated to be most predominant in circulation, but in any given year, all trivalent vaccines contain the same 3 strains (2 influenza A viruses [one each of the H1N1 and H3N2 subtypes] and 1 influenza B virus [Victoria lineage]), and all quadrivalent vaccines contain the 3 strains in the trivalent vaccine plus an additional strain of influenza B virus from the Yamagata lineage.
Although the virus strains themselves are standardized across vaccines, there are many differences among the vaccine products in terms of manufacturing processes, dose, adjuvant, route of administration, and patient population for approved use (Table).3 For most flu vaccines, candidate vaccine viruses are provided to private manufacturers by CDC or World Health Organization (WHO) partner laboratories; the manufacturers then propagate these “reference viruses” for use in large-scale vaccine production.10 Previously, all reference viruses were grown in eggs before they were provided to manufacturers; the manufacturers were then able propagate the viruses in either mammalian cell culture (Flucelvax) or fertilized hen’s eggs (all other vaccines besides Flublok) before viral inactivation and antigen purification. However, for the 2017-18 flu season, the manufacturer of Flucelvax received approval to use reference viruses that were grown in cells, rather than eggs; as a result, the H3N2 component in Flucelvax is now derived from viruses that were grown entirely in cell culture, rather than egg-grown reference viruses propagated in cell culture.8,10 It is thought that using cell-grown viruses may lead to more effective vaccines, particularly for the H3N2 virus subtype, because the viruses grown in mammalian cells are more similar to “wild-type” flu viruses in circulation.8,11 When viruses are propagated in eggs, they may undergo changes in their antigenic structure as they adapt to the egg environment: for H3N2 viruses, egg adaptation has been noted to change the glycosylation of certain hemagglutinin proteins that are part of a key antibody epitope.11 These changes may decrease similarity to “wild-type” viruses and thereby decrease vaccine effectiveness.8 At the time of writing, no clinical studies are available to confirm the theoretical benefit of vaccine viruses grown entirely in cell culture, but research is ongoing in this area.
The production methods for the live attenuated vaccine, FluMist, are slightly different than those described above: the virus is still propagated in eggs, but the reference viruses used in this vaccine are weakened, cold-adapted, and temperature sensitive.10,12 There is also a recombinant influenza vaccine, Flublok. This vaccine does not use eggs or mammalian cells in the production process.10 The viruses used to produce the Flublok vaccine are produced by combining hemagglutinin proteins from “wild-type” viruses with portions of another virus that grows well in insect cells. The recombinant viruses are allowed to propagate in insect cells before extraction and purification.
Table. Characteristics of available influenza vaccines.3
Antigen Per Dose
Route of Administration
IIV4, standard dose
Fluzone Intradermal Quadrivalent
18 to 64 years
ccIIV4, standard dose
2 to 49 years
IIV3, standard dose
IIV3, high dose
aIIV3, standard dose
*Jet injector administration approved for use in patients aged 18 to 64 years only.
Abbreviations: aIIV3=adjuvanted inactivated influenza vaccine, trivalent; ccIIV4=cell culture-based inactivated influenza vaccine, quadrivalent; ID=intradermal; IIV3=inactivated influenza vaccine, trivalent; IIV4=inactivated influenza vaccine, quadrivalent; IM=intramuscular; LAIV4=live attenuated influenza vaccine, quadrivalent; RIV3=recombinant influenza vaccine, trivalent; RIV4=recombinant influenza vaccine, quadrivalent.
Comparative Literature for Vaccine Effectiveness
For the most part, data are limited to support the use of any particular flu vaccine over another: the 2017-18 recommendations from the Advisory Committee on Immunization Practices (ACIP) do not express a preference for any of the available influenza vaccine products.3 However, some studies have been conducted to assess the relative effectiveness of different flu vaccines. All studies are limited by the fact that the flu virus and vaccine strains are constantly changing from year to year: therefore, it is not certain that the observed results will hold true in each subsequent flu season. The live attenuated vaccine has not been recommended for use in recent years due to its low effectiveness against influenza A(H1N1)pdm09, a major circulating strain.3 In light of this recommendation, comparative data related to the live vaccine will not be further discussed here. Available evidence for other comparisons is summarized below, with a focus on literature that addresses endpoints of effectiveness rather than immunogenicity.
Recombinant Influenza Vaccine (RIV) vs. Inactivated Influenza Vaccines (IIVs)
A large randomized noninferiority study (N=9003) in adults over 50 years of age compared RIV4 to standard-dose IIV4 (Fluarix Quadrivalent).13 In this population, the rate of laboratory-confirmed influenza-like illness was 2.2% in patients who received RIV4 and 3.2% in patients who received IIV4, resulting in a 30% lower probability of influenza-like illness in patients who received RIV4 (95% confidence interval [CI], 10 to 47; p=0.006). The authors of the study concluded that RIV4 was both noninferior and superior to IIV4 for preventing influenza-like illness in the older adult population.
High-Dose IIV vs. Standard-Dose IIVs
A recent systematic review and meta-analysis of 7 trials in elderly patients (age greater than 65 years) found that the risk for laboratory-confirmed influenza infection was 24% lower among patients who received the high-dose IIV vs. a standard-dose IIV (risk ratio, 0.76; 95% CI, 0.65 to 0.90).14 However, this finding was based on results from only 2 of the 7 trials included in the meta-analysis, and both of these trials were conducted in ambulatory, medically stable patients. The authors of the meta-analysis concluded that more trials are needed to examine the overall impact of high-dose flu vaccines in the elderly population.
An analysis of Medicare beneficiary data from the 2012-13 and 2013-14 flu seasons found that among patients over the age of 65 years, the comparative effectiveness of high-dose and standard-dose vaccines varied by flu season.15 In the 2012-13 flu season, the high-dose vaccine was 36.4% more effective than the standard-dose vaccine for reducing mortality in this population (95% CI, 9.0 to 56). However, in the 2013-14 flu season, it was only 2.5% more effective (95% CI, -47 to 35). Overall, taking both seasons into account, the high-dose vaccine was 24% more effective than the standard-dose vaccine (95% CI, 0.6 to 42). The rate of post-influenza death was 0.028/10,000 person-weeks in patients who received the high-dose vaccine and 0.038/10,000 person-weeks in patients who received the standard-dose vaccine (risk difference of -0.01/10,000 person-weeks; 95% CI, -0.019 to -0.002). During the 2012-13 flu season, the H3N2 viruses were more common in circulation, so it is possible that the high-dose vaccination demonstrates better effectiveness than standard-dose vaccinations when H3N2 viruses are widespread. A retrospective study of community-dwelling veterans in the 2010-11 flu season did not find any benefit to high-dose vaccination vs. standard-dose vaccination in terms of influenza-related hospitalization, except among the subgroup of patients 85 years or older.16 However, a retrospective study of veterans age 65 years and older in the 2015-16 flu season found that the high-dose vaccine was 25% more effective than the standard-dose vaccine for preventing influenza- or pneumonia-related hospitalization (95% CI, 2 to 43).17
Adjuvanted IIV vs. Non-Adjuvanted IIVs
One adjuvanted IIV is currently available in the United States. Fluad, an intramuscular (IM) trivalent IIV, contains the squalene-based adjuvant known as microfluidized emulsion 59 (MF59).3,18 It is hypothesized that adding this adjuvant induces a broader, more rapid immune response to vaccination by activating local immune cells and promoting recruitment of antigen-presenting cells; this increased immuno-stimulation may be particularly useful in elderly patients, whose immune responses tend to be weaker overall.18 Limited studies are available comparing the adjuvanted flu vaccine to non-adjuvanted vaccines. A recent systematic review and meta-analysis included 3 studies comparing the adjuvanted vaccine to non-adjuvanted IM vaccines, and 1 study comparing the adjuvanted vaccine to non-adjuvanted intradermal vaccines. All 4 studies were observational and conducted outside the United States. Three of the 4 studies included only elderly patients (aged 65 years or older). In adjusted analyses, the adjuvanted vaccine tended to be more effective than the non-adjuvanted IM vaccine for reducing the risk of influenza-like illness or influenza-related hospitalization; however, it was not more effective than the non-adjuvanted intradermal vaccine for reducing risk of influenza-related hospitalization. No meta-analysis could be performed on the data due to variations in trial design, setting, comparators, and outcomes.
Effectiveness of influenza vaccination varies from year to year, and may depend on several factors, including the degree of similarity between vaccine viruses and circulating strains. Some studies suggest that the RIV, high-dose IIV, and adjuvanted IIV may be more effective than standard-dose IIVs in the elderly population; however, comparative evidence for other vaccines and/or other populations is not available.3 Live attenuated vaccines have not been recommended for the past few years due to an observed lower effectiveness against the influenza A(H1N1)pdm09 virus.3 There is speculation that cell-grown viruses (as opposed to egg-grown viruses) may produce vaccines that are more effective against circulating H3N2 viruses, but no clinical studies are yet available to assess this hypothesis, and the CDC does not make a preferential recommendation for one injectable flu vaccine over another.5,8 In spite of the decreased effectiveness that has been observed so far in the 2017-18 flu season, the CDC continues to recommend vaccination to reduce the risk of influenza illness and serious complications.5 While effectiveness is low for H3N2 viruses in adults, the effectiveness against H3N2 in children aged 6 months to 8 years is estimated at 59%; effectiveness for H1N1 viruses is estimated at 67%, and effectiveness for influenza B viruses is estimated at 42%. Therefore, the vaccine may still provide some benefit in the prevention of illness and/or influenza-related complications.
1. Estimated influenza illnesses, medical visits, hospitalizations, and deaths averted by vaccination in the United States. Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/about/disease/2015-16.htm. Updated April 19, 2017. Accessed February 16, 2018.
2. The flu season. Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/about/season/flu-season.htm. Updated July 26, 2016. Accessed February 16, 2018.
3. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices – United States, 2017-18 influenza season. MMWR Recomm Rep. 2017;66(2):1-20.
4. Situation update: summary of weekly FluView report. Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/weekly/summary.htm. Updated February 9, 2018. Accessed February 16, 2018.
5. Flannery B, Chung J, Belongia E, et al. Interim estimates of 2017–18 seasonal influenza vaccine effectiveness — United States, February 2018. MMWR Morb Mortal Wkly Rep. 2018;67:180-185.
6. Vaccine effectiveness – how well does the flu vaccine work?. Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/about/qa/vaccineeffect.htm. Updated October 3, 2017. Accessed February 21, 2018.
7. Njoku J. Influenza. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861§ionid=146071550. Accessed February 20, 2018.
8. Frequently asked flu questions 2017-2018 influenza season. Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/about/season/flu-season-2017-2018.htm. Updated January 31, 2018. Accessed February 20, 2018.
9. Types of influenza viruses. Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/about/viruses/types.htm. Updated September 27, 2017. Accessed February 22, 2018.
10. How influenza (flu) vaccines are made. Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/protect/vaccine/how-fluvaccine-made.htm. Updated November 7, 2016. Accessed February 21, 2018.
11. Dugan V, Blanton L, Elal A, et al. Update: influenza activity – United States, October 1-November 25, 2017. MMWR Morb Mortal Wkly Rep 2017;66:1318-1326.
12. FluMist [package insert]. Gaithersburg, MD: MedImmune; 2017.
13. Dunkle LM, Izikson R, Patriarca P, et al. Efficacy of recombinant influenza vaccine in adults 50 years of age or older. N Engl J Med. 2017;376(25):2427-2436.
14. Wilkinson K, Wei Y, Szwajcer A, et al. Efficacy and safety of high-dose influenza vaccine in elderly adults: A systematic review and meta-analysis. Vaccine. 2017;35(21):2775-2780.
15. Shay DK, Chillarige Y, Kelman J, et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccines among US Medicare beneficiaries in preventing postinfluenza deaths during 2012-2013 and 2013-2014. J Infect Dis. 2017;215(4):510-517.
16. Richardson DM, Medvedeva EL, Roberts CB, Linkin DR. Comparative effectiveness of high-dose versus standard-dose influenza vaccination in community-dwelling veterans. Clin Infect Dis. 2015;61(2):171-176.
17. Young-Xu Y, Van Aalst R, Mahmud SM, et al. Relative vaccine effectiveness of high-dose versus standard-dose influenza vaccines among Veterans Health Administration patients. J Infect Dis. 2018.
18. Domnich A, Arata L, Amicizia D, Puig-Barbera J, Gasparini R, Panatto D. Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly: A systematic review and meta-analysis. Vaccine. 2017;35(4):513-520.
The information presented is current as of February 16, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.
What is the role of Giapreza (angiotensin II) in shock?
What is the role of Giapreza (angiotensin II) in shock?
Shock is a life-threatening, acute state of circulatory failure manifested as hypotension that leads to tissue hypoxia, which in turn can result in multi-organ failure or death.1 There are 4 basic types of shock: cardiogenic, hypovolemic, obstructive, and distributive. One form of distributive shock is septic shock. Although the overall incidence rate of shock is unknown, sepsis appears to be the most common cause.2,3 In a recent trial of 1,600 patients with undifferentiated shock, septic shock was the most common form, accounting for about 60% of all cases, followed by cardiogenic and hypovolemic shock at about 16% each, and obstructive shock in 2% of patients.3 The rates of mortality associated with severe sepsis and septic shock are approximately 25% in-hospital and 45% at 2 years.4
The Surviving Sepsis Campaign (SSC): International Guidelines for Management of Sepsis and Septic Shock: 2016 and the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) are guidelines used to care for patients with shock.5,6 These guidelines focus on the definition and clinical criteria to identify sepsis and septic shock. In addition, a stepwise treatment approach, including supportive care, is outlined. Fluid management is a key component and the administration of at least 30 mL/kg of intravenous (IV) crystalloid fluid given within the first 3 hours is the first-line therapeutic strategy; however, it is often insufficient to stabilize the patient’s blood pressure. Adrenergic agents are frequently required to correct the hypotension. The SCC guidelines state norepinephrine is the drug of choice for patients with septic shock, followed by addition of vasopressin or epinephrine.5 The goal is to raise blood pressure to a target mean arterial pressure (MAP) of at least 65 mm Hg and/or decrease the dose of norepinephrine. This guideline recommends using dopamine as an alternative vasopressor agent to norepinephrine only in select patients (e.g., patients with low risk of tachyarrhythmia and absolute or relative bradycardia). Other than these recommendations, the guideline is not specific in prioritizing any one vasoactive agent as second-line.
In addition to these resuscitative measures, antimicrobial therapy should be initiated early in septic shock, with empiric broad-spectrum therapy based on the suspected source of infection and all likely pathogens.5 Appropriate antibiotic therapy is one of the most important elements of resolution of septic shock, and is closely associated with mortality risk.
Angiotensin II (AT2) is a naturally occurring hormone component of the renin-angiotensin-aldosterone system (RAAS) and is a potent vasoconstrictor.7,8 Giapreza, a synthetic angiotensin II, was approved by the Food and Drug Administration (FDA) on December 21, 2017. Giapreza has been studied in patients with distributive shock and is indicated as an IV infusion to increase blood pressure in adults with septic or other distributive shock.9
Intravenous AT2 for the treatment of high-output shock (ATHOS trial) was a pilot study conducted to determine the appropriate dose required to reduce norepinephrine requirements.10 This study included 20 patients with distributive shock and a cardiovascular Sequential Organ Failure Assessment (SOFA) score of 4 who were randomized to either AT2 infusion at 20 ng/kg/min (n=10) or placebo (n =10) plus standard care titrated to a MAP of 65 mm Hg. The primary endpoint was the effect of AT2 on the dose of norepinephrine required to maintain a MAP of 65 mm Hg. Angiotensin II, compared to placebo, resulted in a reduction in the mean norepinephrine dose at 1 hour (7.4 mcg/min vs. 27.6 mcg/min, p=0.06) and 2 hours (7.3 mcg/min vs. 28.6 mcg/min, p=0.06).
Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) was a phase 3, randomized, double-blind, placebo-controlled trial.11 The study included patients who were 18 years of age or older with vasodilatory shock despite IV volume resuscitation of at least 25 mL/kg over 24 hours and administration of high doses of vasopressors (defined as norepinephrine >0.2 μg/kg/min or the equivalent dose of another vasopressor). Patients were randomized to AT2 initiated at 20 ng/kg/min or placebo. Randomization was stratified based on (1) MAP (<65 mm Hg or ≥65 mm Hg) and (2) Acute Physiology and Chronic Health Evaluation II (APACHE II) score (≤30, 31 to 40, or ≥41 on a scale of 0 to 71, with higher scores indicating greater disease severity). The study excluded patients with burns covering more than 20% of their body surface area; those with acute coronary syndrome, bronchospasm, liver failure, mesenteric ischemia, active bleeding, abdominal aortic aneurysm, or an absolute neutrophil count <1000 per mm3; and those who were receiving venoarterial extracorporeal membrane oxygenation or treatment with high-dose glucocorticoids. The primary efficacy endpoint for this study was MAP response at 3 hours (defined as MAP >75 mm Hg or an increase in MAP of at least 10 mm Hg from baseline without an increase in the dose of background vasopressors). The secondary endpoints were changes in the cardiovascular SOFA score and the total SOFA score between baseline measurement and 48 hours.
The study included 321 patients, of whom 163 patients received AT2 and 158 received placebo.11 Baseline characteristics were well balanced between groups; the average age was approximately 64 years and the median APACHE II score was 28. Sepsis was the cause of shock in 259 of the 321 patients (80.7%). The primary endpoint was reached by 69.9% of patients in the AT2 group and 23.4% of patients in the placebo group (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; p<0.001). In addition, there was a significantly greater increase in MAP in the AT2 group than the placebo group (12.5 mm Hg vs. 2.9 mm Hg; p<0.001) during the first 3 hours. There were no significant differences in total SOFA score at 48 hours; however, mean change in cardiovascular SOFA score at hour 48 was significantly greater in the AT2 group than in the placebo group (−1.75 vs. −1.28; p=0.01). All-cause mortality was not statistically significant at day 7 (29% in AT2 group vs, 35% in the placebo group; hazard ratio [HR], 0.78; 95% CI, 0.53 to 1.16; p=0.22) or at day 28 (46% in AT2 group vs. 54% in the placebo group; HR, 0.78; 95% CI, 0.57 to 1.07; p=0.12).
Although ATHOS-3 demonstrated an improvement in the primary outcome of target MAP with use of AT2, the study’s limitations preclude establishing its place in therapy. The trial included patients defined as unresponsive to usual treatment; however, the mean baseline MAP was 66 mm Hg which is above the target MAP of 65 mm Hg recommended in the SSC guideline. Therefore, it is unclear whether patients who are truly unresponsive to usual treatment with lower baseline MAP would benefit from AT2. Furthermore, the significant increase in MAP observed with AT2 compared to placebo within a 3-hour period could have resulted in unblinding. The exclusion of patients with burn injury, acute coronary syndrome, active bleeding and other shock syndromes limits the external validity of the results. Other key treatments in management of septic shock were not fully discussed in the study including the type of fluid resuscitation and antimicrobial therapy. The study was also underpowered to detect a difference in mortality.
Safety and adverse events
A recent systematic review of safety of over 1,000 published studies from 1941 to 2016 utilizing AT2 infusion doses ranging from 0.05 to 3,780 ng/kg/min supports that AT2 has an acceptable safety profile.12 The most common adverse effects were mild or moderate and included headache, sensation of chest pressure/tightness, dyspepsia/nausea, bradycardia, and orthostatic hypotension/dizziness. A concern with AT2 is the potential for exacerbation of underlying diseases such as asthma and congestive heart failure. In ATHOS-3, adverse events were reported in 87.1% of the patients who received AT2 and in 91.8% of the patients who received placebo.11 More patients in the placebo group discontinued due to adverse events (21.5% vs 14.1%). Venous and arterial thromboembolic events occurred in 12.9% and 5.1% of patients treated with AT2 and placebo, respectively, and significance was not reported. Although not discussed in detail in the ATHOS-3 publication, thromboembolic events such as deep vein thrombosis are a concern with AT2. The prescribing information recommends patients receive concurrent venous thromboembolism prophylaxis.9
Dosage and administration
Giapreza (2.5 mg/mL) will be available in 1 and 2 mL vials.9 The recommended starting dose is 20 ng/kg/min with titration in increments of up to 15 ng/kg/min every 5 minutes as necessary to achieve target blood pressure or to a maximum of 80 ng/kg/minute in the first 3 hours. Maintenance doses should not exceed 40 ng/kg/minute. Once the underlying shock has sufficiently improved, Giapreza can be tapered every 5 to 15 minutes by increments of up to 15 ng/kg/min based on blood pressure. Administration through a central venous line is recommended.
Giapreza is a synthetic form of AT2 recently approved by the FDA as an IV infusion to increase blood pressure in patients with septic or other distributive shock. The aforementioned clinical trials have studied Giapreza as an adjunctive treatment to norepinephrine, or other vasoactive equivalents in comparison to placebo. Current clinical trials have shown some promising results regarding MAP response, and reducing norepinephrine doses with Giapreza. However, study limitations and the lack of mortality benefits and head-to-head clinical trials with other vasoactive agents makes it difficult to assess the role of Giapreza in shock. Additional clinical studies to establish the place of Giapreza in this practice setting are needed.
- Gaieski D, Mikkeslsen M. Definition, classification, etiology, and pathophysiology of shock in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 23, 2018.
- Maclaren R., Dasta J. Use of vasopressors and inotropes in the pharmacotherapy of shock. In: DiPiro JT, Talbert RL, Yee GC, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. McGraw-Hill Companies, Inc.; 2017. www.accesspharmacy.com. Accessed January 23, 2018.
- Du Y, Wang L, Shi H, Gao M. Comparison of clinical effect of dopamine and norepinephrine in the treatment of septic shock. Pak J Pharm Sci. 2015;28(4 Suppl):1461-1464.
- Bauer DR, Lam SW, Oyen LJ. Severe sepsis and septic shock. In: Erstad B, ed. Critical Care Pharmacotherapy. Lanexa, KS: American College of Clinical Pharmacy; 2016:298-318.
- Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304-377.
- Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801-810.
- Timothy W Smith, James P Morgan. Actions of angiotensin II on the heart. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 23, 2018.
- Parker R, Nappi J, Cavallari L. Chronic heart failure. In: DiPiro JT, Talbert RL, Yee GC, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. McGraw-Hill Companies, Inc.; 2017. www.accesspharmacy.com. Accessed January 23, 2018.
- Giapreza (Angiotensin II) [prescribing information]. San Diego, CA: La Jolla Pharm Co; 2017.
- Chawla LS, Busse L, Brasha-Mitchell E, et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014;18(5):534.
- Khanna A, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419-430.
- Busse LW, Wang XS, Chalikonda DM, et al. Clinical experience with IV angiotensin II administration: a systematic review of safety. Crit Care Med. 2017;45(8):1285-1294.
Melika Fini, Pharm.D.
PGY1 Pharmacy Resident
College of Pharmacy
University of Illinois at Chicago
The information presented is current as January 23, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.
What data are available for intravenous immune globulin (IVIG) in Clostridium difficile infection?
What data are available for intravenous immune globulin (IVIG) in Clostridium difficile infection?
Clostridium difficile is a gram-positive, toxin-producing, spore-forming anaerobic bacterium that causes diarrhea and colitis, often after antibiotic use, which may progress to pseudomembranous colitis, toxic megacolon, colon perforation, sepsis, and death.1,2 Treatment for C. difficile infection (CDI) typically involves vancomycin, fidaxomicin, or metronidazole depending on severity, and fecal microbiota transplant is recommended for patients with multiple recurrences.3 Despite treatment, approximately 25% of patients experience a recurrent episode of CDI.1 Risk factors for recurrent C. difficile infection (CDI) include older age, extended or recent hospital stay, severe underlying disease, and lack of antitoxin A antibody response.
Intravenous immune globulin (IVIG), a preparation of human immunoglobulin G (IgG) manufactured from human plasma, has been studied in patients with recurrent, refractory, and severe CDI.4,5 The exact mechanism by which IVIG may exert its therapeutic effect in CDI is unknown; however, there is a theory that IVIG may passively transfer antibodies against C. difficile toxin A and possibly toxin B.4,6 There is evidence that asymptomatic patients colonized with C. difficile had higher serum antitoxin A IgG level response compared to patients who developed diarrhea, and that patients with lower serum antitoxin A IgG levels were more likely to have recurrent C. difficile-associated diarrhea than patients with higher levels.7,8 Another study showed that antitoxin A IgG antibody levels increased after IVIG administration in children with CDI.9 The IDSA/SHEA guideline for management of CDI states that IVIG 150 to 400 mg/kg has been used in patients with fulminant CDI who do not respond to metronidazole or vancomycin; however, the guideline notes that controlled trials assessing IVIG efficacy have not been conducted and therefore, does not provide a recommendation on its use.3
Common adverse events of IVIG include flu-like symptoms (eg, myalgia, headache, chills, nausea, and fever).4 Rare, but serious, adverse events include anaphylaxis, renal failure, aseptic meningitis, and acute cardiovascular events. Since anaphylaxis is more common in patients who are immunoglobulin A (IgA) deficient, it has been recommended to use an IgA-depleted IVIG product in patients with known IgA deficiency. Sucrose-based IVIG has also been associated with nephrotoxicity.4,10
The current identified literature evaluating IVIG for CDI is limited to case reports and retrospective chart reviews (Tables 1 and 2).6,9-24 Retrospective chart reviews have found conflicting data regarding its efficacy, while published case reports have described positive findings. Many of the retrospective analyses had major limitations, such as small sample size, lack of a control group in several studies, lack of a standard definition of severe disease across studies, and potential confounders (eg, different baseline characteristics between groups or concurrent standard therapy).6,11-15 The optimal dose and duration of IVIG have yet to be defined, as a range of doses and durations were used. The studies and case reports listed in Tables 1 and 2 did not reveal significant safety concerns with use of IVIG in patients with CDI; however, they were not specifically designed to assess safety.6,9-24
Table 1. Retrospective analyses of IVIG in CDI.6,11-15,18
Shahani and Koirala 20156
N=21 patients (mean age, 69.8 years) with severe CDAD who received IVIG
N=21control patients (mean age, 60.9 years) with CDAD and severe sepsis
Median time to IVIG after starting standard therapy: 4 days (range, 1 to 8 days)
Single dose of IVIG 400 mg/kg
Patients also received standard therapy with oral vancomycin and IV metronidazole
Mortality was 18.2% in the IVIG group and 22.7% in the control group (p=NS)
LOS was longer in the IVIG group vs control group (26.1 vs 15 days; p=0.02)
Length of diarrhea was 12.1 days in the IVIG group vs 8.4 days in the control group (p=NS)
Patients in the IVIG group were older (p=0.05) and had more severe disease (p=0.02) compared to patients in the control group
N=18 patients (median age, 84 years) with CDI who received IVIG for severe cases or lack of response to standard treatment
N=18 control patients (median age, 83 years) with CDI who received standard treatment
Single dose of IVIG 400 mg/kg
Patients also received standard treatment: metronidazole and/or vancomycin
Median hospital LOS after first positive CDI toxin: 36 days with IVIG vs 33 days without (p=NS)
At 30 days, no difference in patients recovered/recovering (15 vs 15 patients) or ongoing infection (3 vs 3 patients)
No patients required surgery
N=21 patients (mean age, 68 years) with severe CDC and pancolitis (n=12), severe ileus with cessation of diarrhea, abdominal distention, and requirement for TPN (n=5), or severe hypotension (n=4)
IVIG 200 to 1250 mg/kg (mode: 250 mg/kg for 1 to 3 days) (doses based on clinical decision)
Adjuvant treatment (n=8): IVIG administered ≤ 4 days of CDAD diagnosis
Second-line treatment (n=13): IVIG > 4 days of CDAD diagnosis
9 of 21 patients (43%) survived
Mean time to complete resolution after IVIG administration: 10 days (range, 2 to 20 days)
Variables positively associated with mortality: APACHE II score on day 1 of IVIG (p=0.006) and lactate level on day of IVIG infusion (p=0.004; p=NS after adjustment for additional factors)
N=18 patients (mean age, 67 years) with severe CDAD received IVIG matched with N=18 patients (mean age, 72.5 years) with severe CDAD who did not receive IVIG at a single institution
Single dose of IVIG 200 to 300 mg/kg plus standard therapy
Mortality, colectomies, and LOS did not differ between groups
Death: 3 of 18 patients in both groups (p=NS)
Colectomies: 3 of 18 patients in both groups (p=NS)
LOS: 25.1 ± 18 days with IVIG vs. 32.9 ± 33 days without IVIG (p=NS)
N=14 patients (median age, 79 years; range, 54 to 91 years) with refractory, recurrent, or severe CDAD at a single institution
Median length of symptoms prior to IVIG: 29 days (range, 3 to 90 days)
Median of 11 days (range, 3 to 37 days) of vancomycin and 10 days (range, 0 to 29 days) of metronidazole
IVIG (Flebogamma®) 150 to 400 mg/kg
2 patients received 2 doses after 3 weeks due to inadequate response (n=1) and recurrence (n=1)
Patients were continued on vancomycin or metronidazole
Overall response to IVIG: 9 of 14 patients (64%)
Response based on type:
- Recurrent CDAD: 5 of 6 patients
- Refractory CDAD: 4 of 6 patients
- Hematologic malignancy and CDAD: 0 of 2 patients
- Severe CDAD: 6 of 8 patients
Median time to resolution of symptoms: 10 days (range, 2 to 26 days)
Of 9 patients with complete response, 3 had recurrence within 1 month
1 patient died 3 weeks after second IVIG infusion after a recurrence; 4 other patients died due to other causes
No patients reported side effects
N=5 patients (age range, 66 to 97 years) with protracted and/or recurrent CDAD at a single institution
Median duration of diarrhea: 50 days (range, 45 to 64 days)
IVIG (Viagam S; Octagam) 300 to 500 mg/kg (most common: 400 mg/kg) for one dose (n=2), two doses (n=2) and six doses (n=1)
3 of 5 patients had good therapeutic response with resolution of CDAD within 11 days
1 patient died of intractable CDAD (patient who received 6 doses)
1 patient experienced recurrence within 6 weeks
Abbreviations: CDAD=Clostridium difficile-associated diarrhea; CDC=C. difficile colitis; CDI=C. difficile infection; IV=intravenous; IVIG=intravenous immune globulin; LOS=length of stay; NS=not significant; TPN=total parenteral nutrition.
Table 2. Case reports of IVIG used in CDI.9,10,16-24
68 year old with severe refractory NAP-1 psudomembranous CDC associated with megacolon
IVIG (Gamunex-C 10%) 1 gram/kg on first day, then 0.5 gram/kg on days 2 and 3.
6 days after IVIG infusions, imaging revealed residual disease in right colon, so patient received IVIG 1 gram/kg 1 week following initial dose
Complete resolution of abdominal pain and diarrhea
77 year old with severe pseudomembranous CDC with severe sepsis and renal failure
Single dose of IVIG 400 mg/kg over 12 hours
IVIG administered after 25 days of vancomycin and metronidazole
Resolution of diarrhea, fever, and leukocytosis without recurrence
49 year old with septic shock secondary to CDI and severe pseudomembranous colitis
IVIG 400 mg/kg for 5 days plus bowel rest
IVIG started after 3 days of medical treatment. Vancomycin was continued for 14-day course.
Hemodynamic and symptoms improved significantly.
70 year old with severe CDC and multiorgan system failure
IVIG 30 grams for 4 doses on days 2 to 6 of hospitalization
Metronidazole and vancomycin were continued for 14 days
Complete resolution of leukocytosis and diarrhea within a week of hospitalization
34 year old with severe CDAD
Single dose of IVIG 300 mg/kg
Resolution of hypotension, tachycardia, and fever
57 year old with persistent CDAD and colitis
IVIG (VIGAM®) two sets of three infusions one week apart (dose not reported)
Patient received vancomycin
Resolution of diarrhea after 12 days
Hassoun and Ibrahim 200721
72 year old with severe persistent CDC
IVIG 400 mg/kg (Gammagard S/D) over 4 hours with slowly increasing dose
Patient was premedicated with acetaminophen and steroids
Patient continued on tapering vancomycin for 6 weeks
Complete resolution of diarrhea within 6 days and complete resolution of bowel dilation after 7 days
57 year old with relapsing CDI over course of 6 months
IVIG 400 mg/kg for 3 days
Diarrhea stopped within 1 week; however, patient developed constipation
Patient 1: 77 year old with recurrent CDAD
Patient 2: 75 year old with recurrent CDAD
Patient 3: 69 year old with recurrent CDAD
Patient 4: 82 year old with recurrent CDAD
IVIG 400 mg/kg for one dose then repeated after 21 days
Patients also received tapering vancomycin
Patient 1: Resolution of diarrhea with no recurrence after 10 months
Patient 2: Successfully treated with no recurrence over 8 months
Patient 3: Successfully treated with no recurrence after 7 months
Patient 4: Resolution of diarrhea and no recurrence after 5 months
Patient 1: 63 year old with refractory CDAD and pseudomembranous colitis
Patient 2: 64 year old with refractory CDAD and pseudomembranous colitis
Patient 1: IVIG 300 mg/kg
Metronidazole and vancomycin were continued for 10 days
Patient 2: IVIG 200 mg/kg
Patient 1: Rapid improvement in diarrhea. Patient experienced recurrence 1 month later which responded to metronidazole.
Patient 2: Diarrhea and fever resolved within 24 hours without recurrence.
Five children aged 6 to 37 months (median age, 18 months) with relapsing CDC and low levels of serum C. difficile toxin A antibody
Median duration of diarrhea: 7 months
IVIG 400 mg/kg every 3 weeks
All patients experienced resolution of colitis during maintenance IVIG therapy and cleared C. difficile toxin B from stool
One patient experienced relapse of CDC so was retreated with IVIG and experienced resolution of GI symptoms after 2 doses
Higher anti-toxin IgG levels after third IVIG infusion vs before infusion (p=0.01) but no difference in IgA antitoxin levels
No side effects of IVIG reported
Abbreviations: CDAD= Clostridium difficile-associated diarrhea; CDC=C. difficile colitis; CDI=C. difficile infection; GI=gastrointestinal; IgA=immunoglobulin A; IgG=immunoglobulin G; IV=intravenous; IVIG=intravenous immune globulin; NAP1=North American pulsed field type 1.
Overall, there are limited data to support IVIG for CDI, and current data includes case reports and retrospective chart reviews in patients with recurrent, refractory or severe disease. An optimal dosing strategy has not been established. Based on current data, IVIG may be considered in patients with severe or recurrent disease unresponsive to other therapies and in whom the benefit outweighs risk. Randomized, controlled trials are needed in order to further define the role of IVIG in CDI.
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The information presented is current as of February 1, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.