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. 2009 Jul;7(3):216–234. doi: 10.2450/2009.0094-09

Recommendations for the use of albumin and immunoglobulins

Giancarlo Liumbruno 1,✉, Francesco Bennardello 2, Angela Lattanzio 3, Pierluigi Piccoli 4, Gina Rossettias, as Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) Working Party5
PMCID: PMC2719274  PMID: 19657486

Appendix A

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Table I.

Grades of Recommendations

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Blood Transfusion. 2009 Jul;7(3):216–222. doi: 10.2450/2009.0094-09

Albumin

Introduction

Human albumin is a physiological plasma-expander; its limited availability and high cost make it essential to define recommendations for its appropriate use, as an alternative to other therapeutic strategies including solutions of crystalloids and non-protein colloids, and have also stimulated numerous studies, which have sometimes reached contradictory conclusions1–8.

In 1998 a meta-analysis of 30 randomised trials suggested that the use of albumin was associated with an increased mortality rate among critically ill patients9,10. This conclusion, also reached by two subsequent Cochrane reviews11,12, was not confirmed by a meta-analysis in 2001 or by more recent studies13–23.

A review in 2006 showed that renal damage can be induced by the use of hydroxyethyl starch and gelatine in sepsis and surgery24.

The limited power of all these studies could lie in their having combined results from heterogeneous types of patients with different baseline albumin concentrations25,26.

Notions of physiology

Albumin is the main factor determining the oncotic pressure of blood and, therefore, the regulation of plasma volume and tissue fluid balance; it is also involved in the transport of numerous endogenous substances, such as unconjugated bilirubin and hormones, and exogenous ones, including drugs27–29.

The body content of albumin is 4–5 g/kg, distributed predominantly in the extracellular space; 30–40% is found in the intravascular compartment (40–50 g/L of plasma) and is responsible for about 80% of the osmotic pressure of the plasma19.

It has not been clearly determined whether there is a threshold concentration of albumin below which its oncotic function is compromised to a clinically relevant degree; there is, however, a consensus that oncotic activity remains physiologically adequate at values of albumin ≥ 2 g/dL and total proteins ≥ 3.5 g/dL.

The infusion of human albumin causes, within a few minutes, the movement of fluids from the interstitial space into the circulation; this passage of fluids is, however, limited or absent in dehydrated patients unless the dehydration is corrected.

The half-life of endogenous albumin is about 3 weeks, while that of blood-derived albumin is only 12–16 hours and is reduced notably in conditions of increased capillary permeability.

Preparations of albumin

Solutions of albumin are prepared from the plasma of healthy donors. The albumin is pasteurised at 60 °C for 10 hours 30. It can be infused independently of the recipient's blood group.

Preparations of 5%, 20% and 25% have been registered. The solutions of 5% human albumin have an osmotic pressure almost identical to that of normal plasma; the 20% and 25% solutions are hyperosmotic. All the preparations contain 130–160 mEq of sodium per litre.

Indications

On the basis of clinical evidence, the use of albumin can be indicated in acute conditions31, in which it is necessary to expand the volume and maintain the circulation, and in some chronic states of low serum albumin; there are some widely shared and fully agreed indications for the appropriate use of human albumin and indications that are occasionally appropriate, that is, when other criteria are fulfilled (table I)32,33. Albumin is also used in all cases in which there is a contraindication to the use of non-protein colloids.

Table I.

Indications for the use of albumin

Indication Notes GoR
Appropriate indications (for which there is widespread consensus)
Paracentesis 5 g of albumin/L ascitic fluid removed, after paracentesis of volumes > 5 L. 1C+
Therapeutic plasmapheresis For exchanges of > 20 mL/kg in one session or > 20 mL/kg/week in more than one session. 2C+
Spontaneous bacterial peritonitis In association with antibiotics. 1C+
Occasionally appropriate indications (when other criteria are fulfilled)
Heart surgery Last-choice treatment after crystalloids and non-protein colloids. 2C+
Major surgery Albumin should not be used in the immediate post-operative period. 2C+
Only indication for use: serum albumin < 2 g/dL after normalisation of circulatory volume.
Cirrhosis of the liver with refractory ascites Generally ineffective, except in patients with serum albumin < 2 g/dL. 2C
Contraindications to the use of non-protein colloids

  • - pregnancy and breastfeeding;

  • - perinatal period and early infancy;

  • - acute liver failure;

  • - moderate-severe renal failure (particularly when anuria/oligouria);

  • - dialysis treatment in the presence of severe abnormalities of haemostasis and baseline albumin < 2 – 2.5 g/dL;

  • - intracranial haemorrhage;

  • - hypersensitivity.

 2C
Haemorrhagic shock Only in the case of : 1A

  • - lack of response to crystalloids or colloids;

  • - contraindication to the use of non-protein colloids.
Hepatorenal syndrome In association with vasoconstricting drugs. 2B
Nephrotic syndrome Only in patients with albumin < 2 g/dL with hypovolaemia and/or pulmonary oedema. 2C
Organ transplantation In the post-operative period after liver transplantation to control ascites and peripheral oedema, to replace the loss of ascitic fluid from the drainage tubes, if albumin < 2.5 g/dL with a haematocrit > 30%. 1C
Burns In the case of burns of > 30% body surface area, after the first 24 hours. 2C+
Dose
The dose needed to obtain a serum albumin ≥ 2.5 g/dL is calculated using the following formula:
Dose (g) = [desired albumin concentration (2.5 g/dL) − actual albumin concentration (g/dL)] x plasma volume (0.8 x kg)
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GoR: Grade of Recommendation

Acute conditions

Haemorrhagic shock (occasionally appropriate indication)

Albumin is used as a second choice (Grade of recommendation: 1A)8–16,18,32–38, when solutions of crystalloids or non-protein colloids (first choice treatment) have already been used at maximum doses without having produced a clinically adequate response and in cases in which non-protein colloids are contraindicated.

Crystalloid and colloid solutions must not be considered as blood replacements when oxygen-transporting capacity is reduced. Albumin 5% must be used.

Major surgery (occasionally appropriate indication)

The use of albumin may be indicated in subjects undergoing major surgery (> 40% resection of the liver, extensive intestinal resection) when, after normalisation of circulatory volume, the serum albumin is < 2 g/dL (Grade of recommendation 2C+)14,15,17,18,31–33,39,40.

The use of albumin in the immediate post-operative period is never advised for any other type of operation.

Burns (occasionally appropriate indication)

There is no indication to use albumin in the resuscitation phase in the first 24 hours after burn injuries, that is, in the period of increased capillary permeability. Subsequently, albumin 5% is indicated, using different doses according to the amount of body surface area (BSA) involved (Grade of recommendation: 2C+)7,15,18,38,41,42:

  • - BSA 30 – 50%: 0.3 mL x kg x % of burnt BSA, in 24 hours;

  • - BSA 50 – 70%: 0.4 mL x kg x % of burnt BSA, in 24 hours;

  • - BSA 70 – 100%: 0.5 mL x kg x % of burnt BSA, in 24 hours.

In the post-resuscitation phase, once the problems of circulatory volume caused by the marked capillary permeability have been overcome, albumin 5% or 20% is infused at a dose of 1 – 2 g/kg/die if:

  • - albumin < 1 g/dL (end-point 2 g/dL);

  • - albumin 1–2 g/dL and the patient cannot tolerate an enteral diet or has massive tissue oedema or pulmonary dysfunction, which could be aggravated by a low oncotic pressure (end-point 2 g/dL).

Heart surgery (occasionally appropriate indication)

Albumin can be used as a post-operative volume expander, as a last choice of treatment after crystalloids or non-protein colloids, following heart surgery.

Crystalloids are the first choice for priming the circuitry in the case of extracorporeal circulation43,44; the association with non-protein colloids can be preferable to avoid the accumulation of fluid in the pulmonary interstitium (Grade of recommendation: 2C+)14,43–46.

Organ transplantation (occasionally appropriate indication)

Albumin can be useful in the post-operative period following liver transplantation, in order to control the ascites and peripheral oedema and to replace the loss of ascitic fluid through the drainage tubes; it is administered in the following circumstances: albumin < 2.5 g/dL, pulmonary capillary pressure < 12 mmHg, haematocrit > 30% (Grade of recommendation: 1C)13,32,33,47.

There is not definitive evidence that albumin and/or non-protein colloids are effective during or after kidney transplants32,33.

Therapeutic plasmapheresis (appropriate indication)

The use of albumin is appropriate only for the exchange of large volumes of plasma: more than 20 mL/kg in a single session or 20 mL/kg/week in successive sessions. In the case of exchange of small volumes of plasma, it is worth considering, for cost-benefit reasons, crystalloid solutions or the association of albumin/crystalloids (Grade of recommendation: 2C+)32,33,48–50.

Chronic states of low albuminaemia

Liver cirrhosis with refractory ascites

There is a lack of consensus on the use of albumin in advanced liver disease, but there is some evidence to support its use in the following circumstances: 1) ascites not responsive to diuretics; 2) large volume paracentesis; 3) hepatorenal syndrome; 4) spontaneous bacterial peritonitis.

Ascites not responsive to diuretics (occasionally appropriate indication)

This is the most controversial indication. Albumin is usually ineffective, except in patients with serum albumin < 2 g/dL. Subjects with ascites are at risk of diuretic-induced hyponatraemia and deteriorating renal function (prerenal uraemia); the risk is highest in subjects with hypoalbuminaemia and advanced disease. Albumin can improve the response to diuretics and prevent complications related to the treatment, favouring the passage of fluid from the peritoneal space to the vascular compartment; it can also correct the altered pharmacokinetics of loop diuretics typically seen in patients with cirrhosis. The patients who can gain most benefit from this treatment are those in the most precarious clinical condition, with hypovolaemia and ascites that responds poorly to diuretics: in these cases albumin can be administered even when the concentration of albumin is > 2.5 g/dL (Grade of recommendation: 2C)51–59.

Large volume paracentesis (appropriate indication)

Total paracentesis is considered the treatment of choice in subjects with refractory or tense ascites. A paracentesis volume > 5L can, in some cases, lead to hypovolaemia and particularly unfavourable haemodynamic changes, with the possible risk of:

  • - deterioration of renal function;

  • - dilutional hyponatraemia;

  • - rapidly recurrent ascites;

  • - shortened survival.

In order to reduce the risks in such cases, albumin is used at a dose of 5 g/L of fluid removed, in a single administration at the end of the paracentesis. The 20% – 25% preparations are preferable (Grade of recommendation: 1C+)32,33,55,60–64.

Hepatorenal syndrome (HRS) (occasionally appropriate indication)

HRS consists of a deterioration in renal function, which occurs in 10% of subjects with advanced cirrhosis and ascites65. It is considered the extreme outcome of the haemodynamic dysfunction of cirrhosis, associated with impaired cardiac function due to the reduced venous return.

The deterioration in renal function can be rapidly progressive (type 1 HRS) or stable-slowly progressive (type 2 HRS); the mortality rate of patients with type 1 HRS is very high, with a median survival (without therapy) of less than 1 month.

The treatment of choice is liver transplantation. Medical treatment consists of a combination of vascoconstrictors and high doses of albumin (Grade of recommendation: 2B)32,33,65–68.

Spontaneous bacterial peritonitis (appropriate indication)

Spontaneous bacterial peritonitis is a common and severe complication of ascitic cirrhosis and occurs in about 20 – 30% of patients; it is characterised by spontaneous infection of the ascitic fluid, in the absence of abdominal sources of infection, and can evolve, in about 30% of the cases, into HRS.

Albumin 20% – 25%, in association with antibiotics, can be used in the treatment of spontaneous bacterial peritonitis and reduces the probability of the onset of HRS and mortality (Grade of recommendation: 1C+)69–74.

Nephrotic syndrome (occasionally appropriate indication)

Short-term infusion of albumin 20% – 25%, in association with diuretics, is appropriate in patients with serum albumin < 2 g/dL, with marked hypovolaemia and/or acute pulmonary oedema and/or acute renal failure (Grade of recommendation: 2C)32,33,75–77.

Malnutrition syndromes (occasionally appropriate indication)

Albumin must not be used for nutritional purposes; the correct treatment is enteral nutrition, using peptide-based formulas, or total parenteral nutrition.

However, the administration of albumin can be useful in patients with diarrhoea who cannot tolerate enteral nutrition in the following circumstances: volume of diarrhoea > 2 L/die; serum albumin < 2 g/dL; continuing diarrhoea despite the administration of short-chain peptides and mineral formulas; no other cause to explain the diarrhoea (Grade of recommendation: 2C)32,33.

Inappropriate indications

Albumin is not indicated in the following conditions (table II)32,33:

Table II.

Inappropriate indications for the use of albumin.

1) Albuminaemia > 2.5 g/dL
2) Chronic hypoalbuminaemia in the absence of oedema and/or acute hypotension
3) Malnutrition
4) Wound healing
5) Non-haemorrhagic shock
6) Ascites responsive to diuretics
7) Burns, in the first 24 h
8) Protein losing enteropathies and malabsorption
9) Acute or chronic pancreatitis
10) Haemodialysis
11) Cerebral ischaemia
12) Acute normovolaemic haemodilution in surgery
13) Ovarian hyperstimulation syndrome
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  • - albuminaemia > 2.5 g/dL (with the exception of the particular cases listed above);

  • - hypoalbuminaemia in the absence of oedema and acute hypotension;

  • - malnutrition;

  • - wound healing;

  • - non-haemorrhagic shock78,79;

  • - ascites responsive to diuretics;

  • - burns in the first 24 hours;

  • - protein-losing enteropathies and malabsorption;

  • - acute or chronic pancreatitis;

  • - haemodialysis80–83;

  • - cerebral ischaemia84;

  • - acute normovolaemic haemodilution in surgery;

  • - ovarian hyperstimulation syndrome85–87.

Calculation of the dose of albumin to administer

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Legend:

2.5 g/dL: desired concentration of albumin; kg: body weight; 0.8: coefficent to calculate the volume of plasma.

Monitoring indices for clinical auditing

The use of albumin therapy in the following circumstances:

  • - albuminaemia > 2.5 g/dL;

  • - malnutrition;

  • - non-haemorrhagic shock;

  • - ascites responsive to diuretics;

  • - acute or chronic pancreatitis;

Side effects and adverse reactions

Albumin is usually well tolerated. However, immediate allergic-type reactions are possible with fever, shivers, nausea, vomiting, urticaria, hypotension, increased salivation, and effects on respiration and heart rate32,33,88. Very fast infusions (20 – 50 mL/minute) can cause a brusque fall in systemic blood pressure and, in elderly subjects and those at risk of congestive heart failure, it can induce manifest congestive heart failure, particularly when the more concentrated solutions of albumin are used. Albumin is considered a safe blood derivative from the point of view of transmission of infections, although there are some questions about the potential transmission of prions.

Recommendations

It is recommended that the details of the product infused, including the batch number, are registered in the patient's clinical records.

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Blood Transfusion. 2009 Jul;7(3):223–232. doi: 10.2450/2009.0094-09

Immunoglobulins

Introduction

Immunoglobulins (IG) are registered for a limited number of indications1, but are used much more extensively in clinical practice. Many of the uses do not always appear fully justified by the data in the literature.

Intravenous immunoglobulins (IVIG) are used as replacement therapy in immunodeficiency states and in the treatment of autoimmune diseases and systemic inflammatory disorders.

In Italy preparations of soluble IG have been available for subcutaneous infusion since 2007.

Notions of pharmacokinetics

Following intravenous administration, normal human IG are immediately and completely bioavailable: the peak serum level is dose-related. The IG distribute relatively quickly between the plasma and extravascular fluids; the equilibrium between the intravascular and extravascular compartments is reached after approximately 3–5 days2,3. The initial decrease in serum levels is the result not only of the extravascular redistribution, but also of other factors, including metabolism of denatured molecules and clearance of immune complexes that may have formed after an interaction with an antigen. The half-life of IG is estimated to be about 18–32 days, which is similar to that of endogenous IgG. There is, however, a considerable individual variability that reflects various factors, including the level of IG before the infusion, the peak level after the infusion and the presence of infections or burns.

Preparations of immunoglobulins

IVIG, like all other plasma derivatives, are prepared using pools of human plasma; this leads to significant idiotypic diversity, which guarantees the recipient a greater antibody cover. The preparations of IVIG contain structurally and functionally intact immunoglobulins, with a normal half-life and proportion of the subclasses: 95% of monomeric IgG, small quantities of dimers, variable quantities of IgA and IgM2,4–10. They do not contain high molecular weight immune complexes or contaminants such as vasomotor peptides and endotoxins.

They are prepared from plasma from healthy donors and, furthermore, undergo industrial processing4,5,10, chemical and physical removal and inactivation of bacteria and viruses.

Mechanism of action

In humoural immunodeficiencies, the IG are administered intravenously to replace those that are lacking because of a deficiency in their production.

Numerous studies have shown that IVIG also have powerful immunomodulatory and anti-inflammatory effects, although the in vivo mechanisms of these effects are partly unknown. Various mechanisms have been proposed over time to explain the effects of IVIG in disorders of immune system regulation2,7,11–25:

  • - interaction of the Fc fragment with specific receptors (FcγR)2,7,17,19,25;

  • - control of the complement pathway and activation of mechanisms inducing solubilisation of circulating immune complexes2,7,15,18,25;

  • - interaction with the idiotype anti-idiotype network2,7,17,18,23,25;

  • - modulation of the production of some cytokines and their antagonists2,7,13,17,18,25;

  • - increased catabolism of IgG2,7,17;

  • - apoptosis of B and T cells through activation of the Fas receptor (apoptosis stimulating fragment -CD95)7,14,25;

  • - blockage of the binding between T cells and superantigens2,7,11,25;

  • - control of autoreactivity and induction of tolerance to self2,7,18,25;

  • - inhibition of the differentiation and maturation of dendritic cells2,24,25.

Indications

Table I, drawn from the Gazzetta Ufficiale N. 260 of 6/11/20021, provides a summary of the indications and doses recommended for the diseases that are listed1,2,7,18,23,25–69. Table II, on the other hand, presents the clinical conditions for which the routine use of IVIG is not recommended, despite their being reports of the use of this product; the low levels of evidence are due to the lack of studies in sufficiently large series of patients, in turn a consequence of the rarity of the diseases2,7,18,25,35,36,44,45,51–58,64,70–96.

Table I.

Recognised indications for IVIG (Gazzetta Ufficiale of 06/11/2002, N. 260)1

Indication Dose Frequency of administration
Immunodeficiencies
Primary immunodeficiency7,18,26–36,46,47 initial dose: 0.4–0.8 g/kg every 2–4 weeks to obtain an IgG level of at least 4–6 g/L
maintenance: 0.2–0.8 g/kg
Secondary immunodeficiency7,18,26,29,31–45 0.2–0.4 g/kg every 3–4 weeks to obtain an IgG level of at least 4–6 g/L
Children with AIDS7,18,33–36,39 0.2–0.4 g/kg every 3–4 weeks
Immunomodulation
ITP or Werlhof’s syndrome7,18,25,35,36,44,45,48–50 0.8–1.0 g/kg on day 1, possibly repeated a single time within 3 days
or 0.4 g/kg/die for 2–5 days
Guillain-Barré syndrome2,7,18,23,25,35,42–44,46,47,51–64 0.4 g/kg/die for 3–7 days
Kawasaki’s disease7,18,25,26,35,36,65–69 1.6–2 g/kg in several doses over 2–5 days in association with ASA
or 2 g/kg in a single dose in association with ASA
Allogeneic bone marrow transplantation
Treatment and prophylaxis of infections and GvHD7,18,25,35,36,44,45 0.5 g/kg every week from day –7 until 3 months after the transplant
Persistent deficit of the production of antibodies7,35,36,44,45 0.5 g/kg every month until normalisation of the levels of antibodies
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Table II.

Clinical conditions for which the routine use of IVIG is not recommended, although their use has been reported

Clinical conditions Indications and dose GoR
Haematology
Alloimmune neonatal thrombocytopenia7,35,36,44,45,71,73,75 IVIG are recommended in symptomatic neonates, at high risk of intracranial bleeding, if other strategies have been unsuccessful, not tolerated or contraindicated. 2C
IVIG can be used prior to delivery in high-risk mothers, with a history of alloimmune neonatal thrombocytopenia and foetal or neonatal thrombocytopenia. 1g/kg per week (to the mother).
Autoimmune haemolytic anaemia (AEA)7,25,35,36,44,45,70 IVIG can play a role in patients with AEA due to warm antibodies (Ab) not responsive to corticosteroids or splenectomy, or in those in whom the abovementioned treatments are contraindicated. 2C
0.4 g/kg/die for 5 days.
Haemolytic disease of the newborn (HDN)7,36,44,45,71,72 IVIG are recommended in neonates with severe HDN (0.5–1g/kg/die for three doses), if other therapeutic strategies are not feasible. The IVIG may be given to the mother before delivery if other strategies have been unsuccessful, not tolerated or contraindicated. 2C
Immune-mediated neutropenia7,44,45 IVIG may have a role in patients in whom other strategies have been unsuccessful, not tolerated or contraindicated. 2C
Post-transfusion purpura7,36,44,45,73,74 IVIG may be considered in severely affected patients. 2C
Pure red cell aplasia44,45,96 IVIG can be used in patients with documented Parvovirus B19 infection and severe anaemia. 2C
0.4 g/kg every 28 days.
Refractoriness to platelet transfusion7,73 IVIG may have a role in patients in whom other strategies have been unsuccessful, not tolerated or contraindicated. 2C
Infectious diseases
CMV prophylaxis in solid organ transplants7,18 IVIG can be used in CMV-negative recipients of CMV-positive organs. 2C+
0.4 g/kg every 28 days.
Neurology
Acute disseminated encephalomyelitis44,64 IVIG can be considered if first-line therapy (high-dose steroids) is ineffective or contraindicated. 2B
2g/kg in 2 days for children or in 2–5 days for adults.
Chronic inflammatory demyelinating polyneuropathy2,7,18,25,35,36,44,51–58,64,79–84 IVIG are recommended as an equivalent choice to therapeutic plasmapheresis in the acute phase in children and adults. 1A
Their use in chronic treatment is currently suggested only from observational studies. 2C
0.4 g/kg/die for 5 days
Intractable childhood epilepsy44,51,64 IVIG can play a role in some syndromes (e.g. West,Lennox-Gastaut) as a last strategy, particularly in patients who could be candidates for surgical resection. 2C
Lambert-Eaton syndrome2,36,44,51,52,55,56,64,86 IVIG can be considered in patients with a severe syndrome, if other strategies have been unsuccessful, not tolerated or contraindicated. 0.4 g/kg/die for 5 days. 2C+
Multifocal motor neuropathy2,7,18,25,36,44, 51–58,64,77,78 IVIG can be considered in patients who have a progressive and symptomatic multifocal neuropathy, diagnosed on the basis of electrophysiological findings that exclude other possible conditions that do not respond to this treatment. 0.4 g/kg/die for 5 days. 2C+
Multiple sclerosis2,7,18,25,35,44,51–53,55,64,85 IVIG can be considered in patients with moderate or severe manifestations of multiple sclerosis in recurrence-remission, in whom other strategies have been unsuccessful, not tolerated or contraindicated. 2C
Myasthenia gravis2,7,35,44,51–53,55,56,64,76 IVIG can be considered in patients with myasthenic crises (0.4 g/kg/die for 5 days or 2g/kg for 2 days). 2C+
Maintenance treatment is still experimental.
Stiff-person syndrome2,7,18,25,36,44,52,55,56, 64,87,88 IVIG were found to be effective in one randomised clinical study (14 patients); they may have a role if GABA-ergic drugs have been ineffective or contra-indicated. 2B
2 g/kg/month.
Rheumatology
Dermatomyosites, Polymyosites2,7,18,25, 36,44,51–53,55,56,64,89 IVIG can be used in patients with active, severe disease in whom other strategies have been unsuccessful, not tolerated or contraindicated. 0.4 g/kg/die for 5 days. 2C+
Systemic lupus erythematosus (SLE)7,25,53 IVIG can be used in patients with active, severe SLE in whom other strategies have been unsuccessful, not tolerated or contraindicated. 2C+
Systemic vasculitides7,36 IVIG can be used in patients with active, severe disease, particularly in those with ANCA-positive vasculitis or other systemic vasculitis, in whom other strategies have been unsuccessful, not tolerated or contraindicated. 2C+
Renal transplantation
Pre-transplant desensitisation7,35,90–95 IVIG can be used (also together with plasmapheresis) in patients with high pre-transplant levels of anti-HLA Ab as a desensitising strategy. 2B
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GoR: Grade of Recommendation

Finally, table III lists the inappropriate indications2,7,22,26,36,40,44,45,51,52,54,56,64,71,97–106.

Table III.

Inappropriate indications for the use of IVIG

Clinical conditions GoR
Haematology
Acquired inhibitors of FVIII44,45 2C
Acquired von Willebrand’s disease44,45 2C
Aplastic anaemia44,45 2C
Diamond-Blackfan anaemia22,26 2C
TTP and uraemic-haemolytic syndrome44,45 2C
Infectious diseases
Burns (prophylaxis from infections)22,26 2C
HIV infection (adult)22,26 2C
Surgery and/or trauma (prophylaxis)7 1A
Rheumatology
Inclusion body myositis2,22,26 1A
Rheumatoid arthritis (juvenile and adult)7,105 1A
Miscellaneous
Acute cardiomyopathy22,26,99 2C
Acute idiopathic dysautonomia22,26 2C
Acute lymphoblastic leukaemia22,26 1A
Acute renal failure22,26 1A
Adrenoleucodystrophy44,64 2C
Amyotrophic lateral sclerosis44,51,64 2C
Autism7,44,64 2C
Autoimmune bullous dermatoses22,26,36 2C
Autoimmune childhood neuropsychiatric disorders associated with streptococcal infections44,64 2C
Behçet's disease22,26 2C
Bronchial asthma7,98 1A
Chronic fatigue syndrome22,26 2C
Congenital cardiac arrest22,26 1A
Cystic fibrosis22,26 1A
Diabetes mellitus7 2C
Diabetic neuropathy44,64 2C
Endotoxaemia22,26 2C
Euthyroid ophthalmopathy22,26 2C
Haemolytic transfusion reaction44,45 2C
Haemophagocytic syndrome22,26 2C
HTLV-1-associated myelopathy22,26 2C
Inclusion body myositis44,56,64 2C
Inflammatory bowel diseases (Crohn’s disease, ulcerative colitis)7 2C
Lower motor neurone syndrome22,26 2C
Lyell’s syndrome7,102 2C
Lyme radiculoneuritis22,26 2C
Nephritic syndrome22,26 2C
Nephrotic syndrome22,26 1A
Non-immunological thrombocytopenia22,26,44,45 2C
Opsoclonus-myoclonus44,64 2C
Paraneoplastic cerebellar degeneration22,26,51 2C
Paraproteinaemic neuropathy44,51,52,56,64,101 2C
Parvovirus infection (in general)22,26 2C
POEMS syndrome (polyneuropathy, organomegaly endocrinopathy, protein M, skin alterations)22,26,44,51,64 2C
Polyneuropathy in the critically ill patient44,64 2C
Progressive lumbo-sacral plexopathy22,26 2C
Rasmussen’s syndrome22,26,44,51 2C
Recurrent abortions7,71,97 1A
Recurrent otitis media22,26 2C
Reiter’s syndrome22,26 2C
Streptococcal septic shock22,26,40 2C
Uveitis22,26 2C
Viral myocarditis (presumed)100 2C+
Vogt-Koyanagi-Harada syndrome22,26 2C
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GoR: Grade of Recommendation

Replacement therapy

The use of IVIG for the treatment of patients with primary or secondary antibody deficiencies was authorised in the USA in 1981, since when it has been possible to exploit this product, by then purified of the high molecular weight aggregates responsible for severe reactions, using the Cohn-Oncley separation technique4.

Compared to the previous treatment based on intramuscular IG, the use of IVIG enabled higher doses of IG to be administered, thus permitting normalisation of blood levels. The aim of treatment is to maintain serum levels (before the next infusion) of IgG > 5 g/dL; the clinical condition of the patient must, of course, always be evaluated33.

Reaching these levels leads to the patient having fewer febrile episodes and, in general, reductions in the number of recurrent infections, days spent in hospital and time on antibiotic treatment, an improvement in indices of respiratory function and, in paediatric patients, an increase in body weight, which is an indicator of an improved quality of life.

Primary deficiencies

  • - Humoural immunodeficiencies22,26:
    1. X-linked agammaglobulinaemia;
    2. common variable immunodeficiency;
    3. immunodeficiency with hyper-IgM;
    4. transient childhood hypogammaglobulinaemia (sometimes);
    5. deficiencies of IgG subclasses (sometimes with or without IgA deficiencies).
  • - Combined immunodeficiencies22,26:
    1. all types of severe combined immunodeficiencies;
    2. Wiskott-Aldrich syndrome;
    3. ataxia-telangiectasia;
    4. short-limbed dwarfism;
    5. X-linked lymphoproliferative disease.

Treatment with IVIG is indicated if the level of IgG is below 5 g/L. It takes 3 to 6 months after the start of treatment for a balance to be reached. The recommended starting dose is 0.4–0.8 g/kg of body weight; this should be followed by 0.2–0.8 g/kg every 2–4 weeks, in order to achieve minimum IgG levels > 5 g/dL (Grade of recommendation: 1A)1,7,18,26–36.

Secondary deficiencies

  1. In lymphoproliferative diseases with antibody deficits (multiple myeloma, chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma) the use of IVIG, to maintain plasma IG levels > 4–6 g/L, is indicated for patients with a documented deficiency in antibodies and recurrent infections; the dose is 0.2–0.4 g/kg every 4 weeks (Grade of recommendation: 1A)1,7,18,26,29,31–45.

  2. Acquired immunodeficiency syndrome in childhood: IVIG can be used in HIV-positive children with hypogammaglobulinaemia to prevent opportunistic infections, in cases of recurrent bacterial infections and/or ineffective antibiotic and antiretroviral therapy; the dose is 0.2–0.4 g/kg every 4 weeks (Grade of recommendation: 2C+)7,18,33–36,39,46,47.

  3. Allogeneic bone marrow transplantation: IVIG can be used in the treatment of infections and the prophylaxis of GvHD, at the dose of 0.5 g/kg every week from 7 days before the transplant until 3 months after it. In the case of a persistent deficit in antibody production, the dose is 0.5 g/kg every 4 weeks until the levels of IgG normalise (Grade of recommendation: 2C)1,7,18,25,35,36,44,45.

  4. Prematurity: prophylaxis with IVIG may play a role in the management of low birth weight neonates (< 1,500 g) or in those with severe infections; the dose is 0.4–0.7 g/kg in 1–7 administrations22,26.

Immunomodulation

For some years IVIG have also been used in immunomodulatin therapy. High doses of IVIG have immunosuppressive and anti-inflammatory effects and have, therefore, been used in the treatment of autoimmune and/or inflammatory diseases, as well as in haematological, rheumatological and neurological conditions.

The only indications for which there is recognised to be high levels of evidence are: ITP, Kawasaki’s disease and Guillan-Barré syndrome.

  • e) In ITP, IVIG are, in any case, used after other pharmacological treatments have failed; the exceptions to this are acute episodes associated with bleeding or cases in which surgery is considered necessary; in these situations the recommended dose is 0.8–1 g/kg on the first day, which can be repeated within 3 days, or 0.4 g/kg/die for 2–5 days (Grade of recommendation: 1A)7,18,25,35,36,44,45,48–50.

  • f) The recommended dose in Kawasaki’s disease is 1.6–2 g/kg, in divided administrations over 2–5 days or 2 g/kg in a single administration; this latter method of administration has been shown to be more effective in preventing aneurysmal complications of the coronary arteries. Concomitant treatment with acetylsalicylic acid (ASA) is recommended (Grade of recommendation: 1A)7,18,25,26,35,36,65–69.

  • g) The dose in Guillain-Barré syndrome is 0.4 g/kg/die for 3–7 days (Grade of recommendation: 1A)2,7,18,23,25,35,42–44,51–64.

IVIG are used in numerous other conditions; nevertheless, their routine use is not recommended and they should be employed only in particular situations or as an alternative to other therapeutic measures. Table II lists the diseases for which the use of IVIG has been suggested based on their mechanism of action, results of uncontrolled, single clinical trials or authoritative opinion drawn from clinical experience, descriptive studies or single case reports.

Monitoring indices for clinical auditing

Administration of IVIG treatment in the following conditions:

  • - replacement therapy when IG > 6 g/L;

  • - immunomodulation in diseases for which there are not recognised indications.

Side effects and adverse reactions

Side effects of variable severity occur in 1–15% of treated patients, but are usually of limited clinical importance. They include headache, shivers, hyperthermia, fever, allergic reactions, nausea, vomiting, joint pains, and hypotension to the point of anaphylactic shock, even in patients who have not shown signs of hypersensitivity to previous administrations2,5,7,107. Although the aetiology remains uncertain, it seems that aggregates of IgG, IgG-dimers and activation of the complement pathway may be involved. The aggregates are able to activate complement even in the absence of the antigen7.

Patients with an antibody deficiency more frequently have reactions, including anaphylactic ones; slow infusion seems to lower the risks. Most of these reactions resolve with temporary interruption of the infusion or a slowing of its rate of administration, or can be prevented by giving ASA, paracetamol or anti-histamines before the treatment and/or hydrocortisone during it107. Severe anaphylactic reactions have occurred in patients with IgA deficiency. Although the content of IgA in IVIG preparations is modest and, in any case, varies between products, small amounts can cause fatal reactions, especially in patients with anti-IgA immunoglobulin E2,7.

Thromboembolic events have been reported, particularly in elderly patients, in patients with previous cerebral or cardiac ischaemia, in overweight patients, those who are markedly hypovolaemic and in immobilised subjects108–110.

Rare cases of reversible aseptic meningitis have also been observed in patients with neurological and neuromuscular diseases treated with high doses of IVIG111. The symptoms appear within 6–24 hours of the end of the infusion and disappear without sequelae in 3–5 days.

Increases in creatinine and/or renal failure, particularly acute, have been observed rarely in elderly, diabetic, poorly hydrated patients, with pre-existing renal disease or who are taking nephrotoxic drugs. These problems are probably related to damage caused to the renal tubules by the saccharose included in various preparations as a stabiliser112,113.

As far as concerns the possibility of transmitting infectious agents with these plasma-derivatives, there is a potential risk of transmission of spongiform encephalopathies (Creutzfeld-Jacob disease, Gerstmann Straussler-Scheinker disease and fatal familial insomnia), since the prions responsible for these diseases are resistant to standard methods of inactivation. Furthermore, solvent/detergent inactivation is ineffective against viruses that do not have a lipid envelope, such as HAV and parvovirus B19114.

Precautions and recommendations

It is recommended that the details of the product infused, including the batch number, are recorded in the clinical records.

Side effects can be partly prevented by injecting the product slowly at the beginning and monitoring the patient for the appearance of any symptoms. Monitoring should be particularly careful for patients who have never received IVIG, those being given a different preparation from a previous one and when a long period has passed between one infusion and another; in such cases the patients should monitored during the infusion and for the first hour after its completion. All other patients should be observed for at least 20 minutes after the product has been administered.

All patients must be well hydrated prior to the infusion and production of urine and levels of serum creatinine should be monitored. Furthermore, it should be ascertained whether the patient has diabetes or pre-existing renal failure, is taking loop diuretics or nephrotoxic drugs; in these patients preparations containing saccharose, used as a stabiliser, should be avoided.

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