Conditions: R-T

Rasmussen syndrome is a chronic, progressive, focal encephalitis that is commonly accompanied by focal seizures, hemiparesis and cognitive decline. It is generally considered to be a disease of childhood, with most cases occurring in children younger than 10 years, although adult onset cases do occur. Conventional anticonvulsant therapy is usually ineffective and hemispherectomy may be helpful in the correct setting.

Immunomodulatory therapy may be useful and, of the different therapies, IVIg may be most useful. Other therapies to consider include methylprednisolone and rituximab.

Ongoing supply of IVIg would be based on evidence of stabilisation of either seizure frequency or cognitive decline.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Evidence of probable benefit (Category 2a).

IVIg may be indicated in select cases not responding to steroids, or when steroids and other alternative treatments (e.g. thalidomide) are contraindicated.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Small case studies only - Insufficient data (Category 4a).

Replacement therapy for life-threatening infection due to hypogammaglobulinaemia related to other diseases or medical therapy.

The following secondary causes of hypogammaglobulinaemia are considered elsewhere:

1. Acquired hypogammaglobulinaemia secondary to haematological malignancies or stem cell transplantation
2. HIV in children
3. Solid organ transplantation

No included studies (Category 4b).

Recurrent and/or severe bacterial infections may arise from hypogammaglobulinaemia of diverse causes.

Hypogammaglobulinaemia may arise from protein losing states, malnutrition and medical immunosuppression. In most cases, successful management of the underlying condition will reverse the immunodeficiency, restoring immunocompetence. In some cases, recurrent or severe infection may arise from secondary immunodeficiency where the underlying cause cannot be reversed, or where there are unwanted effects of removing or reducing immunosuppressive therapy. New immunosuppressive regimens such as monoclonal B-cell depletion with rituximab or similar agents do not generally induce hypogammaglobulinaemia at standard doses.

However, repeated cycles of B-cell depletion in combination with other agents used to treat life-threatening immune- mediated diseases may increase rates of infection related to hypogammaglobulinaemia.

Hypogammaglobulinaemia secondary to underlying disease or medical therapy (including haemopoietic stem cell transplantation [HCST]) with all the following:

1. Serum IgG less than the lower limit of the reference range on two separate occasions;

AND

2. Underlying cause of hypogammaglobulinaemia cannot be reversed or reversal is contraindicated;

AND

3. At least one of the following:
   1. One invasive or life-threatening bacterial infection (e.g. pneumonia, meningitis, sepsis) in the previous year; or
   2. Clinically active bronchiectasis confirmed by radiology.

Reversible underlying cause of hypogammaglobulinaemia.

The following conditions should not be approved under this indication:

1. Acquired hypogammaglobulinaemia secondary to haematological malignancies or stem cell transplantation
2. HIV in children
3. Transplantation related immunomodulation (solid organ transplantation).

Six-monthly review to assess clinical benefit.

Cessation of IVIg should be considered, at least after each 12 months of therapy, extended as required to enable cessation of therapy in September/October, with repeat clinical and/or immunological evaluation before re- commencement of therapy.

Written confirmation from the treating physician that:

• an annual review has been undertaken;
• the patient had demonstrated clinical benefit;
• a trial period of cessation of IVIg for the purpose of immunological evaluation is medically contraindicated on safety grounds.

In principle, IVIg should be continued or renewed only if there is a demonstrated clinical benefit.

Maintenance dose: 0.4 g/kg every four weeks, modified to achieve IgG trough level of at least the lower limit of the age-specific serum IgG reference range.

Loading dose: One additional dose of 0.4 g/kg in the first month of therapy is permitted if the serum IgG level is markedly reduced.

Chronic suppurative lung disease: Dosing to achieve IgG trough level of up to 9 g/L is permitted if chronic suppurative lung disease is not adequately controlled at an IgG trough level at the lower limit of the age-specific serum IgG reference range.

Subcutaneous administration of immunoglobulins is a suitable alternative to IVIg in this disease.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

IVIg may be indicated in certain highly selected cases where other treatments have not been effective.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Small case studies only - Insufficient data (Category 4a).

IVIg may be indicated in:

• highly sensitised patients awaiting transplantation;
• transplant recipients with acute antibody-mediated rejection with clinical evidence of graft dysfunction; and
• transplant recipients as treatment or prophylaxis for rejection where conventional immunosuppressive therapy is contraindicated; for example, in a patient with life-threatening infection in whom conventional immunosuppression will place the patient at greater risk, or when the transplant is at risk.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Small case studies only - Insufficient data (Category 4a).

Prevention of infections in individuals with frequent infections who have demonstrated failure to mount protective IgG antibody responses to vaccine antigen challenge despite normal total serum IgG levels.

Small case studies only; insufficient data (Category 4a).

The term 'specific antibody deficiency' describes failure of specific antibody response to an antigen challenge, and is most often used in the more restrictive sense of applying to polysaccharide antibody responses only.

Patients who have normal total IgG levels but impaired production of specific antibodies, including those with isolated deficient responses to numerous polysaccharide antigens after vaccination, can present a diagnostic challenge. IgG replacement therapy should be provided when there is well-documented severe polysaccharide non-responsiveness and evidence of recurrent infections with a documented requirement for antibiotic therapy and ongoing recurrent infections despite antibiotic prophylaxis (Orange et al. J Allergy Clin Immunol, 2006; 117: S525-53).

It is now generally agreed that IgG subclass level estimation in serum is relatively poorly predictive of infectious risk and is of limited value in the definition of those patients most likely to benefit from IVIg therapy.

Further research investigating clinical and laboratory features of this disorder is required.

To access IVIg for a period of 12 months, the following qualifying criteria must be met:

1. A clinical immunologist must be consulted to confirm the diagnosis;

AND

2. Frequent bacterial infections despite oral antibiotic therapy consistent with best practice recommendations;

AND

3. Documented failure of serum antibody response to unconjugated pneumococcal or protein vaccine challenge.

1. Isolated IgG subclass deficiency in the absence of evidence of specific antibody deficiency.
2. Low total IgG. This should be considered under primary or secondary immunodeficiency.

Natural history of specific antibody deficiency remains poorly defined, although antibody production will improve for many patients over time, particularly children.

To be eligible to receive IVIg for a further 12 months, the following is required:

Written confirmation from the treating clinical immunologist that:

• an annual review has been undertaken;
• the patient had demonstrated clinical benefit;
• a trial period of cessation of IVIg for the purpose of immunological evaluation is medically contraindicated on safety grounds.

Cessation of IVIg should be considered, at least after each 12 months of therapy extended as required to enable cessation of therapy in September/October.

This should particularly be considered in patients who do not have suppurative lung disease or bronchiectasis. An immunoglobulin washout period of four to six months is necessary to enable an accurate assessment. Prophylactic antibiotics may be considered to cover the period of IVIg cessation. Patients may qualify for further IVIg therapy:

• under other immunodeficiency criteria (e.g. common variable immunodeficiency [CVID]) depending on the results of subsequent immune evaluation; or
• rarely under specific antibody deficiency following re-emergence of severe significant infection requiring hospitalisation.

In principle, IVIg should only be continued or renewed if there is a demonstrated clinical benefit.

Note that re-vaccination with pneumococcal polysaccharide vaccine is not recommended because of safety concerns, and the potential for specific hyporesponsiveness induced by repeated vaccination (O’Brien et al. Lancet Infect Dis 2007; 7: 597-606).

IgG subclass deficiency

1. New patients
   IVIg is not funded for new patients diagnosed with IgG subclass deficiency.
2. Patients who were receiving IVIg for IgG subclass deficiency before initial publication of the Criteria (December 2007)

Without clinically active bronchiectasis or suppurative lung disease:

3. These patients should have ceased IVIg and had their immunological status re-evaluated. Patients with a confirmed IgG deficiency have become eligible under another indication (e.g. primary immunodeficiency with antibody deficiency). Patients without a confirmed IgG deficiency have ceased IVIg therapy. Patients who were receiving IVIg for IgG subclass deficiency before initial publication of the Criteria (December 2007)

Without clinically active bronchiectasis or suppurative lung disease:

• These patients should have ceased IVIg and had their immunological status re-evaluated. Patients with a confirmed IgG deficiency have become eligible under another indication (e.g. primary immunodeficiency with antibody deficiency). Patients without a confirmed IgG deficiency have ceased IVIg therapy.

With clinically active bronchiectasis or suppurative lung disease over the previous 12 months: To be eligible to receive IVIg for a further 12 months, the following is required:

1. Written confirmation from the treating clinical immunologist that:
   • an annual review has been undertaken;
   • the patient has demonstrated clinical benefit; and
   • a trial period of cessation of IVIg for the purpose of immunological evaluation is medically contraindicated on safety grounds.

AND

Written confirmation by a second physician that cessation of IVIg for the purpose of immunological evaluation is medically contraindicated on safety grounds. Cessation of IVIg should be considered, at least after each 12 months of therapy extended as required to enable cessation of therapy in September/October.

Note: The above criteria for initial and ongoing access to IVIg funded by all governments under the National Blood Arrangements will be reviewed in light of emerging evidence at the next review of the Criteria.

Maintenance dose: 0.4 g/kg every 4 weeks.

Loading dose: not approved.

Subcutaneous administration of immunoglobulins (SCIg) is a suitable alternative to IVIg in this setting.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Treatment of significant functional impairment in patients who have a verified diagnoses of stiff person syndrome.

Evidence of probable benefit (Category 2a).

Patients with stiff person syndrome present with symptoms related to muscular rigidity and superimposed episodic spasms. The rigidity insidiously spreads involving axial muscles, primarily abdominal and thoracolumbar, as well as proximal limb muscles. Typically, co-contraction of truncal agonist and antagonistic muscles leads to a board-like appearance with hyperlordosis. Less frequently, respiratory muscle involvement leads to breathing difficulty and facial muscle involvement to a mask-like face.

Investigations that may be useful for diagnosis include auto-antibodies to GAD-65 or GAD-67, EMg recordings from stiff muscles that may show continuous discharges of motor unit, and CSF oligoclonal bands.

Significant functional impairment in patients who have a verified diagnosis of stiff person syndrome made by a neurologist.

Review

Regular review by a neurologist is required; frequency as determined by clinical status of patient.

For stable patients on maintenance treatment, review by a neurologist is required at least annually.

Effectiveness

Objective indicators of relief of symptoms of stiffness, including:

• improvement or stabilisation of activities of daily living (ADL) scores;
• other specialised scoring systems, such as distribution- of-stiffness index and heightened sensitivity scale.

Induction: 2 g/kg in 2 to 5 divided doses.

Maintenance: 1–2 g/kg, 4–6 weekly.

Aim for the minimum dose to maintain optimal functional status.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Susac syndrome is a rare, microangiopathic disorder characterised by encephalopathy, hearing loss and retinal artery branch occlusions. Case reports show benefit of IVIg therapy in combination with corticosteroids, with or without other immunosuppressive agents.

Dose: 1–2 g/kg/month for one year providing documented clinical improvement.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Note: Effectiveness of IVIg therapy may be difficult to determine due to the fluctuating course of disease.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Small case studies only - Insufficient data (Category 4a).

Systemic capillary leak syndrome is an extremely rare condition that is characterised by life-threatening attacks of reversible capillary hyperpermeability accompanied by haemoconcentration and hypoalbuminaemia.

A diagnosis by a consultant physician, emergency specialist or intensive care unit specialist is required.

Other therapies may be appropriate.

Approval will be provided for an initial period of 12 months only.

Clinicians requesting ongoing IVIg therapy after the initial 12 month period are required to confirm in writing that the patient experienced a reduced number of severe episodes requiring hospital admission when treated with IVIg.

Maximum dose of 1–2 g/kg per month.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Small case studies only - Insufficient data (Category 4a)

To limit the progression of TEN or SJS/TEN when administered in early stages.

Small case studies only; insufficient data (Category 4a).

TEN is a rare, life-threatening hypersensitivity reaction to certain medications, such as sulphonamides, antibiotics, non-steroidal anti-inflammatory drugs and anti-convulsants. Drug-induced epidermal apoptosis has been proposed as possible pathogenesis. SJS is a less extensive manifestation of the same phenomenon.

TEN and SJS are characterised by severe bullous reaction with extensive destruction of the epidermis, and morphologically by ongoing apoptotic keratinocyte cell death that results in the separation of the epidermis from the dermis.

The term SJS is now used to describe patients with blistering and skin detachment involving a total body surface area of <10%. SJS/TEN describes patients with 10–30% detachment, and TEN describes patients with >30% skin detachment.

TEN or SJS/TEN overlap with all the following:

1. Diagnosis by a dermatologist;

AND

2. Body surface area (erythema and/or erosions) of 10% or more;

AND

3. Evidence of rapid evolution.

Notes:

• IVIg should be initiated as early as possible, preferably within 24 hours of diagnosis.
• Urgent skin biopsy should be performed for confirmation but should not delay IVIg therapy if indicated.
• The Adverse Drug Reactions Advisory Committee should be notified of the inciting medication.

SJS alone

2 g/kg, preferably as a single dose, or divided over three consecutive days.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Streptococcal TSS: In view of the high mortality risk, IVIg is indicated for early use in both adults and children.

Staphylococcal TSS: IVIg is indicated where rapid improvement is not obtained with fluid resuscitation and inotropes.

In both conditions IVIg is used in addition to surgical intervention, antibiotic therapy and supportive measures.

Small case studies only; insufficient data (Category 4a).

TSS is a life-threatening illness characterised by hypotension and multi-organ failure. It may be caused by Staphylococcus aureus (rarely isolated) or Streptococcus pyogenes that produce and release superantigenic exotoxins. The exotoxins activate T-cells on a large scale resulting in a massive release of inflammatory cytokines.

Streptococcal TSS is defined by:

I    Group A Streptococci ( enes) isolated from:

• (IA) a normally sterile site (e.g. blood, cerebrospinal fluid, pleural or peritoneal fluid, tissue biopsy, surgical wound); or
• (IB) a non-sterile site (e.g. throat, sputum, vagina, superficial skin lesion).

IIA. Hypotension: systolic pressure = 90 mmHg in adults or in the 5th percentile for age in children; and

IIB. Two or more of the following:

1. Renal impairment: serum creatinine for adults at least twice the upper limit of normal for age; in patients with existing renal disease, elevation over baseline by a factor of at least 2;
2. Coagulopathy: platelet count of ≤100×10⁹/L or disseminated intravascular coagulation, defined by prolonged clotting times, low fibrinogen level, and the presence of fibrin degradation products;
3. Liver involvement: alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin level at least twice the upper limit of normal for age; in patients with existing liver disease, elevation over baseline by a factor of 2;
4. Adult respiratory distress syndrome, defined by acute onset of diffuse pulmonary infiltrates and hypoxaemia in the absence of cardiac failure; or evidence of diffuse capillary leak manifested by acute onset or generalised oedema; or pleural or peritoneal effusions with hypoalbuminaemia;
5. Generalised erythematous macular rash that may desquamate;
6. Soft tissue necrosis, including necrotising fasciitis or myositis; or gangrene.

A definite case is an illness fulfilling criteria IA and II (A and B).

A probable case is an illness fulfilling criteria IB and II (A and B) where no other aetiology is identified.

(Working group on Severe Streptococcal Infections 1993).

Staphylococcal TSS is defined by:

1. Fever: temperature ≥38.9°C;
2. Hypotension: systolic blood pressure ≤90 mmHg in adults or in the 5th percentile for age in children;
3. Diffuse macular rash with subsequent desquamation one to two weeks after onset (including palms and soles);
4. Multisystem involvement (three or more of the following):
   1. Hepatic: bilirubin or aminotransferase ≥2 times normal;
   2. Haematologic: platelet count ≤100×10⁹/L;
   3. renal: blood urea nitrogen or serum creatinine level ≥2 times normal;
   4. Mucous membranes: vaginal, oropharyngeal or conjunctival hyperaemia;
   5. gastrointestinal: vomiting or diarrhoea at onset of illness;
   6. Muscular: severe myalgia or serum creatine phosphokinase level ≥2 times upper limit;
   7. Central nervous system: disorientation or alteration in consciousness without focal neurological signs and in the absence of fever or hypotension.

A confirmed case is a case with all of the manifestations described above. However, in severe cases death may occur before desquamation develops.

A probable case is an illness with all but any one of the manifestations described above (Wharton et al 1990).

Prognosis

Streptococcal TSS has a mortality rate of 30–80% in adults and 5–10% in children, with most deaths secondary to shock and respiratory failure.

Staphylococcal TSS can also be fatal but mostly has a better prognosis.

1. Diagnosis of streptococcal or staphylococcal TSS in accordance with criteria listed above, preferably with isolation of organism;

AND

2. Failure to achieve rapid improvement with fluid resuscitation, inotropes, surgery, antibiotic therapy and other supportive measures.

2 g/kg as a single dose.

Schrage et al. Clin Infect Dis 43: 6, 743-6 reported differences between various preparations of IVIg and their ability to neutralise streptococcal superantigens. They commented that 'the variations between IVIg preparations from different manufacturers are most likely caused by the different geographical regions from which the plasma samples were collected and might reflect differences in … group A streptococcal … exposure.' The clinical significance of these findings is not yet known.

Darenburg et al. Clin Infect Dis 38: 836-42 suggested that higher doses of IVIg might be required for staphylococcal TSS than streptococcal TSS, based on in vitro neutralisation of superantigens.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.