Essay: Immunoglobulin use and effects

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XX journal articles were selected for presentation because they contain new safety data or other information relevant to Nanogam / intravenous immunoglobulin (IVIG). Short summaries of the selected articles are presented by topic.
Peter and Chappel conducted a review of the current immunoglobulin products (SCIG and IVIG), adverse reactions, treatment specifics (e.g. dose and route). Key safety steps in the production of immunoglobulins include acquisition of plasma and y-globulin, removal of aggregate and anticomplementary activity, inactivation or removal of viruses, stabilization for storage.
The adverse reaction experienced during IVIG and/or SCIG were classified as followed
– Common (20-40%): infusion site pain, swelling, erythema (up to 75% in SCIG), anxiety, malaise, fatigue, myalgia, arthralgia, back pain, fever, chills, flushing, tachycardia, hypo- and hypertension, headache
– Less common (<5%): aseptic meningitis, hyponatremia (IVIG only), neutropenia, hemolyticanemia, interference with vaccine effectiveness and/or immunodiagnosis and eczema (IVIG) - Rare (<0.1%): anaphylactoid reaction, severe thrombosis (IVIG) and blood-born infectious disease) IVIg and SCIG are equally effective as bacterial infection prophylaxis and choice depends mostly on availability in countries. Intravenous and intramuscular products can safely be administration subcutaneously, however subcutaneous/intramuscular products not intravenously. IVIG and SCIG administration have several advantages and disadvantages compared to each other. Advantages of IVIg - Less frequent infusions - Less local reactions - Easy administration of high doses - Quick increase in serum levels Advantages of SCIG - Less systemic reactions - No intravenous administration - More stable IgG levels - Self-infusion at home more acceptable than IVIg in some countries They concluded that the only life-saving option in most patients with PID is life-long Ig replacement therapy. The effectiveness of the treatment is dependent on multiple factors (immunoglobin products themselves, type of PID, patient-related factors). It is essential to monitor the patients regularly, perform long-term follow-up and keep a close relationship between the patients and the multidisciplinary clinical teams. More countries are drafting guidelines for Ig treatment to standardize treatment. Risks Health Canada performed a safety review to assess available information regarding the risk of thrombosis (blood clots) and to decide if the Canadian product information for all immunoglublins should be updated. The review included national and international adverse reaction reports, literature and what is known about the use of these products both in Canada and internationally. It was concluded that was enough evidence to update the safety information for all immunoglobulins. The Canadian health authority undertook the following actions: - The Canadian product information for all immunoglobulin products has been updated to include a Boxed Warning and an updated Warnings and Precautions section with information regarding the risk of thrombosis, by describing the type of events that may occur as well as risk factors. - A risk communication will be issued to inform about the risk of thrombosis with immunoglobulin products. - Monitoring of thrombosis cases for all immunoglobulin products will continue, with a particular focus on the intramuscular and subcutaneous immunoglobulin products. Salge-Bartels et al studied if activation of platelets and monocytes could be involved in thromboemoblic events (TEE) associated with IVIG treatment, just like factor XIa. Twenty samples were taken from five different companies to test the influence on thrombus formation in whole blood. Further testing of batches affiliated and not affiliated with TEEs included thromboelastometry, activation and adhesion of platelets, and surface expression of monocyte tissue factor. XIa was used as an comperator. To analyze the anti-CD154-reactive proteins in IVIG a Western blot was used. Results showed that IVIg supplementary to factor XIa raised macroscopic clotting in whole blood. All IVIg products in a similar degree activated the expression of Fc??RII-dependent tissue factor expression and adding XIa had no effect. The ADP and TRAP-6-elicited response was increased by IVIG. IVIG increased platelet-monocyte adhesion and annexin V binding to platelet microvesicles, and promoted platelet adhesion to IVIG-coated surfaces. The TEE affiliated batches showed the most response. The data showed that IVIG affects the hemostatic balance by modulating the activation of platelets and monocytes. These effects are separate or supplementary to FXIa. These interactions seem to be affected by CD154-related proteins and has to be further studies to clarify how. Germishuizen et al performed a review aimed on scientific rationale, merits, and applications of several analytical methods of quantifying the thrombogenic potential of IVIG and SCIG products and intermediates to meet the latest regulatory requirements. Activated factor XI (FXIa) is identified as the likely cause of IVIG related thromboembolic events (TEEs). The increase TEEs related to IVIG led to recalls of IVIG products and an increase in regulatory oversight and requirements of manufacturing processes of these products. The process of manufacturing IVIG products needs to prevent activation of FXI to FXIa, remove clotting factor contaminants and show the absence of procoagulant activity to be compliant with the updated EU regulation. Manufacturers should quantify the thrombogenic potential to validate the capacity of IVIG and SCIG manufacturing processes to remove procoagulant contaminants and to establish the safety of the final products. Non-activated partial thromboplastin time (NaPTT), thrombin-generation assay (TGA), FXIa assays are currently the best methods to evaluate the thrombogenic potential of the intermediate and final Benadiba et al performed a retrospective review of the Quebec Hemovigilance system database, after a patient experienced a thrombotic complication after treatment with IVIG at the Sainte-Justine Hospital. In 11 years (2003-2013) eight cases of thrombosis after IVIG therapy were reported (seven in adults and one in the pediatric population) (respective rate of 0.06 case and 0.17 case per 100,000 gram of IVIG given). IVIG-related thrombosis is a rare serious adverse event predominately in adults. Vinod et al 2014 report a case of a 69-year old male with Guillain Barre syndrome, healthy and without addictions, was admitted to the hospital on day 4 of the illness with progressive weakness of all the 4 limbs for 3 days. The patient did not have any medical history of preceding diarrheal illness, upper respiratory tract infection, or exposure to organophosphate insecticides. He was diagnosed with symmetric areflexic quadriparesis with weakness of neck flexors. Therapy with IVIG (Norglobin) and venous thrombosis prophylaxis (enoxaparin) was started on the same day. On day 5 the patient was admitted to the intensive care unit as he had progressive paralysis with involvement of lower ccranial nerves and respiratory muscles and needed endotracheal intubation, mechanical ventilation and nasogastric tube feeding. The patient had autonomic dysfunction with episodes of hypertension and tachycardia on days 4 and 5, which resolved by day 6. On day 8, when the last infusion of IVIg was almost ready. The patient suddenly experienced hypotension with excessive sweating and restlessness. An electrocardiogram showed ST segment elevation in leads V to V, suggesting acute anterior wall ST elevation myocardial infarction (MI). The patient was treated with inotropes and his blood pressure increased and received thrombolytic treatment. Inotropes gradually decreased and stopped after 8 hours. Echocardiography showed hypokinesia of the interventricular septum and anterior wall of left ventricle with an ejection fraction of 40%. Troponin T was positive. Additional treatment included antiplatelet drugs (aspirin and clopidogrel), atorvastatin and enoxaparin. After hemodynamic stability was realized the patient also received metoprolol and enalapril. After the patient was weaned of the ventilator and extubated, he was discharged on day 20 on hematinics and his muscle power gradually recovered. Thronby et al conducted a literature review to evaluate the treatment options to reduce IVIG-related migraines or headaches. A total of six clinical studies and two case reports were included in this review. The migraines and headaches were treated with hydration, using another IVIG product, decreased infusion rates, or treating with oral analgesics, opioids, propranolol, sumatriptan, or dihydroergotamines before, during, or after the IVIG infusion. Most of the patients reacted positive to treatment, implying that various treatments could be effective. It was recommended to treat the patients on an individual basis, pharamcotherapeutic or non-pharmacotherapeutic, considering the patient's medical history, type of IVIG used and patient's condition. Nguyen et al describes a side effect of high-dose IVIG that is under recognized, hemolytic anemia. As there are no established guidelines on the treatment of patients with Guillain-Barr?? syndrome (GBS) who relapse or do not improve after a standard course of IVIG of plasma exchange (PE) treatment, the clinical course and side effects of these patients was reviewed. In total five patients were reviewed who all received at least two courses of the standard dose of IVIG (total >4g/kg), four for the indication of GBS and one who inadvertently received a high dose of IVIG for Miller Fisher syndrome. Three patients, who all had non-O blood types, experienced clinically significant hemolytic anemia and required blood transfusion. The other two patients with blood type O, developed mild anemia without clinical symptoms and they showed no signs of hemolysis.
Patients receiving high doses of immunoglobulin for the treatment of primary antibody deficiencies (PADs) run the risk of hemolysis. In this observational study over a two year period by Quinti et al 2014 the occurrence of hemolysis was monitored in 162 patients with PADs who received IG at replacement doses (142 IVIG and 20 SCIG). Six patients showed signs and symptoms of immunoglobulin-induced hemolysis and two asymptomatic patients were identified out of a randomly selected group of 16 patients. It was concluded that there is a risk of hemolysis in patients with long-term therapy of immunoglobulin at replacement doses.
Quest et al report a case regarding a 77-year-old female with CVID who was treated with IVIG since 1996 as prophylaxis for infections. During an IVIG infusion, she experienced hypertension and dyspnea and was treated with increasing oxygen supplementation and intubation. A chest radiograph showed bilateral lung infitrates and no infections or circulatory overload. After 24 hours the patient was extubated and after several days discharged from the hospital. The patient continued using IVIG. She had not since or previously received this lot number and experienced no incidents. Although TRALI events are very rare, this case further demonstrates that it can occurred after IVIG infusion.
Efficacy and safety
In patients with common variable immune deficiency B lymphocytes are not able to differentiate into switched memory B cells and plasma cells. Furthermore, CVID patients show an oligoclonal increase of CD8+ cells and decline of CD4+T cells. The effect of IVIG treatment seems not only to be related to the replacement of antibodies, but also to active modulation of responses of the immune system. However, this hypothesis has never been verified. Dolcino et al 2014 wanted to prove this by evaluating the gene-expression profiles from Affimetrix HG-U133A and fluorescence-activated cell sorting (FACS) analysis of blood mononuclear cells in 10 patients with common variable immune deficiency (CVID). The study showed that after treatment of IVIG the TNFRSF25 gene (promoting survival of CD8+T cells) was down-regulated and the leptin receptor gene (playing a vital part in CD4+T cell generation) up-regulated, which may be related to respectively the decrease in CD8+ cells and increase in CD4+ T cells after IVIG infusion. Additionally, the increase in switched memory B cells may be related to the regulation of genes such as RGS1. These results support the hypothesis that IVIG treatment also modulates the immune response in CVID.
IVIG treatment in children with Kawasaki disease (KD) is ineffective in 10% to 20% of the cases. If untreated, approximately 15 to 25% of the KD patients have complications. A retrospective review was conducted by Lee et al 2014 to find useful predictors of responsiveness to initial IVIG treatment in KD. Medical records of 91 children diagnosed with KD were reviewed and they were divided into two groups: IVIG-responsive or IVIG-resistant. The fractional change (FC)-CRP and FC-% neutrophil showed significant difference. By multivariate analysis, FC-CRP was confirmed to be an independent predictor for initial IVIG resistance. Fractional change-C-reactive protein might be a useful and important value for predicting initial IVIG resistance in KD patients.
Hodkinson et al 2015 compared IgG trough levels, increment and efficiency in matched pairs of obese and lean patients receiving either replacement or immunomodulatory immunoglobulin therapy. Thirty-one obese patients were matched with a clinically-equivalent lean patient across a range of indications including primary antibody deficiency or autoimmune peripheral neuropathy. This study shows that, at a population level, obese patients achieved a higher trough and increment (but not efficiency) for a given weight-adjusted dose compared with the lean patients. The pharmacokinetics of Ig in obese and lean patients is significantly different at a cohort level. However, due to the huge amount of patient variability, the influence of obesity on the clinically appropriate dose of Ig is too unreliable at an individual level to justify application of a general reduction in dose for all patients with a BMI exceeding 30. This is particularly true for PID (replacement therapy) patients where no difference in the two cohorts could be demonstrated, and individualised dosing is already practised. In patients receiving Ig for immunomodulation it was concluded that it may be possible to reduce the dose in some obese patients relative to their lean equivalents without affecting outcome, however this should only be undertaken on an individual basis once the patient has been stabilised, and is not appropriate for all patients. Across all dose regimes a high BMI (body mass index) cannot be used to predict reliably the patients in whom dose restriction is clinically appropriate.
Saji et al 2014 describes the effects of anticytokine therapy for IVIG resistance patients with acute Kawasaki disease. Ten to twenty% of the patients with acute Kawasaki disease demonstrate incomplete or lack of effect when treated with IVIG. These patients frequently present with cardiac complications (e.g. coronary arterial aneurysm). More than 500 paediatric patients for whom IVIG and intravenous methylprednisolone pulse therapy was not significantly effective were treated with Remicade (infliximab). Remicade was effective and safe for treating the patients with IVIG-resistant KD, however ten to 20% of the patients were resistant to Remicade. Re-treatment with IVIG or steroids was also effective. Remicade showed promising results for reducing the fever duration, CRP and WBC counts, but a decline in the incidence of coronary aneurysm was not supported.
Ye et al 2014 observed and compared the effectiveness of plasma exchange (PE) and IVIG as treatment for Guillian-Barre Syndrome (GBS). Sixty-four adult patients with GBS were included in this prospective clinical study. It was concluded that the patients treated with PE and IVIG for GBS showed a high response. Therapy with PE showed more significant improvements (better improvement of nerve function defect, better reduction of blood immunoglobulin, fibrogen and lower monocytes %, and therefore PE can be helpful in the early rehabilitation of patients.
To compare efficacy of IVIG versus plasma exchange (PE) in treatment of mechanically ventilation adults with GBS in intensive care unit a study was set up. The prospective, non-randomized study, realized in a medical ICU from 2006 to 2010 was conducted in patients with GBS who needed MV. The patients were divided in two groups: one treated with IVIG and one with plasma exchange (PE). The duration of the hospitalization and requiring mechanically ventilation was shorter in the IVIG group compared to the PE group. Additionally, in the IVIG group the recovery of motility was quicker than in the PE group.
Bichuetti-Silva et al conducted a two year prospective observational study in 117 patients with PID receiving IVIG replacement therapy every three to four weeks. In total 1765 infusions were performed and immediate infusion-related adverse reaction after 38 infusions. Malaise, headache, and abdominal pain were most common, and tightness of the throat and seizure were reported as severe. All reactions improved when IVIG therapy was temporarily or completely stopped and symptomatic medications were started. In sixteen of the reactions the patient had an acute infection. The low occurrence rate and few severe reactions prove the safety of IVIG as treatment of PID.
Moffett et al reviewed a large hospital database to identify pediatric patients with an ICD-9 code or mucocutaneous lymph node syndrome and treated with at least one dose of IVIG. 16.3% of the patients were resistant to IVIG treatment. Patients admitted to hospitals in the highest quartile of resistance were more likely to be African-American and have a C-reactive protein drawn, and less likely to have an echocardiogram performed and an erythrocyte sedimentation rate drawn. The occurrence of IVIG resistance of KD patients varies highly among pediatric hospitals and treatment patterns. Further study of the diagnostic methods and treatment is warranted.
Yanagimoto et al 2014 re-evaluated the low serum immunoglobulin G (IgG) levels of KD patients prior to treatment with IVIG. One of the risk factors for coronary artery abnormalities (CAAs) is low levels of serum IgG. As the dose of IVIG changed from 0.2-0.4 g/kg/day for 5 days to a single high dose of 2 g/kg, this risk factor has to be re-evaluated. Therefore, clinical hospital records of patients with KD were reviewed. In total 197 patient who received a single high dose of IVIG within 7 days of illness were included, including 22 IVIG nonresponders and 16 patients with CAAs. The serum immunoglobulin levels and coronary artery diameters measured by echocardiogram were transformed to z-scores. The z-scores for IgG (IgGz) values between patients with and without CAAs were showed no differences. Nonresponders had higher IgGz values than responders and logistic regression analysis demonstrated that these values were an independent risk factor for IVIG resistance. The results of this study did not show that low IgGz values were a risk factor for CAAs in KD patients and that higher values before treatment seem to have an increased risk of resistance to initial IVIG treatment.
Yamamoto et al 2015 investigated if serum ferritin levels could be a predictor of patients with Kawasaki disease who are resistant to IVIG treatment. 85 patients were enrolled in this retrospective study; 57 IVIG responders and 28 non-responders. Serum ferritin levels and the scoring systems for the prediction of non-responsiveness to initial IVIG therapy were compared between these two groups. Non-responders showed significantly higher serum ferritin levels. In two of the three prediction scoring systems, non-responders also showed significantly higher scores than responders, but many non-responders had low scores of these scoring systems. More than half of the patients with a low score of these scoring systems had high serum ferritin level (‘ 165 ng/ml). In conclusion serum ferritin level might be useful marker for the prediction of resistance to initial IVIG treatment and could be an important complementary marker to the prediction scoring systems.
Bla??ek et al performed a clinical routine study to evaluate the efficacy and safety of human normal immunoglobulin 10% liquid ((KIOVIG??/GAMMAGARD LIQUID?? [IVIG 10%]). The overall efficacy (in 81.8% of the patients) and tolerability (in 87.5%) were assessed as good or very good. One serious ADR and no severe ADRs occurred. The results regarding efficacy and safety of IVIG 10% in routine clinical practice were comparable to those of previous studies.
Bauhofer et al performed a prospective non-interventional study to better identify the safety profile and treatment methods of Intratect?? in patients with primary and secondary immunodeficiencies. This is the interim analysis of the data collected at routine clinic visits. 1,313 patients with different causes of immunodeficiency were monitored of which 836 patients were treated, 37,2% with IVIG. A total of 21,995 infusions of Intratect?? were administered 689 adverse events were reported of which 225 were related to treatment with Intratect??. The ADR rate was 1.0% per infusion and seven of the 225 ADRs were classified as serious. All events resolved or were resolving at the time of reporting. It was concluded that the treatment of primary and secondary immunodeficiencies was correlated with low rate of ADRs and the occurrence of serious ADRs were rare.
Soler-Palac??n et al performed a retrospective study of all patients with primary immunodeficiencies (PID) in a third level Pediatric University Hospital with the aim to evaluate the change from SCIG to IVIG. Twenty-three patients with PID were studied. Treatment was changed from SCIG to IVIG in nine patients; eight due to vacation and one due to administration issues. Eight patients discontinued SCIG use indefinitely; five for convenience, one due to adverse effects, one due to coagulopathy and one due to autoimmune thrombocytopenia. The patients did not experience any severe infections requiring hospitalization. Conclusion: changing the treatment of PID from SCIG to IVIG brought considerable advantages for the patients and their caregivers in terms of convenience and it conserved the effectiveness and safety of the treatment. Healthcare providers should be flexible with this dual therapy to optimize the patient’s quality of life.
Cocito et al investigated the shift from IVIG to SCIG in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). 87 patients (66 CIDP; 21 MMN) affected by immune-mediated peripheral neuropathies who showed a sustained clinical response to IVIG, were included in this short-term nationwide prospective observational study. Patients were evaluated by means of the Overall Neuropathy Limitation Scale, Medical Research Council Scale and Life Quality Index questionnaire, both at the time of therapeutic shift and after 4 months of subcutaneous Ig treatment. A sustained clinical efficacy was observed after the switch to subcutaneous immunoglobulin: the Overall Neuropathy Limitation Scale score improved in the group of 66 CIDP patients (P = 0.018), with only one subject reporting a worsening of 1 point, and remained stable in the group of 21 MMN patients (P = 0.841), with one subject reporting a worsening of two points. An improvement in the patient’s perception of therapeutic setting was reported in both groups. In conclusion: this study showed that SCIG and IVIG were clinical equal and the patient’s perception of the treatment setting with SCIG improved.
Bal et al compared the efficacy and safety of hospital-based IVIG and home-based self-administered SCIG in children with primary deficiency diseases (PIDD) switched from IVIG to SCIG. This observational study included 18 patients (2-18 years) with different types of PIDD. They switched from treatment with IVIG at a dose of 400 mg/kg every 4 weeks (Kiovig?? or Octagam??) to SCIG 100 mg/kg weekly (Subcuvia??). A retrospective analysis of IVIG treatment was performed over the last year. To examine the differences between the treatments the number of respiratory tract infections, the IgG serum levels and the frequency of adverse events were evaluated. The SCIG group showed a higher serum level of IgG, which was stable and in the IVIG group the levels were high after the administration of IVIG rapidly followed by a fall over the next days. The patients treated with SCIg experienced less frequent respiratory tract infections and this group also experienced less adverse events (e.g. 1 local vs. 9 systemic). In conclusion: SCIG is significantly more effective and safer as treatment for primary immune deficiency diseases in children. Also the levels of IgG stabilize during SCIG treatment, which is comparable to the physiological concentrations.
Danieli et al performed a literature review of SCIG in immune-mediate diseases as an alternative for IVIG. The disadvantages of IVIG treatment are high costs, risk of serious systemic side effects and administration via intravenous route. They concluded that SCIG is suitable for the treatment of patients with neurological autoimmune disorders (e.g. demyelinating neuropathies and inflammatory myopathies). The advantages of SCIG compared to IVIG are more stable serum IgG levels, increased immunity for infections in patients with long-term glucocorticoids and/or immunosuppressants treatment, reduced global costs of the treatment, no intravenous administration and less change of fluid overload or hyperosmolarity. The patient’s quality of life increased providing the possibility to be treated at home and therefore do not need the help of healthcare providers or to be hospitalized. The treatment satisfaction significantly improved as it was easier to plan daily activities, there were less infusion-related events and the treatment is flexible. SCIG treatment in selected patients with immune-mediated neuropathies or myopathies, for whom immunosuppressants were contra-indication or standards therapeutic regimens were not effective, is a reasonable option due to the reduced amount of adverse reactions improving quality of life and immunosuppressants/ steroid sparing effects.
Soler-Palac??n et al performed a retrospective study of all patients with primary immunodeficiencies (PID) in a third level Pediatric University Hospital with the aim to evaluate the change from SCIG to IVIG. Twenty-three patients with PID were studied. Treatment was changed from SCIG to IVIG in nine patients; eight due to vacation and one due to administration issues. Eight patients discontinued SCIG use indefinitely; five for convenience, one due to adverse effects, one due to coagulopathy and one due to autoimmune thrombocytopenia. The patients did not experience any severe infections requiring hospitalization. Conclusion: changing the treatment of PID from SCIG to IVIG brought considerable advantages for the patients and their caregivers in terms of convenience and it conserved the effectiveness and safety of the treatment. Healthcare providers should be flexible with this dual therapy to optimize the patient’s quality of life.
Lim and Jung retrospectively reviewed the medical records of 216 patients to study the clinical outcomes of a single high dose of IVIG combined with dexamethasone as therapy in patients with KD. 110 patients were treated with IVIG (2g/kg) and 106 with IVIG and dexamethasone (0.3 mg/kg/day for three days). The IVIG and dexamethasone combination group showed a significantly shorter febrile period, shorter hospitalization duration, needed fewer retreatments with IVIG and had lower C-reactive protein levels. The combination group also showed lower occurrence of coronary artery lesions and the outcomes were less severe, although not significant. They concluded that the combination therapy of a single high-dose of IVIG with dexamethasone increased the clinical course of patients with KD.
Region specific
Goldacker et al studied the impact of plasma origin. evidence for Diversity of specific antibodies is achieved by pooling over 1000 donors usually of a given geographic region. Especially for tick-borne encephalitis (TBE), regional vaccination rates differ widely among populations due to the epidemiology of the disease.
Specific antibody titers were analyzed against TBE in comparison to total IgG levels in 162 serum samples collected from 110 PAD patients substituted with polyvalent intravenous IgG or subcutaneous IgG. Some patients received different IgG products over time leading to a total number of 122 different patient-IgG product combinations. Positive TBE-specific IgG levels were detected in 35 cases when measured by standard ELISA and could be confirmed by demonstration of neutralizing antibodies in 31 cases. The detection of specific antibody levels correlated with the geographic origin of the IgG preparations. No titers were detectable in patients substituted with IgG products from North-American donors, whereas variable degrees of anti-TBE titers were observed in patients receiving products from different European countries. These data support regional plasma donation in order to address the diverse local infection profile.
Due to disease-associated impairment of vaccination responses, patients with primary antibody deficiencies depend on the quality and quantity of passive protection via the application of polyvalent IgG preparations. Optimal vaccination status of the plasma donors according to official regional recommendations can greatly contribute to the quality of the product.
Safety ‘ general
Peter and Chappel 2014 outline the current general principles of immunoglobulin replacement therapy (IVIG and SCIG) for primary immunodeficiencies. The treatment with high-dose immunoglobulin was not discussed. The frequency of the adverse reactions were grouped in to common (20-40%), less common (<5%) and rare (<0.1%). The common reactions included infusion site pain, swelling and erythema, anxiety, malaise fatigue, myalgia , arthralgia, back pain, fever, chills, flushing, tachycardia, headache, hypo- and hypertension. Less common reactions were aseptic meningitis, hyponatremia, neutropenia, hemolyticanemia, interference with vaccine effectiveness and/or immunodiagnosis and eczema. The reactions specified as rare were anaphylactoid reaction, severe thrombosis and blood-borne infectious disease. Off-label use ' general A review performed by Cantarini et al 2014 showed that the efficacy of intravenous immunoglobulins for systemic sclerosis in different regimens (1-2 g/kg of body weight, administered over 2-5 consecutive days) has been described in a limited number of trials and small case series, showing benefits in skin, articular, and lung interstitial disease symptoms. However, studies on IVIG in systemic sclerosis still remain few, and further randomized controlled trials should be undertaken to assess their clinical effectiveness or define the optimal dosage and times of administration. Navajas and Rada performed a systemic review of the Epistemonikos database to investigate the use of IVIG as therapy for toxic epidermal necrolysis and Stevens-Johnson syndrome, which is still controversial. A systemic review of the Epistemonikos database was performed. Six systematic reviews were identified which included 39 primary studies. In conclusion the efficacy of IVIG therapy is questionable as the of the evidence is very low, the occurrence of serious adverse events is probable and the costs are high. It was concluded that IVIG therapy in toxic epidermal necrolysis and Stevens-Johnson syndrome should only be used in the setting of a clinical trial with the exception of cases where other treatments failed and there are no resource constraints. Alabdali et al investigated the current evidence for the efficacy of IVIG in myasthenia gravis (MG) and the outcomes used to prove this. They found class 1 evidence for the effect of IVIG therapy in MG patients worsening MG and good evidence in myasthenia crisis. Controlled studies were not available for examining long-term maintenance therapy and the evidence consisted only of class III retrospective studies. The outcome of the quantitative myasthenia gravis score, a functional scale, was preferred as it has showed responsiveness, but a scale incorporating patient-reported outcomes and the patients complaint of fatigue is likely to be preferable. In general, IVIG treatment was well tolerated in the trials. A retrospective review of Ahluwalia et al 2014 evaluated the effectiveness of IVIG, systemic corticosteroids, or both in treating mycoplasma pneumoniae-associated Stevens-Johnson syndrome (mpSJS) in children. Retrospective series of 10 pediatric mpSJS cases were stratified into four treatment groups: IVIG alone, IVIG and systemic corticosteroids together, systemic corticosteroids alone, and supportive care. It was concluded that treatment with systemic corticosteroids as monotherapy or in combination with IVIG may be preferable to IVIG alone. Further large-scale studies are warranted to evaluate this hypothesis. Only a fraction of patients do benefit from disease modifying treatments in relapsing remitting multiple sclerosis (RRMS) and data on IVIG are controversial, it has been suggested that there is a subpopulation of patients with good clinical response to IVIG. In the prospective, multicenter, open label, exploratory study by Berger et al 2014 RRMS patients receiving IVIG therapy were genotyped and several immune parameters were collected. To distinguish between potential responders and non-responders each of the observed genotypes was combined with the corresponding scores of 65 immune parameters in a stepwise approach. Non-responders were defined as being positive for 4 or more out of 9 individual scores. Responders scored either 0 or 1, while non-responders scored between 7 and 9 (p=1.2'10-7). In summary, combination of genomic and functional immune parameters allowed prospective discrimination between responders and non-responders towards IVIG therapy in this learning panel of RRMS patients and will be confirmed in a validation study. Imashuku et al 2014 described the follow-up of eight Japanese children with Langerhans cell histiocytosis (LCH)-related neurodegenerative central nervous system (ND-CNS) disease who were treated with IVIG for >3 years. IVIG appeared to be most beneficial when it was administered soon after ND-CNS disease diagnosis when the Expanded Disability Status Scale (EDSS) scores were low (1.0-2.5). The patients who began receiving IVIG when their high EDSS scores were higher (4.5-7.0) appeared to obtain less benefit. To prevent progression of ND-CNS disease in patients with LCH, it is recommended to introduce IVIG early and to continue this therapy for >3 years.
Soares et al 2014 assessed the clinical and cost-effectiveness of IVIG for severe sepsis and septic shock and evaluated the value of conducting n randomized controlled trial (RCT). It was found that there was a large degree of statistical heterogeneity in the clinical evidence of the efficacy of the treatment and the origin of this diversity was unclear. The cost-effectiveness of IVIG appears within the borderline region of estimates considered to represent value for money in the National Health Service, but these results are associated with significant uncertainty and appear highly sensitive to the alternative clinical effectiveness models applied. The analyses suggested that there is need for a further RCT. However, before investing in a new RCT, further research is needed both into the mechanism(s) of action of IVIG and from a dose-ranging/finding study.
Almansa et al 2015 provide an overview of the problems in clinical trials with IVIGs in sepsis. IVIGs have not yet demonstrated robust evidence in the benefit for treatment of sepsis. In spite of multiple clinical trials performed with IVIG in sepsis, it remains an experimental therapy for this severe condition. Nonetheless, these trials do not address a number of potential confounding factors, concerning both the patient and the IVIG preparations, which could greatly affect the final result. To name a few, endogenous levels of immunoglobulin isotypes and subclasses are not assessed prior to treatment. The presence/absence of patient antibodies against the microorganism(s) causing sepsis is not evaluated. The accuracy of antibiotic prescription is not included as an adjusting variable. The degree of patient immunosuppression (previous or induced by sepsis) is not documented. In turn, the concentration and antimicrobial specificities of the antibodies contained in the batches of IVIG are not assessed. Neither the pharmacokinetics of IVIG nor its potential immunomodulatory effects are evaluated. In addition, the concept of ‘window of opportunity’ for IVIG administration following diagnosis of sepsis is not considered. In conclusion, addressing these factors could help to individualise treatment with IVIG for sepsis, which could enhance the opportunities of this drug to show benefits in terms of survival in this severe condition.
Miescher et al 2015 evaluated standard IVIG as an alternative to intravenous cytomegalovirus hyperimmune immunoglobulin (CMVIG) for prophylaxis and therapy of cytomegalovirus (CMV) disease by measuring the ELISA and neutralizing titres of CMV-specific antibodies in CMVIG and IVIG preparations. The higher anti-CMV neutralization capacity of CMVIG per gram of IgG vs. standard IVIG suggests that standard IVIGs are not equivalent to or interchangeable with CMVIG.
Hung et al 2015 performed a systematic review and meta-analysis of published randomized controlled trials (RCTs) and prospective studies that evaluated the efficacy of IVIg in managing postpolio syndrome, which indicated that IVIg is unlikely to produce significant improvements in pain, fatigue or muscle strength. Thus, routinely administering IVIg to patients with PPS is not recommended based on RCTs. However, a potential effect in younger patients with lower limbs weakness and intense pain requires confirmation from further well-structured trials.
Nguyen et al described a case report of a positive clinical outcome with IVIg as monotherapy in recurrent pemphigoid (PG). A 32year old female developed PG in the first pregnancy and had a stillbirth. PG recurred during the second trimester of her second pregnancy. Systemic corticosteroid therapy was cause for concern since patient developed gestational diabetes. Patient was unwilling to use insulin. IVIg was used as a treatment of last resort. The dose was 2g/kg/cycle. It was given every two weeks antepartum and every three weeks for three months postpartum. PG resolved with four weeks of IVIg therapy. Serum and tissue immunopathological studies were negative prior to delivery. A healthy neonate was born. No adverse events to IVIg were observed. No disease was observed ten months postpartum.
Sakthiswary and D’Cruz 2014 performed a systemic review to examine the efficacy of IVIG in adult patients with systemic lupus erythematosus. It was concluded that IVIG reduced the SLE disease activity scores significantly and also improved the complement levels.
Camara et al performed an observational retrospective, single-centre clinical study to study the efficacy of IVIG in the treatment of SLE. 52 patients with SLE were included and were treated with at least one cycle of IVIG (400 mg/kg/day for 5 days); 27 for active disease and concomitant infection while 26 were resistant to standard therapy. The indications for IVIG in the SLE patients were mainly cutaneous, haematological, neuropsychiatric and heart involvements. In 17 out of the 27 patients (62.96%) and in 18 out of the 26 patients (69.23%) a total or partial effect was observed. Seven of these patients showed experienced a recurrence of the symptoms within the first two years. IVIG was effective in selected symptoms such as haematological and cardiac involvement or when other therapies were not available, e.g. patients with active disease and concomitant infection.
Yamazaki et al described two case reports regarding two patients with a severe leukocyte adhesion deficiency type 1 (LAD-1) phenotype. In both patients a single homozygous defect that involves a missense mutation (c.817G>A) that encodes for a G273R substitution in CD18 was identified. The patients were treated with immunoglobulin as an adjunctive therapy and they responded positively. It was proposed that it is safe and efficacious to treat patients with LAD-1 before hematopoietic stem cell transplantation and helpful to control infections. Subcutaneous immunoglobulin appeared to help wound healing in refractory ulcers in these patients.
Calic et al 2014 reports that a multiple sclerosis patient presented with multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome 3.5 months after starting treatment with fingolimod and 4.5 months after discontinuing natalizumab (NTZ). The patient was subsequently treated with IVIG as the only treatment for MS along with mirtazapine and mefloquine. The patient’s symptoms improved and stabilized.
Fresno et al reports two case reports describing two patients with refractory recurrent pericarditis (RRP) after cardiac surgery. The patients were treated with high-dose IVIG (2 g/kg) and the treatment was effective for RRP.
Corr??a et al 2014 reports a severe case of periodontal destruction after long-term treatment with IVIG for neuropathy. The patient extracted his own maxillary anterior teeth due to high mobility. The patient was diagnosed with generalized and severe periodontitis. There were no significant changes in the genetic or microbiological features detected. This case suggests that worsening of periodontal disease could be recognized as a new adverse event of IVIG. Immune complex formation, complement activation and a direct effect in osteoclasts could be considered as mechanisms. In conclusion, prior to the treatment of IVIG it is important for patients to undergo a dental evaluation.
A retrospective review of clinical charts by Garcia-Geremias et al 2015 was conducted to document response to IVIg treatment in consecutive patients with treatment-refractory uveitis. In three out of four cases IVIg was an effective adjunctive therapy with neither immediate nor longer-term adverse events observed and well tolerated for the management of treatment-refractory uveitis.
Koike et al conducted a multicenter double-blinded trial which indicated that IVIg treatment for EGPA patients with residual peripheral neuropathy should be considered even when laboratory indices suggest remission of the disease.
Idiopathic pulmonary fibrosis (IPF) is a fatal disorder without specific treatments. Although the efficacy of intravenous immunoglobulin (IVIG) therapy for autoimmune diseases has been reported, that for IPF remains unknown. In an exploratory, multicenter, nonrandomized, and prospective trial performed by Enomoto et al 2015, patients with progressive IPF were treated with IVIG once monthly and it showed that the treatment may be effective and tolerable in patients with IPF.
Goebel et al 2014 designed a study protocol to confirm the effect of low-dose intravenous immunoglobulin treatment for complex regional pain syndrome (LIPS). For most patients with long lasting complex regional pain syndrome (CRPS) established analgesic therapy does not work and in many patients this is also the case for alternative pain treatments, e.g. neuromodulation devices or rehabilitation methods. LIPS is a multicenter (United Kingdom), double-blind, randomised parallel group, placebo-controlled trial, designed to evaluate the efficacy, safety, and tolerability of intravenous immunoglobulin (IVIg) 0.5 g/kg plus standard treatment, versus matched placebo plus standard treatment in 108 patients with longstanding complex regional pain syndrome. The primary outcome of the study is to compare the pain intensity in the IVIG group and placebo group. The primary objective of the study is to confirm the efficacy and investigate the effect size of IVIG therapy in CRPS patients.
Xie et al evaluated the efficacy and safety of high dose IVIG as prophylactic treatment in patients with Systemic Cappillary Leak Syndrome (SCLS, Clarkson disease). A longitudinal follow up study was performed with 29 patients who were treated with IVIG by their healthcare provider and received questionnaires recording symptoms since the beginning of their SCLS. Eighteen of the 22 patients who responded, were treated with a monthly dose of IVIG prophylaxis. After IVIG treatment was started the average annual attack frequency declined from 2.6/patient to 0/patient. During IVIG treatment 15 out of 18 patients did not experience any significant SCLS episodes and they had a medical history of one or more episodes. The results suggest that SCLS attacks and the frequency of residual symptoms related to those attacks, are strongly reduced by prophylactic treatment with monthly IVIG, which also showed minimal adverse events.
Umeda et al described a case report of a 42-year old with Churg-Straus syndrome (CSS) seven years after he was diagnosed with chronic eosinophilic pneumonia. The patient was treated with intravenous methylprednisolone was not effective. Therefore, therapy with intravenous cyclophosphamide and IVIG was started and the patient recovered from peripheral eosinophilia and leg pain significantly improved. A second dose of IVIG was administered one month later improving all the symptoms further. It was deemed important that CSS was diagnosed in an early stage and treatment with IVIG and cyclophosphamide was started soon after.
Widiapradja et al researched the efficacy of IVIg in ischemia in mice. Flow cytometry analysis of IVIg in ischemia and reperfusion injury in vivo revealed decreased infiltration of leukocytes implying that the endothelium was involved. Permeability analysis of endothelial cells of the mouse brain in vitro, showed that the loss of permeability caused by loss of oxygen and glucose, was inhibited by IVig and western blotting showed also the prevention by IVIg of down-regulation of tight junction proteins caused by that deprivation. It was concluded that IVIg protects against endothelial cell dysfunction and death in ischemic stroke.
Charles et al describe a case regarding a 57-year old woman who was diagnosed with scleromyxedema resistant to multiple treatment regimens. In November 2011 she experienced an initial episode of epileptic seizure and a post-seizure coma, subsequently she experienced confusional state with visual hallucinations. Within a few day the events resolved spontaneously. CT scan , MRI, EEG and infection screening showed no abnormalities whereby neurological involvement associated with scleromyxedema was suspected. In December 2012 and August 2013 she again experienced two epileptic episodes and confusional state. Now the confusional state lasted for two months and treatment with plasmapheresis and IVIG was started leading to a quick recovery of all neurological symptoms and boost of her general condition.
Cavazzuti et al performed an restrospective study to observe the effect of early IgM-enriched immunoglobulin (IgM) treatment on 30-day mortality rate in septic shock patients. Of the 168 patients included into the study, 92 received IgM therapy. The IgM group showed a higher 30-day survival (75 vs 53.9%). These findings were confirmed by multivariate analysis and propensity score ‘matching. The early treatment of IgM may increase the survival in patients with septic shock. However, Texoris et al stated that the limits of this retrospective study (e.g. no baseline analysis of the patients) which could influence the outcome. Although the results of prospective studies are contradictory to these findings, the significant increase in survival in the IgM patients cannot be denied and support further prospect interventional studies and studies to determine the immune mechanisms of IgM.
Nobile-Orazio et al made a retrospective comparison between the treatment with IVIg or intravenous methylprednisolone (IVMP) in patients with CIPD. They previously reported that treatment for six months of CIPD with IVIG was more effective and better tolerated than IVMP. IVIG treatment was effective in 24 of the 32 patients and IVMP in 13 of 24 patients. After a follow-up period of 1-60 months after discontinuation of treatment, 24 of 28 IVIG patients and 10 of the 13 IVMP patients relapsed. The median time to relapse was 4.5 months after discontinuation of IVIG and 14 months after IVMP. Patients treated with IVIG or IVMP, showed a comparable relapse percentage after discontinuation of treatment, however the median time between discontinuation and relapse was significant shorter in the IVIG treatment group.
Almansa et al 2015 provided an overview regarding a number of confounding factors for efficacy of IVIG as treatment of sepsis. Up to now clinical trials did not provide sufficient evidence for IVIG as treatment for sepsis. These trials do not take into account a number of potential confounding factors in the patient as well as the IVIG e.g. endogenous levels of Ig, degree of patient immunosuppression, antimicrobial specificities of antibodies in the batches of Ivig and potential immunomodulatory effects. When these factors would be addressed in individual patient treatment with IVIG for sepsis, this could increase efficacy and overall survival rates of patients with this severe disease.
Rayamajhi et al 2015 conducted a randomized double-blind placebo-controlled trial to investigate the efficacy of IVIG containing virus-specific neutralizing antibodies in children with Japanese encephalitis (JE) virus (JEV). JEV is a flavivirus transmitted by mosquitos closely related to the West Nile virus and there is no known viral treatment for any flavivirus. In total 22 children were included in the trial, from which 13 had confirmed JE; 11 received IVIG with anti-JEVE neutralizing antibody (Immunorel) and 11 placebo. Three patients children died; 1 in the IVIG group during treatment and two in the placebo group after being discharged. In overall, the outcomes did not differ in the two treatment groups. JEV negative children showed passive transfer of anti-JEV antibodies. JEV positive children treated with IVIG had The JEV-specific neutralizing antibody titres in the JEV positive children treated with IVIG was approximately 16 times higher than in the placebo group and this was more than could be explained by passive transfer alone. The IVIG group also showed higher interleukine-4 and 6 IVIG seems to be a promising option as treatment for JE which justifies further study.
Kubisz et al 2015 performed a literature review to evaluate the use of IVIG in immune tolerance induction (ITI) in inherited haemophilia A, together with a personal experience with high-dose regimen using human plasma-derived factor VIII containing von Willebrand factor and pulsed IVIg. Factor VIII inhibitors are a serious problem of inherited haemophilia A and is preferably treated with ITI, however the effectiveness is 70-80%. Addition of immunomodulatory agents could improve the outcome of ITI. Since the use of the Malm?? regimen, IVIG was for its modifying and regulating capacities of immune functions. The case of three patients with severe inherited haemophilia A and inhibitors was described. In all cases it showed at least a partial effect and the patients experienced no adverse reactions. The addition of IVIG seems to be a promising addition for the treatment of patients with poor prognosis or previous failure of ITI, although the evidence was limited.
Cid et al 2014 describe a case report of rituximab, plasma exchange (PE) and IVIg as therapy for severe human leukocyte antigen (HLA) alloimmune platelet refractoriness (PR). A common and serious complication in patients treated with long-term packed red blood cell and platelet transfusions is PR caused by HLA alloimmunization. PR because of HLA allominuzation was diagnosed in a woman with a medical history of myeloid leukemia secondary to myelodysplastic syndrome. As it was difficult finding HLA-compatible platelet donors by cross-reactive groups in our panel of HLA-typed platelet donors, the patient was treated with rituximab, PEs and IVIG. The HLA antibodies level decreased from a panel-reactive antibody of 89-0%. Thence a hematopoietic progenitor cell transplantation could be performed with random donor platelets. The combination of rituximab, PE, and IVIG could be an potential treatment option to resolve severe PR due to poly-specific HLA alloimmunization.
Boonyapredee et al 2014 present a case of a 57 year old patient who underwent a renal transplant. Eight weeks post-transplant an allograft biopsy was performed which showed Banff classification 1b acute cellular rejection, with insufficient evidence to diagnose BK virus-associated nephropathy. Therapy with IVIG was started and no other changes to the patient’s immunosuppressive therapy were made. Subsequently, plasma and urine BK increased and allograft function further decreased. A second biopsy showed clear BK viral nephropathy. BK viremia and creatinine decreased only after immunosuppression reduction and starting treatment with leflunomide. Further study is needed to define the safety and efficacy of IVIg as treatment of BK infection.
Paridaans et al 2015 conducted a study to evaluate the effectiveness of IVIG used to prevent fetal intracranial hemorrhage (ICH) in fetal and neonatal alloimmune thrombocytopenia at a lower dose, i.e. 0.5 g/kg. A total of 23 pregnant women with human platelet antigen alloantibodies and an affected previous child without ICH were included in the study and randomized to receive 0.5 or 1 g/kg IVIG per week. In both groups no ICH was observed. The risk of adverse outcomes in FNAIT pregnancies treated with IVIG at 0.5 g/kg is very low, similar to that using 1 g/kg, although our uncompleted trial lacked the power to conclusively prove the noninferiority of using the low dose.
Neonatal hemochromatosis is a rare gestational disease resulting in severe fetal liver disease with extrahepatic iron overload sparing the reticuloendothelial system. Baruteau et al, 2014 performed a study aimed to assess the effect of antenatal treatment with IVIG on the outcome of pregnancies in women with a past history of documented neonatal hemochromatosis likely due to gestational alloimmune disease (GALD), and to analyse IVIG tolerance. It showed that the antenatal treatment with IVIG improves the outcome of pregnancies despite mild signs of transient neonatal liver disease.
Christiansen et al 2014 conducted a single-centre, randomized, double-blind, placebo controlled trial to determine whether infusions with intravenous immunoglobulin (IVIg) during early pregnancy increase live birth rate in women with secondary recurrent miscarriage compared with placebo. A group of 82 women with unexplained secondary recurrent miscarriage and at least four miscarriages were selected for the trial and they were randomly assigned to repeated infusions with IVIg or placebo (albumin) from the time of positive pregnancy test to gestational week 15 or pregnancy loss. In this trial, which is the largest so far, IVIg did not increase the live birth rate in patients with secondary recurrent miscarriage and the treatment cannot be recommended in clinical practice.
Wong et al(2014) report in a Cochrane review that Paternal cell immunization, third-party donor leukocytes, trophoblast membranes, and intravenous immunoglobulin provide no significant beneficial effect over placebo in improving the live birth rate in women with previous unexplained recurrent miscarriages. Because immunological aberrations might be the cause of miscarriage in some women, several immunotherapies have been used to treat women with otherwise unexplained recurrent pregnancy loss.
Nyborg et al 2014 conducted a study to assess outcome in terms of live-birth rate after fresh or frozen IVF/ intracytoplasmic sperm injection assisted reproductive technology (ART) cycles where immunomodulation was given to patients with recurrent pregnancy loss after prior ART treatment. Fifty-two patients with a history of at least three consecutive pregnancy losses after ART who underwent at least one further ART cycle with concurrent immunomodulation were included. It was concluded that immunomodulation with a combination of IV immunoglobulin and prednisone is a promising treatment for recurrent pregnancy loss after ART, but randomized placebo-controlled trials are needed.
Nguyen at al 2015 described a case regarding a positive clinical outcome with IVIg as monotherapy in recurrent pemphigoid gestationis. Pemphigoid gestationis (PG) is an autoimmune blistering disease associated with pregnancy. It is characterized by the presence of autoantibodies against bullous pemphigoid antigens in the basement membrane zone. A 32 year old female developed PG in the first pregnancy and had a stillbirth. PG recurred during the second trimester of her second pregnancy. Systemic corticosteroid therapy was cause for concern since patient developed gestational diabetes. Patient was unwilling to use insulin. Intravenous immunoglobulin (IVIg) was used as a treatment of last resort. The dose was 2 g/kg/cycle. It was given every two weeks antepartum and every three weeks for three months postpartum. PG improved within four weeks of IVIg therapy. Serum and tissue immunopathological studies were negative prior to delivery. A healthy neonate was born. No adverse events to IVIg were observed. No disease was observed ten months postpartum.
Chung et al researched the efficacy of rituximab (RTX) and IVIG combination therapy (RIT) in patients with chronic antibody-medicated rejection (CAMR). They previously presented a study in which was concluded that RIT was effective as treatment of CAMR, however there was no control group of patients without RIT. Fifty-nine patients were grouped in 25 patients who received RIT and 29 who did not (historical control (HC)). The RIT patients experienced no serious adverse and only one case of herpes zoster infection was observed. The glomerular filtration rate/month was significantly reduced and the allograft survival rate higher in the RIT group compared to the HC group. Patients with a low proteinuria showed a better survival rate in both groups. Patients with high proteinuria in the RIT group showed a higher survival than the HC group. Therapy with RIT is recommended for delaying the progression of CAMR without serious adverse events, and is not restricted by high proteinuria.
Foetal and neonatal
Van der Lugt et al described the neonatal outcome and management in neonates with FNAIT treated antenatally with IVIG. A total of 22 neonates were included of whom 12 (55%) had severe thrombocytopenia at birth (platelet count ’50??109/L). Most neonates (67%, 8/12) with severe thrombocytopenia received a platelet transfusion after birth. None of the neonates required postnatal treatment with IVIG. Three neonates had petechiae and haematomas, without clinical consequences. One foetus suffered from intracranial haemorrhage, which was detected just before the planned start of antenatal IVIG at 28 weeks’ gestation. In conclusion antenatal maternal IVIG and, if necessary, postnatal matched platelet transfusions, are effective and safe for the treatment of FNAIT.
Cos and Rodr??guez-Martorell reported a case of eight months old patient with severe heamophilia A after a hemarthrosis. The patient was treated with regular factor replacement therapy on-demand. At the age of six an inhibitor was detected (1.75-2.5 BU). An immunotolerance induction (ITI) program was started, however the inhibitor persisted and the parents decided to discontinue the program after three months. The patient started therapy with recombinant activated FVII in bleeding episodes and thirteen months later the titer spiked to 37 BU. At age eleven, treatment with plasma-derived FVIII (Fhanhdi) and IVIG (Flebogamma) was started and after sixteen months the inhibitor was eliminated. This treatment was continued for three more months and changed to FVIII prophylaxis. Currently the patient had no inhibitors.
Lejeune et al reported a case of dicygotic twins with persistent congential parvovirus B19 infection (CPB19). The twins were born premature after 29 weeks and 4 days of gestation due to CPB19 which caused fetal hydrops and high levels of viremia in both twins. After they were discharged, they were readmitted to the hospital with critical aplastic crisis, when they were three months old. After treatment with IVIG was initiated, the viremia levels decreased and subsequently the hemoglobin levels stabilized in both infants. IVIG treatment seems to be effective to introduce viral remission and to normalize erythropoiesis in infants with congenital pure red cell aplasia due to CPB19.
A retrospective study by Yen et al 2015 analyzed 67 neonates with culture-confirmed severe enteroviral infection, defined as hepatitis with coagulopathy and thrombocytopenia. The peak serum AST level was correlated with the clinical outcome and patients with a serum AST level > 1000 IU/L, particularly > 2000 IU/L, had a significantly higher case-fatality rate. In most cases, the serum AST level peaked within three days of illness onset, which suggests that frequent sampling for monitoring serum AST level is mandatory for neonates with possible severe enteroviral infection. Once a serum AST level is higher than 1000 IU/L, IVIG therapy may be considered to be administered to achieve a better clinical outcome.
Atikan et al 2015 reported a case of a perforated appendicitis after administration of IVIG for neonatal hyperbilirubinaemia. The child was born after an uneventful pregnancy to a 29-year-old mother via elective caesarean section with a birth weight of 2500 grams. At the 98th hour of life, the newborn was admitted to the neonatal intensive care unit with jaundice. Laboratory tests of the infant revealed unconjugated hyperbilirubinemia (19 mg/dl), high lactate dehydrogenase level and mild anemia (hematocrit = 34%). There were signs of hemolysis in the blood smear. The infant had a blood group of Rh (+) and direct Coombs test was strongly positive. There were no other pathological signs or symptoms in her physical examination and laboratory tests. Intensive phototherapy was started according to the clinical practice guidelines of AAP for the management of hyperbilirubinemia in newborns. IVIG therapy was given in a dose of 1 g/kg over 6 hours due to rapidly increasing bilirubin levels despite 6 hours of intensive phototherapy.
The patient developed abdominal distention, bilious retention and bloody stools 10 hours after IVIg therapy was completed. Repeated blood count and bio-chemical tests revealed thrombocytopenia (89000/mm3), leukopenia (3500/mm3) and elevated C-reactive protein (3.3 mg/dl, N < 0.8 mg/dl) with no other abnormality. D- dimer level was also normal. Abdominal X-ray showed intestinal dilatation and pediatric surgery was consulted for possible Necrotizing Enterocolitis (NEC) and peritonitis. Patient was put on antibiotics as soon as blood and urine cultures were obtained. Yellow-green colored and cloudy peritoneal lavage fluid had a bilirubin of 640 mg/dl (180 mg/dl conjugated), lactate dehydrogenase 1760 U/L, amylase and lipase levels below < 3 U/L. Upon these finding, the patient was operated with the suspicion of bowel perforation. A localized perforation in the appendix of cecum was observed during laparotomy. Other parts of intestines were found healthy. Differential diagnostic tests to exclude other causes of neonatal appendicitis; such as sepsis, urinary tract infection, congenital cytomegalovirus infection, cystic fibrosis and Hirschsprung's disease were all negative. Histopathological examination showed inflammation and tissue damage in appendix. The patient was completely recovered and was discharged within 4 days after surgery. In this case, there were no known risk factors or underlying diseases. However, the presence of NEC cases reported after IVIg administration, had brought a possible effect of IVIg for the development of appendicitis to mind. A 37 year old female with a medical history of gravida 1 and parity 0 delivered a neonate who experienced liver failure and died only 17 hours after delivery although there were no symptoms during the pregnancy or delivery. Based on a positive using immunohistochemical staining of membrane attack complex (MAC IHC) staining, the neonate was diagnosed with neonatal hemochromatosis (NH). Subsequently, the woman had two spontaneous miscarriages. She conceived again and after 14 weeks of gestation IVIG (1g/kg/week) was administered. She had no complications and had an at term delivery of a healthy neonate. The neonate had slight abnormal liver functions and iron metabolism, from which it recovered without any treatment. Treatment with IVIG significantly improved the outcome of the neonate. Ohlsson and Lacy 2015 conducted a meta-analysis to assess the efficacy of IVIG for mortality and morbidity caused by suspected or proven infection in neonates and in a subgroup analysis the effects of IgM-enriched IVIG on mortality from suspected infection. The immune system of neonates is underdeveloped and they rely on maternal immunoglobulin transported to the fetus after a gestational age of 32 weeks. In theory, therapy with IVIG could reduce the morbidity and mortality caused by infections. No reduction in mortality during hospitalization, or death or major disability at two years of age was shown in the analysis. Also IgM-enriched IVIG did not significantly reduce mortality during hospitalization. Therefore, routine IVIG or IgM-enriched IVIG treatment to avoid mortality in infants with suspected or proven neonatal infection Kumar et al 2014 report a case of a neonate who experienced apnea after the treatment of Rh hemolytic disease (RHD) with IVIg. The neonate was born premature, O Rh-positive and clinically normal at birth. Her first born child did not have neonatal jaundice. The mother did not receive anti-D immunoglobulin and anti-D titer was not performed. At 11h he experienced icterus. Laboratory results included hemoglobin - 12.8 g/dl, total serum bilirubin (TSB) - 6.4 mg/dl, reticulocyte count-18 %, positive indirect Coomb's test and evidences of hemolysis in peripheral smear. He was treated with intensive phototherapy, however at 42h the TSB increased to and the first double-volume exchange transfusion (DVET) was administered. A second dose of DVET at 96h at a TSB level of 18.4 mg/dl. IVIg treatment (1 ml/kg/h) was started to avoid further DVET. After 10 minutes of starting the infusion, he suddenly experienced apnea, bradycardia and desaturation which reacted to positive pressure ventilation (PPV). The treatment with IVIg was discontinued immediately. The neonate showed no signs of anaphylactic reaction, shock, hypo/hyperthermia, hypoglycemia, hematuria and dyselectrolytemia. IVIg therapy was restarted after 1h at 0.5 ml/kg/h. within 2 minutes he experienced apnea again and needed PPV. After discontinuation of IVIg, the neonate remained stable. Complete blood count, sepsis screen including blood culture, coagulation profile and renal function test remained normal. Apnea was never before reported it was emphasized to be cautious with the use of IVIG in neonates. Linn??r et al 2014 performed an observational study to document the clinical efficacy of Ivig treatment in streptococcal toxic shock syndrome (STSS) patients. The effect of IVIG was evaluated in STSS patients prospectively identified in a nation-wide Swedish surveillance study conducted between April 2002 and December 2004. 67 patients were included in the study; 23 with IVIG treatment and 44 without. No significant differences as seen between the groups, except that the IVIG group was slightly younger and had had a higher degree of necrotizing fasciitis (56% vs 14%). The primary end point was survival at day 28. Analysis results showed that the Simplified Acute Physiology Score, clindamycin and IVIg impacted the survival. In conclusion: Ivig and clindamycin treatment significantly improved survival in patients with STSS. Paediatric Kovacevic et al 2015 described a case series of 12 youths treated with intravenous immunoglobulin (IVIG) for pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS)/ pediatric acute-onset neuropsychiatric disorder (PANS). Although it is a clinically based series, the case reports provide new information about the short-term benefits of IVIG therapy, and are the first descriptions of long-term outcome for PANDAS/PANS patients. This case series demonstrates the benefits of IVIG therapy for youths with PANDAS/PANS, including those who had been symptomatic for several years prior to treatment. Although the generalizability of this retrospective report is limited, the selected cases represent the breadth of symptom presentations in PANDAS/ PANS and provide additional evidence that IVIG may be useful in the management of children with moderate-severe symptoms. Kim and Kim report a case of a 33-month-old boy with KD with small coronary artery aneurysm (CAA). IVIG treatment within the first ten days of the illness significantly reduce the occurrence of CAA. The patient was admitted to the hospital with a fever for three days and skin rash, red eyes and lips, and increasing left neck pain for two days. On day two of the hospitalization he was diagnosed with KD with acute myocarditis and the first dose of IVIG was administered. As his condition did not improve, a second dose of IVIG was given on the fourth day of admission without effect. On the sixth day a third dose was given together with dexamethasone and the Kawasaki symptoms slowly disappeared. On day ten the symptoms reappeared. On day fourteen the fever was gone and he was discharged two days later. That night he was readmitted with bilateral conjunctival injection, fissured red lips and edematous hands. An echocardiogram showed a small aneurysm of the left main coronary artery. On day seventeen he was treated with IVIG, aspirin and clopidogrel and he showed improvement immediately after the infusion. Heitink et al 2014 performed a systematic review and meta-analysis regarding clinical and laboratory predictors of chronic immune thrombocytopenia (ITP) in children. Childhood ITP is a rare autoimmune bleeding disorder. Most children recover within 6 to 12 months, but individual course is difficult to predict. The review and meta-analysis showed that children with mucosal bleeding at diagnosis or treatment with intravenous immunoglobulin alone developed chronic ITP less often. They concluded that the protective effect of intravenous immunoglobulin is remarkable and needs confirmation in prospective randomized trials as well as future laboratory studies to elucidate the mechanism of this effect. Privette et al presented a case regarding a 3-year old girl with cutaneous manifestation of Ataxia- Telangiectasia (AT). The girl visited the emergency department with ataxia, poor growth and various ulcerated plaques on her arm which she had for two years. She was treated with IVIG and mometasone (topical steroid). After six weeks of treatment, she recovered completely from the skin lesions. Gokturk et al evaluate the effect of IVIG on H1N1 influenza in immunocompromised children. The hospital records of 21 children with H1N1 who were hospitalized, were retrospectively studied. High fever, cough, fatigue and vomiting were the predominant signs of the influenza and fourteen patients had lower respiratory tract symptoms. Six patients had PID and were treated with IVIG replacement three-weekly. They did not need to be admitted to the intensive care unit nor die. Even the average duration of their cough, fever and hospitalization was lower, although this decrease was not statistically significant. This is the first study that demonstrated a possible positive effect of IVIG replacement treatment in patients with H1N1 influenza and PID. Prasad and Chaudhary performed a retrospective study for the efficacy of IVIG as treatment of pediatric patients with acute myocarditis and/or early dilated cardiomyopathy (DCM). Medical records of a Pediatric Critical Care Unit were reviewed and in total 28 patients were included (12 patients received two days of IVIG therapy, 1 g/kg/day). The IVIg group showed an increased ejections fraction and decreased end diastolic diameter of the left ventricle. It was concluded, that IVIG therapy of acute myocarditis and/or early DCM improved recovery of the function of the left ventricle and decreased the episodes of fulminant arrhythmias in children. Kapoor et al described as case report regarding an 18-month-old boy with typhoid fever who developed GBS. The child was treated with intravenous antibiotics and intravenous immunoglobulin and recuperated. Bello-Espinosa et al 2015 described the experience of a pediatric epilepsy center the efficacy of IVIG in children with drug-resistant seizures. Twenty-seven children (3-17 years old) were included in the analysis. Twenty-two of the 27 children showed a positive clinical response ('50% reduction) from baseline and five did not respond. It was concluded that IVIg showed a potentially high efficacy in the treatment of children with drug-resistant epilepsies. IVIg reduced multiple seizure types in a variety of epilepsy etiologies, including those of unknown cause. Elderly Molinaro et al reported two case reports of IVIg as treatment of membranous nephropathy in elderly patients. Membranous nephropathy is a common cause of nephrotic syndrome in elderly patients. A range of infections are a significant source of morbidity and mortality in these patients. These two cases described IVig as effective long-term prophylaxis of infections in elderly patients with membranous nephropathy and no risks for the renal function. It was concluded that IVIG without sucrose is a safe prophylactic option in patient with nephrotic syndrome and IgG levels below 600 mg/dL. Arai et al studied if the use of IVIG (10%) in Japanese patients with mild to moderate Alzheimer's disease was safe and tolerable. Sixteen patients were included in the study, 12 received IVIG and 4 placebo. The two treatment groups showed no significant differences in the occurrence of adverse events. In total there were four serious adverse events and they were all assessed as not related to the study treatment. No clinically significant abnormalities or findings related were observed regarding safety. In conclusion, IVIG treatment was safe and well tolerated. Case report Charhon et al 2015 report a case of circulatory collapse following IVIG treatment. A 61 year old female with a medical history of polycystic liver and kidney disease complicated by chronic kidney failure. In 2011 she experienced a chronic kidney graft rejection and developed liver failure. On 08-JUN-2011 she received liver and kidney transplants and the surgery was uneventful. The kidney transplantation was delayed by 3 hours because T-cell lympocytotoxic and B-cell cytotoxic cross-matches were positive. Two days later, the total bilirubin and creatinine levels increased respectively to 243 mmol/L and 103 mmol/L. During IVIG infusion the patient experienced circulatory collapse with a decrease of systolic blood pressure from 130 mmHg to 60 mmHg. She became hypoxic and required orotracheal intubation and was treated with norepi-nephrine. The patient showed signs of consciousness disorder, a temperature of 38 8C, but no sign of tachycardia. IVIG therapy was discontinued. She received approximately 5 g of the 60 g scheduled for day 1. After mechanical ventilation, clinical improvement was observed. Infectious liver and kidney rejection were suspected. It was decided to re-challenge with IVIG treatment the next day without exceeding the second step infusion rate. On July 13th, the duration of IVIG administration was 17 h instead of 3 h 30 min without any notable AEs to report. All in all, she received 65 g of IVIG. The following days, both liver and renal functions improved. The patient was discharged in a stable condition on August 10th, 2011. In July 2012, liver and renal functions were still normal. According to the Naranjo probability scale, the relationship between IGIV and circulatory collapse in this case is ''probable''. However, it could not be definitely excluded that severe hypotension was related to a collapse secondary to an infectious disease. Septic shock was considered because of fever and immunosuppressive drugs, before suspecting IVIG. It was for this reason why this patient received norepinephrine and not epinephrine in the case of this circulatory collapse without tachycardia or cutaneous symptoms. However, in this case, we were able to halt norepinephrine treatment 8 hours later, whereas norepinephrine weaning is generally longer for septic shock than presented in our case report [8]. Moreover, a low dose of norepinephrine was used. The rapid clinical improvement after cessation of IVIG does not support a septic shock hypothesis. Clinicians should be aware that IVIG therapy can cause circulatory collapse even at infusion rates recommended by the manufacturer. Moreover, they should be informed that re-challenge by decreasing the infusion rate associated with close clinical monitoring is possible in order to achieve IVIG therapy. Sugimoto et al described a case regarding a patient with X-linked agammaglobulinemia (XLA) treated with IVIG, who experienced tubulointerstitial nephritis. Urinary ??2-MG and serum creatinine levels improved after treatment with steroids. Drug reactions and collagen disease were not likely causes of tubulointerstitial nephritis . Although BK virus was ruled out, IgG in the ??-globulin preparation might have reacted with a pathogen present in the patient to form low-molecular-weight immune complexes that were deposited in the tubular basement membrane.

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