Disclaimer:  The information contained below involves the use of medications that can cause serious adverse events in certain patients due to concomitant medical conditions, drug-drug or drug-herbal interactions.  The information is not intended to establish a standard of practice but is rather a summary of my clinical experience in managing immunoglobulin-related side effects.  Currently no standard treatment regimens have been established and the use of any medication must be individualized to each patient, taking into account all potential adverse events that can occur as a result of their administration.

Fortunately, most patients treated with immunoglobulin products either do not experience immunoglobulin-related side effects or side effects are mild and can be easily managed.  However, there are a number of side effects that I have observed in clinical practice that are require or are resolved with medical intervention.  Some of these side effects are somewhat unique to immunoglobulin therapy.  As there were no standards present when we started administering immunoglobulin products, much of this information was gained by trial and error.  Other clinicians having their own experiences can share their information using the blog on this website. 

Pretreatment Regimens:  Many clinicians prefer to pretreat patients with oral medications such as Tylenol (acetaminophen) or Benadryl (diphenhydramine) to minimize any potential side effects, especially if patients are being administered in a non-clinical setting such as in their home.  The disadvantages to doing this is that some side effects may be masked and/or occur after the infusion is completed and the nurse has left the home.  Additionally, diphenhydramine can cause drowsiness and other unwanted side effects.  One pretreatment recommendation that is gaining popularity is asking the patient to hydrate before, during and after the infusion.  Although not well documented, hydration does appear to reduce the likelihood of a number of minor/moderate side effects and unless the patient is fluid restricted, this should probably be recommended for all patients receiving immunoglobulin therapy.

SIDE EFFECT MANAGEMENT - PERSONAL EXPERIENCE

MINOR SIDE EFFECTS     
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Headache During The Infusion and/or Hypotension/Hypertension
The exact mechanism of these reactions is not well established, but is probably the result of administration of a high concentration of immunoglobulin proteins or possible related to very low levels of potential contaminants that are not removed in the manufacturing purification process. 

Headaches that occur during the infusion are often associated with mild to moderate hypotension or hypertension.  These headaches during the infusion are relatively common and are often  the result of too high of an infusion rate.  Simply slowing the infusion often results in a rapid reversal of these symptoms and often this is a sign of a patient's maximum tolerated infusion rate for that particular  product.  The infusion can also be stopped until the symptoms subside and then restarted at a slower infusion rate.  If the symptoms do not resolve or are moderate to severe in nature, these should be treated as serious and medically managed as appropriate.  Headache can also be the result of a blood clot in the brain or veins in the eyes (See Thromboembolic Events Below) and therefore this must be ruled out if it does not quickly resolve or other signs or symptoms of a thromboembolic event are present.   If the headaches are especially bothersome, other brands of intravenous immune globulins or subcutaneous administration can be tried.

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Flu-Like Symptoms    
The exact mechanism of these reactions is not well established, but again is probably the result of administration of a high concentration of immunoglobulin proteins or related to very low levels of potential contaminants that are not removed in the manufacturing purification process. 

These symptoms often occur hours to days after an infusion  and can be mild to moderate in severity.  Slowing the infusion rate or pre and post treatment with Tylenol (acetaminophen), aspirin or other non-steroidal medications such as Motrin (ibuprofen) may be helpful if they are not contraindicated for the patient.  If the symptoms are especially bothersome, other brands of intravenous immune globulins or subcutaneous administration can be tried.  These do seem to be infusion rate related as we treated several patients with extended infusion times (12-24 hours) utilizing portable infusion pumps and subcutaneous therapy which mimics a slow infusion rate both seem to be effective here.

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Rash     
A rash can occur as a result of an allergic reaction to a component in the  immunoglobulin solution or an allergen that has not bee effectively removed during the manufacturing purification process. 

Generally, rashes can be treated with a single dose of an antihistamine such as diphenhydramine and/or a corticosteroid such as methylprednisolone, although in some cases a more prolonged course of therapy with these medications may be necessary.  Once a patient has experienced a rash, pretreatment with antihistamines may be sufficient in preventing a recurrence and after a period of time the pretreatment can be withheld to determine if it is still necessary.  In severe cases, other brands of intravenous immune globulins or subcutaneous administration can be tried.

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Severe Post-Infusion Headache  (Aseptic Meningitis)    
A severe headache that often occurs after an infusion and may last for hours to days after an infusion is most often due to immunoglobulin induced inflammation in the spinal cord, known as aseptic meningitis (sterile meningitis).  As mentioned above, Headache can also be the result of a blood clot in  the brain or veins in the eyes (See Thromboembolic Events Below) and therefore this must be ruled out if it does not quickly resolve or other signs or symptoms
of a thromboembolic event are present.

Aseptic meningitis is more common with individuals with a history or migraine headaches and is often described as severe and debilitating.  Unfortunately, pretreatment is generally ineffective although there are some reports of success utilizing medications commonly used to treat migraine headaches as a pretreatment regimen.  While aggressive pain management is generally necessary to make patients more comfortable, the severe headache can last 24-72 hours.  Aggressive hydration and very slow intravenous infusions can be tried initially but if these headaches are not controlled, often they can be prevented by utilizing a different immunoglobulin product (many different products may need to be trialed) or alternatively, these patients are ideal candidates for subcutaneous administration where the risk of aseptic meningitis is low.  The goal should be to prevent these headaches from occurring due to their severity.

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Anaphylactoid/Anaphylactic
Anaphylactoid or anaphylactic reactions are usually the result of a reaction to a low level of a contaminant present in the immunoglobulin product but could also be a reaction to immunoglobulins themselves.

While I have not witnessed an anaphylactic reaction to immunoglobulin therapy, I have witnessed about six cases of anphylactoid
reactions.  Anaphylactoid reactions present as a slowly progressing tightness in the chest, difficulty breathing, redness around the neck area and hypertension.  The infusion should be stopped and typically the administration of intravenous diphenhydramine and methylprednisolone will reverse the symptoms within 15-20 minutes.  While these symptoms will also resolve on their own within 30-60 minutes, often patients are very afraid and unless these medications are contraindicated, the patient will be comfortable within a much shorter period of time if intervention with medications is employed.  There may also be a threshold of corticosteroid (methylprednisolone in this case) that is effective as 125 mg was effective in all patients that received this whereas in two patients where a lower dose was administered, it was ineffective in reversing symptoms.  

Whether or not to continue the infusion after symptoms resolve should be a decision between the clinician and the patient.  In my experience, symptoms may return in some patients and not in others.  Pretreatment with antihistamines and steroids is probably
useful for the next several infusions before attempting to discontinue this regimen if the same brand of intravenous immunoglobulin is continued.  If the patient is switched to another brand of intravenous immunoglobulin or subcutaneous administration is employed, pretreatment may not be necessary, although close monitoring of the patient is advised and these medications should be on hand in the event the patient experiences this reaction with the alternative brand/administration route of immunoglobulin.

Anaphylactic reactions are generally treated first with epinephrine and antihistamines along with the possible addition of a corticosteroid.  These are life-threatening reactions and much be managed immediately! 

It is interesting to note that we found that anaphylactoid reactions generally did not respond to epinephrine, suggesting a potential difference in mechanism of action between the two reactions.

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Rigors (Uncontrollable Shaking and Fever/Chills)
Rigors are likely due to a contaminant present in the immunoglobulin preparation or may be the body's response to a particular immunoglobulin present in the preparation.

Rigors presents as uncontrollable shaking and often associated with an increase in temperature with chills and is very similar to that seen with intravenous administration with an antifungal agent (amphotericin).  Given our experience in treating rigors associated with amphotericin, we found that administration of intravenous diphenhydramine and methylprednisolone followed by the intravenous infusion (IV Push) of the narcotic Demerol (meperidine) what very effective in halting these symptoms.  I have also been told that other narcotic such as morphine or hydromorphone are equally effective and this is helpful as some patients may not tolerate meperidine or it may be contraindicated due to previous reactions or other drug-drug reactions. 

Whether or not to  continue the infusion after the symptoms resolve should be a decision between the clinician and the patient.  Most patients are very scared after experiencing this reaction as it is severe and do not want to continue.  In some patients the symptoms will return and in others it will not, so this must be a careful decision.  While premedication can be employed for subsequent infusions if the same brand of immunoglobulin is used, in all cases we changed brands of immunoglobulin and patients did not experience this reaction with the product they were switched to.  However, our experience was only in about six patients, so there is no guarantee that the patient will not experience this reaction with a different brand of intravenous immune globulin and clinicians should be prepared to treat this reaction if it recurs.  Alternatively, patients can be switched to subcutaneous therapy where the incidence of rigors is very low.

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Severe Back and Leg Pain
The exact mechanism of these reactions is not well established, but is probably  the result of administration of a high concentration of immunoglobulin proteins  or possibly related to very low levels of potential contaminants that are not removed in the manufacturing purification process. 

Severe back and leg pain is rare but can occur during the early portion of an infusion and the onset is dramatic.  Patients describe the pain as excruciating.  Again, our standard treatment of diphenhydramine and methylprednisolone were given along with liberal amounts of intravenous narcotics to make the patient comfortable.  The infusion can be restarted once the patient is comfortable but the reaction can recur and often patients are not willing to continue due to the intensity of the pain.  Interestingly, this side effect does appear to be one which diminishes over the next couple of infusions although our experience was limited to three patients where we continue the same brand of intravenous immunoglobulin (although utilizing different lot numbers).  With premedication of the three drugs mentioned above, the patients had either mild or no symptoms with the second infusion and none with their third infusion and premedication was discontinued.  In two other patients, a different intravenous immunoglobulin product was used and no premedication was necessary.

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Thromboembolic Events
Thromboembolic events are caused by blood clots that form as a result of immunoglobulin therapy and can cause a number of issues such as heart attack, stroke, deep vein thrombosis in the leg or arm, retinal vein occlusion resulting in impairment or loss of eyesight or a pulmonary embolism (blood clot in the lung).  While first reported in 1986, these came to the forefront in 2010 and 2011 when three manufacturers either withdrew or phased out their products due to an increase in number of these serious side effects.  While a number of mechanisms were purported to be responsible for immunoglobulin increasing the risk of clotting, that fact that immunoglobulin therapy makes blood more viscous and the potential contaminant of a clotting agent called Factor XIa (FXIa) were considered to be most likely.  As a result of analyses by the FDA and manufacturers of lots that caused a higher than expected incidence of thromboembolic events, FXIa was determined to be the primary cause of increased clotting and a reduction of this factor resulted in a greatly reduced incidence of this side effect.  

Despite reduced levels of FXIa in immunoglobulin products, thromboembolic events still do occur, especially in patients with risk factors for thrombosis or previous thromboembolic events.  This would imply that the other proposed mechanisms may still play a role in the risk for these side effects.  Whether or not patients at high risk who are receiving immunoglobulin therapy should be treated with medications to reduce clotting has not been established, although there is one report from Australia where patients experiencing clotting of arterio-venous fistulas (a surgical procedure performed for dialysis) were treated with aspirin and low-molecular weight heparin which was effecting in reducing the clotting risk.

__________________________________________________________________________________Hemolysis/Hemolytic Anemia
Hemolysis is the destruction of red blood cells and if enough cells are destroyed a patient may experience hemolytic anemia.  There are a number of mechanisms proposed for this but most evidence points to antibodies against red blood cells (primarily Types A, B and AB) that are not removed sufficiently during the manufacturing purification processes.  These antibodies attack those types of red blood cells and can cause them to break apart.

Hemolysis and Hemolytic Anemia due to immunoglobulin therapy was not much of an issue until some of the newer 10% intravenous products entered the marketplace.  A number of studies have shown that levels of these antibodies are higher in some of these products and does appear to mirror the higher incidence of hemolytic anemia in patients being treated with those products.  The signs and symptoms of hemolysis and hemolytic anemia generally show up within days or weeks of an immunoglobulin treatment.  While mild hemolysis may present as fatigue, more significant hemolytic anemia can be life-threatening and require blood transfusions.  It is therefore important for patients to report any signs of potential hemolysis/hemolytic anemia to their physician immediately in order to perform appropriate blood testing for proper diagnosis and treatment.  While there is little published evidence as to how to prevent this side effect, it does appear to be primarily associated with high doses given over a short period of time.  Therefore, patients receiving high doses should have these administered over 2-3 days or even every other day with those products at high risk for hemolysis.