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Abstract & Commentary
Synopsis: Higher than usual doses of intravenous immune globulin (IVIG) were more effective in preventing infections and reducing the duration of illness, but the added cost is hard to justify for most stable patients.
Source: Eijkhout HW, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypoglobulinemia. Ann Intern Med. 2001;135:165-174.
About half the patients with x-linked hypoglobulinemia or combined variable immunodeficiency syndrome in The Netherlands were studied to see whether 300 mg/kg or 600 mg/kg (400 mg/kg and 800 mg/kg in children) every 4 weeks was better in preventing infections and reducing illness.
In a crossover design, they randomized 41 patients from 15 centers to initially receive either the high-dose or low-dose regimen for 9 months, then gave them 3 months on their previous (baseline) regimen, then another 9 months of the opposite regimen they received initially.
They observed 135 infections in the standard-dose therapy patients (90.2% had 1 or more infections) and 103 (83.7% had 1 or more infections) in the high-dose program. The time until an infection occurred was shorter (81.5 days) in the standard regimen than in the high-dose one (123 days). They also found the duration of symptoms to be less at 3.5 ± 2.6 and 2.5 ± 2.4 days, respectively. Half of the infections were respiratory.
They also studied hospitalizations, abscences from work or school, and compared children with adults. No significant findings were noted, but it was obvious some patients were more likely to get infected than others. There was, however, a greater improvement in peak expiratory flow rates at the end of the higher dosage (37 L/min) than the lower dosage (11 L/min) and a reduction in antibiotic use although neither difference was statistically significant. The immune globulin levels achieved were clearly higher for the high-dose program than for the low-dose one (trough levels of 9.4 vs 6.5 g/L). There was no significant difference in carriage of respiratory pathogens.
Side effects of the IVIG were also studied for the 1057 infusions and little difference was found other than a higher incidence of headache and nausea with the 600 mg/kg dose.
Comment by Alan D. Tice, MD, FACP
Immune globulin is a life-saving product for hypoglobulinemic individuals. Questions remain, however, about the appropriate doses needed for optimal benefit, especially in light of its cost and, lately, scarcity of the product.
The finding of a reduced number of infections with higher doses is no surprise, although prior studies have not demonstrated such clear statistical significance. It is also a bit troublesome given the cost and scarcity of IVIG in the United States. Eijkhout and colleagues suggest the higher dose would cost $5000 for each adult for each 6 months. In the United States, where IVIG costs about $90/g, the costs for a 100 kg male would be an added $2700 per dose or $16,200 for each 6 months.
It is quite possible that even higher doses of IVIG would be of added benefit but it is hard to know what the limits are of cost-effectiveness. Eijkhout et al’s suggestion of giving the higher dose to people who have at least 2 serious infections per year is a reasonable one, although they do not indicate whether the cases in their series were simply sicker, older, or more debilitated than the others.
Although it was not noted, another approach might be to continue most people on a regular dose until they develop an infection, at which time a double dose, or possibly even more, should immediately be given. This might reduce the severity and shorten the duration of the illness and be cost effective in regard to hospitalization and return to work.
Eijkhout et al point out the value of keeping the trough level of immune globulin above 5 g/L as has been demonstrated before. Their correlation of better outcomes with the higher levels may be valuable, but if the trough is the measure to follow, it would seem dosing every 2 weeks would be better than every 4—which was not noted to be of value by the limited observations they made. More studies are needed.
The immune globulin preparation was a Netherlands product. How it compares with those available in the United States is not known. The side effects of the IVIG preparation used in the study were relatively minor, but may have been less than some of the other products commonly available. Extraction methods vary among manufacturers, and so do side effects.
The need for IVIG is clear for hypoglobulinemia but it has value in other diseases such as Kawasaki and pediatric AIDS as well. It would probably be possible to prove its value in a number of other disease states as well if the supplies were plentiful enough and the cost were not too great. Unfortunately, the shortage of IVIG remains a problem with the extreme need for purity and safety because it is a biological extract. The chances of reducing the cost are small given the potential legal consequences of a bad batch such as the case with hepatitis C which Baxter Healthcare is still trying to pay off.
Alan Tice of Infections Limited, Tacoma, Wash., is Associate Editor of Infectious Disease Alert.