Albumin May Predict Prognosis in Guillain-Barré Syndrome

Pauline Anderson

January 11, 2017

A simple measurement of serum albumin concentration could represent a prognostic biomarker in patients with Guillain-Barré syndrome (GBS) treated with intravenous immunoglobulin (IVIG), a new study suggests.

The study showed that 35% of patients with GBS developed hypoalbuminemia (serum albumin <3.5 g/dL) 2 weeks after IVIG treatment and that low albumin levels after treatment were strongly related to a severe clinical course and poor outcome.

GBS is a postinfectious immune-mediated neuropathy causing rapidly progressive weakness of limbs, and respiratory failure in 25% of cases.

"Albumin is a low-cost and routine test that is probably already available for most patients admitted with GBS," said study author Bart C. Jacobs, MD, PhD, professor in neurology and immunology, Departments of Neurology and Immunology, Erasmus Medical Center, University Hospital Rotterdam, the Netherlands.

Dr Bart C. Jacobs

Results of the study "could potentially be used in the future to predict the clinical course and outcome in this unpredictable disease." 

Their findings were published online December 27 in JAMA Neurology.

Urgent Need

Given the acute onset of GBS, there's an "urgent need" to find a biomarker that can be used within the first 2 weeks of onset, Dr Jacobs and colleagues write. This, they said, would allow a more personalized approach to monitor treatment efficacy and anticipate outcome.

Serum albumin has already been identified as an independent factor associated with outcome in amyotrophic lateral sclerosis and failure of IVIG therapy in Kawasaki disease. It's used as a routine diagnostic indicator of overall health, for example, and is included in a comprehensive metabolic panel.

Researchers used data on patients from two previously conducted randomized trials in which clinical data and serum samples were prospectively collected. Samples were taken at standardized time points and were stored at –80°C until use.

The current study included information on 174 patients, mean age 49.6 years, who received the same standard high dose of IVIG therapy (2 g/kg over 5 days).

Researchers used two strategies to assess the possible influence of serum albumin on disease severity. They stratified patients in tertiles based on the serum albumin level before or 2 weeks after starting IVIG therapy, and they also divided patients into two groups: those with hypoalbuminemia and those within the reference range of serum albumin levels (3.5 to 5.5 g/dL).

In the acute phase of GBS before treatment, circulatory albumin levels were within the reference range in most patients (median, 4.2 g/dL), and only 12.8% of 156 patients presented with hypoalbuminemia. Two weeks after IVIG was started, serum albumin levels decreased compared with levels before treatment (median, 3.7 g/dL; P < .001) and more patients had hypoalbuminemia (34.5%).

"We had not anticipated that such a high proportion of patients with GBS would develop hypoalbuminemia," Dr Jacobs told Medscape Medical News.

It's unclear whether GBS itself, IVIG, or both causes the further decrease in albumin level during the first 2 weeks of treatment, he said.

Respiratory Failure

Researchers found that a low serum albumin level was associated with an increased chance of respiratory failure before treatment (36.4%; P = .001) or after treatment (54.7%; P < .001).

Patients with low levels after treatment had a poorer GBS disability score and Medical Research Council sum score (the sum of the score of six muscles, which ranges from 0 for total paralysis to 60 for normal strength) throughout the study and at the end of follow-up (both P < .001).

As the authors noted, low albumin levels obtained before treatment revealed "a limited but potentially relevant association with poor outcome, especially to the chance of respiratory failure" and that the variability of the serum albumin levels 2 weeks after IVIG was started was "most pronounced."

Patients who maintained a serum albumin level within low-normal or high-normal range after treatment recuperated faster than hypoalbuminemic patients. About 90% of those with normal serum albumin concentrations could walk unaided after 6 months compared with about 65% of those with hypoalbuminemia.

Multiple regression analysis found that serum albumin levels at 2 weeks after treatment were an independent factor associated with respiratory failure and inability to walk at 3 and 6 months.

The strength of the association was noteworthy, said Dr Jacobs. "Serum albumin is one of the strongest predictors of outcome in GBS that I have ever seen."

Despite the strong association, some patients with high albumin still developed respiratory failure, "indicating that monitoring of albumin levels cannot replace the standard clinical monitoring of respiration," noted Dr Jacobs. "All patients with GBS potentially are at risk for respiratory failure in the acute stage of disease and should be monitored."

Although hypoalbuminemia has been identified in previous studies as a predictor of poor outcome in various disorders, "to my knowledge this is the first report on albumin as a prognostic marker in GBS," he said.

Surprising Finding

The study found no strong association between an increase in serum IgG levels after IVIG and a decrease in albumin levels, which was somewhat surprising to investigators.

"My hypothesis was that serum albumin and IgG levels were related, since they bind to the same neonatal Fc-receptor that prevents degradation," explained Dr Jacobs.

"But the study only showed a weak association between IgG and albumin levels, suggesting that the underlying mechanism is more complex."

Levels of albumin, which is produced in the liver, decrease with age, but the adverse effect of low serum albumin concentration was still significant after the analyses were corrected for age.

In addition to age, other factors affecting albumin levels might include inflammation and infections. IVIG treatment itself could result in saturation of at least part of the neonatal Fc-receptors that protect both IgG and albumin from degradation, said Dr Jacobs.

GBS has a highly variable clinical course and outcome. Some patients have a rapid and full recovery, while others remain on a ventilator for months and are severely disabled for the rest of their life.

Despite the difference in disease severity, patients receive the same standard treatment. But additional therapy in the first 2 weeks of the disease could prove effective, said Dr Jacobs.

"To be able to adjust the treatment, however, would require prediction of the long-term outcome in individual patients already in the very early stage of the disease. Serum albumin levels may help identify patients who need additional early treatment the most."

He stressed that the study findings need to be confirmed in an independent study before albumin levels are used to predict outcome in clinical practice.

The International GBS Outcome Study might provide some answers. Some 1500 patients with GBS at more than 150 centers from 19 countries are included in this observational cohort study.

"An analysis of albumin and IgG levels, other biomarkers, and clinical predictors hopefully will lead to an accurate prognostic model for clinical practice," said Dr Jacobs.

Zika Spread

In an accompanying editorial, Richard A.C. Hughes, MD, Institute of Neurology, University College London, United Kingdom, noted that the incidence of GBS will increase as a result of the spread of the Zika virus around the world.

Dr Hughes points out that 40% of albumin is in the blood and 60% is in the extravascular space, and the normal albumin concentration in humans is 3.5 to 5.1 g/dL.

"It is not surprising that low serum albumin concentration is associated with a poor prognosis in GBS because such an association is common in many diseases and after surgery."

If the current results are confirmed, serum albumin concentrations may "provide an easily measured biomarker" to add to other clinical factors affecting outcome, including older age, preceding diarrheal illness, and greater weakness, said Dr Hughes.

He stressed the need for such a biomarker that will allow early accurate prognosis. He noted that although eventual improvement and recovery are usual, between 3% and 10% of patients with GBS die, 10% to 20% are left unable to walk without aid after a year, and persistent fatigue and pain are common even with treatment.

"We need to identify the patients with a poor prognosis and find new, more effective treatments than the standard intravenous immunoglobulin or plasma exchange," he writes.

Results of the current study suggest that serum albumin is a "leading candidate" for a biomarker, but if a low serum albumin is merely a surrogate marker for inflammation, "a more direct measurement of an acute-phase protein, such as C-reactive protein, would also be worth exploring," Dr Hughes concluded.

Medscape Medical News also asked Michael T. Andary, MD, professor, residency program director, Department of Physical Medicine and Rehabilitation, Michigan State University College of Osteopathic Medicine, East Lansing, to comment on the study.

"This is an interesting retrospective look at blood albumin levels as a marker and possibly a predictor for outcome from GBS," said Dr Andary.

The study "does an excellent job" of documenting that patients with low albumin are sicker, have worse outcomes, and are more likely to need ventilatory support, said Dr Andary.

While many clinicians have likely seen this in their own practice, "it's hard to see how this will alter very much the management of the patient," especially ventilator support.

"We will still give the support, medical care and rehabilitation the patient needs, whether the albumin is high or low," said Dr Andary. "I don't see any indication from this data that patients with low albumin should be treated any differently, but likely will get longer treatment and have a slightly worse outcome."

This study was supported by a grant from the Prinses Beatrix Spierfonds. Dr Jacobs reported receiving grants from the GBS-CIDP Foundation International, Baxalta, CSL-Behring, and Grifols.

JAMA Neurol. Published online December 27, 2016. Study abstract, Editorial extract

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