From the Journals

Arginine deficiency implicated in novel hemorrhagic fever fatality


 

FROM SCIENCE TRANSLATIONAL MEDICINE

Deficiency of the amino acid arginine is implicated in the low platelet counts of severe fever with thrombocytopenia syndrome (SFTS), and a measure of global arginine bioavailability had prognostic value for mortality from the causal bunyavirus, according to a metabolomics analysis of serum from SFTS patients.

Platelets Prof. Erhabor Osara/Wikimedia Commons/CC ASA 4.0

The new study also reported results from a randomized, controlled trial of intravenous arginine supplementation in SFTS; the 53 patients who received 20 g of arginine once daily had faster viral clearance than the 60 patients who received supportive care only and a placebo infusion (P = .047). Also, SFTS patients who received arginine had quicker resolution of liver transaminase elevations (P = .001).

There was no survival benefit in arginine administration, though the study’s first author, Xiao-Kun Li, MD, and colleagues noted low overall fatality rates in arginine-treated and placebo groups, at 5.7% and 8.3%, respectively.

Severe fever with thrombocytopenia syndrome is caused by a bunyavirus first identified in 2009; SFTS is being seen with increasing frequency in mainland China, Korea, Japan, and the United States. Infection with the virus “is associated with a wide clinical spectrum, with most of the patients having mild disease but more than 10% developing a fatal outcome,” wrote Dr. Li and the other researchers in Science Translational Medicine.

In the case of individuals with SFTS who fare poorly, previous work had implicated a disordered host immune response leading to severe thrombocytopenia with subsequent bleeding and disseminated intravascular coagulation, said Dr. Li and colleagues. The exact pathogenesis of this mechanism had been unknown, however, so the investigators used a metabolomics analysis on serum samples from prospectively observed SFTS patients. “[W]e determined arginine metabolism to be a key pathway that was involved in the interaction between SFTS [virus] and host response,” they wrote.

In a prospective cohort study that used liquid chromatography–tandem mass spectrometry, Dr. Li of the Beijing Institute of Microbiology and Epidemiology and colleagues examined 166 metabolites from 242 clinical samples to perform the metabolomics analysis. Of the SFTS patients in the study, 46 had both acute and convalescent samples that were matched with 46 healthy controls and 46 patients with fever not caused by SFTS. In a separate analysis, a series of samples were drawn from 10 patients who died of SFTS and matched to 10 who survived the infection and 10 healthy controls.

Statistical analyses allowed the investigators to identify metabolomics signatures that were unique for each sample group. Alteration of the arginine metabolism pathway stood out as the most pronounced differentiator in acute SFTS infection and fatality, wrote Dr. Li and coauthors. “By extracting the relative concentrations of arginine-related metabolites along the pathway, we found that arginine RC was significantly reduced in the acute phase of SFTS compared to healthy controls,” they wrote (P less than .001).

Patients who succumbed to SFTS had even lower arginine concentrations than did those who survived; arginine levels climbed during recovery for survivors, but stayed low in serum samples from SFTS fatalities.

There’s a logical mechanism by which arginine could contribute to platelet dysfunction and thrombocytopenia, noted Dr. Li and collaborators: Arginine is a nitric oxide precursor, and this pathway is known to be a potent inhibitor of platelet activation.

Low arginine levels would have the effect of taking the brakes off platelet activation, and the investigators did find increases in platelet-monocyte complexes and platelet apoptosis in SFTS virus infection (P = .007 and P less than .001, respectively), which further suggests “that platelet hyperactivation might contribute to reduced platelet counts in circulation,” they wrote.

Low arginine levels also have the effect of suppressing T-cell activity, and mediators along this pathway were also altered in patients with SFTS, and even more profoundly altered in patients who died of SFTS.

Dr. Li and colleagues probed the metabolomics data to see whether a global arginine bioavailability ratio (GABR), expressed as arginine/(ornithine + citrulline), could be used to prognosticate clinical outcome in SFTS virus infection. After multivariable analysis, they found that decreased GABR was associated with fatality (P = .039). Further, a low GABR early in infection was prognostic of later fatality, with an area under the receiver operating curve (ROC) of 0.713.

In the double-blind, randomized, placebo-controlled trial of arginine supplementation during SFTS, Dr. Li and coinvestigators found that arginine supplementation did not significantly alter most other laboratory values besides liver transaminases. However, blood urea nitrogen concentration was elevated in those who received arginine, and arginine supplementation was also associated with slightly more vomiting. Serum sampling also revealed that platelet activation and T-cell activity were both corrected in patients given arginine, which gives clues to the means by which arginine supplementation might boost host immune response and promote viral clearing and return to homeostasis of clotting pathways.

Limitations of the clinical trial included relatively small sample sizes and the fact that individuals with severe bleeding were excluded from participation in the trial. Also, the study didn’t account for dietary arginine intake, acknowledged Dr. Li and coauthors.

However, the metabolomics and clinical work taken together used state-of-the-art analytic methods and rigorous experimental design to show “the causal relationship between arginine deficiency and platelet deprivation or immunosuppression by SFTSV infection,” wrote Dr. Li and colleagues.

Disturbance in the arginine–nitric oxide pathway is likely “to be a key biochemical pathway that also plays [a] part in other viral hemorrhagic fever,” said the investigators. “The potential of arginine in treating such infectious diseases [with] similar clinical features as SFTS warrants exploration.”

The study was partially funded by a Bayer Investigator Award; Dr. Li and coauthors reported no other conflicts of interest.

SOURCE: Li X-K et al. Sci Transl Med. doi: 10.1126/scitranslmed.aat4162.

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