Ribavirin For Hantavirus Cardiopulmonary Syndrome. . . It’s Back to the Drawing Board

Abstract & Commentary

Synopsis: Although a definitive answer could not be reached because of small sample size, no evidence of benefit from the treatment of hantavirus cardiopulmonary syndrome with ribavirin was detected.

Source: Mertz GJ, et al. Placebo-Controlled, Double-Blind Trial of Intravenous Ribavirin For the Treatment of Hanatavirus Cardiopulmonary Syndrome in North America. Clin Infect Dis. 2004;39:1307-1313.

After only 36 patients were enrolled in more than 5 years in a multicenter, randomized trial comparing ribavirin therapy to placebo in patients with hantavirus infection in the United States the study was terminated and the results analyzed. Immunocompromise and shock were among the exclusion criteria.

Only 23 of the 36 proved to have serological evidence of hantavirus infection; 10 received ribavirin and 13 received placebo. Although attempts were made to include patients with hantavirus prodromal syndrome, all 23 with proven infection had hantavirus cardiopulmonary syndrome. The introduction of extracorporeal membrane oxygenation (ECMO) during the trial and its use in 7 patients further compromised (or, at least, complicated) the data analysis. The proportion who survived to 28 days and did not require ECMO was 70% in those assigned ribavirin and 62% in placebo recipients. Two patients in each group died, including 3 of 7 patients treated with ECMO. A futility analysis based on the trends observed indicated that more than 1000 patients would have to be enrolled to have a chance of demonstrating a significant difference between treatment groups.

Comment by Stan Deresinski, MD, FACP

Hantaviruses, including Sin Nombre, the virus prevalent in the southwestern United States (most of the patients in this study were enrolled in New Mexico), are susceptible to ribavirin in vitro. A placebo controlled randomized trial in China, published 14 years ago demonstrated significantly improved survival with ribavirin treatment in patients with hemorrhagic fever with renal syndrome, which is caused by Hantaan virus.1

In contrast to the disease in Eurasia in which the kidneys are a prime target, the North American hantaviruses commonly cause pulmonary involvement. While such involvement has led to the commonly used sobriquet of hantavirus pulmonary syndrome, the authors of the study reviewed here prefer the term hantavirus cardiopulmonary syndrome because they indicate that almost all the fatalities are caused by cardiogenic shock.

The infection generally starts abruptly, with influenza-like symptoms followed, after several days, with the appearance of a non-productive cough and breathlessness, heralding the onset of pulmonary edema. Hypotension, with associated hemoconcentration, may occur. Hemodynamic measurements reveal, consistent with cardiac failure, a low cardiac index and an elevated systemic vascular resistance—findings directly opposite to those seen in septic shock. The fatality rate is approximately 36%.

The earliest laboratory finding that distinguishes this infection is thrombocytopenia. Leukocytosis with the appearance of early forms is characteristic, as is the appearance of reactive lymphocytes in the peripheral blood contemporaneously with the development of pulmonary edema. It is reported that the combination of thrombocytopenia together with the appearance of myelocytes and immunoblasts in the peripheral blood is strong evidence of hantavirus infection in the proper setting.

This trial represented a valiant attempt to perform a randomized clinical trial in the treatment of an infection that occurs at low frequency and for which there was no effective rapid diagnostic test during the prodromal phase. The patients with proven hantavirus infection enrolled in this trial had advanced severe disease. This is documented by the fact that the median time from first administration of drug or placebo to either death or initiation of ECMO was 4 hours for the former and 24 hours for the latter. Thus, while the investigators conclude that ribavirin was not of benefit in these critically ill patients, the possibility of benefit during the prodromal phase cannot be excluded. Early sensitive and specific diagnosis, however, remains elusive.

Reference

1. Huggins JW, et al. Prospective, Double-Blind, Concurrent, Placebo-Controlled Clinical Trial of Intravenous Ribavirin Therapy of Hemorrhagic Fever With Renal Syndrome. J Infect Dis. 1991;164:1119-1127.

Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.