Efficacy of SARS Treatments Inconclusive

ATLANTA, Sept. 12 -- As the severe acute respiratory syndrome (SARS) epidemic moved round the world in 2002-03, clinicians tried a range of interventions against the coronavirus. Now it seems that they may have been futile, at best.

In fact, some - such as ribavirin and corticosteroids - seem to have done harm, according to Lauren Stockman, M.P.H., of the CDC here reported in the September online journal PLoS Medicine.

With colleagues from James Cook University Hospital in Middlesbrough and the Liverpool School of Tropical Medicine in Liverpool, both in the United Kingdom, Stockman analyzed 54 studies of various attempts to treat the mysterious respiratory disease, as well as 15 in vitro studies.

The review, commissioned by the World Health Organization, looked at the use of ribavirin, corticosteroids, Kaletra (lopinavir and ritonavir), type I interferon (IFN), intravenous immunoglobulin (IVIG), and SARS convalescent plasma from both in vitro studies and SARS patients. The researchers also looked for clinical trial evidence of treatment for acute respiratory distress syndrome.

The bottom line, Stockman and colleagues reported, is that most of the studies were inconclusive, except for those that showed possible harm.

In the 54 treatment studies, the researchers found:

• 30 studies looked at the effects of ribavirin and 26 were classified as inconclusive, while four showed possible harm.
• In 29 studies of steroid use, 25 were inconclusive and four were classified as causing possible harm.
• And seven studies of convalescent plasma or IVIG, three of IFN type I, and two of Kaletra were inconclusive.

Some studies looked at more than one intervention, the researchers noted.

In the case of ribavirin, three studies, each with more than 100 patients, found a fall in hemoglobin levels after ribavirin treatment. From 36% to 61% of patients developed hemolytic anemia, which is a known complication of the drug, although the researchers noted that lack of control groups makes it impossible to rule out the possibility that the anemia was caused by the SARS coronavirus itself.

A fourth study found that more than 29% of SARS patients had some degree of liver dysfunction indicated by alanine aminotransferase (ALT) levels higher than normal; the proportion of patients with this complication rose to more than 75% after ribavirin therapy.

Four studies contained evidence of possible harm from corticosteroids:

• A randomized, double-blind, placebo-controlled trial measured plasma viral load across time after fever onset and found that steroid use within the first week of illness was associated with delayed viral clearance.
• A case-controlled study found that patients with psychosis received higher cumulative doses of steroids than patients without psychosis. The difference -- 10,975 mg versus 6,780 - was significant at P=0.017.
• A Chinese study reported diabetes onset associated with methylprednisolone therapy.
• Another Chinese study - uncontrolled and retrospective with 40 SARS patients -- reported avascular necrosis and osteoporosis among patients getting steroids.

Ribavirin, type I interferon, and Kaletra showed in vitro activity against the SARS coronavirus, the researchers said.

The data are inconclusive at least partly because most of the studies reviewed were essentially descriptions of the natural course of the disease and had not been designed to evaluate the effects of treatment, the researchers noted.

While SARS appears to have receded as a threat, it or another novel disease could appear again, Stockman and colleagues noted, adding that clinical trials should be designed so that treatment efforts can be reliably assessed.