SARS: Systematic Review of Treatment Effects

Abstract

Background

The SARS outbreak of 2002–2003 presented clinicians with a new, life-threatening disease for which they had no experience in treating and no research on the effectiveness of treatment options. The World Health Organization (WHO) expert panel on SARS treatment requested a systematic review and comprehensive summary of treatments used for SARS-infected patients in order to guide future treatment and identify priorities for research.

Methods and Findings

In response to the WHO request we conducted a systematic review of the published literature on ribavirin, corticosteroids, lopinavir and ritonavir (LPV/r), type I interferon (IFN), intravenous immunoglobulin (IVIG), and SARS convalescent plasma from both in vitro studies and in SARS patients. We also searched for clinical trial evidence of treatment for acute respiratory distress syndrome. Sources of data were the literature databases MEDLINE, EMBASE, BIOSIS, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to February 2005. Data from publications were extracted and evidence within studies was classified using predefined criteria. In total, 54 SARS treatment studies, 15 in vitro studies, and three acute respiratory distress syndrome studies met our inclusion criteria. Within in vitro studies, ribavirin, lopinavir, and type I IFN showed inhibition of SARS-CoV in tissue culture. In SARS-infected patient reports on ribavirin, 26 studies were classified as inconclusive, and four showed possible harm. Seven studies of convalescent plasma or IVIG, three of IFN type I, and two of LPV/r were inconclusive. In 29 studies of steroid use, 25 were inconclusive and four were classified as causing possible harm.

Conclusions

Despite an extensive literature reporting on SARS treatments, it was not possible to determine whether treatments benefited patients during the SARS outbreak. Some may have been harmful. Clinical trials should be designed to validate a standard protocol for dosage and timing, and to accrue data in real time during future outbreaks to monitor specific adverse effects and help inform treatment.

Abstract

A systematic review and comprehensive summary of reported treatments of SARS-infected patients, requested by the WHO expert panel on SARS, could not determine whether any treatments benefited patients.

Editors' Summary

Background.

Severe acute respiratory syndrome (SARS) is caused by a virus; the main symptoms are pneumonia and fever. The virus is usually passed on when people sneeze or cough. SARS became a much-talked about disease in 2003, when over 8,000 cases and 774 deaths occurred worldwide. The situation was alarming, because the first-ever cases had only just appeared in 2002, in China, so the best way to treat this new disease was unknown. Not many drugs are effective against viruses, and all doctors can usually do with a viral disease is to treat specific symptoms (e.g., fever and inflammation) and rely on the body's own immune system to fight off the virus itself. However, in recent years a number of antiviral drugs have been developed (for example, several are in use against HIV/AIDS), so there was hope that some of them might be active against SARS. Steroids were also often used in SARS treatment to try to reduce the inflammation of the lungs. In order to find out which, if any, of the potential treatments for SARS were effective, a number of research studies were carried out, both during and since the recent outbreak.

Why Was This Study Done?

Health care decisions should be based on all the information that is available. It is important to try to bring together all the reliable evidence that exists on each possible treatment for a disease. The process of doing so is called a systematic review. In October 2003 the World Health Organization (WHO) established an International SARS Treatment Study Group, consisting of experts experienced in treating patients with SARS. The group recommended a systematic review of potential treatments for SARS. In particular, it was considered important to summarise the available evidence on the use of certain antiviral drugs (ribavirin, lopinavir, and ritonavir), steroids, and proteins called immunoglobulins, which are found naturally in human blood. The WHO group wanted to know how these treatments affected the virus outside the body (“in vitro”) and whether it helped the condition of patients and reduced the death rate, particularly in those patients who developed the dangerous complication called acute respiratory distress syndrome (ARDS). This study is a systematic review conducted in response to the WHO request.

What Did the Researchers Do and Find?

They did no new work with patients or in the laboratory. Instead they conducted a comprehensive search of the scientific and medical literature for published studies that fitted their carefully predefined selection criteria. They found 54 SARS treatment studies, 15 in vitro studies, and three ARDS studies that met these criteria. Some of the in vitro studies with the antiviral drugs found that a particular drug reduced the reproduction rate of the viruses, but most of the studies of these drugs in patients were inconclusive. Of 29 studies on steroid use, 25 were inconclusive and four found that the treatment caused possible harm.

What Do These Findings Mean?

From the published studies, it is not possible to say whether any of the treatments used against SARS were effective. No cases of SARS have been reported since 2004 but it is always possible that the same or a similar virus might cause outbreaks in the future. It is disappointing that none of the research on SARS is likely to be useful in helping to decide on the best treatments to use in such an outbreak. The authors discuss the weaknesses of the studies they found and urge that more effective methods of research be applied, in a timely fashion, in any similar outbreaks in the future. While the systematic review suggests that we do not know which if any of the potential treatments against SARS are effective, its recommendations mean that researchers should at least be better prepared to learn from potential future outbreaks.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030343.

• Wikipedia entry on SARS (Wikipedia is a free online encyclopedia that anyone can edit)

• MedlinePlus pages on SARS

• Wikipedia entry on systematic reviews, which includes links to other Web sites where more detailed information may be found