Closer to a Cure for the Common Cold?

The search for a "cure for the common cold" resembles in some ways a late 20th-century quest for the holy grail, and although new and remarkable medical discoveries are reported almost daily, the skeptics reiterate that medicine still cannot cure the most frequent infectious disease, the common cold. It is not that accomplished scientists have not tried, and the literature is filled with accounts of these attempts. But the goal has evaded researchers for years, and it is in this context that we should evaluate the report of Turner and colleagues¹ in this issue of THE JOURNAL.

The approaches to research into treatment of the common cold can be roughly divided into 2 large categories: the antiviral and the anti-inflammatory. Acute viral respiratory tract infections are brief events, in which symptoms first appear when the immune response is already active, and, in most instances, the virus is at, or even past, its peak. Symptoms are thought to be produced by a combination of viral replication and the immune response. In rhinovirus infections, which are responsible for about 70% of upper respiratory tract infections, actual damage by the virus appears to be minimal, although the virus is probably the trigger for a cascade of locally released mediators, which combine with the immune response to produce the familiar symptoms of rhinorrhea, nasal congestion, cough, and sometimes fever.

The brevity of the process poses a considerable challenge to those searching for a cure. Several antivirals, particularly interferon (alfa or beta) and pirodavir, have shown promise when administered prophylactically,^{2 - 3} only to lose measurable activity as therapeutic agents.^{4 - 5} On the anti-inflammatory side, antihistamines, decongestants, and nonsteroidals are widely used for relief of symptoms, although their effects, while usually measurable in carefully conducted studies, are both limited in extent and partial in scope.^{6 - 8}

Turner and colleagues¹ have examined an important new concept in antiviral research: inhibition of viral spread through blockage of specific cellular receptors. This idea has been tested as part of the search for new treatments for human immunodeficiency virus infection, the receptor in this instance being the CD4 molecule, and the treatment modality soluble CD4.⁹ Early trials were not successful, but despite setbacks, this idea remains viable. Moreover, there is some evidence that naturally occurring chemokines, which circulate in the blood and combine with a "second receptor" for human immunodeficiency virus, can slow the progress of human immunodeficiency virus infection.¹⁰

This field received a major boost when Abraham and Colonno¹¹ discovered that most of the rhinovirus serotypes (90 of the 101 described types¹² ) used a single cellular receptor, the intercellular adhesion molecule 1. It was quickly clear that blocking this receptor might be a route to the successful prevention or treatment of most rhinovirus colds. The earliest attempts to do this, using monoclonal antibody, were not successful,¹³ and led to the soluble-receptor approach described by Turner et al.

The study by Turner et al contains some hopeful features. The investigators performed 4 separate experiments, all using the highly reproducible infection model of rhinovirus inoculation in adult volunteers.¹⁴ The 4 studies examined 2 different preparations of the soluble intercellular adhesion molecule called tremacamra (formerely BIRR 4) that were started at 2 different times in relation to the experimental rhinovirus infections. The later time was 12 hours after inoculation, and the results with the intervention started at this later time appear to be the same as those with the preinoculation intervention, leading to optimism about possible efficacy in treatment of symptomatic infections. The authors, however, rightly still call their postinoculation application "prophylaxis," rather than "treatment," since symptoms had not yet appeared. Previous antiviral drugs have faltered when used for treatment, and it remains to be seen whether tremacamra will have effects when given after symptoms have started, particularly in naturally occurring colds.

Questions also arise whether these results can be generalized to other rhinovirus infections. While many rhinovirus serotypes use the intercellular adhesion molecule 1 as a receptor, it seems likely that their susceptibility to inhibition with soluble intercellular adhesion molecule 1 will vary. Rhinovirus 39, the subject of this study, appears to be particularly susceptible to small concentrations of tremacamra. Further research is needed to see whether the results are similar with other virus types.

The issue of toxic effects also must be addressed. Although it did not appear that undue toxic effects occurred in this study, and an immune response to tremacamra could not be detected, it is uncertain what will happen with repeated administrations. It is possible that lower or less frequent doses would have a similar effect. This might decrease the likelihood of local or systemic toxic effects on repeated use.

Moreover, it is important to consider the impact a treatment might have for colds in general, even if that treatment is shown to be effective against 90% of rhinovirus serotypes that share this common receptor. Not all colds are rhinovirus-induced. Even though diagnostic tools for identification of the viral causes of respiratory tract infections have improved over the past few years, particularly with the introduction of polymerase chain reaction for rhinoviruses and coronaviruses, it is unlikely that these tools would be practical for outpatient or office use in the near future. Thus, should tremacamra be shown to be effective for clinical use, it might be wise to restrict its use to times when rhinoviruses are known to be common, particularly the fall and spring.

Ultimately, the best treatment formula for colds may prove to be anti-inflammatory drugs combined with antivirals. Previous attempts to do this have been variably successful,¹⁵ but it will be useful to investigate whether combination treatment is superior to either approach alone.

Despite the encouraging findings of the study by Turner et al, it is clear that the "cure for the common cold" is still not in hand. Tremacamra appears to be a promising candidate, however, and researchers and clinicians may be a little closer to the goal. The next step will be determining whether tremacamra can be used to treat symptomatic rhinovirus infection or to prevent clinical colds in the field. Only then may the elusive holy grail of an effective cure for the common cold truly be in sight.