Abstract
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While these phenomena are important and perhaps not widely known, they are not unprecedented and are fully consistent with known pathophysiological principles of disease. The key to understanding why these events occur—and could have been anticipated—is the concept of “sanctuary sites.”
Sanctuary from Immune Response
The mammalian immune response to an invading organism is a coordinated and widespread inflammatory reaction that involves many cells, organs, and tissues of the body. This reaction can not only lead to control of invading microorganisms such as viruses, bacteria, fungi, and parasites but also has a role in destroying cancer cells (tumor surveillance). The immune system is a powerful weapon that confers a major evolutionary advantage on mammals. However, in certain contexts the immune response can inflict a substantial amount of collateral damage while combating an invader. Indeed, the symptoms and tissue damage that result from many infectious diseases are the result of the immune system's response rather than the direct damage caused by the microbe. When this collateral damage occurs in delicate tissues such as the brain, it can be deadly. In some instances—such as autoimmune diseases like lupus and rheumatoid arthritis—the immune system mistakenly attacks “innocent” host cells as if they were invaders.
To limit the possibility of immune responses causing deleterious effects, animals have evolved a means of sequestering especially vulnerable areas from the immune system. The brain and central nervous system, the male genital tract, and the eye are such sites. These sites are known as sanctuary sites in medical parlance because of the relative lack of immune system policing that occurs there.
How the Sanctuary Is Maintained
Sanctuary sites are separated from the immune response primarily by a simple physical barrier. To keep immune system cells, which are circulating in the bloodstream, from inflicting damage to the brain and central nervous system, a blood-brain barrier and a blood-cerebrospinal fluid (CSF) barrier exist. The blood-testes barrier, in which developing sperm are shielded from potential immune system attack, plays a similar role. These barriers, maintained by very tight cellular junctions through which few things can pass, serve not only to keep bloodstream invaders out but also hamper the ability of immune cells to enter. The rarity of infections such as encephalitis and meningitis attests to the effectiveness of this barrier, as it is extremely difficult for an invader to gain access to these immune-privileged sites. In the rare case in which a sanctuary site infection occurs, the barrier is loosened, allowing immune cells access. In that case the risk of collateral damage is outweighed by the benefit of controlling the infection.
Accounting for Sanctuary Sites
While from an evolutionary standpoint sanctuary sites allow certain delicate areas protection from the onslaught of inflammation during infection or, in the case of the male genital system, allow developing sperm to be spared attack from the immune system, these sites must be taken into account during the treatment of certain illnesses. There are some examples that are useful for understanding the concept of how a sanctuary site alters management of some conditions.
Infections of the Brain and Spinal Cord
An infection of the brain and spinal cord is a medical emergency in which minimizing the time to effective therapy is of the essence. Delays in diagnosis and care can lead to severe complications and even death. In these infections, one of the complicating matters is that the blood-brain barrier must be overcome, not only by the immune system, but also by antibiotics that must reach their targets, which lie behind the barrier. Only certain drugs are capable of crossing the blood-brain barrier in high enough quantities to be useful, and therefore they are the first-line drugs used to treat these infections.
Cancers
In metastatic cancers, malignant cells from various sources may find sanctuary from chemotherapy drugs in the brain or testes. In some instances, such as with certain forms of small cell lung cancer, prophylactic radiation of the brain is performed in the event that undetectable tumor cells have found sanctuary there. 4
Filovirus Sanctuaries
Ebola infection is a systemic filovirus infection in which large amounts of virus course through the blood and organs of the infected individuals. The virus is capable, in what appear to be rare instances, of crossing the blood-brain barrier during acute illness. 5 Because of the relative paucity of cases prior to the West African outbreak, complications that occur in a minority of patients may have not been well documented or noticed and are only now being fully appreciated in light of the more than 28,000 cases that have occurred during this outbreak.
While Dr. Ian Crozier's well-publicized development of a post-recovery Ebola eye infection appeared novel, careful attention to the medical literature describing the 1995 Kikwit outbreak reveals that nearly 16% of survivors who were studied had lingering eye symptoms. 6 It is hypothesized that the eye, in this setting, is a sanctuary site for Ebola in which the virus can linger unperturbed for some amount of time.
It had also been well known that Ebola (and the related filovirus Marburg) have the capacity to remain in the seminal vesicles, in which most of the seminal fluid is produced, of survivors for up to 3 months post-recovery. 7 In the current outbreak, it has been established that the genital sanctuary for Ebola may extend up to 9 months in some patients—a fact that will make complete control of the infection more difficult as survivors could potentially reignite the outbreak via sexual transmission. 8
Nurse Pauline Cafferkey's case, in which a presumed Ebola relapse occurred from her central nervous system into her blood, also illustrates the importance of sanctuary sites. In this case, about which much more information is needed to fully explain her condition, it could be hypothesized that not only did the central nervous system provide sanctuary for the virus, but treatment with the experimental antibody ZMAb (a precursor of the drug Zmapp), which she received, may have set her up for a relapse. The ZMAb, like naturally occurring antibodies, would not normally be able to cross the barrier between the blood and central nervous system. The rapid clearing of the virus from the blood by the ZMAb may have quieted the immune system before full immunity could develop, 9 thereby predisposing her to systemic infection when the virus reemerged from its central nervous system sanctuary. Interestingly, in guinea pig and non-human primate studies, ZMAb showed less robust protection than ZMapp. 10 Another possibility, which will be able to be tested, is that some virus was able to mutate and escape the effects of ZMAb, something noted in animal models with the ZMapp-precursor MB-003. 11
Infections such as Ebola are systemic events in which the virus disseminates to many sites in the body, including sites that may be inaccessible to the immune system and some drugs. These sanctuary sites must be taken into consideration in designing treatment regimens and should be anticipated in the clinical management of Ebola patients. The occurrence of the largest Ebola outbreak in history has afforded medicine the opportunity to study this virus in heretofore unavailable large populations, conduct real-time research, and move experimental therapeutics considerably closer to market. What the latest developments of Ebola illustrate is that there is much left to learn from this virus to prepare for the next outbreak as well as to fully extinguish the current one.