virology blog

About viruses and viral disease

acute

Long-term effects of Ebolavirus infection

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filovirusThe thousands of survivors of the Ebolavirus outbreak in western Africa – more than at any other time – are fortunate to have survived the disease. However, their health problems are not behind them. A new study shows that the survivors of Ebolavirus have long-term sequelae more than 2 years after infection.

Acute infections caused by viruses such as Ebolavirus are characterized by rapid production of infectious virus particles, followed by resolution and elimination of infection by the host. However, chronic symptoms may persist for a long time after the infection is cleared. There have been long-term health consequences identified in survivors of previous Ebolavirus outbreaks. These include joint and muscle pain, vision and hearing loss, abdominal pain, bleeding, malaise, and psychological problems. Some patients were unable to perform their previous jobs for up to one year.

The long term health consequences of infection was studied in detail for the 2007 outbreak of Bundibugyo ebolavirus in Uganda. Survivors (49) were contacted 29 months after the outbreak and provided information about health status and their ability to function, and blood samples were obtained for further study. Controls for the study were seronegative contacts.

The results show that survivors of Bundibugyo ebolavirus infection are at significantly greater risk than controls for long term health problems. These include ocular problems (pain, blurred vision), loss of hearing, sleep difficulty, and joint pain. Other issues are abdominal and back pain, fatigue, impotence, severe headaches, memory problems and confusion. No differences in results of blood analyses were observed between the two groups. This study only included adults; children who have recovered should also be examined as their health care needs may be different.

These results confirm that there are long-term sequelae of Ebolavirus infection. The basis for the complications is not known, but is likely a consequence of tissue damage due to viral replication and the immune response. Whether or not virus was present in the patients was not determined. However it is known that Ebolavirus can persist in the testicles and eye long after it is absent from serum.

Other serious viral infections are also accompanied by long term health effects. For example, 29% of Lassa virus survivors have hearing loss, while joint pain persists for 3-5 years in about 10% of those infected with chikungunya virus.

Ebolavirus is a highly lethal virus, and those who survive infection are fortunate. Despite recovering, their health problems are not over. The size of the recent outbreak provided impetus for clinical trials of vaccines and antivirals; now research is needed to determine how to best care for the many survivors.

Update: The NIH has announced a study in Liberia to examine the long-term consequences of Ebolavirus infection.

Chronology of an acute infection

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poliomyelitisThe clinical signs of an acute viral infection – characterized by rapid onset of disease with a short but sometimes severe course – are often obvious. These include coughing, sneezing, rashes and poxes, or headache. What takes place within the body while these symptoms develop?

Examination of the time course of an acute infection such as poliomyelitis reveals significant differences in the onset of clinical symptoms and appearance of virus or antiviral antibodies. The data in the figure (click for a larger view) come from studies of the disease in humans, which was common in the US until the early 1960s and therefore was extensively described in many medical texts. Within 2 days of exposure, virus levels begin to rise in feces and throat secretions, but no signs of disease are evident until day 7, when headache, sore throat, and nausea develop. The appearance of these non-specific symptoms (e.g. not unique to infection with any particular viral infection) correspond with peak levels of virus in the blood. Both subside by day 10. Antiviral antibodies begin to accumulate in the blood at the end of the viremic stage, around days 9-10.

Ninety-nine percent of all poliovirus infections end at this stage. In the remainder, the virus enters the central nervous system where it multiplies rapidly and reaches peak levels at day 13-14. At this time, headache and nausea return, accompanied by stiffness, pain, and in some cases, paralysis. During this central nervous system phase of the infection, levels of virus in throat secretions decline but remain high in the feces.

This typical pattern of acute infection has several practical consequences. Shedding of virus soon after exposure, in the pre-symptomatic period, facilitates the spread of infection. These individuals do not develop serious illness and remain in contact with others. By the time symptoms appear – either the mild symptoms or paralysis – virus in the blood is already declining. An antiviral compound given at this time would have no effect on the outcome of disease. Antibodies peak late in infection – too late to have a significant impact on the course of disease. This finding provided the early clues that lymphocytes, not antibodies, play a major role in clearing many acute viral infections.

If this hand-drawn schematic looks dated, it is because it was taken from a 1959 book entitled “Viral and Rickettsial Infections of Man”, edited by Rivers and Horsfall. It contains chapters written by the virology luminaries of the time, including George Hirst, Igor Tamm, A.D. Hershey, John Enders, Edwin Lennette, Albert Sabin, Jonas Salk, and David Bodian. Much of the information is dated, but some of it – including the course of poliomyelitis – established the basic principles of viral pathogenesis that will never be obsolete.

Acute viral infections

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102961732_223f281698_mAn acute viral infection is characterized by rapid onset of disease, a relatively brief period of symptoms, and resolution within days. It is usually accompanied by early production of infectious virions and elimination of infection by the host immune system. Acute viral infections are typically observed with pathogens such as influenza virus and rhinovirus. Ebola hemorrhagic fever is an acute viral infection, although the course of disease is unusually severe.

Often an acute infection may cause little or no clinical symptoms – the so-called inapparent infection. A well-known example is poliovirus infection: over 90% are without symptoms. During an inapparent infection, sufficient virus replication occurs in the host to induce antiviral antibodies, but not enough to cause disease. Such infections are important for the spread of infection, because they are not easily detected. During the height of the polio epidemic in the US, the quarantine of paralyzed patients had no effect on the spread of the disease,  because 99% of the infected individuals had no symptoms and were leading normal lives and spreading infection. Inapparent infections probably are important features of pathogens that are well-adapted to their hosts. They replicate sufficiently to ensure spread to new hosts, but not enough to damage the host and prevent transmission.

Acute infections begin with an incubation period, during which the genomes replicate and the host innate responses are initiated. The cytokines produced early in infection lead to classical symptoms of an acute infection: aches, pains, fever, malaise, and nausea. Some incubation periods are as short as 1 day (influenza, rhinovirus), indicating that the symptoms are produced by local viral multiplication near the site of entry. For some infections, incubation periods can last many days (papilloma, 50-150 days) or even years (AIDS, 1-10 years). In these infections, the symptoms are likely produced by virus- or immune-induced tissue damage far from the site of entry.

An example of a classic acute infection is uncomplicated influenza. Virus particles are inhaled in droplets produced by sneezing or coughing, and begin replicating in ciliated columnar epithelial cells of the respiratory tract. As new infectious virions are produced, they spread to neighboring cells. Virus can be isolated from throat swabs or nasal secretions from day 1 to day 7 after infection. Within 48 hr after infection symptoms appear; these last 3 days and then subside. The infection is usually cleared by the innate and adaptive responses in 7 days. However, the patient usually feels unwell for several weeks, a consequence of the damage to the respiratory epithelium, and the cytokines produced during infection.

Acute viral infections are responsible for epidemics of disease involving millions of individuals each year, such as influenza and measles. When vaccines are not available, acute infections are difficult to control – most are complete by the time the patient feels ill, and the virus has already spread to another host. This characteristic makes it exceedingly difficult to control acute infections in large populations and crowded areas (such as colleges, nursing homes, military camps). The outbreaks of norovirus gastroenteritis this winter – a classic acute infection – highlights the problem. Antiviral therapy cannot be used, because it must be given early in infection to be effective. There is little hope of treating most acute viral infections with antiviral drugs until rapid diagnostic tests are become available. But the point is moot – there are no antivirals for most common acute viral diseases.

The rapid clearance of acute viral infections is a consequence of robust host defenses. The same virus may cause a long-term, or persistent infection, in immunocompromised hosts. An example is norovirus infection, which is self-limiting in immunocompetent hosts, but causes a chronic infection in immunosuppressed kidney transplant recipients. We will consider the characteristics of persistent viral infections in another post.

Westhoff, T., Vergoulidou, M., Loddenkemper, C., Schwartz, S., Hofmann, J., Schneider, T., Zidek, W., & van der Giet, M. (2008). Chronic norovirus infection in renal transplant recipients Nephrology Dialysis Transplantation, 24 (3), 1051-1053 DOI: 10.1093/ndt/gfn693