Newly discovered viruses
Although humans are affected by an enormous range of microorganisms, almost all newly discovered emerging pathogens are viruses that are often zoonotic or vector-borne. These emerging viruses often have high baseline mutation rates, allowing them to adapt relatively easily to new hosts and enabling them to take advantage of new epidemiological opportunities provided by the changing environment. A range of apparently new human viral pathogens has been reported increasingly in international outbreak information over the last few years. How they will influence global public health remains to be seen.
Emerging viruses that may be of particular public health importance include (1) respiratory SARS-like coronaviruses; (2) Garissa and Ngari viruses, Alkhurma virus and Lujo virus—discovered during investigations of haemorrhagic fever; (3) KI and WU human polyomaviruses, new human coronaviruses, human bocavirus, human parechovirus, and mimivirus—causing predominantly respiratory disease; (4) Toscana and, Usutu viruses—causing viral meningitis and encephalitis; (5) Merkel cell polyomavirus—with oncogenic potential. The human pathogenicity of other emerging viruses, e.g. Vesivirus, Ljungan virus, Aichi virus, Titi Monkey adenovirus, gamma-retrovirus, and Saffold virus is less certain.
Coronaviruses (CoV) are single-stranded RNA viruses commonly associated with respiratory illness and less often with gastrointestinal and neurological disease in a wide variety of mammals and birds. The severe acute respiratory syndrome (SARS) outbreak of a new human coronavirus, SARS-associated coronavirus (SARS-CoV), between November 2002 and July 2003 spread across 5 continents and caused over 700 human deaths. This pandemic triggered renewed interest in this area, leading to increased understanding of the origin of SARS-CoV, as well as the discovery of two previously unknown human coronaviruses.
In the early phase of the outbreak, the infecting SARS viruses showed closer similarities to animal viruses than later on in the pandemic. Virological studies suggest that the animal viruses crossed over to humans on more than one separate occasion, so repeated similar events should be expected in the future. Bats are increasingly recognized as reservoirs of emerging viruses. The discovery of species-specific, SARS-like coronaviruses in horseshoe bats with the same genome organization as human SARS coronaviruses indicates that a human SARS virus originated in one or more bat species. It is likely that an intermediate animal host is also required to allow modification of the mutating progenitor virus before transmission to humans is possible. Understanding this reservoir might help to prevent future human outbreaks of SARS-CoV.
New human coronaviruses
Two new human coronaviruses have been discovered since the SARS epidemic: HCoV-NL63 and HCoV-HK. HCoV-NL63 was first identified in a child with bronchiolitis in the Netherlands. Studies published in 2004 and 2005 found 8 to 9% of children aged under 5 years with known respiratory illness were positive for HCoV-NL63 by polymerase chain reaction (PCR), while tests for common respiratory viruses were negative. Longitudinal studies showed that seroconversion usually occurred by the age of 3.5 years. Significant sequence heterogeneity exists and it is likely therefore that there are two closely related genotypic subgroups.
In 2005, another human coronavirus was discovered, HCoV-HKU1. It was first described in Hong Kong in a 71-year-old man with pneumonia who had recently returned from China. It has since been reported in patients in Australia and the United States of America. Common clinical findings in young children included rhinorrhoea, cough, fever, and abnormal breath sounds on auscultation. The possibility of central nervous system infection and hepatitis (in a liver transplant recipient) were suggested in two separate patients in one study. Genomic and phylogenetic analysis suggests that this virus is most closely related to the mouse hepatitis virus, a coronavirus studied since the 1930s.
The double-stranded DNA human polyomaviruses, JC virus and BK virus, are ubiquitous worldwide and are pathogenic in immunocompromised hosts. In 2007, two new human polyomaviruses were described, KI virus and WU virus. They share a phylogenetic relationship and together may form a new subclass. They have been isolated primarily from respiratory secretions. KI was discovered after molecular screening of respiratory samples. WU was first detected by high-throughput sequencing of respiratory secretions from a patient with an acute respiratory disease of unknown aetiology. Analysis of two more cohorts in different continents revealed that the majority of patients positive for WU were aged under 3 years, and that all infected adults were immunocompromised. The clinical spectrum of the disease included upper and lower respiratory tract infection, bronchiolitis, croup, and, rarely, gastroenteritis. However, the role of these viruses as respiratory pathogens has since been questioned after further studies detected them both in asymptomatic children and those concurrently infected with other respiratory viruses. Studies to establish the role of WU and KI in immunocompromised adults have been inconclusive. The relatively high seroprevalence of these viruses in healthy blood donors suggest that a benign primary infection with these viruses occurs in childhood, followed by a period of latency and subsequent reactivation in the context of immunosuppression.
In 2008, another novel polyomavirus termed ‘Merkel Cell polyomavirus’ was found to be integrated within the cellular genome of cells of the rare skin cancer Merkel cell carcinoma which primarily occurs in elderly and immunosuppressed people. This is consistent with the oncogenic potential of other polyomaviruses. Merkel cell polyomavirus has also been isolated in respiratory samples from symptomatic adult and paediatric patients though its precise role as a pathogen in this context is yet to be confirmed.
Human bocavirus (HBoV) is a nonenveloped, single-stranded DNA virus in the family Parvoviridae, first described in September 2005 following isolation by random PCR in pooled respiratory samples from hospitalized children in Sweden. HBoV is closely related to canine minute virus and bovine parvovirus. The only other parvovirus known to be pathogenic in humans is parvovirus B19, the cause of fifth disease in children (Chapter 7.5.20).
Although Koch’s postulates have not yet been fulfilled, supportive molecular evidence demonstrated this virus in respiratory samples from children with lower respiratory tract disease who tested negative for common respiratory viruses. It has been found most commonly in children aged under 3 years, particularly in preterm infants with mild to severe respiratory symptoms. Although a study conducted in the Netherlands showed no difference between the detection of HBoV in children with or without LRTI in paediatric intensive care, higher levels of HBoV were seen in the symptomatic patients compared to asymptomatic controls. This may reflect differences in viral load of acute infection versus asymptomatic shedding. A more recent study of patients hospitalized with acute LRTI in Argentina in 2010 found a bimodal age distribution of HBoV (<1 year and >30 years) with a significantly higher rate of coinfection (predominantly with RSV) found in children compared to adults.
Related viruses HBoV2, HBoV3, and HBoV4 have more recently been identified in faecal samples of children in several countries including the United Kingdom, Pakistan, and Thailand. An association with acute gastroenteritis has been described: in one study, HBoV2 was the third most prevalent virus seen in children with AGE after rotavirus and astrovirus. Absence of HBoV2 in more than 6500 paediatric respiratory samples in one study suggests a very different tissue tropism to HBoV despite its close phylogenetic lineage.
Further quantitative studies are needed before the precise role of these viruses in human disease is reliably established.
Single-stranded RNA vesiviruses of the Calciviridae family are common marine microorganisms, but are also known to infect land mammals. They cause a broad spectrum of disease in animals including vesicular rash, encephalitis, haemorrhagic disease, spontaneous abortion, and hepatitis. Their effect on humans is not well established, but a recent seroprevalence study has shown that 12% of tested successful blood donors had evidence of past exposure to vesivirus. This was significantly higher (29%) in patients with hepatitis of unknown but suspected infectious cause, and even higher (47%) in patients with hepatitis of unknown cause associated with blood transfusion or dialysis. Vesivirus viraemia was also shown to be present in some of those tested.
New parechoviruses: Human parechovirus and Ljungan virus
Human parechovirus and Ljungan virus are the two species of the genus parechovirus of the family Picornaviridae. Human parechoviruses are single-stranded RNA viruses which differ from other family members in having only three, rather than four, capsid proteins, and in exerting atypical cytopathic effects. HPeV-1 and HPeV-2 were previously designated Enterovirus 22 and 23 but were reclassified in 1999. By the end of 2011 16 human parechovirus genotypes had been described.
HPeV infections are common, with at least 95% of the adult population positive for HPeV-specific antibodies. Most infections are thought to predominantly affect neonates and young children and, although the clinical spectrum of disease differs between the viruses, it has been compared to infection with enterovirus. Earlier studies of HPeV-1 suggested infection resulted in more gastrointestinal and respiratory illness which was often severe, and was occasionally found as a co-pathogen with other respiratory viruses such as respiratory syncytial virus (RSV). The role of HPeV-1 as a respiratory pathogen has since been challenged. HPeV-2 and HPeV-3 have been shown to present as sepsis-like syndromes, predominantly affecting neonates. Children with HPeV-3 positive CSF specimens in the United States of America showed a predominance of male infants presenting with sepsis-like syndromes in a late summer/autumn distribution. This seasonal distribution was not reflected in a similar survey in the United Kingdom, in which patients presented in the spring in even-numbered years, and were almost always infants less than 3 months of age. The combination of prominent abdominal distension with erythematous rash has been described in four of eight infants with confirmed HPeV infection; such symptoms are postulated to be important clues to the diagnosis in the absence of a raised CRP or lymphocyte count.
More recently described HPeV-8 (Brazil, 2009) and HPeV-10 (Sri Lanka, 2010) were both found in stool specimens of children with acute gastroenteritis. It is also likely that further novel human parechoviruses will be discovered and their contribution as human pathogens investigated..
Another parechovirus, Ljungan virus (LV) has recently been postulated as a major aetiological agent in sudden infant death syndrome (SIDS). LV mainly affects rodents and is known to be associated with perinatal rodent death both in the wild and in laboratory mice. Interestingly, a strong epidemiological link between small rodent numbers and human intrauterine fetal death has been described in Sweden. In addition, LV has been detected in brain, heart and lung tissue in cases of SIDS. Whether true causation can be proven is yet to be established.
Aichi virus is a novel human picornavirus which was initially described in 1991 and linked epidemiologically with food- and water-associated diarrhoea, although its role in the aetiology of acute gastroenteritis is yet to be established. A recently published study overcame previous technical difficulties in using specific molecular detection methods to look at stool samples from patients in Germany with acute gastroenteritis over a 1 year period. Viral shedding with Aichi virus appeared unrelated to the severity of symptoms, and no food association was found despite investigation. A detection rate of 2% was seen across all age groups, comparable to similar studies elsewhere in Europe and Asia. However, there was a distinct geographical and temporal association more in keeping with faeco-oral transmission than a point-source outbreak.
Human cardiovirus: Saffold virus
Investigation of an 8 month old girl with pyrexia of unknown origin, led to the discovery in 2007 of a novel cardiovirus of the family Picornaviradae, named Saffold virus (SAFV). Several strains of SAFV have since been described and have been detected in faecal and respiratory specimens of children worldwide, from a patient with aseptic meningitis and from children with nonpolio acute flaccid paralysis, though causality has not yet been proven. Interestingly, SAFV is grouped with Theiler’s murine encephalomyelitis virus (TMEV) which is known to cause a multiple sclerosis-like syndrome in mice. Although this may be the first human cardiovirus, a specific clinical association is yet to be found..
Usutu virus, named after a river in Swaziland, was first isolated from mosquitoes in South Africa in 1959. It is a mosquito-borne flavivirus of the Japanese encephalitis group and was isolated once from a man with fever and rash. Although a virus of tropical or subtropical Africa, the epidemiology might be changing, following its isolation from several bird species during a die-off in Austria in 2001. This reflects the pattern of the emergence of West Nile virus in the United States of America in 1999, which first affected birds and subsequently humans. Neuroinvasive infection secondary to Usutu virus was reported for the first time worldwide in 2009 when USUV was detected by RT-PCR in CSF and serum samples in two immunocompromised patientsin Italy who had both received blood transfusions. Clinical symptoms in both patients included fever (>39.5°C), headache, and neurological disease. The extent of the human pathogenic potential of USUV remains to be seen, but there is concern that it may follow a recurrent theme of flavivirus emergence in previously cooler climates following climate change. Surveillance systems already in place in areas of endemic West Nile virus could be adapted to detect more cases of Usutu virus if surveillance in wild birds and vectors indicated a need.
Garissa and Ngari virus
Genetic reassortment of segmented RNA viruses such as influenza is well known to have an important role in the emergence of viruses with new disease potential and host range. There is less genetic information on bunyaviruses, but there is increasing evidence that this mechanism could account for their evolution and increase their potential to cause disease in humans.
The first association of Ngari virus with human haemorrhagic fever (HF) was discovered during an extensive investigation of a large outbreak in Kenya, Tanzania, and Somalia in 1997 to 1998. A previously unidentified member of the orthobunyavirus genus (family Bunyaviridae) was found in two cases. The virus was initially named Garissa virus, but subsequent genetic analysis showed that it was not a separate orthobunyavirus but had arisen by genetic segment reassortment between two known orthobunyaviruses, Bunyamwera virus and Ngari virus. Further sequence analysis of multiple orthobunyaviruses revealed that Ngari virus is a reassortment Bunyamwera virus.
Alkhurma virus, a re-emerging tick-borne flavivirus, is related to Kysanur Forest disease and shares clinical features with Dengue Fever. It was first described in a butcher in Saudi Arabia in the 1990s, and over the next 10 years, had a case fatality rate of around 25%. In 2009, 4 further sporadic cases were described in Jeddah in the post Hajj period and all may be linked to the slaughtering/processing of sheep. The cases have highlighted the need to further understand the epidemiology of this re-emerging disease.
Lujo virus is a novel, genetically distinct, highly pathogenic arena virus associated with haemorrhagic fever with an exceptionally high case fatality rate of 80%. It was first isolated in South Africa in 2008 during a nosocomial outbreak of 5 cases following the transfer of the index case from Zambia. The technique of unbiased pyrosequencing used during the investigation of this outbreak may well be useful in identifying other novel pathogens in the future.
Toscana virus (TOSV) is an arthropod-borne bunyavirus transmitted by sandflies. Two genotypes have been described (TOSV A and B) with different geographical distributions. Though TOSV was first identified in Italy in 1971, epidemiological studies and clinical research over the last three decades has shown that it is an increasingly important cause of seasonal aseptic meningitis and encephalitis across the Mediterranean. It is the most common cause of this disease in Italy from May to October and has also been associated with human infection in France. Lethal infections and long-term sequelae have been reported. The RNA of TOSV has been isolated in a different species of sandfly in France from that in Italy, although there is no confirmation that human disease is arthropod-borne.
With a diameter of 600 nm and with a dsDNA genome of 1.2 Mb, mimivirus is the largest virus so far discovered. It was initially thought to be a Gram-positive coccoid bacterium and is visible with the light microscope.
The virus species Acanthamoeba polyphaga mimivirus is within a family of its own, the Mimiviridae. Phylogenetic analysis has shown its relationship to other large DNA viruses including the Iridoviridae and Poxviridae, though its precise position in the phylogenetic tree remains under debate. Discovered during the investigation of respiratory pathogens using an amoeba coculture system, it may have originated in marine environments. Although it replicates within amoebae, it is yet to be shown to multiply effectively in mammalian cells. Mimivirus may have a role in respiratory disease. A pneumonic illness can be produced in mice and a laboratory technician occupationally exposed to high concentrations of mimivirus antigens developed a subacute, spontaneously resolving pneumonia with seroconversion to Mimivirus. The prevalence of antibodies to mimivirus was 9.66% in 376 Canadian patients with community acquired pneumonia compared to 2.3% of healthy controls. Two studies of pneumonia in intensive care units have shown seroconversion to the virus in more patients with ventilator-associated pneumonia than in controls. Seropositivity to mimivirus in ventilated patients in a prospective matched cohort study was associated with longer duration of ventilation and longer ICU stay. There was no mortality difference between seropositive patients and matched seronegative controls. Mimivirus antibodies have been found to be more prevalent in populations admitted from nursing homes and in those rehospitalized after discharge. These seroprevalence studies must be interpreted cautiously because of possible cross-reactivity with other pathogens. More recent studies using real-time PCR have also been inconclusive. Although mimivirus DNA was recovered from a bronchoalveolar lavage of a patient with relapsing pneumonia in the absence of other causative pathogens, a prevalence study in 69 ventilated patients in an intensive care setting found no evidence of mimivirus infection using real-time PCR. A study of paired serological and DNA detection in lower respiratory sampeles may be useful in investigating the role of mimivirus in respiratory disease.
Gamma-retrovirus: xenotropic murine leukaemia virus-related virus
A novel retrovirus termed xenotropic murine leukaemia virus-related virus (XMRV) was linked previously to prostate cancer in the United States but not in Europe. In 2009, it was reported that 68 of 101 patients with chronic fatigue syndrome in the USA were infected with the virus though this finding has not been replicated in a similar United Kingdom cohort. It may be that these findings reflect differences in the prevalence of this virus in North America and Europe rather than a specific association with CFS per se.
Titi Monkey adenovirus
An outbreak of fulminant pneumonia affected 34% of New World monkeys housed in a closed colony in the United States. The Virochip microarray was used to identify the causative agent, a novel adenovirus—the Titi Monkey adenovirus (TMAdV). An exposed worker subsequently developed an acute respiratory tract infection lasting 4 weeks and seroconverted to TMAdV. A critically ill family member of this person also developed symptoms and tested positive serologically, suggesting potential for primate–human and human–human transmission of this novel agent.
Abed Y, et al. (2006). Human parechovirus types 1, 2 and 3 infections in Canada. Emerg Infect Dis, 12, 969–75.Find this resource:
Allander T, et al. (2005). Cloning of a human parvovirus by molecular screening of respiratory tract samples. Proc Natl Acad Sci U S A, 102, 12891–96.Find this resource:
Allander T, et al. (2007). Identification of a third human polyomavirus. J Virol, 81, 4130–36.Find this resource:
Arthur JL, et al. (2009). A novel bocavirus associated with acute gastroenteritis in Australian children. PLoS Pathog, 5, e1000391.Find this resource:
Babakir-Mina M, et al. (2011). The novel KI, WU, MC polyomaviruses: possible human pathogens?. New Microbiol, 34, 1–18.Find this resource:
Charrel RN, et al. (2005). Emergence of Toscana virus in Europe. Emerg Infect Dis, 11, 1657–63.Find this resource:
Charrel RN, et al. (2005). Low diversity of Alkhurma hemorrhagic fever virus, Saudi Arabia, 1994–1999. Emerg Infect Dis, 11, 683–88.Find this resource:
Chen EC, et al. (2011). Cross-species transmission of a novel adenovirus associated with a fulminant pneumonia outbreak in a New World monkey colony. PLoS Pathog, 7, e1002155.Find this resource:
Drexler JF, et al. (2009). Novel human parechovirus from Brazil. Emerg Infect Dis, 15, 310–13.Find this resource:
Drexler JF, et al. (2011). Aichi virus shedding in high concentrations in patients with acute diarrhea. Emerg Infect Dis, 17, 1544–8.Find this resource:
Erlwein O, et al. (2010). Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS One, 5, e8519.Find this resource:
Esper F, et al. (2006). Coronavirus HKU1 infection in the United States. Emerg Infect Dis, 12, 775–79.Find this resource:
Gaynor AM, et al. (2007). Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog, 3, e64.Find this resource:
Gerrard SR, et al. (2004). Ngari virus is a Bunyamwera virus reassortant that can be associated with large outbreaks of hemorrhagic fever in Africa. J Virol, 78, 8922–26.Find this resource:
Ghietto LM, et al. (2011). High frequency of human bocavirus 1 DNA in infants and adults with lower acute respiratory infection. J Med Microbiol. Epub ahead of print Nov 24 2011.Find this resource:
Harvala H, et al. (2008). Epidemiology and clinical associations of human parechovirus respiratory infections. J Clin Microbiol, 46, 3446–53.Find this resource:
Harvala H, et al. (2011). Comparison of human parechovirus and enterovirus detection frequencies in cerebrospinal fluid samples collected over a 5-year period in Edinburgh: HPeV type 3 identified as the most common picornavirus type. J Med Virol, 83, 889–96.Find this resource:
Kim Pham NT, et al. (2010). Novel human parechovirus, Sri Lanka. Emerg Infect Dis, 16, 130–32.Find this resource:
Nguyen NL, et al. (2009). Serologic evidence of frequent human infection with WU and KI polyomaviruses. Emerg Infect Dis, 15, 1199–1205.Find this resource:
Pyrc, K et al. (2007). The novel human coronaviruses NL63 and HKU1. J Virol, 81, 3051–57.Find this resource:
Raoult D, et al. (2007). The discovery and characterization of Mimivirus, the largest known virus and putative pneumonia agent. Clin Infect Dis, 45, 95–102.Find this resource:
Ren, L et al. (2009). Saffold cardiovirus in children with acute gastroenteritis, Beijing, China. Emerg Infect Dis, 15, 1509–11.Find this resource:
Smith AW, et al. (2006). Vesivirus viremia and seroprevalence in humans. J Med Virol, 78, 693–701.Find this resource:
Vabret A, et al. (2005). Human coronavirus NL63, France. Emerg Infect Dis, 11, 1225–29.Find this resource:
van de Pol AC, et al. (2009). Human bocavirus and KI/WU polyomaviruses in pediatric intensive care patients. Emerg Infect Dis, 15, 454–57.Find this resource:
Vincent A, et al. (2009). Clinical significance of a positive serology for mimivirus in patients presenting a suspicion of ventilator-associated pneumonia. Crit Care Med, 37, 111–8.Find this resource:
Wang LF, et al. (2006). Review of bats and SARS. Emerg Infect Dis, 12, 1834–40.Find this resource:
Wattier RL, et al. (2008). Role of human polyomaviruses in respiratory tract disease in young children. Emerg Infect Dis, 14, 1766–68.Find this resource:
Weissenbock H, et al. (2002). Emergence of Usutu virus, an African mosquito-borne flavivirus of the Japanese encephalitis virus group, central Europe. Emerg Infect Dis, 8, 652–56.Find this resource: