In December 2016, an owner of a Wisconsin (USA) in-home rattery was hospitalized with fever, leukopenia, elevated transaminases and proteinuria. Although no typical acute kidney injury (AKI) was reported, the patient was serologically diagnosed with an acute Seoul orthohantavirus (SEOV) infection. However, mild and atypical clinical presentations are a constant feature of SEOV-induced HFRS forms, as repeatedly shown hereunder [1
]. A family member later developed similar symptoms, but was not hospitalized [2
]. In late December, 2016, a report of mild AKI followed in an 18-year-old female from Tennessee (USA) (hematuria and peak serum creatinine level of 1.27 mg/dL). In April 2017, a second case was reported in her 38-year old mother who was hospitalized for gastro-intestinal symptoms with dyspnea and even milder AKI (peak serum creatinine 1.13 mg/dL, with mild thrombocytopenia of 143,000/µL). In the latter case, SEOV RNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). Both cases appeared to have been caused by pet rat-transmitted SEOV, and both recovered without treatment or complications [3
]. The USA Center of Disease Control and Prevention (CDC) launched a nationwide investigation, identifying 31 rat-breeding facilities with human and/or rat SEOV infection in 11 USA states, six of which exchanged rats with Canadian ratteries. A total of 24/183 (13.1%) US or Canadian residents associated with these facilities were found to be serologically SEOV-positive, resulting in three hospitalizations in the USA. No AKI was mentioned, and spontaneous recovery occurred, whereas no serious illness was reported from Canada [2
]. Similar cases, with or without AKI, and all induced by apparently healthy pet rats, were described in the UK [5
] and in France [7
]. Recently, increasing reports of wild and pet rat-associated SEOV-induced hantavirus disease in the USA and Europe reflected a renewed awareness of the disease outside of Asia, breaking years of misconceptions about the true distribution and clinical aspects of hantavirus diseases.
The decades-long assumption that HFRS was limited to the Old World, and HCPS restricted to the Americas, ignored the remarkable global progress made by pioneer hantavirologists in the early 1980s. Rat-transmitted hantavirus or SEOV is the second oldest isolated hantavirus (1980) [8
], the first isolated hantaviral pathogen in the USA (1984) [9
], and the most widely distributed hantaviral pathogen, due to the omnipresence of its reservoir and vector, the brown or Norway rat (Rattus norvegicus
). Before the unexpected 1993 discovery of two other autochthonous American hantaviral pathogens, Sin Nombre orthohantavirus (SNV), followed by Andes orthohantavirus (ANDV), early hantavirology in the USA focused primarily on SEOV and its possible impact on human health. A 1994 compilation of the then existing world literature confirmed hantavirus-antibodies, -antigen, and -virus isolation in two different classes of animals (mammals and birds), eight different orders, 24 different families and a total of 164 different species, mostly small mammals. Of these, the rat was by far the species yielding most positive results, i.e., in 34 different countries for the brown rat, 20 countries for the roof rat (Rattus rattus
), 19 countries for non-specified Rattus
species (which may include pet rats), and in 13 countries for laboratory rats [10
]. To date, SEOV is still the only hantavirus with multiple isolations in four different continents (Asia, Europe, America, and Africa) (see hereunder), a unique accomplishment by different hantavirus researchers beginning 1980s, considering the inherent difficulties associated with isolating hantaviruses. So far, the limited attempts for pet rat isolations of SEOV, both from rats and humans, have been unsuccessful.
In the Far East, and particularly in China, extensive annual mixed epidemics, caused by prototype Hantaan orthohantavirus (HTNV) and/or SEOV, resulted in tens of thousands of human infections yearly. In contrast, although American authors once called “the SEOV prevalence in [wild] rats in many United States cities among the highest recorded globally
], there has been little noticeable impact over the subsequent three decades on human morbidity and/or mortality in North America. Similarly, North-American pet rats have had only limited reported consequences for public health so far [2
]. The novel notion, however, that even fancy pet rats might infect their owners or breeders with a zoonotic agent (SEOV), previously thought to be limited to wild rats, has the potential to dramatically change our insights about the global importance of rat-transmitted HFRS, since pet rat trade is international, and likely also to be found beyond Europe and North America [13
Additionally, outbreaks among laboratory workers in Asia, Russia, and Europe in the 1960s and 1970s, associated with SEOV-infected laboratory rats [13
], played a pivotal role in understanding the “new” human illness, later called HFRS after a World Health Organization (WHO) meeting, during which the clinical characteristics of HFRS were, be it succinctly, described [14
]. This early clinical and epidemiological knowledge was overshadowed a decade later with the discovery of a new and often lethal disease caused by SNV or ANDV, and called HCPS [15
In Section 3
, “Overview”, we discuss the recorded history of SEOV [10
] and SEOV-induced human infections in four continents, followed by the current status of pet and domesticated rat SEOV infections.
4. Current Situation
In 2012, a Welsh pet agouti rat owner developed a severe MOF, with a combination of AKI, progressive lung and liver involvement, coagulation disorders and lactic acidosis, initially ascribed to overwhelming sepsis, needing 38 days of ventilatory support and 21 days of renal replacement therapy, but ending in full pulmonary and renal recovery. Ultimately, SEOV infection was confirmed by IFA, but SEOV viremia was not detected [6
]. Rat-borne SEOV was traced back to a pet rat breeding site in Cherwell, England, where two owners were apparently also infected in 2011, one asymptomatically, the other requiring hospitalization for AKI with thrombocytopenia, secondary to a then unidentified viral illness [5
]. These cases launched an investigation in the UK into the extent of SEOV infection among pet or domestically bred rats and their owners or breeders. IFA SEOV-IgG seropositivity in 27/79 (34.1%) was found among breeders versus much lower IgG prevalences in all other control groups (farmers and other professions with rat-exposure), encompassing 844 human serum samples. No clinical complications were found [164
]. By contrast, the extended Cherwell rat study revealed SEOV RNA presence in different organs of 17/21 (81%) rats, and anti-SEOV antibodies in 100% (20/20) in blood tested by PRNT and ELISA [95
]. These findings were much higher than the preliminary RNA RT-PCR screening of Cherwell rat blood alone, which found 7/21 (33%) positivity [5
]. Partial L segment sequencing of SEOV viruses from Cherwell and Cheltenham (another English pet rat SEOV strain) clustered closely together with two wild rat strains, American NYC Baxter and British Humber, and with IR 461, a lab rat strain [95
In France, the link between infecting rats and human HFRS cases was demonstrated by highly similar nucleotide sequences derived from both patient and rats [7
]. After a SEOV-HFRS outbreak in 2006 among eight students of the Shenyang Pharmaceutical University, Liaoning Province, China, phylogenetic analysis revealed that the same SEOV strain had affected both patients, laboratory rats, and wild rats, the latter captured on the grounds of the concerned pharmaceutical building. This confirmed for the first time the triple scenario that SEOV-infected wild rats can infect laboratory rats, which in turn can infect humans [78
This paucity of SEOV cases in the West and in Africa contrasts with the long-standing recognition of cases in the East, particularly in China, even since the early 1980s. The prevalence of SEOV-infected rats is similar in many parts of Asia to that found in Europe, the Americas and Africa, and appears to have been fundamentally unchanged over decades.
Human SEOV-HFRS has until recently (2012) been underestimated in the West [1
]. The reasons for this are not clear, but differences in the degree of exposure and the availability of diagnostic testing probably play a role: in China, virtually all HFRS cases are serologically screened with HTNV, which cross-reacts with SEOV. In contrast, in Europe, serologic screening relies primarily on PUUV antigens [7
], while in the Americas, SNV and/or ANDV antigens are most frequently used, and HTNV and/or SEOV antigens are not [16
], thus probably missing some isolated SEOV cases. In parts of Europe, Dobrava-Belgrade orthohantavirus (DOBV), another murid pathogen isolated in 1988, can cause important cross-reactions with SEOV in IFA and ELISA serology [22
]. Serologic analysis using two commercial European immunoblots was misleading in the first reported SEOV-HFRS case in Germany. The commercial Hantavirus Profile 1 Immunoblot (Euroimmun, Lübeck, Germany) lacked a SEOV antigen, and the recom
Line HantaPlus IgG and IgM blot assays (Mikrogen, Martinsried, Germany) showed reactivity for the three murid pathogens DOBV, HTNV, and SEOV, but yielded the weakest result for SEOV nucleocapsid protein. The final diagnosis was only possible after RT-PCR examination on the earliest available acute serum sample after hospitalization in Hamburg, Germany [22
]. In this aspect, it is useful to remember that if the IgG IFA screening of the first British series of North-Irish farmers with acute hantavirus-induced AKI had been performed only with the then classical antigens PUUV and HTNV, but without the Chinese SEOV antigen R22, 13/15 (86.7%) of the cases would have been missed in 1994, which is unacceptable [94
In contrast, Canadian and British military personnel, both originally suspected of severe SEOV-induced MOF during the Bosnian War, were later shown to be in fact DOBV infections [166
]. Another possible explanation for the striking East–West difference in SEOV-HFRS incidence is that American SEOV strains might be less virulent than their Asian counterparts [133
]; however, SEOV phylogenetic trees show American SEOV strains clustering closely with Asian strains. In a recent South-Korean study applying next generation sequencing, multiple strains of SEOV of worldwide origin were examined. A phylogenetic tree of sequences of small RNA segments revealed a grouping of strains from the UK and the USA, clustering together with another group containing American Tchoupitoulas, Japanese Sapporo and Korean strains, including prototype SEOV 80-39. These findings are not suggestive of a fundamental difference between infecting wild rat strains (e.g., Humber and NYC Baxter), lab rat strains (e.g., Sapporo and all the British IR strains), or pet rat strains (e.g., Cherwell). [167
]. This may be to be expected, since all are carried by the same rat species, R. norvegicus
. Nor was the phylogenetic tree suggestive of a recent introduction of all these rat strains in the respective countries, since IR 461 was isolated in 1984, and stemming from Belgian laboratory rats, that were presumably infected with the same SEOV already in the 1970s [95
]. In summary, the paucity of recognized SEOV cases outside Asia may reflect insufficient medical awareness of the “atypical” and often very mild aspects in SEOV-HFRS cases, implying even HFRS cases with preserved normal kidney function throughout [1
]. JE Childs, familiar with the wild rat problem in Baltimore, MD, describes the current situation as follows: “physician awareness of this rare disease is negligible, and public health surveillance non-existent. Acute illness caused by SEOV, does not have a unique presentation, and signs and symptoms are consistent with a wide range of diseases” [13
The current problem of SEOV infection in pet rats likely arose from SEOV-infected wild brown rats, visiting commercial or domestic ratteries, rather than stemming from laboratory rat colonies [106
], although the latter scenario was also proven by RT-PCR in China [78
]. Laboratory rats today are generally free of SEOV infection due to strict adherence to the total eradication of infected rats [57
], followed by a worldwide policy of continuous SEOV screening, imposed traceability of rat batches, and/or other preventive techniques [7
]. These policies are probably not in place in small, private ratteries [7
], and in view of the sometimes high SEOV prevalence in wild brown rats, it is not surprising that infected domesticated rat colonies became established, and human infections followed. The lesson learned from recent British and American pet rat investigations is that pet rat owners and breeders are at increased risk of SEOV infection due to frequent close contact with their companion animals, but when present, acute disease is rarely severe or life threatening. This is based on the repeated observation that SEOV infection usually resulted in very mild illness [3
], without mention of renal involvement [2
], but with the possible exception of missed initial proteinuria [1
]. Since proteinuria and even all degrees of concomitant AKI are almost always spontaneously self-remitting within 2–3 weeks in most cases of HFRS [6
], the initial fear that rat-borne SEOV represents a newly discovered public health problem might not be justified. A heightened clinical acumen for the mild and/or atypical presentation of SEOV-HFRS is, however, clearly needed in the West.
Since the 1976 original discovery of HTNV, a large body of evidence has accumulated over the ensuing four decades regarding the global distribution and clinical characteristics of hantaviral infections in both humans and small mammal hosts.
With increasingly sophisticated technology and enhanced clinical awareness, many specific hantaviruses are now recognized; however, SEOV remains the most widely distributed hantavirus. SEOV is maintained in nature among chronically infected brown rats that are found in virtually every corner of the world, living in close association with humans, yet the incidence of SEOV human infections varies widely between Asia, where its pathogenic potential is well recognized, and the remainder of the world, where very few human cases have been documented. The even greater exposure to SEOV-infected pet rats, potentially likewise on a global scale, might significantly change this situation.
SEOV infections should be considered in patients presenting with a febrile illness associated with transient thrombocytopenia and proteinuria, accompanied by rapidly resolving hepatitis, especially if a history of possible exposure to brown rats is elicited.