2. Diseases caused by hantaviruses
Hantaviruses pathogenic to humans have been classified into Old World hantaviruses (OWHVs) and New World hantaviruses (NWHVs) based on their geographical distribution. OWHVs, the major etiological agents of HFRS, include HTNV, SEOV, and DOBV viruses, which are distributed in Asia and Europe. NWHVs, the major etiological agents of HCPS/HPS, include ANDV and SNV viruses, which are distributed in South America and North America.4 Globally, about 150,000 to 200,000 HFRS or HCPS/HPS cases are reported annually, with case fatality rates (CFR) between 1%−15% (HFRS) to 30%−50% (HCPS/HPS).5
HFRS was first documented in Korea in 1951.2 This disease is usually divided into five phases, including fever, hypotension, oliguria, polyuria, and recovery, with the hallmark feature of acute kidney injury, after the incubation period of 2−3 weeks. Acute kidney injury may cause kidney swelling, proteinuria, and hematuria.6Symptoms of HFRS include fever, headache, low back pain, visual impairment, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea, and bloody stool), and proteinuria.3 Meanwhile, hemorrhagic symptoms caused by thrombocytopenia include petechiae of the skin and mucosa, hematuria, hemoptysis, conjunctival congestion, gastrointestinal bleeding, and even intracranial hemorrhage. Disseminated intravascular coagulation (DIC) may also occur in severe HFRS cases. The hypotension phase is characterized by sudden hypotension and shock caused by microvascular leakage, which may lead to sudden deaths.5 The oliguria phase is caused by renal failure, with the symptoms of oliguria (usually <400 mL/day) and proteinuria. In the diuretic phase, renal function gradually recovers with an increase in urine output. While renal function can recover completely after a long recovery period, chronic renal failure and hypertension may also occur.7 In addition to the typical renal disease caused by HFRS, some patients present with extrarenal symptoms, such as acute respiratory distress syndrome (ARDS), cholecystitis, pericarditis, and encephalitis.6 Infection with PUUV in humans can lead to a mild form of HFRS termed nephropathia epidemica (NE).8
HCPS/HPS was first documented in North America in 1993.3 This disease is usually divided into the prodromal, cardiopulmonary, and recovery phases, with the hallmark features of microvascular leakage and ARDS, after the incubation period of 1−7 weeks.3 The prodromal symptoms are similar to the fever phase of HFRS, such as fever, headache, myalgia, nausea, and vomiting. It also includes flu-like symptoms (e.g., cough and dyspnea) accompanied by thrombocytopenia.5 The cardiopulmonary phase lasts for several days with tachycardia, arrhythmias, and cardiogenic shock. Leakage of pulmonary capillaries in this phase can cause respiratory failure, pulmonary edema, hypotension, bilateral pulmonary infiltration, and pleural effusion. Acute kidney injury and proteinuria also occur in some HCPS/HPS patients. HCPS/HPS can lead to acute deaths during the cardiopulmonary phase.9
HTNV was first discovered in South Korea in 1978.10HTNV is mainly distributed in China, South Korea, Russia, and Vietnam.5,11 More than 90% of global HFRS cases are reported from mainland China, with most of them being caused by HTNV.12 About 9,000−12,000 HFRS cases are reported in China each year, with a CFR of approximately 1%. These cases are distributed throughout China.13 In South Korea, about 400−600 cases of HFRS are reported annually, with a CFR 1%−2%.14
SEOV was first discovered in South Korea in 1982.15While SEOV mainly circulates in China and South Korea, it is the only hantavirus that is globally distributed.16 This is consistent with the global distribution of its hosts Norway rats (Rattus Norvegicus ).17 SEOV infection accounts for about 25% of HFRS cases worldwide, with a CFR less than 1%.3
DOBV was first discovered in Slovenia in 1992.18 It is mainly distributed in Slovenia, Czech Republic, Poland, Russia, Serbia, Greece, Germany, Denmark, France, and other European countries.19 The pathogenicity of DOBV varies according to its genotypes. The Dobrava and Sochi genotypes are highly pathogenic, with a CFR of 10%−15%.20 The Kurkino genotype is less virulent and causes only mild HFRS, with a CFR of 0.3%−0.9%. The Saaremaa genotype does not cause mortality.19
PUUV was first discovered in Finland in 1980.21 PUUV is mainly distributed in central, northern, and eastern European countries.5 It caused more than 3000 HFRS cases each year in Europe between 2010 and 2020. They are usually mild, with a CFR of 0.1%−0.4%.3,5
ANDV was first discovered in Argentina in 1995.22 ANDV is mainly distributed in Argentina and Chile and causes dozens of HCPS/HPS cases annually with a CFR about 40%. ANDV can be transmitted among humans.23
SNV was first detected in 1993 in the USA.24 SNV circulates in the USA, Canada, and Mexico, and causes dozens of HCPS/HPS cases annually with a CFR of 30%−35%.25,26
Other viruses in Orthohantavirus , such as Tula virus(TULV) in many Eurasia countries,27 Bayou virus(BAYV) in USA,28 Choclo virus (CHOV) in Panama,29 and Laguna Negra virus (LANV) in South America,30 have been identified as pathogenic to humans.