Rischi emergenti

INFEZIONI VIRALI

Alfredo Scalzini

- West Nile Virus

- Chikungunya

- Hepatitis G virus

- TTV

West Nile Virus: The Agent

• Flaviviridae

– Flavivirus

• Single stranded RNA

• Infects humans, birds,

mosquitoes, horses and

other mammals

West Nile Virus: Transmission

Amplifying hostsBirds

VectorsVectorsVectorsVectorsCulex sp., Aedes sp., Ochlerotatus sp.

Incidental hostsIncidental hostsIncidental hostsIncidental hostsHumans, horses, and other

animals

West Nile Virus: History

• 1937: West Nile District, Uganda• 1962, 2000: France• 1973-74: South Africa• 1996: Romania

– First outbreak in industrialized urban area• 1998: Italy• 1999

– Russia– United States, New York

• First occurrence in the western hemisphere

West Nile Virus: Epidemiology

First record in Italy in 1998, an outbreak of infection in horses in the marsh Fucecchio, Tuscany.

No human case.

West Nile Virus: Epidemiology

2002 World Distribution

West Nile Virus: EpidemiologyHuman neuroinvasive disease in Italy

2008 2009

West Nile Virus: Epidemiology

Confirmed cases of West Nile neuroinvasive disease in Italy, August -September 2009 (n=16)

SURVEILLANCE FOR HUMAN WEST NILE VIRUS DISEASE

• Alternate Routes of Transmission • Since 2003, ArboNET has collected information on known or possible

non-mosquito modes of WNV transmission. Of the 24,656 cases reported during 2003–2008, 11 (0.04%) were reported as having been acquired in a laboratory setting. Although not confirmed as the source of infection in all cases, 36 (0.1%) patients with WNV disease had received a blood transfusion or organ transplant within 30 days of illness onset. Of 11,026 females with WNV disease reported since 2003, 124 (1%) had been pregnant at the time of illness onset. Two infant cases were reported as having been acquired in utero. Although nine cases were reported to have been in breastfed infants, the probable source of infection in most of these instances was considered to be mosquitoes, not breastfeeding.

MMWR April 2, 2010

Transfusion-associated WNV transmission was first detected in 2002, when 23 transfusion recipients were infected after receiving platelets, red blood cells, or fresh frozen plasma from 16 viremic blood donors (31). National blood donation screening began in 2003 but has not eliminated WNV transfusion transmission. Through 2008, 10 breakthrough WNV transmissions occurred from blood donations that had virus levels below the limit of detection (32–34). Transmission via donated organs also was first documented in 2002, when WNV infection developed in four recipients of organs from a common donor (35). WNV transmission via organ transplant was documented again in 2005 when WNV infection developed in three of four organ recipients (36).

MMWR April 2, 2010

• Eurosurveillance, Volume 16, Issue 41, 13 October 2011

• Rapid communications• West Nile virus: the Italian national transplant network reaction to an alert in the north-eastern

region, Italy 2011

• A Nanni Costa ()1, M R Capobianchi2, G Ippolito2, G Palù3,4, L Barzon3,4, G Piccolo5, B Andreetta6, M Filippetti1, D Fehily1, L Lombardini1, P Grossi7

• National Transplant Centre, Italian National Institute of Health, Rome, Italy

• National Institute for Infectious Diseases (INMI) “L. Spallanzani”, Rome, Italy

• Department of Histology, Microbiology and Medical Biotechnology, University of Padova, Italy

• Regional Reference Centre for Infectious Diseases, Microbiology and Virology Unit, University Hospital, Padova, Italy

• Department of Infectious Diseases, University of Insubria, Varese, Italy

• North Italy Transplant Interregional Coordinating Transplant Centre, Ospedale Maggiore Policlinico, Milan, Italy

• Veneto Regional Coordinating Transplant Centre, Azienda Ospedaliera di Padova, Padua, Italy

• We report four cases of West Nile virus (WNV) transmission following a single multiorgan donation in north-eastern Italy. The transmissions were promptly detected by local transplant centres. The donor had been tested for WNV by nucleic acid amplification test (NAT) prior to transplantation and was negative. There were no detected errors in the nationally implemented WNV safety protocols. Case reportsIn August 2011, a multiorgan and tissue retrieval was carried out in north-eastern Italy from a donor who was a resident in the same area. The donor’s organs (kidneys, lungs, heart and liver) were successfully transplanted to recipients in other Italian regions, including the north-eastern region. The donor’s health status was confirmed prior to donation, by blood- and instrumental-tests and detection of markers for transmissible diseases (hepatitis B surface antigen, hepatitis C virus antibodies, human immunodeficiency virus 1/2 antibody, Treponema pallidumParticle Agglutination Assay), in addition to interviews with relatives. In line with transplant procedures, the donor cause of death was not related to any transmissible disease. Moreover, due to special procedures in place for prevention of West Nile virus (WNV) in this part of Italy, a donor blood sample had tested negative for WNV by nucleic acid amplification test (NAT).

• Ten days after transplantation, two patients who had each received a respective kidney, developed fever and neurological symptoms, suggestive of West Nile neuroinvasive disease. The purpose of this rapid communication is to describe how, despite testing strategies in place for WNV, transmissions occurred and how the Italian National Transplant Network responded to the WNV transmissions associated with a multiorgan transplant, in the context of negative nucleic acid amplification test (NAT) results in the donor.

~80%Asymptomatic

~20%“West Nile Fever”

<1%CNS

disease

~10% fatal(<0.1% of total infections)

West Nile Virus: Human Infection “Iceberg”

1 CNS disease case=

~150 total infections

Very crude estimates

West Nile Virus: Human Disease

• Incubation period of 2-15 days

• Most illness: “West Nile fever”

– Self-limited dengue-like illness

– Fever, headache

– Fine maculopapular rash (more frequent in children)

– Lymphadenopathy

– Nausea, vomiting

• Rarely pancreatitis, hepatitis, myocarditis

West Nile Virus: Human Disease

• Severe neurologic illness categories

– Meningitis

• Fever, nuchal rigidity, CSF pleocytosis

– Encephalitis

• Altered mental status

– “Meningoencephalitis”

– Acute flaccid paralysis

West Nile Virus: Movement Disorders

• Tremor– Sometimes associated with other viruses– Documented in 15 (94%) of prospective series patients– Static / kinetic; sometimes with movement– Occasionally disabling

• Myoclonus– Observed in 10 (63%); described in 12 overall– Upper extremity, facial involvement most frequent– Nocturnal myoclonus

• Both tremor and myoclonus—onset generally > 5 days following initial symptoms

West Nile Virus: Parkinsonism

• Parkinsonism observed in 11 (68%)

– Cogwheel rigidity

– Bradykinesia

– Postural instability

• Rest tremor not observed

• Seen both in encephalitis and meningitis cases

West Nile Virus: Flaccid Paralysis

• Previously described; not “new” syndrome

• Relatively young; lack of premorbid conditions

• May have absence of fever, headache

• Clinical hallmarks:– Onset during acute infection– Asymmetry of weakness– Absence of sensory changes– Elevation of CSF protein and WBC

West Nile Virus: Flaccid Paralysis

• Multiple alternative diagnoses (stroke, GBS, myopathy)—Rx with heparin, IVIG

• Syndrome actually localized to spinal anterior horn cells—resultant poliomyelitis

• Recognition could limit unnecessary diagnostic procedures, treatment

• Little or no improvement short-term

West Nile Virus: Rhabdomyolysis

• Rhabdomyolysis—acute destruction of skeletal muscle cells

• Infrequent manifestation of viral infection

• September 2002—rhabdomyolysis reported in Chicago WNV patients

• 14 total cases identified

• Trauma, medication effect unlikely

• Further studies to assess association

West Nile Virus: Other Clinical Syndromes (?)

• Flaccid paralysis with sensory symptoms– Neuropathic pain– Causalgia– Paresthesias

• Peripheral neuropathy, polyradiculopathy

• Optic neuritis

• Acute demyelinating encephalomyelitis (ADEM)

• Prenatal WNV infection with CNS developmental abnormalities– WNV as a teratogen?

West Nile Virus: Clinical Outcomes

• Current data limited

• Fatality rates

– 10% fatality rate in CNS disease

– Elderly, immunosuppressed

– Independent risk factors unknown

• Long-term outcomes in New York:

– >50% with continued impairment at 1 year

– Only 37% considered fully recovered

West Nile Virus: Clinical Outcomes

• Short-term prospective data– No deaths– Most patients (14/16; 88%) eventually went home

• Follow-up – Persistent / chronic headache– Concentration, memory difficulties– Overwhelming fatigue– Persistence of tremor, parkinsonism

• Paralysis—no short-term improvement

~ 80%Asymptomatic

~10% fatal(<0.1% of total infections)

West Nile Virus: Human Infection “Iceberg” Revisited

1 CNS disease case=

~?? total infections

Febrile illness alone less frequent?~?%

“West Nile Fever”

<?%CNS

disease

ChikungunyaIn Swahili it means ‘to become contorted’

The name is derived from the Makonde word meaning "that which bends up"

in reference to the stooped posture developed as a result of the arthritic symptoms of the disease

Chikungunya: The Agent• Togaviridae

– Alpha Virus, single stranded RNA-virus

• Species – Chikungunya Virus

• Several distinct variants of the virus

• The A226V mutation in the coat

protein caused the virus to more

easily invade and multiply in the

mosquitoes

Chikungunya: History• 1952: Tanzania, Africa

• 1963: India

• 1999: Port Klang, Malaysia

• 2005: French island of Réunion in the Indian Ocean, Mauritius, Madagascar, Mayotte and the Seychelles

• 2006: Hong Kong and Malaysia

• August 2007: Italy (first indigenous cases in Emilia Romagna)

Chikungunya: Epidemiology

Chikungunya: Epidemiology

Chikungunya: Epidemiology

Patient “zero”

Chikungunya: Epidemiology

Trend of the epidemic of Chikungunya in Italy (July-September 2007)

Epidemiological Triangle

The Environment

The Vectoraedes, culex and mansonia species

The HostThe main virus reservoirs are monkeys, but other primates,

mammalsand birdscan also be affected

The Virus

The mosquito picks up the virus from an infected person during the viraemic period –within five days from the day of starting of symptoms.An infected mosquito will remain infected all its life span and can transmit the virus each time it bites

Chikungunya: Symptoms

• Incubation period of 3-12 days

• Viremia last for 5 days (infective period)

• Flu-like symptoms, severe headache and chills

• High grade fever (40°C)

• Headache, nausea, vomiting, abdominal pain and low back pain

Chikungunya: Symptoms

• Conjunctival injection and slight photophobia

• Arthralgia or arthritis affecting multiple joints

• Petechial or maculopapular rash usually involving the limbs and trunk

• Very similar to those of Dengue but unlike in Dengue, no hemorrhagic or shock syndrome

• Mother to fetus transmission can occur

Chikungunya: The Arthralgia

• The small joints of the lower and upper limbs

• Migratory poly arthralgia not much effusions

• Larger joints may also be affected (knee, ankle)

• Pain worse in the morning, less by evening

• Joints may be swollen and painful to the touch which can be debilitating

• Some patients have incapacitating joint pains

• Arthritis may last for weeks or months

Chikungunya: Rare Clinical Features

• Multiple aphthous-like ulcers over scrotum, crural areas and axilla

• Unilateral or bilateral lymphedema of the limbs

• Lymphadenopathy not common

• Multiple ecchymotic spots in children

• Vesiculo-bullous lesions in infants

• Sub-ungual hemorrhages

• Severe menigo-encephalitis: may be fatal

Chikungunya: Clinical Outcomes• Usually it is a self limiting, it is not considered to be fatal viral illness

• Patients do have prolonged fatigue for several weeks

• In February 2005, an outbreak was recorded on the French island of Réunion in the Indian Ocean. As of May 18, 2006, 258.000 residents have been hit by the virus in the past year (out of a population of about 777.000): 219 official deaths have been associated with chikungunya

• Life long immunity, once one suffers this infection

• Chikungunya is not considered to be fatal. However, in 2005-2006, 200 deaths have been associated with chikungunya on Réunion island.

NUOVI VIRUS EPATITICI

GBV-A

GBV-B

GBV-C/HGV

TTV

Nel 1967 il siero di un chirurgo (GB)affetto da epatite acuta itterica fuinoculato in scimmie; furono identificati2 flavivirus: GB virus GBV-A e GBV-B.Sieri di pazienti con epatite non A-Ereagenti in Elisa agli Ab antiproteine diGBV-A e GBV-B furono sottoposti a RT-PCR portando all’identificazione di unanuova sequenza nucleotidica definitaGBV-C.

Virus dell’epatite G/GB virus C

Tale RNA virus con un genoma di9392 nucleotidi che codifica per unapoliproteina di 2873 aminoacidi, hauna identità del 100% per gliaminoacidi e dell’85.5% per inucleotidi nei confronti del virus HGVidentificato e sequenziato dallaGenelab.

In donatori di diverse nazionalità: 779 con ALT normali 1.7% HGV RNA+709 con ALT elevate 1.5% HGV RNA+

(Science 1996, 271:505-8)

In politrasfusi (USA) 47% HGV RNA+(Lancet 1996, 347:1632)

Prevalenza di HGV

In tossicodipendenti HCV Ab+: 24% HGV RNA+

(N Engl J Med 1996, 334:195-6)

3.1% HGV RNA+ di 519 emodializzati rispetto allo 0.9% di 448

donatori di sangue (N Engl J Med 1996, 334:1485-90)

Prevalenza di HGV in Giappone

HGV RNA+Donatori abituali 1.7%Td 10-46%Emodializzati 22%Politrasfusi 19%

Dai 2 ai 5 milioni di statunitensi sono HGV RNA+

Prevalenza di HGV in USA (dati CDC)

49 epatopatici non A-E, HGVRNA+ :acuti 35%cronici 39%100 donatori 1%

“GBV-C may be an important agent,contributing, at least in Italy, to a significantnumber of cases of hepatitis of unknownetiology.”

Prevalenza di HGV RNA a Brescia (Fiordalisi et. al. J Inf Dis 1996, 174 (1): 181-3)

Conclusioni CDC:���� HGV è responsabile di infezionee viremia���� L’HGV e l’HCV spessocoinfettano���� non è chiaro se l’HGV siaepatotropo���� manca una chiara associazioneepidemiologica tra epatiti (acute ocroniche) e HGV.

Patogenesi di GBV-C/HGV

“… the majority of patients with

prospectively followed HGV

infections have no evidence of

liver damage.”

(Zanetti et al. Res Virol 1997; 148 (2): 119-22)

“...we recently observed that HGV infection, although frequent in

blood donors and recipients of ourcountry, has no effect on the

severity of liver disease and hasoften a natural progression toward

recovery…”(Prati et al., Blood 1998; 92(9):3460-4)

Per ora i CDC non raccomandano

la determinazione di HGV RNA nel

sangue da trasfondere.

402 donatori: 7.5% TTV+347 pz prima della trasfusione: 11% TTV+L’incidenza di nuove infezioni da TTV era del4.7% in non trasfusi e 26% in 182 trasfusi. Di45 pz con epatite acuta C, 40% eranocoinfettati da TTV (senza peggioramentoclinico).“We found no association between TTV andnon A-E hepatitis … TTV may not be aprimary hepatitis virus”

(Matsumoto et al., Hepatology 1999; 30(1): 283-8)

TTV DNA nel 93% pz β-talassemici e nel 22% donatori di sangue italiani.

“… no definite relation was observedbetween the results of TTV DNAdetermination and ALT patterns… .Particular viral strains may have differentpathogenetic effects in inducing transfusionassociated disease”.

(Prati, Blood 1999; 93(5):1502-5)

The role of TT virus in acute viral hepatitis (Kanda, Hepatology 1999; 29(6):1905-8)

TTV DNA+ in:

� 43% pz con epatite non A-E� 42% con epatite C� 29% con epatite A� 24% con epatite B� 37% soggetti sani

“…no etiologic role for TTV could be established.”

“… the pathologic role of this virus, which seemed in our study to be

limited despite the important prevalence of this virus in blood

donors, must be defined”

PREVALENZA E FATTORI DI RISCHIO PER INFEZIONE DA TTV

• PREVALENZA VIREMIA IN 150 PZ.DIALIZZATI (PCR): 28 %

• PREVALENZA VIREMIA INDONATORI SANGUE: 5.3 %

Gallian e coll. TT virus infection in frenchhemodialisis pts: study of prevalence and risk

factors. J Clin Microbiol 1999: 37(8):2538-42