avian influenza infection in human

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Faculty of medical MicrobiologyNobel College : 

Faculty of medical MicrobiologyNobel College Seminar paper “Avian Influenza A (H5N1) Infection in Humans” Presented by: Bishu Shrestha (74005) Bivek timalsina (74006) Chetan Shakya (74007) Jinata Dahal (74008)

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Article originally published in New England Journal of Medicine By: John H. Beigel et.al. (The writing committee of the World Health Organisation consultation on human influenza A/H5) 2000;353:1374-85

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This medical review article have following headings, each describing their respective cateroies: 1. Introduction 2.Incidence 3.Transmission 4 Clinical Features 5.Pathogenesis 6.Case detection and Management 7.Prevention 8.Conclusion

Introduction : 

Introduction An unprecedented epizootic avian influenza A (H5N1) virus highly pathogenic crossed the species barrier in Asia- cause many human fatalities and posses pandemic threat This articles describes the features of human infection with influenza A (H5N1) and reviews recommendation for prevention and clinical management presented in part at the recent WHO meeting on Case Management and Research on Human Influenza A/H5, held in Hanoi , May 10-12, 2005.

Incidence : 

Incidence The occurance of human influenza A H5N1 in Southeast Asia has paralled large outbreak of avian infleuenza A (H5N1) The largest number of cases has occurred in Vietnam, and the first human death was recently reported in Indonesia. The frequencies of human infection have not been determined and seroprevalence studies are needed. Expanding distribution Recrent outbreak in Kazakstan, Mongolia and Russia Indicate more human population are at risk

Transmission : 

Transmission Human influenza is transmitted by inhalation of infectious droplets and droplet nuclei, by direct contact and perhaps by indirect(fomite) contact, with self inoculation into the upper respiratory tract or conjunctival mucosa

Animal to human : 

Animal to human From exposure to live poultry No significant risk related to eating or preparing poultry products or exposure to person with influenza A(H5N1) disease Exposure to ill poultry and butchering of birds were associated with seropositivity for influenza Recently most patients have had a history of direct contact with poultry

Human to human : 

Human to human In several household clusters and in one case of apparent child to mother transmission No cases of human to human transmission by small particle aerosols has been identified

Environment to human : 

Environment to human Oral ingestion of contaminated water during swimming and direct intranasal or conjunctival inoculation during exposure to water are other potential modes as is contamination of hands from infected fomites and subsequent self inoculation The widespread use of untreated poultry feaces as fertilizer is another possible risk factor

Clinical Features : 

Clinical Features The clinical spectrum based on descriptions of hospitalized patients The clinical frequencies ranges from milder illnesses, subclinical infections, and atypical presentations Most patients have been previously healthy young children or adults

Incubation : 

Incubation The incubation period may be longer than for other known human influenzas Most cases: within two to four days after exposure ; recent reports indicate similar intervals but with ranges of up to eight days The case-to-case intervals in household clusters have generally been 2 to 5 days, but the upper limit has been 8 to 17 days, possibly owing to unrecognized exposure to infected animals or environmental sources.

Initial Symptoms : 

Initial Symptoms initial symptoms : high fever >38°C and an influenza-like illness with lower respiratory tract symptoms Upper respiratory tract symptoms are present only sometimes Rarely causes conjuctivitis Diarrhea, vomiting, abdominal pain, pleuritic pain, and bleeding from the nose and gums : early in the course of illness in some patients Watery diarrhea without blood or inflammatory changes are more common than human influenza and may precede respiratory manifestations by up to one week One report described that some patients have an encephalopathic illness and diarrhea without apparent respiratory symptoms

Clinical Course : 

Clinical Course Lower respiratory tract manifestations develop early in the course of illness In one series, dyspnea developed a median of 5 days after the onset of illness (range, 1 to 16) Respiratory distress, tachypnea, and inspiratory pain are common Sputum production is variable and sometimes bloody Almost all patients have clinically apparent pneumonia; radiographic changes include diffuse, multifocal, or patchy infiltrates; interstitial infiltrates; and segmental or lobular consolidation Radiographic abnormalities were present a median of 7 days after the onset of fever in one study (range, 3 to 17)

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Progression to respiratory failure has been associated with diffuse, bilateral, ground-glass infiltrates and manifestations of the acute respiratory distress syndrome (ARDS) Multiorgan failure with signs of renal dysfunction and sometimes cardiac compromise including cardiac dilatation and supraventricular tachyarrhythmias has been common Other complications: ventilator associated pneumonia, pulmonary haemorrhage, pneumothorax, Reye’s syndrome and sepsis syndrome. Continue…..

Mortality : 

Mortality The fatality rate among hospitalized patients has been high In contrast to 1997, when most deaths occurred among patients older than 13 years of age, recent avian influenza A (H5N1) infections have caused high rates of death among infants and young children The case fatality rate was 89 percent among those younger than 15 years of age in Thailand Death has occurred an average of 9 or 10 days after the onset of illness (range, 6 to 30), and most patients have died of progressive respiratory failure

Laboratory Findings : 

Laboratory Findings Common laboratory findings : leukopenia, particularly lymphopenia; mild-to-moderate thrombocytopenia; and slightly or moderately elevated aminotransferase levels Marked hyperglycemia, perhaps related to corticosteroid use, and elevated creatinine levels

Virologic Diagnosis : 

Virologic Diagnosis Confirmed by: viral isolation, the detection of H5-specific RNA, or both methods Unlike human influenza A infection, avian influenza A (H5N1) infection may be associated with a higher frequency of virus detection and higher viral RNA levels in pharyngeal than in nasal samples The detection of viral RNA in throat-swab samples ranged from 2 to 15 days (median, 5.5), and in pharyngeal swabs 4 to 8 days

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Continue….. Earlier studies also found low viral loads in nasopharyngeal samples Commercial rapid antigen tests are less sensitive in detecting influenza A (H5N1) infections than are RT-PCR assays The results of rapid antigen testing were positive in only 4 of 11 patients with culture-positive influenza A (H5N1) (36 percent) 4 to 18 days after the onset of illness.

Management : 

Management Most hospitalized patients with avian influenza A (H5N1) have required ventilatory support within 48 hours after admission, as well as intensive care for multiorgan failure and sometimes hypotension Broad-spectrum antibiotics, antiviral agents, alone or with corticosteroids, have been used in most patients although their effects have not been rigorously assessed

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Continue….. Early institution of these interventions are beneficial to reduce the mortality rate Cultivable virus generally disappears within two or three days after the initiation of oseltamivir among survivors, but clinical progression despite early therapy with oseltamivir and a lack of reductions in pharyngeal viral load have been described in patients who have died

Pathogenesis : 

Pathogenesis Characterization of virus

Contd.. : 

Contd.. Virulence factors: highly cleavable haemagglutinin that can be activated by multiple cellular proteases Increase resistance to inhibition of interferons and TNFa in vitro and prolonged replication in swine as well as greater elaboration of cytokines, particularly TNFa (because specific substitution in polymerase basic protein 2(Glu 627 Lys) that enhances replication and a substitution in non structural protein 1 (ASP 92 Glu) (1997 study) residue in polybasic cleavage site of haemagglutinin Viruses continue to evolve with changes in antigenicity and internal gene constellations (emergence of expanded host range in avian species and ability to infect felids, enhanced pathogenicity with systemic infection and increased environmental stability. Phylogeny : Z genotye has become dominant 2 distinct clades (evolve) 1. Combodia, Laos, Malaysia, Thailand, and Vietnam 2. China, Indonesia, Japan, South Korea Recently: Separate cluster, Northen Vietnam, Thailand Variable changes near the receptor binding site and one fewer arginine

Pattern of viral Replication : 

Pattern of viral Replication (Virologic course)- incompletely characterised Study: viral replicaiton is prolonged Detection of virus: Nasopharyngeal isolates 6.5 days(1-16) (In Thailand) Interval from onset of illness to first positive culture: 3-16 days Nasopharyngeal replicaiton < than in human influenza (So, study of lower respiratory tract is needed) Majority of faecal sample positive for viral RNA (7 of 9), urine sample negative Replication in gastrointestinal tract (high frequency of diarrhoea among affected patients and the detection of viral RNA in fecal sample. Confirmation: autopsy Highly pathogenic influenza A (H5N1) virus polybasic amino acid sequence at the haemagglutinin cleavage site that is associated with visceral dissemination in avian species Invasive infection- in mammals, human, infectious virus and RNA in Blood, CSF, Feces

Host Immune Response : 

Host Immune Response Low frequency in human despite wide exposure to infected poultry ( because species barrier to acquisition of this avian viruse increased Clusters of cases in family members-common exposeres (genetic factors may affect a host’s susceptibility to disease) The innate immune response to influenza A (H5N1)- contribute pathogenesis 1997 outbreak : elevated blood levels of interleukin-6, TNFa, interferon? and soluble interleukin-2 receptor 2003 : elevated levels of the chemokines, interferon- inducible protein 10, monocyte chemotactic protein 1, monokine induced by interferon found 3-8 days after onset of illness.

Pathological Findings : 

Pathological Findings Documented biopsy analyses severe pulmonary injuries with histopathological changes of diffuse alveolar damage, pneumonia Changes:- filling of alveolar spaces with fibsrinous exudates and red cells, hyaline membrane formation, vascular congestion, infiltration of lymphocytes into the interstitial areas and the proliferation of reactive fibroblasts. Infection of type II pneumocytes Biopsy of bone marrow specimen: reactive histiocytosis with hemophagocytosis, lymphoid depletion and atypical lymphocytes have been noted in spleen and lymphoid tissues Centrilobular hepatic necrosis and acute tubular necrosis

Case Detection And Management : 

Case Detection And Management Possibility of infection- All patient with severe acute respiratory illness- in countries or territories with animal influenza A(H5N1) – particularly patients who have been exposed to poultry. (However some outbreaks in poultry were recognized only after sentinel cases occurred in humans) Early recognition of cases – non specificity of the initial clinical manifestation and high back ground rates of acute Respiratory illness from other causes Consideration in patients with serious unexplained illness (e.g. encephalopathy, diarrhoea) in areas with known influenza A (H5N1) acitvity in humans or animals

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Contd… Diagnostic yield and virologic assays- not well defined Throat sample have better yield than Nasal samples (because human influenza virus) Rapid antigen assays- provide support (but poor negative predictive, lack specificity Detection of viral RNA- greatest sensitivity +for early identivity (because primers and assays) Laboratory confirmation : require one or more (a positive viral culture, Positive PCR assay, positive immunofluorescence test , H5 specific antibody titre in serum)

Hospitalization : 

Hospitalization Whenever feasible- patients (suspected or proven) should be hospitalized in isolation for clinical monitoring, appropriate diagnosis, antiviral therapy If discharged early- both patients and family require education on personal hygiene and infection control measures Supportive care with provision of supplemented oxygen and ventilatory support (foundation of management Nebulizers and high air flow oxygen maskes (for prevention of nosocomial spread of SARS)

Antiviral Agents : 

Antiviral Agents Suspected patient : promptly receive a neuraminidase inhibitor (pending the result) These viruses susceptible to oseltamivir and zanamivir (in vitro) Oral oseltamivir and topical zanamivir are active in animal model Strain from 2004 requires higher oseltamivir doses than 1997 strain (murine study) for more prolonged administration (8 days) Early treatment: great clinical benefit (however use of therapy is resonable when there is ongoing viral replication) Approved doses or doses that are twice as high) placebo controlled clinical study

contd..Approved doses of oseltamivir : 

contd..Approved doses of oseltamivir 75mg/bid- 5 days in adult 30mg/bid- 5 days- 15 kg or less >1 years 45mg/bid- 5 days- 15-23 kg 60mg/bid- 5 days- 23-40 kg 75mg/bid- 5 days >40 kg for early mild cases 150mg/bid- in adult – 7-10 days – sever infections

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Contd.. High level antiviral resistance to oseltamivir (substitution of single A.A in N1 neuraminidase (His 274 Tyr) (Such variants : 16% of children) Oseltamivir resistant H1N1 variants ( less infectious in cell culture and animal) transmissible in ferrets (fully susceptibility to zanamivir and partially susceptible to peramivir) Recent isolates- highly resistance to M2 inhibitors amantidine and rimantidine Agents of treatment: zanamivir, peramivir, ribavirin, interferon a

Immunomudulators : 

Immunomudulators Corticosteroid- frequently used in treating influenza A (H5N1) with uncertain effects. (1997/ 5 patients/ 2 treated later in the course for fibroproliferative phage of ARDS survived) dexamethasone/ Vietnam/ 4 patients died Interferon a : i. Antiviral ii. immunomodulator

Prevention : 

Prevention Immunization No influenza A (H5N1) vaccines : commercially available Early H5 vaccines – poorly immunogenic and require 2 doses of high haemagglutinin Ag content or the addition of MF59 adjuvant to generate neutralizing Ab responses (300 injection of adjuvanted 1997 H5 vaccine induce cross reacting Ab to human isolates from 2004) Reverse genetics has been used for the rapid generation of non virulent vaccine viruses from recent isolates Vaccine (under study) Inactivated vaccine (H5N1 human isolates from 2004)- immunogenic at high heamagglutinin doses Adjuvants like alum : needed Live attenuated, cold adopted intranasal vaccines are under development ( single dose in young children)

Hospital Infection control : 

Hospital Infection control Nosocomial pathogen Reduce transmission to health care workers and other patients in non pandemic situation ( on the interventions used to contain SARS) N-95 masks> surgical mask (multiple ones) Chemoprophylaxis with 75 mg of oseltamivir once daily for 7-20 days for person with unprotected exposure Pre exposure prophylaxis ( if person to person transmission with increased efficiency or high exposure)

Household and close contacts : 

Household and close contacts House hold contacts of persons with comfirmed case of influenza A ( H5N1)- post exposure prophylaxis Contacts of patient with proven or suspected virus should monitor their temperature and sympotms Although risk of secondary transmission is low, self quarantine for a period of one week after last exposure is appropriate Person to persion transmission needs quarantine For others having unprotected exposure to infected person or environmental source (poultry)- post exposure prophylaxis

Conclusion : 

Conclusion Primary source of influenza A(H5N1) infection in human in Asia- infected birds Transmission between human is very limited at present but continued monitoring is required to know viral adaptation in human host Avian influenza A(H5N1) in human differ from influenza due to human viruses including route of transmission, clinical severity, pathogenesis, response to treatment Case detection : is confounded by the non specificity of initial manifestations of illness (detailed contact, travel histories and knowledge of viral activity in poultry) Commercial rapid Ag test: insensitive and confirmatory diagnosis requires sophisticated lab support

Contd.. : 

Contd.. Avian influenza A (H5N1) : higher viral titres in the throat than nose (unlike human influenza) Throat swab or LRT sample : more sensitive Recent isolates : fully resistant to M2 inhibitors (for treatment increased base of oseltamivir is warranted- severeillness Despite recent progress, knowledge of the epidemiology, natural history, management of influenza A (H5N1) disease in human is incomplete There is urgent need for more coordination in clinical and epidemiologic research among institutions in countries with case of influenza A (H5N1) internationally



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