This Guide on the clinical management of pandemic (H1N1) virus infection Prof. AHMED ABDELRAHMAN DEPARTMENT OF CHEST MENUFYIA UNIVERSITY HOSPITAL

INFLUENZA Acute respiratory illness caused by infection with influenza viruses. Affects the upper and/or lower respiratory tract and is often accompanied by systemic signs and symptoms: fever - headache myalgia - weakness

H1 – H16 N1 – N9 N H

Three types: A, B, C A epidemic flu, severe disease Surface proteins determine subtype H (hemagglutinin) H1 – H16 N (neuraminidase) N1 – N9 Influenza A viruses infect multiple species depending on subtype Humans Birds Pigs

What is the Influenza A (H1N1)? Influenza A virus Subtypes 16 different HA antigens (H1 to H16) 9 different NA antigens (N1 to N9) 3 subtypes of HA (H1, H2, and H3) & 2 subtypes of NA (N1 and N2) – caused human disease. found in birds & pigs

H3N2 ("swine flu") is endemic in pigs in China, and in Vietnam H3N2 ("swine flu") is endemic in pigs in China, and in Vietnam. The dominant strain of annual flu virus in January 2006 was H3N2, which is now resistant to the standard antiviral drugs amantadine and rimantadine. The possibility of H5N1 and H3N2 exchanging genes is a major concern. If a reassortment in H5N1 occurs, it might remain an H5N1 subtype, or it could shift subtypes, as H2N2did when it evolved into the Hong Kong Flu strain of H3N2

H5N1  Influenza A virus  subtype it might mutate into a form that transmits easily from person to person. If such a mutation occurs, it might remain an H5N1 subtype or could shift subtypes as didH2N2 when it evolved into the Hong Kong Flu strain of H3N2.

SARS coronavirus The SARS coronavirus, sometimes shortened to SARS-CoV, is the RNA virus virus that causes severe acute respiratory syndrome (SARS)

Influenza - Case Definition Fever ≥ 38.00 C with cough &/or sore throat in the absence of a known cause other than influenza

Estimated incubation period 1-7 days, (likely 1-4 days). Infectious period for a confirmed case of influenza A (H1N1) virus infection is defined as 1 day prior to the case’s illness onset to 7 days after onset.

CLINICAL FEATURES

Clinical Features of Influenza A/H1N1 Uncomplicated disease manifest with fever headache upper respiratory tract symptoms (cough, sore throat, rhinorrhea), myalgia, fatigue, vomiting, or diarrhea.

Complications Clinical syndromes have ranged from mild respiratory illness, to lower respiratory tract illness, dehydration, or pneumonia. URTIs (sinusitis, otitis media, croup) LRT disease (pneumonia, bronchiolitis, status asthmaticus), cardiac (myocarditis, pericarditis), musculoskeletal (myositis, rhabdomyolysis), neurologic ( encephalopathy, encephalitis, febrile seizures, status epilepticus), In children,risk of REYE Syndrome (therefore, NSAIDS contraindicated)

Symptom (%) Fever* (93%) Cough (83%) Shortness of breath (54%) Fatigue/Weakness (40%) Chills (37%) Myalgias (36%) Rhinorrhea (36%) Sore Throat (31%) Headache (31%) Vomiting (29%) Wheezing (24%) Diarrhea (24%)

Influenza A/H1N1 Infections in Children Majority are mild & self limiting Most common are fever(100%) , cough(100%) , sore throat(66%) , myalgia(44%) , vomiting & diarrhea(25%) Uncommon: altered conscious level (10%) , hypotension

Suspected case of pandemic (H1N1) A suspected case of H1N1 infection is defined as an individual with acute respiratory illness and fever and one of the followings; cough, sore throat, shortness of breath, difficulty in breathing or chest pains with onset: Within 7 days of close contact with a person who is probable or confirmed case of H1N1infection, OR Within 7 days of travel to a country/community where there has been one or more confirmed cases of H1N1 infection; OR Resident in a community where there is one or more confirmed cases of H1N1 infection.

Probable case of (H1N1) A probable case of H1N1 infection is defined as an individual with an influenza-like illness who is positive for influenza A that is confirmed by real-time PCR, OR an individual with a clinically compatible illness or died of an acute respiratory illness who is linked to a probable or confirmed case.

Case Definitions Confirmed Case of pandemic (H1N1) A confirmed case of H1N1 infection is defined as an individual with an influenza-like illness with laboratory confirmed pandemic (H1N1) 2009 virus infection by one or more of the following test: Real-time RT-PCR Viral culture

Influenza like illness (ILI) A person with sudden onset of fever of >38 °C and at-least one of the following two respiratory symptoms in the absence of other known causes: dry cough & sore throat 

Severe acute respiratory illness (SARI) A person meeting the case definition of influenza-like illness (sudden onset of fever > 38 0C with at-least one of the following two respiratory symptoms- dry cough, sore throat in the absence of other diagnosis) AND shortness of breath OR difficulty in breathing requiring hospital admission

Acute Respiratory Infection (ARI) For the purposes of this interim guidance, Acute Respiratory Infection (ARI) is defined as an acute respiratory tract illness that is caused by an infectious agent transmitted from person to person. The onset of symptoms is typically rapid, over a period of hours to several days. Symptoms include fever, cough, and often sore throat, coryza, shortness of breath, wheezing, or difficulty breathing.

Complications of Influenza: Respiratory complications are the most common ones (esp secondary infections). At times these complications, eg. an exacerbation of COPD, may be the presenting symptom. Cardiac events are not uncommon. Complications of influenza Major clinical category Respiratory Pneumonia: primary viral, secondary bacterial, combined Upper respiratory: otitis media, sinusitis, conjunctivitis Acute laryngotracheo-bronchitis (croup) Bronchiolitis Complication of pre-existing disease

Cardiovascular Myocarditis & Pericarditis Muscular Rhabdomyositis Rhabdomyolysis with myoglobinuria and renal failure Neurological Encephalitis Reye’s syndrome Guillain-Barré syndrome Transverse myelitis Systemic Toxic shock syndrome Sudden death

DIAGNOSIS

The CXR shows bilateral alveolar opacities in the base of both lungs. The specimen (H&E stain) shows necrosis of bronchiolar walls, neutrophilic infiltrate and diffuse alveolar damage with prominent hyaline membranes. Bacterial cultures were negative on admission, and no evidence of bacterial infection of the lungs.

The CXR shows bilateral alveolar opacities in the base of both lungs.

The specimen (H&E stain) shows necrosis of bronchiolar walls, neutrophilic infiltrate and diffuse alveolar damage.

Real-Time Reverse Transcription-Polymerase Chain Reaction (rRT-PCR) Detection Qualitative for Influenza A, B, H1, and H3 positive for influenza A and negative for H1 and H3 If reactivity of real-time RT-PCR for influenza A is strong (eg, Ct <30), it is more suggestive of a novel influenza A virus.

Risk factors in adults include the following: Chronic respiratory conditions, eg asthma, COPD, OSA Pregnant women, esp. in second or third trimester Obesity (BMI > 30) Other predisposing conditions, such cardiac disease and diabetes mellitus, renal failure, immunosuppression. Adults > 65 years of age esp.

Risk factor for children with ILI Cardiac disease : congenital heart dis. Chr. resp. disease : asthma Chronic renal failure Diabetes mellitus or other metabolic diseases Chr. neurological disease : ms. Dystrophy Impaired immunity:HIV,malignancy Malnutrition or obesity Children < 5 yrs : Higher risk of severe disease & mortality

Recognition of deterioration of Pts with moderate / severe illness need to be admitted and provided with antiviral therapy. Severe illness following influenza occurs in at least 3 ways: 1. severe viral infection with ARDS occurring relatively early in illness related to viral pneumonia (within 1st 4 days) 2. bacterial pneumonia, complicating initial bronchitis caused by influenza, or following apparent recovery from initial illness

Abnormal pulse oximetry – Significant ↓in SpO2 (<92%) low SpO2 can detect severe or complicated influenza in some cases. In people with normal pre-existing respiratory and cardiac function, SpO2 < mid 90’s is abnormal and < low 90s is very abnormal and indicates severe disease.

Severe Disease in Children Apnea Tachypnea Dyspnea Cyanosis Dehydration Altered mental status Extreme irritability

Lower chest wall indrawing Sternal recession Grunting Noisy breathing when calm Increased Respiratory Rate in Children ≥ 50 breaths per min if under 1 yr old ≥ 40 breaths per min if ≥ 1 year old Severe Clinical Dehydration or Clinical Shock in children Reduced skin turgor Sunken eyes or fontanelle

CNS Involvement in children Irritable Unconscious Drowsiness Confusion Seizures Weakness or paralysis Floppy infant

Patients to be hospitalized: All patients fulfilling criteria of ILI with any of the parameters for moderate to severe influenza

Patient Home Assessment 1 Respiratory Difficulties: Shortness of breath, rapid breathing & blue discoloration of lips 2 Coughing of blood or blood streaked sputum 3 Persistent chest pains 4 Persistent diarrhea and / or vomiting 5 Fever persisting beyond 2 days or recurring after 2 days 6 Abnormal behavior , confusion, less responsive , convulsion 7 Dizziness when standing and/or reduced urine production

Home Assessment Tool for pediatric Lethargy or poor oral intake Change in mental status Signs of dehydration Signs of respiratory distress Fits Cyanosis Persistent fever > 2 days

Confirmed Case of Influenza A/H1N1 Infection Individuals with ILI and +ve laboratory test , either by a) PCR b) Viral culture

Antiviral Treatment for Influenza A / H1N1 RECOMMENDATION: All hospitalized patients (ie. those with moderate to severe disease) with confirmed or suspected novel influenza A H1N1. Empirical therapy for suspected patients with severe disease should be considered if the time for H1N1 confirmation is prolonged. The antiviral treatment may be stopped if the results are negative. All individual with co-morbid factors whether they are admitted or not.

Antiviral Therapy Oseltamivir (Tamiflu) dosage: Duration 5 days Adults & adolescents > 13 yrs: 75 mg bd (in severe cases, dosage can be doubled to 150 mg bd) For children (according to weight): <15kg: 30mg bd 15-23kg: 45mg bd 23-40kg: 60mg bd > 40kg: 75mg bd Renal adjustments: patients with a serum creatinine clearance between 10 - 30 ml/min: treated with 75 mg daily for 5 days

Oseltamivir Side Effects Gastrointestinal(40%) : nausea , vomiting , abd. pain/cramps, diarrhea Neuropsychiatric(18%) : sleep problems , insomnia , poor concentration , delirium , feeling confused , hallucinations , bad dreams , nightmares , abnormal behavior

Zanamivir (Relenza) dosage: 10mg (2 puffs) bd for 5days (Adults & children) In patients with bronchospasm: Zanamivir is not recommended for the treatment of patients with underlying airways disease (eg. asthma or COPD). Patients with pulmonary dysfunction should always have a fast-acting bronchodilator available and discontinue zanamivir if respiratory difficulty develops. No dosage adjustment is required in patients with renal impairment

Conclusions Careful clinical assessment of the individual with ILI in primary healthcare setting is important Admission is needed for individual with moderate to severe diseases of any age. Treatment with antiviral is needed only for admitted individuals and those with co-morbid factors whether admitted or not.

The single best way to protect against the flu is to get vaccinated each year. flu shot — an inactivated vaccine (containing killed virus). - for use in people older than 6 months, including healthy people and people with chronic medical conditions. The nasal-spray flu vaccine —made with live, weakened flu viruses that do not cause the flu . - approved for use in healthy people, 2-49 y.o. who are not pregnant.

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