Recommendations for the Management of Children with H1N1 Novel Influenza Infection

Ping-Ing Lee¹, Tzou-Yien Lin², Kai-Sheng Hsieh³, Shyh-Dar Shyur⁴, Shao-Hsuan Hsia², Yung-Feng Huang³, Frank Leigh Lu^1, Betau Hwang⁵, Nan-Chang Chiu⁴, Chun-Yi Lu¹, Ching-Shiang Chi⁶, Po-Yen Chen⁷, Luan-Yin Chang¹, Jong-Min Chen¹, Bor-Luen Chiang¹, Yhu-Chering Huang², Chin-Yun Lee¹,

1  Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

2  Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

3  Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

4  Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan 

5  National Yang-Ming Uvinversity ,Taipei Ciyt Hospital, Zhong Xiao Branch, Taipei, Taiwan

6  Department of Pediatrics, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan

7  Department of Pediatrics , Taichung Veterans General Hospital, Taichung, Taiwan 

Published in Pediatrics and Neonatology:

Ping-Ing Lee, Tzou-Yien Lin, Kai-Sheng Hsieh, Shyh-Dar Shyur, Shao-Hsuan Hsia, Yung-Feng Huang, Frank Leigh Lu, Betau Hwang, Nan-Chang Chiu, Chun-Yi Lu, Ching-Shiang Chi, Po-Yen Chen, Luan-Yin Chang, Jong-Min Chen, Bor-Luen Chiang, Yhu-Chering Huang, Chin-Yun Lee. Recommendations for the management of children with H1N1 novel influenza infection. Pediatr Neonatol 2010;51(1)1-4.

 
　

H1N1 Novel Influenza 

As a member of orthomyxoviridae family, influenza viruses are enveloped viruses containing 8 RNA segments. The main antigenic determinants of influenza A and B viruses are two surface glycoproteins: the hemagglutinin (H) and the neuraminidase (N). A genetic reassortment between influenza A viruses from different animal hosts may lead to an antigenic shift and the risk of a pandemic potential. H1N1 and H3N2 subtypes of influenza A have been circulating all over the world as seasonal influenza since the last H3N2 pandemic in 1968.¹

  In April 2009, the Centers for Disease Control and Prevention of the United States identified two cases of human infection with the H1N1 novel influenza virus. The greatest initial burden of critical illness and death occurred in Mexico between March and June 2009. The virus is a triple-reassortant containing gene segments from swine influenza virus, human influenza virus, and avian influenza virus. Genes for hemagglutinin and neuraminidase come from swine influenza virus.² On June 11, the World Health Organization raised the pandemic influenza phase from 5 to 6. 

Case Definition 

The diagnosis of influenza-like illness should meet all the following two criteria:

1.   Sudden onset of fever (tympanic temperature ≥ 38^OC) and respiratory tract symptoms.

2.   At least one of the following symptoms: muscle aches, headache, extreme fatigue, and poor activity in children.

Many respiratory pathogens other than influenza virus may cause an illness that is indistinguishable from influenza in children, especially for younger children. A contact history, including the presence of influenza-like illness or a laboratory-confirmed influenza infection in other family members or classmates, is an important clue for the diagnosis of influenza in young children. It should be noticed that vomiting and diarrhea are not uncommon in children with seasonal influenza or H1N1 novel influenza virus infection.^3-5 Without a laboratory test, illness caused by H1N1 novel influenza virus cannot be differentiated from that caused by seasonal influenza virus.

Severe complication

        H1N1 novel influenza with severe complication should be reported to the Center for Disease Control of Taiwan within one week, including patients with the following conditions: 1. pulmonary complication that required hospitalization; 2. neurological complication; 3. myocarditis or pericarditis; 4. invasive bacterial infection; 5. needs for intensive care or death.

Risk factors

        Risk factors for severe influenza infection include children ≤ 5 years, adults ≥ 65 years, pregnant women, peoples who have underlying disorders (including abnormal neurological and neurodevelopmental conditions, chronic lung disease, heart diseases, hematological disorders, endocrine disorders, kidney disorders, liver disorders, metabolic disorders, and immunocompromised conditions), and obesity (body weight ≥ 95^th percentile of the normal range).

Among 39 pediatric deaths associated with H1N1 novel influenza infection in the United States, 24 (67%) had at least one high-risk medical condition. Among the 24 children with high-risk medical conditions, 22 (92%) had neurodevelopmental conditions (e.g., developmental delay or cerebral palsy).⁶ Among the first 100 hospitalized patients with H1N1 novel influenza infection reported to Center for Disease Control of Taiwan, 38% had at least one risk factor.⁵

Warning signs

        In children, the appearance of the following signs should alert the families and the physicians that the illness may be deteriorating and the patient needs immediate medical attention:⁷

1.      Tachypnea: The respiratory rate at resting and afebrile conditions exceeds the upper limits listed in Table 1.

Table 1. Upper limits of normal respiratory rate in childen.

Age	Upper limits of normal respiratory rate per minute
< 3 months	60
3 – 11 months	50
1-2 years	40
3-5 years	35
6-11 years	30
12-18 years	20

2.      Dyspnea

3.      Chest wall retractions when afebrile

4.      Cyanosis

5.      Blood-streaked sputum

6.      Chest pain or abdominal pain

7.      Exercise intolerance

8.      Severe or persistent vomiting

9.      Not waking up or not interacting

10.  Being so irritable that the child does not want to be held

11.  Poor oral intake with signs of dehydration, including decreased urine output, and having no tears when crying

12.  Flu-like symptoms that improve but then return with fever and worse cough

13.  Fever with a rash

14.  Changed level of consciousness or other abnormal neurological signs

15.  Persistent fever beyond 72 hours

Pneumonia, including viral pneumonia caused by novel influenza virus per se and secondary bacteria pneumonia, is the most common complication of severe infections.^5,6 Compared with adults, encephalitis is more common in children with seasonal influenza infections,⁸ and this may also be true for H1N1 novel influenza. Laboratory tests of severe infections frequently show the presence of lymphopenia and elevated creatine phosphokinase levels.^5,9

Laboratory diagnosis

Viral culture and reverse transcriptase-polymerase chain reaction (RT-PCR) can reliably identify the presence of H1N1 novel influenza virus in specimens, especially for RT-PCR that has the highest sensitivity and specificity. Rapid screening tests for influenza may detect the presence of antigen from either influenza A or influenza B in respiratory specimens. Although the tests have a high specificity (> 95%), their sensitivities are variable, ranging between 10-70%, for detecting H1N1 novel influenza when compared with RT-PCR. A negative result of screening test does not rule out influenza virus infection.^5,7 These tests cannot distinguish H1N1 novel influenza from seasonal H1N1 or H3N2 influenza A viruses. When a decision is made to use antiviral agents for severe infections, treatment should be initiated as soon as possible without waiting for the test results.

In general, sputum has the highest concentration of virus and should be the most appropriate specimen for virus detection. For patients without available sputum, nasopharyngeal swab should be used for virological tests, including the rapid screening test. Nasal swab and oropharyngeal swab may be associated with a lower sensitivity for virus detection

For all suspected influenza patients with severe complication, appropriate specimens should be sent for viral culture and RT-PCR. Rapid screening test for influenza may be considered in patients with influenza-like illness as defined previously. Patients with influenza-like illness should be managed as novel influenza infection if their close contacts have been confirmed to have influenza A or H1N1 novel influenza infection by any laboratory test within one week before or after the onset of illness of the patient.

Antiviral treatment

H1N1 novel influenza virus is resistant to adamantanes, including amantadine and rimantadine. Neuraminidase inhibitors, including oseltamivir (Tamiflu) and zanamivir (Relenza), are active against H1N1 novel influenza virus.¹⁰ Oseltamivir is approved for use in patients one year and older who have been symptomatic for no more than 2 days. Through the process of Emergency Use Authorization, it can be used in infants younger than one year with suspected or confirmed H1N1 novel influenza infection (Table 2).⁷

Table 2. Recommended dosage of oseltamivir in children

Age and body weight	Dosage
≥ 12 months
> 40 kg	75 mg twice daily
24 – 40 kg	60 mg twice daily
16–23 kg	45 mg twice daily
≤ 15 kg	30 mg twice daily
< 12 months
6-11 months	25 mg twice daily
3-5 months	20 mg twice daily
< 3 months	12 mg twice daily

Zanamivir is formulated for oral inhalation and is approved for the treatment of influenza in patients 7 years of age and older. The recommended dosage is 10 mg (two 5-mg inhalations) twice daily. This inhaled agent is not the treatment of choice for severe influenza infection because it cannot achieve an effective systemic concentration.  

Antiviral agents should be given as soon as possible to achieve the greatest therapeutic effect, but they may be given to patients with manifestations of active infection beyond 2 days of illness. Antiviral agents may not be necessary if the symptoms have lasted for 2 days or more, the fever, if any, has been subsided for more than 24 hours, and there is neither any warning sign nor recognizable complication.

The recommended duration of standard treatment is 5 days. Hospitalized patients with severe complications may require longer treatment courses for up to 10 days. For patients with impaired gastrointestinal function and severe illness, the dose of oseltamivir may be doubled. Intravenous antiviral agents, if available, may also be considered.

Oseltamivir-resistant H1N1 novel influenza virus has been described all over the world, including Taiwan.^11,12 Most of these resistant strains emerged after the start of oseltamivir therapy and are limited in their transmissibility.

Oseltamivir may be given to patients with influenza-like illness with one of the following conditions:

1.      A positive result for influenza A or H1N1 novel influenza by rapid screening test, RT-PCR, or virus culture.

2.      Close contacts having been confirmed to have influenza A virus or H1N1 novel influenza infection by any laboratory test within one week before or after the onset of illness of the patient..

3.      Having risk factors, as defined previously, during influenza pandemic stage.

4.      Fulfill the criteria of severe complications as defined previously.

Other treatment

Approximately 30-40% of fatal cases with H1N1 novel influenza infection have a bacterial coinfection. The most common pathogens are Streptococcus pneumoniae and Staphylococcus aureus.⁶ Chest X-ray findings cannot reliably differentiate between severe influenza pneumonia and secondary bacteria pneumonia. Pneumonic patches and consolidations are commonly seen in both conditions. Antibiotics that are effective against S. pneumoniae and S. aureus may be given empirically to patients with a severe pneumonia. Antibiotics should not be used in patients without complication.

High dose steroid that may compromise the immune function and intravenous immune globulin that may increase the work load of the heart are not recommended in acute phase of H1N1 novel influenza infection.

Oxygen supplement may be given when the arterial oxygen saturation < 92%. Nebulization therapy and noninvasive respirator (such as continuous positive airway pressure) should be avoided in the acute phase to minimize the risk of nosocomial transmission. Mechanical ventilator and extracorporeal membrane oxygenation may be used when necessary.

Immunization

H1N1 novel influenza vaccines available in Taiwan are inactivated split-product influenza vaccines containing mainly hemagglutinin and neuraminidase that are derived from culture of vaccine virus in chicken embryo. For children aged between 6 months and 9 years, two doses of vaccine with an interval of at least 28 days are necessary to mount an adequate immune response. For children older than 10 years, one dose of vaccine may induce a satisfactory immune response. Major adverse events include pain, swelling and erythema of injection site. The incidence of fever after vaccination is about 1-2%

The H1N1 novel influenza vaccine is contraindicated in children with an allergic history to chicken egg, any vaccine component, or any kind of influenza vaccines, and children with an acute illness. Occurrence of serious adverse events after vaccination should be reported to the Center for Disease Control, Taiwan.

 Infection control

        Influenza viruses are transmitted from person to person primarily through droplets transmission and contact with infected respiratory secretions. Hand hygiene and facemasks if necessary may decrease the risk of transmission. The incubation period for influenza ranges from 0.5 to 4 days with an average of 2 days. Virus shedding begins from 24 hours before illness onset and can persist for al least 5 to 7 days. Some persons may shed virus for longer periods, particularly young children, immunocompromized persons, and patients with severe complication. People with influenza-like illness should stay at home until at least 24 hours after they are free of fever (ear or rectal temperature < 38^OC). Hospitalized patients require an exclusion period of at least 7 days from symptom onset and having been afebrile for at least 24 hours.

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