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HHS Pandemic Influenza Plan  Supplement 5 Clinical Guidelines

 

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Table of Contents

Summary of Public Health Roles and Responsibilities For Clinical Guidelines

  1. S5-I.  Rationale
  2. S5-II.  Overview
  3. S5-III.  Clinical Guidelines For The Interpandemic and Pandemic Alert Periods
    1. Criteria for evaluation of patients with possible novel influenza
      1. Clinical criteria
      2. Epidemiologic criteria
    2. Initial management of patients who meet the criteria for novel influenza
    3. Management of patients who test positive for novel influenza
    4. Management of patients who test positive for seasonal influenza
    5. Management of patients who test negative for novel influenza
  4. S5-IV.  Clinical Guidelines for The Pandemoc Period
    1. Criteria for evaluation of patients with possible pandemic influenza
      1. Clinical criteria
      2. Epidemiologic criteria
    2. Initial management of patients who meet the criteria for pandemic influenza
    3. Clinical management of pandemic influenza patients

Box 1. Risk of Novel Influenza in Persons with Severe Respiratory Disease or Influenza-like Illness during the Interpandemic and Pandemic Alert Periods
Box 2. Clinical Evaluation of Patients with Influenza-like Illness during the Interpandemic and Pandemic Alert Periods
Box 3. Special Situations and Exceptions to the Clinical Criteria
Box 4. Home Care Infection Control Guidance for Pandemic Influenza Patients and Household Members

Figure 1. Case Detection and Clinical Management during the Interpandemic and Pandemic Alert Periods
Figure 2. Case Detection and Clinical Management during the Pandemic Period

Table 1. Pandemic Influenza Infection Control Guidance for Healthcare Providers

Appendix 1. Clinical Presentation and Complications of Seasonal Influenza
Appendix 2. Clinical Presentation and Complications of Illnesses Associated with Avian Influenza A (H5N1) and Previous Pandemic Influenza Viruses
Appendix 3. Guidelines for Management of Community-acquired Pneumonia, Including Post-influenza Community-acquired Pneumonia

Table 2. Pneumonia PORT Severity Index (PSI) Calculation
Table 3. Pneumonia Severity Index Risk Classification
Table 4. CURB-65 Scoring System
Table 5. Recommended site of care based on CURB-65 system

Figure 3. Management of Community-Acquired Pneumonia during an Influenza Pandemic: Adults
Figure 4. Management of Community-acquired Pneumonia during an Influenza Pandemic: Children\



Summary of Public Health Roles and Responsibilities For Clinical Guidelines

Interpandemic and Pandemic Alert Periods

Healthcare providers:

  • Be aware of case definitions; procedures for screening, infection control, and laboratory testing; and antiviral regimens for influenza A (H5N1) and other novel influenza viruses.
  • Notify health departments about suspected/confirmed novel influenza cases and fatalities.
  • Collect recommended specimens for diagnosis of novel influenza, and forward specimens to designated state and federal laboratories.

State and local public health agencies:

  • Help educate healthcare providers about novel and pandemic influenza.
  • Provide or facilitate testing and investigation of suspected novel influenza cases.
  • Conduct follow-up of suspected novel influenza cases.

HHS agencies:

  • Develop and disseminate recommendations on the use of influenza diagnostic tests, antiviral drugs, and vaccines during a pandemic (see also Supplement 6 and Supplement 7).
  • Develop a national stockpile of antiviral drugs for use during a pandemic (see also Supplement 6).
  • Work with partner organizations to discuss and resolve clinical issues related to pandemic influenza response.
  • Assist ministries of health and WHO in characterizing cases of human infection with avian influenza A (H5N1) or other novel strains of influenza, particularly with regard to antiviral susceptibility, transmission parameters, and clinical outcomes.
  • Work with state and local health departments to investigate and manage suspected cases of human infection with avian influenza A (H5N1) or other novel strains of influenza.
  • Establish case definition and reporting mechanisms.

Pandemic Period

Healthcare providers:

  • Regularly consult updates on case definitions, screening, laboratory testing, and treatment algorithms for pandemic influenza.
  • Report pandemic influenza cases or fatalities as requested by health departments.
  • Collect recommended specimens for ongoing pandemic influenza surveillance, and forward specimens as requested to designated state and federal laboratories.
  • Report atypical cases, breakthrough infections while on prophylaxis, or any other abnormal cases throughout the duration of the pandemic to public health agencies.

State and local public health agencies:

  • Update providers regularly as the influenza pandemic unfolds.
  • Provide or facilitate testing and investigation of pandemic influenza cases.
  • Work with CDC to investigate and report special pandemic situations.

HHS responsibilities:

  • Update and disseminate national guidelines on influenza diagnostic testing and use of antiviral drugs and vaccines during the pandemic.
  • Develop a pandemic influenza vaccine (see also Part 1 and Supplement 6).
  • Work with healthcare partners to refine clinical management guidelines and issue regular updates on treatment issues.
  • Conduct observational and interventional studies with partner institutions to investigate pandemic influenza pathogenesis and develop disease prevention and treatment strategies.
  • Monitor pandemic influenza cases for antiviral resistance and transmission parameters.
  • Monitor antiviral drug use and inventories.
  • Collect information on clinical features, outcomes, and treatments.

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S5-I. Rationale

Healthcare providers play an essential role in the detection of an initial case of novel or pandemic influenza in a community. If implemented early, identification and isolation of cases may help slow the spread of influenza within a community. Clinical awareness of novel or pandemic influenza disease can also benefit the individual patient, as rapid diagnosis and initiation of treatment can avert potentially severe complications. Detection is complicated, however, by the lack of specific clinical findings and commercially available laboratory tests that can rapidly distinguish novel or pandemic influenza from seasonal influenza. In addition, neither the clinical characteristics of a novel or pandemic influenza virus strain nor the groups at highest risk for complications can necessarily be defined beforehand. Therefore, clinicians face significant challenges in: 1) quickly identifying and triaging cases, 2) containing the spread of infection, 3) beginning an efficient and comprehensive workup, 4) initiating antiviral and other supportive therapy, and 5) anticipating clinical complications.


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S5-II. Overview

Supplement 5 provides clinical procedures for the initial screening, assessment, and management of patients with suspected novel influenza during the Interpandemic and Pandemic Alert Periods, and for patients with suspected pandemic influenza during the Pandemic Period. The Appendices include information on the clinical presentation and complications of seasonal influenza, the clinical features of infection due to avian influenza A (H5N1) virus and previous pandemic influenza viruses, and the management of patients with community-acquired pneumonia or secondary bacterial pneumonia during a pandemic. The guidance is current as of October 2005, and is subject to change as experience is gained. Updates will be provided, as needed, on the CDC website (www.cdc.gov/flu/).

During the Interpandemic and Pandemic Alert Periods, early recognition of illness caused by a novel influenza A virus strain will rely on a combination of clinical and epidemiologic features. During the Pandemic Period (in a setting of high community prevalence), diagnosis will likely be more clinically oriented because the likelihood will be high that any severe febrile respiratory illness is pandemic influenza. During periods in which no human infections with a novel influenza A virus strain have occurred anywhere in the world (Interpandemic Period: Phases 1, 2; see Box 1), or when sporadic cases of animal-to-human transmission or rare instances of limited human-to-human transmission of a novel influenza A virus strain have occurred in the world (Pandemic Alert Period: Phases 3, 4), the likelihood of novel influenza A virus infection is very low in a returned traveler from an affected area who has severe respiratory disease or influenza-like illness. Since human influenza A and B viruses circulate worldwide among humans year-round, the possibility of infection with human influenza viruses is much higher and should be considered. Once local person-to-person transmission of a novel influenza A virus strain has been confirmed (Pandemic Alert Period: Phase 5), the potential for novel influenza A virus infection will be higher in an ill person who has a strong epidemiologic link to the affected area (Box 1).

This supplement is designed to serve as a guide for clinicians, with the understanding that the management of influenza is based primarily on sound clinical judgment regarding the individual patient as well as an assessment of locally available resources, such as rapid diagnostics, antiviral drugs, and hospital beds. Early antiviral therapy shortens the duration of illness due to seasonal influenza and would be expected to have similar effects on illness due to novel or pandemic influenza viruses (see Supplement 7: Antiviral Drug Distribution and Use). Clinical management must also address supportive care and management of influenza-related complications.

Other supplements that cover topics of potential interest to clinicians:

Supplement 1. Pandemic Influenza Surveillance
Supplement 2. Laboratory Diagnostics
Supplement 3. Healthcare Planning
Supplement 4. Infection Control
Supplement 6. Vaccine Distribution and Use
Supplement 7. Antiviral Drug Distribution and Use


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S5-III. CLINICAL GUIDELINES FOR THE INTERPANDEMIC AND PANDEMIC ALERT PERIODS

During the Interpandemic and Pandemic Alert Periods, the primary goal of rapid detection is to quickly identify and contain cases of novel influenza. To limit the need to evaluate an overwhelming number of patients, the screening criteria should be specific, relying on a combination of clinical and epidemiologic features. Although febrile respiratory illnesses are one of the most common indications for medical evaluation, particularly during the winter, during the interpandemic and pandemic alert period, human cases of novel influenza are expected to be quite rare; laboratory diagnosis will most likely be sought for those with severe respiratory illness, such as pneumonia. The main features of detection and clinical management during the Interpandemic and Pandemic Alert Periods are outlined in Figure 1.

  1. Criteria for evaluation of patients with possible novel influenza

    The following criteria are based on the features of recent avian influenza A (H5N1) cases but are intended for use in evaluating suspected cases of infection with any novel influenza A virus strain. During the Pandemic Alert Period, human infections with novel influenza A viruses will be an uncommon cause of influenza-like illness; therefore, both clinical and epidemiologic criteria should be met. The criteria will be updated when needed as more data are collected.

    1. Clinical criteria

      Any suspected cases of human infection with a novel influenza virus must first meet the criteria for influenza-like illness (ILI), defined as temperature of >38°C plus either sore throat or cough. Since lower respiratory tract involvement might result in dyspnea (shortness of breath), dyspnea should be considered as an additional criterion. Therefore, the full clinical criteria are: fever plus one of the following: sore throat, cough, or dyspnea.

      Although recent infections with novel influenza viruses have resulted in severe respiratory illness, the next pandemic influenza virus strain might present with a different clinical syndrome (see Appendix 1 and Appendix 2). In such a situation, the clinical criteria will be modified accordingly and posted at www.cdc.gov/flu.

      Given the large number of influenza-like illnesses that clinicians encounter during a typical flu season, laboratory evaluation for novel influenza A viruses during the Interpandemic and Pandemic Alert Periods is recommended only for:

      • Hospitalized patients with severe ILI, including pneumonia, who meet the epidemiologic criteria (see below), or
      • Non-hospitalized patients with ILI and with strong epidemiologic suspicion of novel influenza virus exposure (e.g., direct contact with ill poultry in an affected area, or close contact with a known or suspected human case of novel influenza.). (See Appendix 2, Supplement 2: Laboratory Diagnostics)
      • Recommendations for the evaluation of patients with respiratory illnesses are provided in Box 2. Exceptions to the current clinical criteria are provided in Box 3.
    2. Epidemiologic criteria

      Epidemiologic criteria for evaluation of patients with possible novel influenza focus on the risk of exposure to a novel influenza virus with pandemic potential. Although the incubation period for seasonal influenza ranges from 1 to 4 days, the incubation periods for novel types of influenza are currently unknown and might be longer. Therefore, the maximum interval between potential exposure and symptom onset is set conservatively at 10 days.

      Exposure risks — Exposure risks fall into two categories: travel and occupational.

      • Travel risks

        Persons have a travel risk if they have: 1) recently visited or lived in an area affected by highly pathogenic avian influenza A outbreaks in domestic poultry or where a human case of novel influenza has been confirmed, and either 2) had direct contact with poultry, or 3) had close contact with a person with confirmed or suspected novel influenza. Updated listings of areas affected by avian influenza A (H5N1) and other current/recent novel strains are provided on the websites of the OIE ( http://www.oie.int/eng/en_index.htm), WHO (www.who.int/en/), and CDC (www.cdc.gov/flu/).

        Direct contact with poultry is defined as: 1) touching birds (well-appearing, sick, or dead), or 2) touching poultry feces or surfaces contaminated with feces, or 3) consuming uncooked poultry products (including blood) in an affected area. Close contact with a person from an infected area with confirmed or suspected novel influenza is defined as being within 3 feet (1 meter) of that person during their illness.

        Because specific testing for human infection with avian influenza A (H5N1) might not be locally available in an affected area, persons reporting close contact in an affected area with a person suffering from a severe, yet unexplained, respiratory illness should also be evaluated.

        Clinicians should recognize that human influenza viruses circulate worldwide and year-round, including in countries with outbreaks of avian influenza A (H5N1) among poultry. Therefore, during the Interpandemic and Pandemic Alert Periods, human influenza virus infection can be a cause of ILI among returned travelers at any time of the year, including during the summer in the United States. This includes travelers returning from areas affected by poultry outbreaks of highly pathogenic avian influenza A (H5N1) in Asia. As of October 2005, such persons are currently more likely to have infection with human influenza viruses than with avian influenza A (H5N1) viruses.

      • Occupational risks

        Persons at occupational risk for infection with a novel strain of influenza include persons who work on farms or live poultry markets or who process or handle poultry infected with known or suspected avian influenza viruses, workers in laboratories that contain live animal or novel influenza viruses, and healthcare workers in direct contact with a suspected or confirmed novel influenza case.

        Information on limiting occupational risk is provided on the Occupational Health and Safety Administration (OSHA) website at: www.osha.gov/dsg/guidance/avian-flu.html.

        During the Interpandemic and Pandemic Alert Periods, when there is no sustained human-to-human transmission of any novel influenza viruses, direct contact with animals such as poultry in an affected area or close contact with a case of suspected or confirmed human novel influenza—for any reason—is required for further evaluation. During the Pandemic Alert Period, Phases 3 and 4, the majority of human cases of novel influenza will result from avian-to-human transmission (see Box 1). Therefore, a history of direct contact with poultry (well-appearing, sick, or dead), consumption of uncooked poultry or poultry products, or direct exposure to environmental contamination with poultry feces in an affected area will be important to ascertain. During the Pandemic Alert Period, Phase 5, a history of close contact with an ill person suspected or confirmed to have novel influenza in an affected area will be even more important.

        Other avian influenza A viruses -- Although the epidemiologic criteria for novel influenza are based on recent human cases of avian influenza A (H5N1), they are intended for use in the evaluation of suspected cases of infection with any novel influenza A virus strain, including other avian influenza viruses. Other avian influenza A viruses that have caused human disease include the highly pathogenic viruses H7N7 and H7N3 and the low pathogenic viruses H9N2 and H7N2 (see Supplement 2, Box 3). Some of these human cases have occurred in Europe (Netherlands) and North America (Canada and the United States). Therefore, the same high-risk exposures defined above for avian influenza A (H5N1) also apply to other avian influenza A viruses. A strong epidemiologic link to an avian influenza outbreak in poultry—even in areas that have not experienced poultry outbreaks of avian influenza A (H5N1)—may raise the index of suspicion for human infection with avian influenza A viruses.

        In the future, other animal hosts (in addition to poultry) or novel influenza A virus subtypes (in addition to H5N1) might become significantly associated with human disease. If such events occur, this guidance will be updated.

  2. Initial management of patients who meet the criteria for novel influenza

    When a patient meets both the clinical and epidemiologic criteria for a suspected case of novel influenza, healthcare personnel should initiate the following activities:

  3. Management of patients who test positive for novel influenza

    If a patient is confirmed to have an infection with a novel influenza virus, healthcare personnel should continue antiviral treatment and all isolation and infection control precautions, and isolate patients with novel influenza from seasonal influenza patients. In addition to prior vaccination against seasonal influenza, such measures may decrease the risk of co-infection and viral genetic reassortment.

  4. Management of patients who test positive for seasonal influenza

    Many suspected novel influenza cases may be found to have seasonal human influenza, particularly during the winter season. It should be recognized that human influenza viruses circulate among people worldwide, including in affected areas with poultry outbreaks of avian influenza A viruses during non-seasonal influenza activity in the United States. For patients with confirmed seasonal influenza, maintain Standard and Droplet Precautions, and continue antiviral treatment for a full treatment course (e.g., 5 days).

  5. Management of patients who test negative for novel influenza

    The sensitivity of the currently available tests for detecting novel influenza viruses in clinical specimens has not been thoroughly evaluated with a full range of specimen types. Consequently, false-negative test results may occur. Therefore, if test results are negative but the clinical and epidemiologic suspicion remains high, continuing antiviral treatment and isolation procedures should be considered. Test results might be negative for influenza viruses for several reasons. Some patients might have an alternate etiology to explain their illness. The general work-up for febrile respiratory illnesses described below should evaluate the most common alternate causes. A certain number of truly infected cases might also test falsely negative, due to specimen collection conditions, to viral shedding that is not detectable, or to sensitivity of the test. Interpretation of negative testing results should be tailored to the individual patient in consultation with hospital infection control and infectious disease specialists, as well as the state or local health department and CDC. In hospitalized patients who test negative for novel influenza but have no alternate diagnosis established, novel-influenza-directed management should be continued if clinical suspicion is high and there is a strong epidemiologic link to exposure to novel influenza. When influenza tests are negative and an alternative diagnosis is established, isolation precautions and antiviral drug therapy for novel influenza may be discontinued based on clinician’s assessment, particularly in the absence of a strong epidemiologic link, if the alternative diagnosis is made using a test with a high positive-predictive value, and if the clinical manifestations are explained by the alternative diagnosis.


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S5-IV. Clinical Guidelines For The Pandemic Period

During the Pandemic Period, the primary goal of rapid detection is to appropriately identify and triage cases of pandemic influenza. During this period, outpatient clinics and emergency departments might be overwhelmed with suspected cases, restricting the time and laboratory resources available for evaluation. In addition, if the pandemic influenza virus exhibits transmission characteristics similar to those of seasonal influenza viruses, illnesses will likely spread throughout the community too rapidly to allow the identification of obvious exposures or contacts. Evaluation will therefore focus predominantly on clinical and basic laboratory findings, with less emphasis on laboratory diagnostic testing (which may be in short supply) and epidemiologic criteria. Nevertheless, clinicians in communities without pandemic influenza activity might consider asking patients about recent travel from a community with pandemic influenza activity or close contact with a suspected or confirmed pandemic influenza case. The main features of clinical management during the Pandemic Period are outlined in Figure 2.

  1. Criteria for evaluation of patients with possible pandemic influenza

    1. Clinical criteria

      Suspected cases of pandemic influenza virus infection should meet the criteria for ILI: temperature of >38°C plus either sore throat or cough. Since lower respiratory tract involvement might result in dyspnea (shortness of breath), dyspnea should be considered as an additional criterion. Therefore, the full clinical criteria are: fever plus one of the following: sore throat, cough, or dyspnea. Although past influenza pandemics have most frequently resulted in respiratory illness, the next pandemic influenza virus strain might present with a different clinical syndrome (see Appendix 1 and Appendix 2). During a pandemic, updates on other clinical presentations will be provided at: www.pandemicflu.gov and www.cdc.gov/flu/.

      Recommendations for general evaluation of patients with influenza-like illness are provided in Box 2. Exceptions to the clinical criteria are provided in Box 3.

    2. Epidemiologic criteria

      During the Pandemic Period, an exposure history will be marginally useful for clinical management when disease is widespread in a community. In addition, there will be a relatively high likelihood that any case of ILI during that time period will be pandemic influenza. Once pandemic influenza has arrived in a particular locality, clinical criteria will be sufficient for classifying the patient as a suspected pandemic influenza case.

  2. Initial management of patients who meet the criteria for pandemic influenza

    When a patient meets the criteria for a suspected case of pandemic influenza, healthcare personnel should initiate the following activities:

  3. Clinical management of pandemic influenza patients

    See Supplement 7 for current antiviral information and treatment strategies.3 In addition to use of antivirals, clinical management of severe influenza should address supportive care and the rapid identification and treatment of secondary complications. During the Pandemic Period, CDC may request virus isolates from persons who fail treatment or antiviral prophylaxis, as these strains may more likely be drug resistant. In addition, randomly collected isolates will be tested for resistance to establish nationwide rates (see Supplement 1).

    Children aged < 18 years with suspected or confirmed pandemic influenza should not be treated with aspirin or other salicylate-containing products because of an increased risk of Reye syndrome (characterized by acute encephalopathy and liver failure) in this age group.

    The major clinical presentations and complications related to seasonal human influenza occur more commonly in persons with certain underlying medical conditions, such as chronic respiratory or cardiovascular disease and extremes of age, and are described in Appendix 1. Limited data are available on risk factors and complications related to infection with novel influenza viruses, and these may change as individual strains evolve. A summary of the clinical presentations and complications associated with recent influenza A (H5N1) viruses is included in Appendix 2. In particular, post-influenza community-acquired pneumonia will likely be a commonly encountered complication, and clinicians will need to be aware of recommended methods for diagnosis and treatment. Guidance on the management of influenza-related pneumonia is presented in Appendix 3.


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Box 1. Risk of Novel Influenza in Persons with Severe Respiratory Disease or Influenza-like Illness during the Interpandemic and Pandemic Alert Periods

Clinicians should recognize that human influenza A and B viruses and other respiratory viruses circulate year-round among people throughout the world, including in countries affected by outbreaks of avian influenza A viruses in poultry. Seasonal human influenza A and B community outbreaks occur in temperate climates of the northern and southern hemisphere, and human influenza activity may occur year-round in subtropical and tropical regions. Outbreaks of human influenza can occur among travelers during any time of the year, including periods of low influenza activity in the United States (e.g., summer).

Phases 1, 2: Interpandemic Period
A novel influenza A virus has been detected in animals but not in humans. During these phases, the risk of human infection with a novel influenza A virus strain is extremely low. The risk of human infection with human influenza viruses or other viruses is much higher in persons living in or traveling to affected areas.

Phases 3, 4: Pandemic Alert Period
A novel influenza A virus has been detected in humans through sporadic animal-to-human transmission in an affected area (e.g., direct contact with infected poultry), and few cases of limited, local human-to-human transmission have occurred (small clusters of cases). During these phases, the risk of human infection with a novel influenza A virus strain is very low. The risk of human infection with human influenza viruses or other viruses is much higher in persons living in or traveling to affected areas.

Phase 5: Pandemic Alert Period
A novel influenza A virus has been detected in humans in larger clusters in an affected area, suggesting that the virus is becoming better adapted to spread among people. During this period, the risk of human infection with a novel influenza A virus strain is higher, depending on specific exposures, in persons living in or traveling to affected areas. Human infection with human influenza viruses or other viruses will occur and should still be considered.


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Box 2. Clinical Evaluation of Patients with Influenza-like Illness during the Interpandemic and Pandemic Alert Periods


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Box 3. Special Situations and Exceptions to the Clinical Criteria

Persons with a high risk of exposure—For persons with a high risk of exposure to a novel influenza virus (e.g., poultry worker from an affected area,* caregiver of a patient with laboratory-confirmed novel influenza, employee in a laboratory that works with live novel influenza viruses), epidemiologic evidence might be enough to initiate further measures, even if clinical criteria are not fully met. In these persons, early signs and symptoms—such as rhinorrhea, conjunctivitis, chills, rigors, myalgia, headache, and diarrhea—in addition to cough or sore throat, may be used to fulfill the clinical criteria for evaluation.

High-risk groups with atypical symptoms—Young children, elderly patients, patients in long-term care facilities, and persons with underlying chronic illnesses might not have typical influenza-like symptoms, such as fever. When such patients have a strong epidemiologic risk factor, novel influenza should be considered with almost any change in health status, even in the absence of typical clinical features. Conjunctivitis has been reported in patients with influenza A (H7N7) and (H7N3) infections. In young children, gastrointestinal manifestations such as vomiting and diarrhea might be present. Infants may present with fever or apnea alone, without other respiratory symptoms, and should be evaluated if there is an otherwise increased suspicion of novel influenza.

*Updated lists of affected areas are provided at the websites of the OIE (http://www.oie.int/eng/en_index.htm), WHO (www.who.int/en/), and CDC (www.cdc.gov/flu/).


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Box 4. Home Care Infection Control Guidance for Pandemic Influenza Patients and Household Members

Most patients with pandemic influenza will be able to remain at home during the course of their illness and can be cared for by family members or others who live in the household. Anyone who has been in the household with an influenza patient during the incubation period is at risk for developing influenza. A key objective in this setting is to limit transmission of pandemic influenza within and outside the home.

Management of influenza patients in the home

Management of other persons in the home

Infection control measures in the home

 


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Figure 1. Case Detection and Clinical Management during the Interpandemic and Pandemic Alert Periods

Situation:    No human cases of novel influenza are present in the community.
                    Human cases might be present in another country or another region of the United States.

Footnotes to Figure 1:

  1. Further evaluation and diagnostic testing should also be considered for outpatients with strong epidemiologic risk factors and mild or moderate illness. (See Box 2).
  2. Updated information on areas where novel influenza virus transmission is suspected or documented is available on the CDC website at http://www.cdc.gov/travel/http://www.cdc.gov/travel/ and on the WHO website at www.who.int/en/.
  3. For persons who live in or visit affected areas, close contact includes touching live poultry (well-appearing, sick or dead) or touching or consuming uncooked poultry products, including blood. For animal or market workers, it includes touching surfaces contaminated with bird feces. In recent years, most instances of human infection with a novel influenza A virus having pandemic potential, including influenza A (H5N1), are thought to have occurred through direct transmission from domestic poultry. A small number of cases are also thought to have occurred through limited person-to-person transmission or consumption of uncooked poultry products. Transmission of novel influenza viruses from other infected animal populations or by contact with fecally contaminated surfaces remains a possibility. These guidelines will be updated as needed if alternate sources of novel influenza viruses are suspected or confirmed.
  4. Close contact includes direct physical contact, or approach within 3 feet (1 meter) of a person with suspected or confirmed novel influenza.
  5. Standard and Droplet Precautions should be used when caring for patients with novel influenza or seasonal influenza (Table and Supplement 4). Information on infection precautions that should be implemented for all respiratory illnesses (i.e., Respiratory Hygiene/Cough Etiquette) is provided at: www.cdc.gov/flu/professionals/infectioncontrol/resphygiene.htm
  6. Hospitalization should be based on all clinical factors, including the potential for infectiousness and the ability to practice adequate infection control. If hospitalization is not clinically warranted, and treatment and infection control is feasible in the home, the patient may be managed as an outpatient. The patient and his or her household should be provided with information on infection control procedures to follow at home (Box 3). The patient and close contacts should be monitored for illness by local public health department staff.
  7. Guidance on how to report suspected cases of novel influenza is provided in Supplement 1.
  8. The general work-up should be guided by clinical indications. Depending on the clinical presentation and the patient’s underlying health status, initial diagnostic testing might include:
    • Pulse oximetry
    • Chest radiograph
    • Complete blood count (CBC) with differential
    • Blood cultures
    • Sputum (in adults), tracheal aspirate, pleural effusion aspirate (if pleural effusion is present) Gram stain and culture
    • Antibiotic susceptibility testing (encouraged for all bacterial isolates)
    • Multivalent immunofluorescent antibody testing or PCR of nasopharyngeal aspirates or swabs for common viral respiratory pathogens, such as influenza A and B, adenovirus, parainfluenza viruses, and respiratory syncytial virus, particularly in children
    • In adults with radiographic evidence of pneumonia, Legionella and pneumococcal urinary antigen testing
    • If clinicians have access to rapid and reliable testing (e.g., PCR) for M. pneumoniae and C. pneumoniae, adults and children <5 yrs with radiographic pneumonia should be tested.
    • Comprehensive serum chemistry panel, if metabolic derangement or other end-organ involvement, such as liver or renal failure, is suspected See Box 2 for additional details.
  9. Guidelines for novel influenza virus testing can be found in Supplement 2. All of the following respiratory specimens should be collected for novel influenza A virus testing: nasopharyngeal swab; nasal swab, wash, or aspirate; throat swab; and tracheal aspirate (for intubated patients), stored at 4° C in viral transport media; and acute and convalescent serum samples.
  10. Strategies for the use of antiviral drugs are provided in Supplement 7.
  11. Guidelines for the management of contacts in a healthcare setting are provided in Supplement 3.
  12. Given the unknown sensitivity of tests for novel influenza viruses, interpretation of negative results should be tailored to the individual patient in consultation with the local health department. Novel influenza directed management may need to be continued, depending on the strength of clinical and epidemiologic suspicion. Antiviral therapy and isolation precautions for novel influenza may be discontinued on the basis of an alternative diagnosis. The following criteria may be considered for this evaluation:
    • Absence of strong epidemiologic link to known cases of novel influenza
    • Alternative diagnosis confirmed using a test with a high positive-predictive value
    • Clinical manifestations explained by the alternative diagnosis
  13. Guidance on the evaluation and treatment of suspected post-influenza community-associated pneumonia is provided in Appendix 3.

     


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Figure 2. Case Detection and Clinical Management during the Pandemic Period

Footnotes to Figure 2:

  1. Antiviral therapy and isolation precautions for pandemic influenza should be discontinued on the basis of an alternative diagnosis only when both the following criteria are met:
    • Alternative diagnosis confirmed using a test with a high positive-predictive value, and
    • Clinical manifestations entirely explained by the alternative diagnosis
  2. Standard and Droplet Precautions should be used when caring for patients with novel influenza or seasonal influenza (Table and Supplement 4). Information on infection precautions that should be implemented for all respiratory illnesses (i.e., Respiratory Hygiene/Cough Etiquette) is provided at: www.cdc.gov/flu/professionals/infectioncontrol/resphygiene.htm
  3. Guidance on laboratory testing during the Pandemic Period can be found in Supplement 2. Generally, specimens should include respiratory samples (e.g., nasopharyngeal wash/aspirate; nasopharyngeal, nasal or oropharyngeal swabs, or tracheal aspirates) stored at 4°C in viral transport media.

    Routine laboratory confirmation of clinical diagnoses will be unnecessary as pandemic activity becomes widespread in a community. CDC will continue to work with state health laboratories to conduct virologic surveillance to monitor antigenic changes and antiviral resistance in the pandemic virus strains throughout the Pandemic Period.
  4. The decision to hospitalize should be based on a clinical assessment of the patient and the availability of hospital beds and personnel.
  5. Guidelines on cohorting can be found in Supplement 4. Laboratory confirmation of influenza infection is recommended when possible before cohorting patients.
  6. The general work-up should be guided by clinical indications. Depending on the clinical presentation and the patient’s underlying health status, initial diagnostic testing might include:
    • Pulse oximetry
    • Chest radiograph
    • Complete blood count (CBC) with differential
    • Blood cultures
    • Sputum (in adults) or tracheal aspirate Gram stain and culture
    • Antibiotic susceptibility testing (encouraged for all bacterial isolates)
    • Multivalent immunofluorescent antibody testing of nasopharyngeal aspirates or swabs for common viral respiratory pathogens, such as influenza A and B, adenovirus, parainfluenza viruses, and respiratory syncytial virus, particularly in children
    • In adults with radiographic evidence of pneumonia, Legionella and pneumococcal urinary antigen testing
    • If clinicians have access to rapid and reliable testing (e.g., PCR) for M. pneumoniae and C. pneumoniae, adults and children <5 yrs with radiographic pneumonia should be tested.
    • Comprehensive serum chemistry panel, if metabolic derangement or other end-organ involvement, such as liver or renal failure, is suspected See Box 2 for additional details.
  7. Guidance on the evaluation and treatment of community acquired pneumonia and suspected post-influenza community-acquired bacterial pneumonia are provided in Appendix 3.
  8. Strategies for the use of antiviral drugs are provided in Supplement 7.
  9. Guidance on the reporting of pandemic influenza cases is provided in Supplement 1.
  10. Patients with mild disease should be provided with standardized instructions on home management of fever and dehydration, pain relief, and recognition of deterioration in status. Patients should also receive information on infection control measures to follow at home (Box 4). Patients cared for at home should be separated from other household members as much as possible. All household members should carefully follow recommendations for hand hygiene, and tissues used by the ill patient should be placed in a bag and disposed of with other household waste. Infection within the household may be minimized if a primary caregiver is designated; ideally, someone who does not have an underlying condition that places them at increased risk of severe influenza disease. Although no studies have assessed the use of masks at home to decrease the spread of infection, using a surgical or procedure mask by the patient or caregiver during interactions may be beneficial. Separation of eating utensils for use by a patient with influenza is not necessary, as long as they are washed with warm water and soap. Additional information on measures to limit the spread of pandemic influenza in the home and community can be found in Supplement 4 and Supplement 8.

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Table 1. Pandemic Influenza Infection Control Guidance For Healthcare Providers

Component

Recommendations

Standard Precautions

See http://www.cdc.gov/ncidod/dhqp/gl_isolation_standard.html

Hand hygiene

Perform hand hygiene after touching blood, body fluids, secretions, excretions, and contaminated items; after removing gloves; between patient contacts. Hand hygiene includes both handwashing with either plain or antimicrobial soap and water and use of alcohol-based products (gels, rinses, foams) that contain an emollient and do not require the use of water. If hands are visibly soiled or contaminated with respiratory secretions, they should be washed with soap (either non-antimicrobial or antimicrobial) and water. In the absence of visible soiling of hands, approved alcohol-based products for hand disinfection are preferred over antimicrobial or plain soap and water because of their superior microbiocidal activity, reduced drying of the skin, and convenience.

Personal protective equipment (PPE)

  • Gloves
  • Gown
  • Face/eye protection (e.g., surgical or procedure mask and goggles or a face shield)
  • For touching blood, body fluids, secretions, excretions, and contaminated items; for touching mucous membranes and nonintact skin
  • During procedures and patient-care activities when contact of clothing/exposed skin with blood/body fluids, secretions, and excretions is anticipated
  • During procedures and patient care activities likely to generate splash or spray of blood, body fluids, secretions, excretions

Safe work practices

Avoid touching eyes, nose, mouth, or exposed skin with contaminated hands (gloved or ungloved); avoid touching surfaces with contaminated gloves and other PPE that are not directly related to patient care (e.g., door knobs, keys, light switches).

Patient resuscitation

Avoid unnecessary mouth-to-mouth contact; use mouthpiece, resuscitation bag, other ventilation devices to prevent contact with mouth and oral secretions. Soiled patient care equipment Handle in a manner that prevents transfer of microorganisms to oneself, others and to environmental surfaces; wear gloves if visibly contaminated; perform hand hygiene after handling equipment.

Soiled linen and laundry

Handle in a manner that prevents transfer of microorganisms to oneself, others, and to environmental surfaces; wear gloves (gown if necessary) when handling and transporting soiled linen and laundry and perform hand hygiene

Needles and other sharps

Use devices with safety features when available; do not recap, bend break or hand-manipulate used needles; if recapping is necessary, use a one-handed scoop technique; place used sharps in a puncture-resistant container.

Environmental cleaning and disinfection

Use EPA-registered hospital detergent-disinfectant; follow standard facility procedures for cleaning and disinfection of environmental surfaces; emphasize cleaning/disinfection of frequently touched surfaces (e.g., bed rails, phones, lavatory surfaces).

Disposal of solid waste

Contain and dispose of solid waste (medical and non-medical) in accordance with facility procedures and/or local or state regulations; wear gloves when handling waste; wear gloves when handling waste containers and perform hand hygiene

Respiratory Hygiene/Cough Etiquette

Source control measures for persons with symptoms of a respiratory infection; implement at first point of encounter (e.g., triage/reception areas) within a healthcare setting. Have the patient cover the mouth/nose when sneezing/coughing; use tissues and dispose in no-touch receptacle; perform hand hygiene after contact with respiratory secretions; wear a mask (procedure or surgical) if tolerated; sit or stand as far away as possible (more than 3 feet) away from persons who are not ill.

Droplet Precautions

http://www.cdc.gov/ncidod/dhqp/gl_isolation_droplet.html

Patient placement

Place patients with influenza in a private room or cohort with other patients with influenza.* Keep door closed or slightly ajar; maintain room assignments of patients in nursing homes and other residential settings, and apply droplet precautions to all persons in the room.

*During the early stages of a pandemic, infection with influenza should be laboratory-confirmed, if possible. Personal protective equipment Wear a surgical or procedure mask for entry into patient room; wear other PPE as recommended for standard precautions.

Patient transport

Limit patient movement outside of room to medically necessary purposes; have patient wear a procedure or surgical mask when outside the room.

Other

Follow standard precautions and facility procedures for handling linen and laundry and dishes and eating utensils, and for cleaning/disinfection of environmental surfaces and patient care equipment, disposal of solid waste, and postmortem care.

Aerosol-Generating Medical Procedures

During procedures that may generate small particles of respiratory secretions (e.g., endotracheal intubation, bronchoscopy, nebulizer treatment, suctioning), healthcare personnel should wear gloves, gown, face/eye protection, and a fit-tested N-95 respirator or other appropriate particulate respirator.

Standard Precautions for home health care
Healthcare providers who enter homes where there is a person with an influenza-like illness should follow the recommendations for Standard and Droplet Precautions. Standard Precautions include performing hand hygiene and respiratory hygiene/cough etiquette, wearing gloves and gowns, using face/eye protection when needed; and following safe work practices.

Droplet Precautions for home health care
Healthcare providers who enter homes where there is a person with an influenza-like illness should follow the recommendations for Standard and Droplet Precautions. Droplet Precautions include all Standard Precautions plus separating the patient from others in the household as much as possible and wearing a surgical or procedure mask for patient interactions. Professional judgment should be used in determining whether to don a mask upon entry into the home or only on entering the patient’s room. Factors to consider in this decision include the possibility that others in the household may be infectious and the extent to which the patient is ambulating within the home.


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Appendix 1. Clinical Presentation and Complications of Seasonal Influenza

Although often quite characteristic, the clinical picture of seasonal influenza can be indistinguishable from illness caused by other respiratory infections. The frequent use of non-specific terms such as "flu" and "influenza-like illness" makes the clinical diagnosis of influenza even more indefinite. Even when the diagnosis of influenza is confirmed, management can be challenging, as influenza virus infection can result in subclinical infection, mild illness, uncomplicated influenza, or exacerbation of underlying chronic conditions to fulminant deterioration, and can result in a wide variety of complications.

This appendix provides a brief description of the common presentations and complications of seasonal human influenza. Novel and pandemic influenza viruses might, however, cause quite different clinical syndromes than seasonal influenza. For instance, seasonal influenza-related complications more commonly affect those at the extremes of age, whereas previous pandemics resulted in disproportionate morbidity and mortality in young and previously healthy adults. It will be essential to describe and disseminate the clinical features of novel or pandemic influenza cases as soon as they are identified. Appendix 2 includes a brief clinical summary of illnesses associated with previous influenza pandemics and with avian influenza A (H5N1) virus in humans.

Presentation

Influenza is difficult to distinguish from illnesses caused by other respiratory pathogens on the basis of symptoms alone. Fever and cough, particularly in combination, are modestly predictive of influenza in unvaccinated adults, as is the combination of fever, cough, headache, and pharyngitis in children. Other constitutional signs and symptoms, such as chills, rigors, diaphoresis, and myalgias, are also suggestive. The positive predictive value of any clinical definition is strongly dependent on the level of influenza activity and the presence of other respiratory pathogens in the community.

Routine laboratory findings
No routine laboratory test results are specific for influenza. Leukocyte counts are variable, although thrombocytopenia and severe leukopenia have been described in fulminant cases. Leukocytosis of >15,000 cells/ml should raise suspicion for a secondary bacterial process. Comprehensive laboratory testing might reveal other influenza-related complications (see below).

Differential diagnosis
The fever and respiratory manifestations of seasonal influenza are not specific and can occur with several other pathogens, including respiratory syncytial virus (RSV), parainfluenza viruses, adenoviruses, human metapneumovirus, rhinoviruses, coronaviruses, and Mycoplasma pneumoniae. In contrast to influenza viruses, most of these pathogens do not usually cause severe disease, particularly in previously healthy adults. RSV and parainfluenza viruses can, however, lead to severe respiratory illness in young children and the elderly and should be considered in the differential diagnosis if circulating in the community. Even if an alternate etiology is determined, viral or bacterial co-infections can still be a possibility.

The tendency for influenza to occur in community epidemics and to affect persons of all ages can sometimes allow the clinician to diagnose seasonal influenza with reasonable certainty in the absence of laboratory testing. Nevertheless, a definitive diagnosis requires laboratory testing. Rapid influenza diagnostic tests and immunofluorescence testing using a panel of respiratory pathogens have become increasingly available for aiding clinical management of patients with suspected influenza. Further information on diagnostic testing for influenza can be found at http://www.cdc.gov/flu/professionals/labdiagnosis.htm.

Complications

Groups at risk for complications of influenza

The following groups are currently recognized by the Advisory Committee on Immunization Practices (ACIP) to be at higher risk for complications of seasonal influenza (e.g., hospitalization; death) compared to healthy older children and younger adults:4

  • Persons aged =65 years
  • Residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions
  • Adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including asthma
  • Adults and children who required regular medical follow-up or hospitalization during the previous year because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications or by infection with human immunodeficiency virus [HIV])
  • Children and adolescents (aged 6 months–18 years) who are receiving long-term aspirin therapy (and are therefore at risk for Reye syndrome)
  • Pregnant women
  • All children aged <2 years
  • All persons with conditions that can compromise respiratory function or the handling of respiratory secretions, or that can increase the risk of aspiration

Excluding the last group, in 2003 approximately 85 million persons in the United States belonged to one or more of these target groups.

Types of influenza complications
Exacerbations of underlying chronic diseases are the most common serious complications of influenza. Complications are frequently related to underlying respiratory disease, such as chronic obstructive pulmonary disease (COPD). In some cases, typical influenza symptoms might be brief or minimal compared to the exacerbation of the underlying disease, particularly in the elderly.

Secondary bacterial pneumonia, another common complication, is characterized by an initial improvement in influenza symptoms over the first few days followed by a return of fever, along with a productive cough and pleuritic chest pain. Findings include lobar consolidation on chest x-ray and, in adults, sputum smears positive for leukocytes and bacteria. The most commonly isolated pathogens are Streptococcus pneumoniae, Staphylococcus aureus, group A Streptococcus, and Haemophilus influenzae.

Influenza virus infection can also result in a primary viral pneumonia. A prominent feature of previous influenza pandemics, primary influenza viral pneumonia is currently a relatively rare outcome of seasonal influenza in adults. In contrast, children with pneumonia are more likely to have a viral etiology, including influenza than a bacterial cause. Primary influenza pneumonia usually begins abruptly, with rapid progression to severe pulmonary disease within 1–4 days. Physical and radiologic findings are consistent with diffuse interstitial and/or alveolar disease, including bilateral inspiratory crackles on auscultation and diffuse pulmonary infiltrates on chest radiographs. Hypoxia and hemoptysis indicate a poor prognosis, and recovery can take up to 1–2 weeks. Mixed viral-bacterial pneumonia is slightly more common than primary viral pneumonia, and, although mixed pneumonia may have a slower progression, the two are often indistinguishable. Bacterial pathogens in mixed infections are similar to those found in secondary bacterial pneumonias.

Bronchiolitis due to influenza is more common in children, with a clinical picture similar to that of RSV or parainfluenza virus infections. Influenza is a cause of croup (laryngotracheobronchitis) in children, and, although influenza viruses are a less common etiology than other respiratory viruses, the illness can be more severe. Children with influenza can also develop otitis media, due to either direct viral infection or secondary bacterial involvement. Similarly, bacterial sinusitis can develop in older children and adults with influenza.

Seasonal influenza can cause a range of cardiovascular complications, most commonly as an exacerbation of an underlying condition such as congestive heart failure. Pregnant women and children with congenital heart defects can also experience worsening cardiac function during an influenza illness. Cardiac inflammation, such as myocarditis and pericarditis, can be found occasionally, although clinical manifestations are rare. Available reports suggest that myocarditis might have occurred more frequently during pandemic years. Influenza virus is not typically identified in heart tissue, suggesting that the host inflammatory response might play a role. Although influenza has been associated in rare instances with sudden death possibly due to cardiac arrhythmia, this outcome has been difficult to investigate.

Gastrointestinal involvement is uncommon with seasonal influenza, although more commonly reported in children. Manifestations can include vomiting and diarrhea, sometimes leading to significant dehydration. Transient hepatic inflammation can occur in rare circumstances.

Myositis related to influenza is another complication more commonly found in children, although more frequently associated with influenza B. Involvement may be limited to pain and weakness of the lower extremities but can progress to rhabdomyolysis and renal failure in some cases.

Among the neurologic complications associated with seasonal influenza, uncomplicated self-limited febrile seizures are the most common, usually occurring in younger children with high fever. Influenza-associated encephalopathy, characterized by an acute alteration in mental status within the first few days of fever onset, is a recently recognized complication of influenza in children. Most reports of influenza-associated encephalopathy have been in Japanese children, but the condition has been reported sporadically in other countries, including the United States. The syndrome can include seizures, neurologic deficits, obtundation, and coma. While most children recover completely, some cases can result in permanent sequelae or death. This condition might be due to an abnormal host inflammatory response without viral infection of the central nervous system. Guillain-Barre syndrome and transverse myelitis have been reported to occur in very rare instances after influenza, but no definite etiologic relationship has been established.

Reye syndrome is another serious neurologic complication associated with influenza. It is characterized by an acute encephalopathy combined with hepatic failure in the absence of inflammation in either the brain or the liver. Hepatic involvement includes fatty infiltration, hypoglycemia, and hyperammonemia, whereas neurologic manifestations include cerebral edema, delirium, coma, and respiratory arrest. Reye syndrome was found to be associated with the use of aspirin in children; its incidence has decreased dramatically since the 1980s after aspirin use was discouraged in children.

Seasonal influenza can be associated with systemic complications, such as sepsis and shock. Sepsis caused by invasive co-infection with Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), or other bacteria, such as Neisseria meningitidis has been reported. Toxic shock syndrome without bacterial co-infection has also been reported.


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Appendix 2. Clinical Presentation and Complications of Illnesses Associated With Avian Influenza A (H5N1) and Previous Pandemic Influenza Viruses

Human infections with different avian influenza A viruses have emerged and caused mild to severe illness in recent years, including H9N2, H7N7, H7N3, and H7N2. One novel subtype, influenza A (H5N1), has repeatedly caused limited outbreaks of severe and fatal human disease in recent years and therefore has been of particular concern.

Human infection with avian influenza A (H5N1)
The H5N1 subtype first came to widespread public attention in 1997, when a poultry outbreak of highly pathogenic avian influenza A (H5N1) in Hong Kong caused illness in 18 humans. These cases were the first identified instances of direct avian-to-human transmission of an avian influenza A virus that led to severe disease. Clinical features ranged from asymptomatic infection or mild upper respiratory symptoms to severe pneumonia and death. Most cases presented with fever, headache, malaise, myalgia, sore throat, cough, and rhinorrhea; a few persons also had conjunctivitis or gastrointestinal distress. Seven persons, mostly children, developed only mild upper respiratory infections, whereas 11 developed severe primary viral pneumonia with rapid deterioration. Most patients in this latter group developed lymphopenia; six developed acute respiratory distress syndrome (ARDS), and five developed multi-organ system failure. Other abnormalities included pulmonary hemorrhage, renal dysfunction, liver failure, pancytopenia, hemophagocytosis, and Reye syndrome (with aspirin ingestion). Notably, none of the patients had secondary bacterial pneumonia. Six of the 18 infected persons eventually died.

Avian influenza A (H5N1) resurfaced in Hong Kong in February 2003, in a father and son returning from Fujian Province, China. Both presented with influenza-like symptoms, chest radiograph abnormalities, and lymphopenia. The father's status rapidly deteriorated, and he developed severe lung involvement and hemophagocytosis; the 8-year-old son recovered. Of note, the father's 7-year-old daughter had also died of a pneumonia-like illness while in China, but the cause of her illness was not determined. The boy reported close contact with live chickens during his visit to China, but no definite source for H5N1 was found.

The most recent human outbreak of avian influenza A (H5N1) has been ongoing since December 2003. This outbreak has been associated with an extensive H5N1 epizootic among poultry in Asia. Transmission continues to be predominantly from birds to humans, although a few instances of limited human-to-human transmission have been suspected.

Reports published from Vietnam and Thailand describe the early confirmed H5N1 cases from this outbreak. These reports characterize human illness with avian influenza A (H5N1) virus infection as a primarily respiratory febrile illness that progresses to severe disease in a high proportion of cases. Among 10 Vietnamese patients,5 all were previously healthy children or young adults (mean age, 13.7 years) who presented to medical attention with fever, cough, and dyspnea. None of the patients had other respiratory symptoms, such as sore throat or rhinorrhea, but seven developed diarrhea. Significant lymphopenia was observed in all 10 cases, and moderate thrombocytopenia occurred. All 10 had marked abnormalities on chest radiograph, and eight patients—all of whom eventually died—required mechanical ventilation for respiratory failure. Respiratory cultures suggested bacterial pneumonia in two patients.

Of 12 cases described from Thailand,6 seven were aged <14 years, and all but one were previously healthy. All of the patients developed fever, cough, and dyspnea, and six patients were reported with myalgia and diarrhea. Decreased leukocyte counts were reported in seven cases, thrombocytopenia occurred in four cases, and increased serum liver enzymes were found in eight. All patients had negative blood cultures. They all had abnormal chest radiographs; nine developed respiratory failure with ARDS, whereas five developed cardiac failure, four had renal failure, and eight ultimately died. In the Vietnamese and Thai cases, respiratory deterioration occurred a median of 5 days after symptom onset, but the range was quite wide.

Whereas all patients described above presented with pulmonary symptoms, subsequently published case reports suggest that other clinical syndromes can occur with H5N1 infection.7,8 In one report, a 39-year-old female with confirmed H5N1 from Thailand was initially admitted with symptoms of fever, vomiting, and diarrhea, and was found to have significant lymphopenia. She developed shortness of breath approximately 12 days after illness onset and soon progressed to ARDS and death. A 4-year-old male from Vietnam presented for medical attention with severe diarrhea, developed acute encephalitis with coma, and died soon thereafter. Although avian influenza A (H5N1) was later detected in throat, stool, serum, and cerebrospinal fluid specimens, the patient had no respiratory symptoms at presentation. This patient's 9-year-old sister died of a similar illness a few days before his illness began, but no H5N1 testing was performed. Asymptomatic H5N1 infection, detected by seroconversion, has been reported. Updated information on avian influenza can be found at http://www.who.int/csr/disease/avian_influenza/en/.

Illnesses associated with previous pandemic viruses
Since most people do not have previous immunity to novel influenza A viruses, an influenza pandemic results in an increased rate of severe disease in a majority of age groups. Nevertheless, the three pandemics of the past century demonstrated significant variability in terms of morbidity. The 1918–19 pandemic was particularly notable in affecting young, healthy adults with severe illness. A significant proportion of patients developed fulminant disease, accompanied by a striking perioral cyanosis, leading to death within a few days. Postmortem examinations in these patients frequently revealed denuding tracheobronchitis, pulmonary hemorrhage, or pulmonary edema. Others survived the initial illness, only to die of a secondary bacterial pneumonia, usually due to Streptococcus pneumoniae, Staphylococcus aureus, group A Streptococcus, or Haemophilus influenzae.

The clinical features of the subsequent pandemics of 1957–58 and 1968–69 were also typical of influenza-like illness, including fever, chills, headache, sore throat, malaise, cough, and coryza, but were milder compared to the 1918–19 pandemic. On a population level, the impact of influenza in 1957–58 was only one-tenth that observed in 1918–19, and the excess death rate in 1968–69 was only half that observed during 1957–58. However, death rates were elevated among the chronically ill and the elderly, and the occurrence of severe complications, such as primary viral pneumonia, was notably increased in healthy young adults during the 1957–58 pandemic, particularly in pregnant women.

Implications for the next pandemic
The characteristic clinical features of the next influenza pandemic cannot be predicted. It is reasonable to assume that most affected persons will have the typical features of influenza (e.g., fever, respiratory symptoms, myalgia, malaise). However, past pandemics have varied considerably with regard to severity and associated complications. Illnesses caused by novel influenza viruses such as avian influenza A (H5N1) might predict the potential characteristics of pandemic influenza, but H5N1 has not adapted to spread easily among humans, and its presentation and severity might change as the virus evolves. Even as the next pandemic begins and spreads, the characteristic features might change, particularly if successive waves occur over several months. Given this potential for a dynamic clinical picture, it will be important for clinicians and public health partners to work together to disseminate updated and authoritative information to the healthcare community on a regular basis.


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Appendix 3. Guidelines For Management of Community-Acquired Pneumonia, Including Post-Influenza Community-Acquired Pneumonia

Rationale
Post-influenza bacterial community-acquired pneumonia will likely be a common complication during the next pandemic and might affect approximately 10% of persons with pandemic influenza, based on data from previous influenza pandemics. Assuming that pandemic influenza will affect about 15%–35% of the U.S. population, approximately 4.4 to 10.2 million cases of post-influenza bacterial community-acquired pneumonia could occur.

Post-influenza bacterial community-acquired pneumonia often presents as a return of fever, along with a productive cough and pleuritic chest pain, after an initial improvement in influenza symptoms over the first few days. Findings include lobar consolidation on chest x-ray and, in adults, sputum smear positive for leukocytes and bacteria. As with other bacterial infections, leukocytosis with increased immature forms may be present, but this finding is neither sensitive nor specific. The most common etiologies of post-influenza bacterial pneumonia are Streptococcus pneumoniae, Staphylococcus aureus, group A Streptococcus, and Haemophilus influenzae. Primary viral pneumonia, with abrupt onset and rapid progression, is more common than bacterial pneumonia in children, yet rare in adults. Physical and radiologic findings in viral pneumonia are consistent with interstitial and/or alveolar disease and include bilateral inspiratory crackles and diffuse infiltrates. Mixed viral-bacterial pneumonia is slightly more common than primary viral pneumonia, but they are often indistinguishable. Bacterial pathogens in mixed infections are similar to those found in secondary bacterial pneumonias. Droplet and Standard Precautions are currently recommended for community-acquired pneumonia of bacterial etiology.(9)

Treatment of community-acquired pneumonia, including post-influenza bacterial community-acquired pneumonia will pose challenges for clinicians during a pandemic. Secondary bacterial pneumonia following influenza virus infection will be difficult to distinguish from community-acquired pneumonia that is not preceded by influenza. Current guidelines for the treatment of adult community-acquired pneumonia (CAP) during the Interpandemic Period de-emphasize the use of diagnostic testing for pathogen-directed treatment and favor empiric therapy with safe and effective broad-spectrum antibacterials, especially extended-spectrum macrolides and fluoroquinolones. However, these antibacterials will likely be in short supply during a pandemic.

The guidelines in this appendix are therefore designed to assist clinicians in managing patients with community-acquired pneumonia, including post-influenza bacterial community-acquired pneumonia, in a setting of high patient volume and limited clinical resources, where the pressure to treat empirically will likely be even greater than during the Interpandemic Period. For adults, the guidance draws heavily from the current draft guidelines for the management of CAP developed jointly by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS).(10,11) For children, the guidance incorporates recommendations from the British Thoracic Society (BTS),(12) a published review,(13) and expert opinion.

Prevention

Efforts to maximize vaccination coverage against Streptococcus pneumoniae is an important component of post-influenza bacterial community-acquired pneumonia prevention during the Interpandemic, Pandemic Alert, and Pandemic Periods. Current guidelines on the use of the 23-valent pneumococcal polysaccharide vaccine among adults and the 7-valent pneumococcal conjugate vaccine among children are available. (14,15)

Site of care: inpatient versus outpatient

Adults

Children

As with pandemic influenza, the decision to hospitalize for post-influenza bacterial community-acquired pneumonia during the Pandemic Period will rely on the physician’s clinical assessment of the patient as well as availability of personnel and hospital resources. Although an unstable patient will be considered a high priority for admission, patients with certain high-risk conditions (see Appendix 1) might also warrant special attention. Home management with follow-up might be appropriate for well-appearing young children with fever alone.


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Table 2. Pneumonia PORT Severity Index (PSI) Calculation

Patient Characteristic

Points Assigned

Demographic Factor

 

     Age
          Male           Female

Number of years
Number of years–10

     Nursing home resident

+10

Comorbid illnesses

 

     Neoplastic disease

+30

     Liver disease

+20

     Congestive heart failure

+10

     Cerebrovascular disease

+10

     Renal disease

+10

Physical examination finding

 

     Altered mental status

+20

     Respiratory rate >30 breaths/minute

+20

     Systolic blood pressure <90 mm Hg

+20

     Temperature <35 C or >40 C

+15

     Pulse >125 beats/minute

+10

Laboratory and /or radiographic finding

 

     Arterial pH <7.35

+30

     Blood urea nitrogen >30 mg/dl

+20

     Sodium <130mmol/l

+20

     Glucose >250 mg/dl

+10

     Hematocrit <30%

+10

     Hypoxemia
     ;<90% by pulse oximetry OR
     <60mm Hg by arterial blood gas

+10

     Pleural effusion on baseline radiograph

+10


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Table 3. Pneumonia Severity Index Risk Classification

PSI Risk Class

Characteristics and Points

Recommended Site of Care

I

Age >50 years + no comorbid conditions, normal range vital signs, normal mental status

Outpatient

II

<70

Outpatient

III

71–90

Outpatient / Brief inpatient

IV

91–130

Inpatient

V

130

Inpatient


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Table 4. CURB-65 Scoring System

Characteristic

Points

Confusion1

+1

Urea >7mmol/l (20mg/dl)

+1

Respiratory rate >30 breaths per minute

+1

Blood pressure (Systolic <90 or diastolic <60 mm Hg)

+1

Age >65 years

+1

1 Based on a specific mental test or disorientation to person, place, or time.


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Table 5. Recommended site of care based on CURB-65 system

Number of Points

Recommended Site of Care

0–1

Outpatient

2

Admit to medical ward

3–5

Admit to medical ward or ICU

Diagnostic testing

Adults
Generally, the etiologies associated with CAP during the Interpandemic Periods will continue to occur during a pandemic. Familiarity with the appropriate use of available diagnostic tests is therefore a key feature of clinical preparedness.

Children
Diagnostic studies for identifying bacterial pneumonia in young children are severely limited.

Antibiotic treatment

Adults and children
Antibiotics, particularly those needed to treat CAP, will likely be in short supply during the Pandemic Period. Therefore, use of empiric therapy for all persons with post-influenza bacterial community-acquired pneumonia will likely not be feasible. Antimicrobial therapy will have to be driven by culture and susceptibility testing of appropriate clinical specimens and by awareness of local antibiotic susceptibility patterns. (See Figures 1 and 2.)


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Figure 3. Management of Community-Acquired Pneumonia during an Influenza Pandemic: Adults


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Figure 4. Management of Community-acquired Pneumonia during an Influenza Pandemic: Children

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