H1N1 Influenza Center

From the Publishers of the New England Journal of Medicine

Diagnostic Testing for 2009 Pandemic Influenza A (H1N1) Virus Infection in Hospitalized Patients Diagnostic Testing for 2009 Pandemic Influenza A (H1N1) Virus Infection in Hospitalized Patients Diagnostic Testing for 2009 Pandemic Influenza A (H1N1) Virus Infection in Hospitalized Patients

Establishing a diagnosis of 2009 pandemic influenza A (H1N1) virus infection in hospitalized patients can be challenging, especially in patients presenting late in their clinical course. Although real-time reverse-transcriptase polymerase chain reaction (RT-PCR) is the most sensitive testing method to detect 2009 H1N1 virus in respiratory specimens,1 results are not accessible right away. Influenza antigen–detection tests produce quick results, but reported sensitivities of rapid influenza diagnostic tests (RIDTs) to detect 2009 H1N1 virus infection in upper respiratory specimens as compared with real-time RT-PCR range from 10 to 70%; therefore, false negative RIDT results are common2 and also occur with direct immunofluorescence assay (DFA).3 One study reported lower RIDT detection for 2009 H1N1 virus than for seasonal influenza viruses.4

Anecdotal reports indicate that some hospitalized patients did not receive antiviral treatment at admission because of a negative result of RIDT or immunofluorescence testing of upper respiratory tract specimens, with later confirmation of 2009 H1N1 by real-time RT-PCR. Empirical antiviral treatment should be started as soon as possible for hospitalized patients with suspected 2009 H1N1 and not withheld, because a negative RIDT or DFA result does not exclude 2009 H1N1 virus infection. Nor should treatment be delayed until real-time RT-PCR results are available.

Several factors in addition to specimen-acquisition issues can influence influenza test results in a patient with suspected 2009 H1N1. The optimal clinical specimen for identification of 2009 H1N1 virus infection in a hospitalized patient is not yet known, and detection may vary according to multiple factors, such as the patient’s age and immune status, the time from illness onset, the concentration and duration of viral shedding, the specimen source and quality, clinical complications, and specimen processing. The 2009 H1N1 virus infects upper respiratory tract epithelial cells, but it can also infect lower respiratory tract tissue.5 Ideally, upper respiratory tract specimens (nasopharyngeal swab, aspirate, or wash; nasal swabs, or combined nasal and throat swabs) should be tested as close to illness onset as possible.

Some patients with severe lower respiratory tract disease tested negative by real-time RT-PCR on upper respiratory tract (nasopharyngeal) specimens but tested positive by real-time RT-PCR on endotracheal specimens because of presumed prolonged viral shedding in the lower respiratory tract.6 One study reported that systemic corticosteroid therapy was associated with prolonged detection of viral RNA in upper respiratory specimens from hospitalized patients with seasonal influenza.7 Clinicians treating patients with respiratory failure and suspected 2009 H1N1 that has not been diagnosed by tests of upper respiratory tract specimens should consider testing lower respiratory tract specimens (endotracheal aspirate, bronchoalveolar lavage) by real-time RT-PCR.8 The limitations of available influenza diagnostic tests need to be understood in interpreting results for patients with suspected 2009 H1N1. Patients with suspected influenza and negative RIDT or DFA results should have appropriate respiratory specimens tested for 2009 H1N1 by real-time RT-PCR.

Tim Uyeki, M.D., M.P.H.
Influenza Division
Centers for Disease Control and Prevention
Atlanta, GA

No potential conflict of interest relevant to this article was reported.

This article (10.1056/NEJMopv0911052) was published on December 2, 2009, at NEJM.org.


  1. Emergency use authorization of rRT-PCR Swine Flu Panel. Atlanta: Centers for Disease Control and Prevention. (Accessed November 24, 2009, at http://www.cdc.gov/h1n1flu/eua/testkit.htm.)
  2. Evaluation of rapid influenza diagnostic tests for detection of novel influenza A (H1N1) virus — United States, 2009. MMWR Morb Mortal Wkly Rep 2009;58:826-829. [Medline]
  3. Ginocchio CC, Zhang F, Manji R, et al. Evaluation of multiple test methods for the detection of the novel 2009 influenza A (H1N1) during the New York City outbreak. J Clin Virol 2009;45:191-195. [CrossRef][Web of Science][Medline]
  4. Faix DJ, Sherman SS, Waterman SH. Rapid-test sensitivity for novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;361:728-729. [Free Full Text]
  5. Childs RA, Palma AS, Wharton S, et al. Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray. Nat Biotechnol 2009;27:797-799. [CrossRef][Web of Science][Medline]
  6. Rello J, Rodríguez A, Ibañez P, et al. Intensive care adult patients with severe respiratory failure caused by influenza A (H1N1)v in Spain. Crit Care 2009;13:R148-R148. [CrossRef][Medline]
  7. Lee N, Chan PK, Hui DS, et al. Viral loads and duration of viral shedding in adult patients hospitalized with influenza. J Infect Dis 2009;200:492-500. [CrossRef][Web of Science][Medline]
  8. Interim recommendations for clinical use of influenza diagnostic tests during the 2009-10 influenza season. Atlanta: Centers for Disease Control and Prevention. (Accessed November 24, 2009, at http://www.cdc.gov/h1n1flu/guidance/diagnostic_tests.htm.)

9 Responses »

  1. Dear Tim,
    I am an Infectious Diseases Physician working in Saudi Arabia. I have come across a young lady with no previous medical illness who was diagnosed with H1N1 in mid pregnancy. This has resulted in a premature delivery of a live baby at 21 weeks gestation.
    Investigations revealed axonal degeneration.
    My question is how often do you see quadriplegia developing following this infection as all other investigations have turned out to be negative?

  2. Untill now is hard for me to understand why CDC recommend an antiviral treatment which has been proved in sistematics reviews by Cochrane´s Colaboration, in seasonal flu, that oseltamivir and zanamivir just only reduce the length of disease in just only half or one day, no more. So why to use in a systemtic way a treatment for flu, when the Chief Director of WHO said in July 4, that flu, this flu, is moderate. I live in Argentina. Every year since many years ago we see people died for complications of flu, and nobody stated a pandemic situation, of course, is an endemic situation, but in view of the facts happened in south america you could see that this flu is less agressive than the older one, and never we need antviral treatment for most of the illness people with flu. WHO, and hope not to be wrong, CDC as well, say that the treatment is necessary in severe disease, but the common sense says how a drug that is not so effective in a mild presentention could be more effective in a severe disease. What do you know that medical journals don´t know for this kind of medical behavviour. We´re talking about a virus which has been present 90 years ago, and the NEJM says that it could be in part the reason why not aging people has been more protected, specially who born before 1957. As a family physician, and also with a PhD in epidemiology, I can´t understand most of the decisition. In 1976, one soldier died in USA, and President Gerald Ford declared and urgent campagin of vaccionation. Is well know that this situation finished with just one death (against the 2 millons that President Ford said), no more people died for this flu, 46 millons of americans receive flu shot, and at least 4,000 people suffered Guillan Barre Syndrome asociated with this vaccination. I recognize the intelligence of the people from CDC, but former people who worked in this year recognized this situation. You could see this in two short videos from “60 minutes” a famous TV news in USA. Are CDC and WHO overreacting? I don´t know, perhaps these doubts if you answer me could me help to understand better the situation. And I think that you´re aware that every day, died more people for guns shot in USA than for swine flu, at least in this “pandemic” situation. I appreciate your time. I lived the peak of the pandemic in my own country, I lived the panic reaction, and at this time, even when the incidence of the virus N1H1 California 2009, is 85% in people older than 5 years, against 99% in the peak of the situation (end of June). When a pandemic panic disease was more strong that virus itself. Now when the press is talking about another issues, people feel that the virus doesn´t exist. Perhaps, you can explain me better the reasons why do you recommend these antiviral in a mild disease. Drugs that not cure, but only reduce the time of the disease, and in the best scenario, reduce in 8% the spreading, against 55% when you wash your hands often. Thanks in advanced for your response.

  3. Dear Musa ,
    Neurologic complications, including seizures, encephalitis, encephalopathy, Reye syndrome, and other neurologic disorders, have been described previously in association with respiratory tract infection with seasonal influenza A or B viruses . For H1N1 ,CDC reported four children with neurologic complications associated with novel influenza A (H1N1) virus infection admitted to hospitals in Dallas County, Texas, during May 18–28 (MMWR July 24, 2009 / 58(28);773-778). Patients were aged 7–17 years and were admitted with signs of influenza-like illness (ILI) and seizures or altered mental status. Three of the four patients had abnormal electroencephalograms (EEGs). In all four patients, novel influenza A (H1N1) viral RNA was detected in nasopharyngeal specimens but not in cerebrospinal fluid (CSF). Antiviral therapy included oseltamivir (four patients) and rimantadine (three patients). All four patients recovered fully and had no neurologic sequelae at discharge. These findings indicate that, as with seasonal influenza, neurologic complications can occur after respiratory tract infection with novel influenza A (H1N1) virus. No data avilable for adults in the time being . Your case may be unique and should written as a case report.

  4. Dear Tim,
    I am an infectious diseases physican working in Jiangsu province China.In my hospital a 74 years old patient who was illed with silicosis was diagnosed with H1n1 two weeks ago through RT-PCR.Administration of oseltamivir (75mg twice a day for 5 days for this boy who weighed 60 kg) was begun but counts of wbc was reduced. Please contact me.

  5. Dear Tim

    I have a patient with no medical problems here in the USA. He was diagnosed with H1N1 Influenza went into multisystem organ failure (Pulmonary, Renal) despite Tamiflu and now recovering from ARDS but ended up with difficulty hearing….. How common is the Neurological sequalae such as hearing problems/ Deafness with H1N1 Influenza?

  6. 1) Can you comment on Tamiflu dosing in Critically ill patients with Renal Failure “especially with the new expert opinion of 150mg q 12 hours in the following situations:

    a) Normal Cr Clearance: Would Tamiflu 150 mg q 12 be ok?

    b) Cr Clearance 10-30: Would 75 mg po q 24 be ok or should we go 75 mg q 12?

    c) Intermittent dialysis: Should we go Tamilfu 75 mg q 24hours or Tamiflu 75 mg q12? The data of 30 mg every other session is limited data that even Roche does not adopt based on even phone calls with them…. this is left open or ” up in the air issue”

    2) Some experts recommend to extend the Tamiflu longer than 5 days to prevent cytokine release which exacerbates ARDS in critically ill patients. Is 10 days enough time or should it be longer and if longer how long?

    3) Regarding to the use of steroids in ARDS management…… to prevent replication of the virus:= How many days should you use the steroids after the illness??? Is 10 days a good number of days?

    4) Have you seen the transaminitis phenomenon with H1Tamilfu and multisystem organ failure?

    5) Do we need IRB approval from our Hospital to get Premavir Since its invetigational drug ? onr can we just request it online if so any kind of consent/ protection that the manufacturor or FDA provides?

    6) How common are Strokes/ Visual loss/ Deafness/ Seizures/ Neurological sequalae after H1N1 as I have heard of several cases in the country with strokes, deafness, aphasia?

    7) When when would the CDC consider the Loeb study published in JAMA to allow us use Surgical masks instead of the N95 masks especially with the national shortage and its cost?


    Those questions are concerning many colleagues across this country and Europe. We appreciate your reply?


  7. Whats is first chicken or eggs?
    The problem is when respiratory infection is chronic despite first line of empiric antibiotics and diagnostic tools for H1N1 are not avalivable in all places, so we have to decide broad spectrum of antibiotics include sometimes antimycotic drugs in those patient with clinical suspect of potential fungus infection based on macroscopical findings under iinvasive diagnosis procedures (FBC) until we have microbiological results and clinical evolution is poor.
    brief clinical case: 27 years old, male. 4 weeks with chronic cougth , bloody secretions, despite antibiotic treatment ( 3 empiric treatment), respiratory failure, leucopenya 3000 cels/mm3 / 41% immature cells and left basal lobar consolidations. Invasive diagnostic procedure was mandatory and show suspected data of associated or primary fungal infections. Antiviral treatment is mandatory without positive test? Big question

  8. Can you comment on the timing of starting Tamiflu. Ideally it should be given within 48 hours, some patients came to the hospital several day after the onset of flu and exhibited severe pneumonia. Is it rational to start Tamiflu even after several days after the onset of illness?

  9. Dear Tim
    What are available tests to know if a particular person has been exposed or immune against H1N1 whether after genuine ifection, exposure or vaccination.