Final Report Confirms A Cluster of Oseltamivir (Tamiflu)-Resistant H1N1 Influenza at Duke Hospital

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An outbreak last fall of oseltamivir (Tamiflu)-resistant H1N1 influenza at Duke University Hospital may have been the result of viral transmission between patients.

Four patients in a hematology-oncology ward at Duke Hospital became symptomatic of fever and respiratory symptoms during a six-day period from Oct. 6-11, 2009. They were subsequently diagnosed with oseltamivir-resistant H1N1 Influenza. All four patients were ill with underlying severely compromised immune systems and other complex medical conditions.

Duke and a team of experts from the Centers for Disease Control and Prevention (CDC) and the State of North Carolina Public Health Department collaborated to investigate the nature of these cases. Their findings were presented at the Fifth Decennial International Conference on Healthcare-Associated Infections on March 20 in Atlanta, Ga.

?We found that the oseltamivir-resistant H1N1 influenza were isolated to the four patients. There was no evidence of spread to additional patients or caregivers on the affected ward,? said Luke Chen, M.D., an infectious diseases specialist at Duke University Medical Center.

The team carried out an epidemiologic investigation and extensively reviewed patients? medical records, infection control measures, and interviewed visitors and health care personnel.

?We were not able to establish that health care workers or visitors had a role in the transmission.?

?We found that our infection control plans were properly implemented,? Chen said. ?The compliance to hand hygiene is monitored by objective auditors at Duke Hospital. The hand hygiene compliance on the affected ward was greater than 92 percent during the study period ? much higher than reports from other institutions. We also implemented contact isolation in addition to droplet precautions for severely immunocompromised patients. At the time of the four infections, the hospital was also operating with a visitor restriction policy, which recommended visits only from adult members of the patient?s immediate family or designated caregivers.?

Among hospitalized patients, influenza can often be hidden under other conditions and the suspicion for influenza might be low because many patients have other medical problems that could be causing their fever or respiratory symptoms, according to Chen.

?One key thing we can learn from this outbreak is that all clinicians and health care workers should suspect the diagnosis of influenza even among very ill patients, who have multiple medical problems,? Chen said. ?We should include influenza in the diagnostic thought process early on and act on it by doing specific tests and placing these patients in appropriate isolation prior to obtaining the results of these tests.?

http://www.dukehealth.org/health_library/news/final_report_confirms_a_cluster_of_oseltamivir_tamiflu_resistant_h1n1_influenza_at_duke_hospital

[Laidback Al]

Re: Final Report Confirms A Cluster of Oseltamivir (Tamiflu)-Resistant H1N1 Influenza at Duke Hospital

?We were not able to establish that health care workers or visitors had a role in the transmission.?

If not health care workers or visitors, how did these patients transmit the virus among themselves? A little more information about contact between these infected patients would be helpful.

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Re: Final Report Confirms A Cluster of Oseltamivir (Tamiflu)-Resistant H1N1 Influenza at Duke Hospital

gs for providing the actual link to the Duke study

http://shea.confex.com/shea/2010/webprogram/Paper3013.html

Cluster of Oseltamivir-Resistant 2009 Pandemic Influenza A (H1N1) Virus Among Immunocompromised Patients on a Hospital Ward — North Carolina

Background:
Sporadic reports of oseltamivir resistance occurred during the 2009 pandemic influenza A (H1N1) (pH1N1) outbreak.

Objective:
We investigated a cluster of febrile and respiratory illnesses caused by oseltamivir-resistant pH1N1 in a hematology-oncology ward to ascertain patient-to-patient transmission.

Methods:
We reviewed patient medical records and infection control measures and interviewed healthcare personnel (HCP). We defined a case of oseltamivir-resistant pH1N1 as fever or respiratory illness and laboratory-confirmed oseltamivir-resistant infection by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) and pyrosequencing in a patient admitted to the ward during September 15–December 4. We confirmed phenotypic oseltamivir resistance by neuraminidase inhibition assay and compared viral isolates from the outbreak with surveillance specimens by using viral genome sequencing.

Results:
During September 21–27, 2009, four patients were admitted to the hematology ward for reasons unrelated to influenza infection (Figure). All were ambulatory and had opportunity to interact outside their rooms before onset of influenza-related illness. Three patients were located in adjacent rooms. An index patient experienced fever on October 6, 8 days after completing 5 days of oseltamivir prophylaxis following exposure to an ill family member. Isolation precautions were instituted 9 days after symptom onset. The remaining three patients experienced fever or respiratory symptoms 1, 3, and 5 days after the index patient. All four patients were immunocompromised and had concurrent problems that can mimic infection or respiratory illness. Twelve HCPs reported influenza symptoms during the study period; none were tested for pH1N1. Five reported working while ill; one of these received oseltamivir. Viral isolates from the four patients had complete genomic homology and the H275Y mutation for oseltamivir resistance, which was not identified in other pH1N1 specimens obtained from the hospital or throughout the state.

Conclusions:
Geographic proximity, temporal association of hospital stay, presence of H275Y mutation and genetic homology strongly indicate patient-to-patient transmission of oseltamivir-resistant pH1N1. An index patient experienced oseltamivir-resistant pH1N1 after receiving oseltamivir; however, the source of resistant virus is unknown. Three remaining patients probably acquired oseltamivir-resistant pH1N1 before diagnosis and isolation of this index patient. Transmission by HCPs cannot be established. Diagnosis of pH1N1 is difficult among immunocompromised hosts with complex comorbidities. Although we detected no other cases, increased diagnostic vigilance and aggressive isolation are necessary to limit potential transmission of oseltamivir-resistant pH1N1 among immunocompromised hosts.



Luke F. Chen, MBBS, FRACP , Duke University Medical Center, Durham, NC
Natalie J. M. Dailey, MD , Centers for Disease Control and Prevention, Atlanta, GA
Agam Rao, MD , Centers for Disease Control and Prevention, Atlanta, GA
Aaron T. Fleischauer, PhD, MSPH , Centers for Disease Control and Prevention, Atlanta, GA
Ian Greenwald, MD , Duke Preparedness and Response Center, Durham, NC
Varough Deyde, PhD , Centers for Disease Control and Prevention, Atlanta, GA
Zack S. Moore, MD, MPH , North Carolina Department of Health and Human Services, Raleigh, NC
Deverick J. Anderson, MD, MPH , Duke University Medical Center, Durham, NC
Larisa V. Gubareva, MD, PhD , Centers for Disease Control and Prevention, Atlanta, GA
Daniel J. Sexton, MD , Duke University Medical Center, Durham, NC
Alicia M. Fry, MD, MPH , Centers for Disease Control and Prevention, Atlanta, GA
Arjun Srinivasan, MD , Centers for Disease Control and Prevention, Atlanta, GA
Cameron R. Wolfe, MBBS , Duke Preparedness and Response Center, Durham, NC

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Re: Final Report Confirms A Cluster of Oseltamivir (Tamiflu)-Resistant H1N1 Influenza at Duke Hospital

B=blue, O=Orange, P=purple, G=green
Ad=admitted, sym=symptoms, sam=sample date, tr=treated, age, gender

NC/39 and NC/49 are likely the same person
For sample dates, we probably should use the IR passage dates rather than the original passage dates.

B is index; prophylactially treated on 9-23
B: ad 9-22, sym 10-06, sam 10-15, tr 10-16
O: ad 9-21, sym 10-07, sam 10-14, no treatment
P: ad 9-27, sym 10-09, sam 10-22, tr 10-22 survived
G: ad 9-24, sym 10-11, sam 10-14, tr 10-15

Patient Information:

A/North Carolina/39/2009 IR 10-15, 43 F Blue Index
HA mutation D225X=A716R, NA mutation G807R
A/North Carolina/49/2009 10-16 43 F (probably is #39) Blue Index
Ha mutation D225G=A716G

A/North Carolina/42/1009 IR 10-14 61 M Orange
HA mutation D225B=G715R This was the only one with a M1/C1 passage history.

A/North Carolina/41/2009 Ir 10-16 67 F Green
No mutation D225

A/North Carolina/40/2009 IR 11-02 58 F Purple
No mutation D225, patient survived

I see it said that 225 mutations were transmitting; but it was only in 2 out of the 4 patients and the second patient had only a mixed signal.

The index case had NA mutation G807R, which clearly did not transmit to the other 3 patients.