Our investigation confirmed that a cluster of oseltamivir-resistant pH1N1 infections occurred among 4 immunocompromised patients within a hematology-oncology ward. Four factors provided evidence of nosocomial transmission of resistant virus—(1) temporal overlap of inpatient stay within the ward, (2) geographic proximity of patients, (3) presence of the H275Y resistance mutation in viral specimens obtained before oseltamivir use, and (4) complete homology of the HA and NA genes on sequencing.
We were unable to establish whether HCP or visitors contributed to viral transmission between patients. No evidence indicated that this variant of oseltamivir-resistant pH1N1 circulated in other parts of the hospital or in surrounding communities in NC. Interestingly, lack of documented transmission of oseltamivir-resistant pH1N1 virus to other patients in or around the ward could suggest that immunocompromised patients may be more at risk of acquiring infection.
Resistance to oseltamivir remains rare among pH1N1 strains; <1.2% of all pH1N1 isolates tested in the United States have been categorized as oseltamivir resistant [2
]. Oseltamivir resistance in pH1N1 influenza has been described among immunocompromised patients and patients with receipt of oseltamivir for post-exposure prophylaxis or for therapy [2
]. Oseltamivir resistance probably emerged in this cluster when a single immunocompromised patient received oseltamivir after exposure to a close contact with influenza. In our case, transmission of oseltamivir-resistant virus from healthy HCP or visitors to case patients is unlikely, because there is no evidence that this variant of oseltamivir-resistant pH1N1 was circulating in other parts of the hospital or in surrounding communities in NC. Neither theory can be proven; the source of oseltamivir-resistant pH1N1 in this outbreak remains unknown.
Genetic analysis of NA genes of viruses from case patients indicated that they were 100% identical at both the protein and nucleotide levels. The isolate A/North Carolina/39/2009 had a mix of nucleotides A and G at position 807, which resulted in a mixture of amino-acids methionine and isoleucine at residue 269 (there is no known significance to this change). Comparison of the NA sequences from viruses from this outbreak with those from 2 viruses (A/North Carolina/05/2009 and A/North Carolina/06/2009) collected earlier in the pandemic and the reference vaccine strain virus A/California/07/2009 revealed that the outbreak strain differed from these viruses by changes at V106I and N248D. These mutations are not unique to the outbreak stain and are present in a large number of already circulating pH1N1 viruses [8
], and compensatory mutations that could have contributed to the transmission of the virus were not detected. Further NA sequencing and analysis of a larger number of pH1N1 viruses would be required to determine the closest ancestor of the outbreak viruses' NA gene.
This is, to our knowledge, the first report of nosocomial transmission of oseltamivir-resistant pH1N1 virus. Three mechanisms of viral transmission are possible. Drug-resistant virus might have been transmitted between patients by HCP or visitors. Six visitors and 12 HCP reported respiratory illness; however, none of these HCP or visitors was specifically tested for pH1N1. Alternately, drug-resistant virus might have been transmitted directly from one patient to another before diagnosis and implementation of pH1N1 isolation precautions. All case patients were ambulatory and had the opportunity to interact directly before diagnosis. Finally, drug-resistant pH1N1 might have been transmitted by a combination of direct exposures between case patients and by HCP or visitors as vectors. Results of air pressure testing indicated that airborne transmission was unlikely; however, we were unable to examine the role of fomites and environmental surfaces in viral transmission.
Patients infected with pH1N1 typically present with fever and respiratory symptoms, although some patients have milder symptoms [17
]. Additionally, diagnosing influenza among immunocompromised patients is difficult. Recognition of pH1N1 infection among immunocompromised patients can be confounded by attenuated symptoms or by the presence of other potential causes of fever or respiratory symptoms [19
]. As a result, early diagnosis of influenza infection and timely implementation of isolation precautions might not occur. Fever and dyspnea occurred in 3 patients in this cluster, but these signs were initially attributed to etiologies other than pH1N1 infection.
Moreover, immunocompromised patients might have fluctuations in the intensity of influenza symptoms. For instance, 2 case patients experienced intermittent fevers, and another case patient reported spontaneous improvement of cough. Such fluctuation of symptoms may be attributable to altered inflammatory response in immunocompromised hosts, leading to difficulty with diagnosis and incorrect interpretation as spontaneous improvement or as response to therapeutic interventions.
Our findings underscore the need for vigilance for pH1N1 infection and other respiratory viral infections in the health care setting, especially among immunocompromised patients. Moreover, influenza and other respiratory viruses should always be considered in the differential diagnosis for fever or respiratory symptoms in any hospitalized patient when the prevalence of such respiratory viral infections is high in the community. Finally, if antiviral drugs are considered for prophylaxis or therapy of influenza infection, clinicians should consult up-to-date guidelines [20
]. Despite antiviral prophylaxis, patients could still develop influenza as a result of failure of chemoprophylaxis [21
]. Symptoms of fever or respiratory illness after oseltamivir prophylaxis should raise suspicion of influenza infection and prompt testing for influenza infection and oseltamivir resistance. Although no “rapid assay kits” are currently available, antiviral resistance can be determined by referring viruses to laboratories to identify markers of NAI resistance.
Transmission of seasonal influenza is well-described in hospitalized settings. However, isolation precautions and hand hygiene can reduce transmission of influenza infections in hospitals [22
]. We suspect case patients were not placed on isolation precautions because the perceived risk for pH1N1 infection was low, even when the patient received oseltamivir chemoprophylaxis or underwent testing to rule out pH1N1 infection. Such delays in initiating isolation precautions could have contributed to transmission of pH1N1. Indeed, guidelines now recommend placing patients with suspected influenza on droplet precautions [23
]. Finally, vaccines can effectively prevent influenza, and infection control programs should incorporate influenza vaccination for personnel in all health care settings.
This investigation had limitations. First, date of illness onset among case patients was difficult to determine because of concurrent medical problems that mimicked symptoms of influenza infection. Additionally, only a limited number of eligible patients were available for our case-control study. The retrospective nature of the investigation limited the ability to test HCP, visitors, or caregivers for pH1N1. Data obtained through interviews were subject to recall bias, social desirability bias, and underreporting. All case patients had died or were terminally ill at the time that the investigation began; we were unable to confirm their interactions with other patients, HCP, or visitors. Finally, although homologous HA and NA genes suggested transmission of a single strain of virus, confirmation would require full genome sequencing.
Results of our investigation indicate that, first, clinicians should include influenza in the differential diagnosis of any patient with fevers or any respiratory illness. Second, infections with pH1N1 or other influenza viruses can occur even in patients who have received antiviral prophylaxis or treatment. Finally, obtaining respiratory specimens and performing viral testing can facilitate early identification of cases. However, initiation of treatment and implementation of isolation precautions should not be delayed while awaiting the results of laboratory tests.