Evaluation of Diagnostic and Therapeutic Approaches for Suspected Influenza A(H1N1)pdm09 Infection, 2009–2010

Variations between practice and national recommendations could inform clinical education in future influenza seasons.

disease caused by this strain rapidly spread, and in June 2009, the World Health Organization (WHO) declared a global pandemic. Disease activity peaked during May-June 2009, again in October 2009, and essentially disappeared by May 2010 (1)(2)(3). As with previous pandemics, the strain reemerged in the United States during the subsequent 2010-2011 infl uenza season and accounted for ≈25% of characterized strains (4).
During the pandemic, the Centers for Disease Control and Prevention (CDC) issued several guidances for healthcare providers for the identifi cation and treatment of patients with suspected infl uenza A(H1N1)pdm09 disease ( Figure 1). Several rapid infl uenza diagnostic tests for identifi cation of the 2009 H1N1 strain were available, but their poor sensitivity soon became clear (5)(6)(7). CDC recommended that the neuraminidase inhibitor oseltamivir be used as a fi rst-line treatment during the pandemic (8). Available data suggested that the drug was clinically effective, but only when given within <48 hours of symptom onset (9)(10)(11). These guidelines changed during the course of the pandemic as real-time epidemiologic, virologic, and clinical data emerged (8,(12)(13)(14)(15).
CDC initially recommended priority use of antiviral drugs for only hospitalized patients and those at increased risk for infl uenza-related complications. This recommendation refl ected the knowledge that most persons infected with A(H1N1)pdm09 virus had selflimited, mild-to-moderate disease; that commercial and stockpiled supplies of oseltamivir were limited; and that the development of resistance was a concern, particularly since no other effective and easily administered antiviral drugs were available (15)(16)(17)(18). Questions remained, however, with regard to the overall risks and benefi ts and appropriate dosage of the drug for very young and obese patients. In September 2009, CDC advised that rapid infl uenza diagnostic tests be prioritized for patients who were hospitalized or for whom a diagnosis of infl uenza could inform clinical decision making. Furthermore, CDC reinforced the idea that presumptive treatment should be administered to this group of patients and expanded the target group for treatment to include outpatients with risk factors for severe disease, even when test results were unknown (5). Clinical judgment was clearly a key factor in the clinical management of patients with possible A(H1N1) pdm09 disease.
Much has been published with regard to the epidemiology, virology, and clinical spectrum of A(H1N1) pdm09 illness (19,20), but no information is available with regard to diagnostic and therapeutic decision making of physicians or their adherence to national guidelines for ill patients. We conducted this study to evaluate the adherence of physicians to contemporaneous national guidelines for diagnosis and use of oseltamivir among patients with suspected or confi rmed A(H1N1)pdm09 virus infection in the inpatient and outpatient settings.

Methods
The study population included all persons who accessed care from May 1 to December 31, 2009, at Harbor-UCLA Medical Center (HUMC) in Los Angeles, California. HUMC is a 538-bed, urban, academic, teaching hospital; it serves a diverse population, which is ≈55% Latino, 11% Caucasian, 24% black, 4% Asian, and 4% Pacifi c Islander.
We conducted a retrospective cohort study to evaluate 3 issues: 1) adherence of clinicians to national recommendations for use of osteltamivir among patients with suspected or confi rmed infl uenza virus infection; 2) appropriateness of patient selection for diagnostic testing; and 3) the likelihood of clinicians to prescribe antiviral drug therapy for persons with known infl uenza-like illness (ILI) or lower respiratory tract infection (LRTI), 2 conditions for which CDC specifi cally recommended antiviral drug therapy. For the fi rst 2 objectives, we identifi ed child and adult inpatients and those seen in the emergency department with A(H1N1)pdm09 disease by using 4 overlapping data sources, including the following: 1) prospectively collected electronic A(H1N1)pdm09 virus laboratory-based surveillance data obtained by the HUMC clinical virology laboratory and the Infection Prevention and Control Department; 2) electronic, pharmacy-based oseltamivir utilization data; and 3) data on point-of-care testing performed in the emergency department. These data were combined, and we reviewed the medical records of all patients with a positive laboratory test for infl uenza in the outpatient setting and of inpatients who had a laboratory test that was positive for infl uenza virus or were prescribed oseltamivir. Approval for human subjects research was obtained from the Los Angeles Biomedical Research Institute.
We performed a comprehensive review of medical records by using a standardized data collection instrument to identify demographic information and clinical characteristics of patients with the illness, including symptoms and signs and results of viral diagnostic testing and chest radiographs. Use of and indications for oseltamivir, including dose and duration of use, were recorded and, if oseltamivir was not prescribed, reasons for not using the drug were noted. We also recorded whether the patient exhibited risk factors for complications and death (from a preselected list that included concomitant cardiopulmonary, renal, liver, endocrine, blood, or metabolic disorders; immunosuppressive conditions; aspirin therapy; and neurologic conditions), diagnoses at admission or discharge, and length of stay.
We defi ned suspected infl uenza as illness in any patient for whom oseltamivir was prescribed by the treating clinician. We defi ned confi rmed infl uenza disease as illness in a patient with a positive laboratory test result for the virus. To evaluate adherence to guidelines, we used the contemporaneous CDC defi nition for ILI (fever and cough with or without sore throat) and defi ned severe illness as requiring intensive care, a documented oxygen saturation of <92%, or both.
To assess the likelihood of clinicians to prescribe antiviral drug therapy for persons with known ILI or LRTI, we identifi ed all inpatients and outpatients with possible upper or lower respiratory tract infl uenza disease by using International Classifi cation of Diseases, Ninth Revision (ICD-9) diagnostic codes as follows: 079 From this group, we randomly selected 100 persons, stratifi ed by age (50 persons <18 and 50 >18 years of age) by using SAS 9.2, Proc Samplesurvey (SAS Institute, Cary, NC, USA). Using medical record review, we then identifi ed persons with ILI (defi ned above) or LRTI, defi ned by the presence of at least 1 specifi c lower respiratory tract sign, including tachypnea, retractions, or hypoxia (oxygen saturation <92%), and/or abnormal auscultatory fi ndings (crackles/crepitations or wheezing), and/or unequivocal and abnormal radiographic fi ndings.
We performed descriptive analyses of the above variables by using SAS version 9.2. Testing of proportions was performed by using χ 2 or Fisher exact test as appropriate. All reported p values are 2-tailed and were considered signifi cant if p<0.05.
Oseltamivir was prescribed for 86 (66%) of 130 children and 89 (87%) of 102 adults with ILI. Oseltamivir was prescribed at the correct dosage and duration of therapy for 229 (95%) of 240 patients, and 216 (90%) of 240 patients received the drug <48 hours after symptom onset. Another 16 received the drug within 72 hours of disease onset. Severe illness was identifi ed in 132 (42%) of 314 patients, 118 (89%) of whom received oseltamivir ( Figure 2).

Inpatients
Of 218 inpatients who received a diagnosis of or treatment for infl uenza, 107 (49%) were children, and 111 (51%) were adults. Laboratory testing was performed for 177 (81%) inpatients, and 74 (42%) were positive for infl uenza virus (Table). Oseltamivir was administered to 198 (91%) of 218 inpatients, among whom 110 (50%) had a negative test or no laboratory testing performed. Of the remaining 88 with a positive test result, 5 did not receive oseltamivir because the patient refused, the patient was "well appearing," or patient's onset of symptoms occurred >48 hours before they received a diagnosis.
Of the inpatients, we identifi ed 68 (64%) of 107 children and 86 (77%) of 111 adults who had ILI at the time of laboratory testing (p<0.04). Oseltamivir was given to 58 (85%) of the 68 children with ILI and 84 (98%) of 86 adults with ILI (p<0.02). Oseltamivir was prescribed for 145 (94%) of 155 inpatients with an underlying medical condition and for 118 (91%) of 129 patients with severe illness.
The median interval from illness onset to initiation of antiviral treatment was 2 days (range 1-8). The dosage or duration of therapy, or both, was incorrect for 11 (5%) inpatients; for 6 inpatients, no adjustment was made for renal insuffi ciency. Of those 6 inpatients, 2 had chronic renal insuffi ciency after a transplant, 1 had diabetic nephropathy, and 3 had pneumonia and renal insuffi ciency. Three obese patients received a doubled dose of oseltamivir.
Receipt of the vaccine against infl uenza A(H1N1) pdm09 virus was documented in 61 (28%) of 218 patients, but 59 (97%) of them received the vaccine at hospital discharge. Only 1 patient had received the seasonal infl uenza vaccine before admission, and none received vaccine at discharge.

Outpatients
We identifi ed 664 patients who underwent rapid infl uenza diagnostic testing, of whom 77 (19%) of 398 children and 19 (7%) of 266 adults tested positive (p<0.001). Twenty percent of tests were carried out on patients without CDC-defi ned ILI and for whom no other indication was present. As noted in Figure 3, only 11%  (73/664) of these tests were performed >2 weeks after CDC actively discouraged their use. Oseltamivir was prescribed for 37 (48%) of 77 outpatient children and 5 (26%) of 19 adults who tested positive for infl uenza (p>0.05), all at the appropriate dose and duration. As recommended, 35 (83%) of 42 received the drug <48 hours from symptom onset, and the remaining patients received the drug within 72 hours of symptom onset. Of 54 (56%) of 96 patients who tested positive and did not receive oseltamivir, 25 (46%) were not treated according to CDC guidelines, and 8 (15%) refused therapy. The reasons for not initiating oseltamivir therapy included onset of symptoms >48 hours previously and lack of an underlying medical condition. For 21 (39%) of the untreated patients, we found no documentation of the reason for withholding therapy.
We found 3 outpatients who had severe illness, none of whom received oseltamivir, and the reasons for withholding therapy could not be determined. Conversely, 16 (3%) of 522 patients with a negative test result received oseltamivir. The most common reasons documented for initiating therapy in this group included an underlying medical condition or concomitant diagnosis of pneumonia, ILI, or both, each consistent with CDC guidelines.

Therapy for Patients with ILI or LRTI Not Tested for Infl uenza Virus
We reviewed records of 50 randomly selected outpatients with ICD-9 codes for ILI who were not tested for infl uenza virus. Only 3 patients (6%) received oseltamivir (as recommended by CDC). Of the remainder who did not receive the drug, the duration of illness was >48 hours, the patient was "well appearing," or no underlying risk factors were found. The median time from illness onset to obtaining medical attention was 3.7 days (range 0-14 days); 22 (44%) sought treatment within 48 hours. Thirteen (26%) had an underlying medical condition (7 children and 6 adults). For each, however, there was an appropriate reason for withholding therapy, per CDC guidelines.
Among 50 outpatients with ILI and LRTI, 14 (28%) were admitted, 2 to the intensive care unit. The median time from illness onset to obtaining medical attention was 3 days (range 0-28 days); 31 (62%) of 50 sought treatment >48 hours after symptom onset. Eight of 25 (32%) children and 5 (20%) of 25 adults received oseltamivir, and 6 patients received the drug <48 hours from symptom onset. Oseltamivir was administered to 6 (38%) of 16 patients with severe illness and to 7 (25%) of 28 who had an underlying medical condition. The reason for not prescribing oseltamivir was documented in 5 charts, and the reasons included were that symptom onset was >48 hours from the visit to the hospital and that the patient was "well appearing." Overall, 13 (68%) of 19 patients with LRTI who sought treatment within 48 hours of illness onset did not receive oseltamivir as recommended by CDC.

Discussion
We believe that this study provides useful information with regard to the diagnostic and therapeutic behaviors of clinicians caring for patients with possible infl uenza virus infection. Although our data refl ect physician behavior during the 2009-10 infl uenza A (H1N1) pandemic, the fi ndings are likely applicable to any infl uenza year because diagnostic test performance, disease intensity, antiviral  agent resistance, and virus strain affect clinical decision making each year. We were interested in 2 general concepts: practice performance when infl uenza was clinically suspected and the potential for missed therapeutic opportunities when it was not. For the former, we found that providers' practices were often consistent with CDC guidelines but notable defi ciencies were also identifi ed. In particular, a substantial proportion of potentially high-risk patients were not empirically treated, and a reason to withhold therapy could not be documented. This dynamic is similar to that for other medical conditions for which clinical practice guidelines are available: provider behavior at variance with the guideline may refl ect available patient-level information or other immediate concerns (22,23). In any case, we have identifi ed potential areas for targeted education of healthcare providers that should be supplemented by rapid dissemination and follow-up of national guidelines if and when they change over time.
We also found inconsistencies in the use of antiviral drug therapy, which was often at variance with contemporaneous guidelines. In our population, 25% of patients who received oseltamivir did not have ILI or another clear indication for treatment. During the pandemic, the drug was recommended for inpatients with ILI and outpatients with ILI and risk factors for severe illness if they had sought treatment within 48 hours of symptom onset (5). However, although too many outpatients without ILI received oseltamivir, too few (32%) received the drug despite having LRTI, a consistent indication for therapy. For most patients with LRTI, we could not identify a reasonable justifi cation for withholding therapy. Not surprisingly, all of these patients received antibacterial agents, yet it remains unclear whether the clinicians actively considered infl uenza virus as a primary pathogen or risk factor for the presumed bacterial superinfection. Infl uenza virus infection and its association with secondary bacterial infection is well documented with infl uenza A(H1N1) pdm09 virus infection and with interepidemic disease (24)(25)(26)(27). Treatment with antiviral drugs in this setting may lessen illness when superinfection exists (26,28). In this circumstance, greater recognition of the possibility of infl uenza virus infection and use of antiviral drug therapy may mitigate illness and lessen hospital costs (29,30).
We found that diagnostic practices were often inconsistent with contemporaneous guidelines. Nearly one third of patients were tested for infl uenza virus, despite the lack of ILI and ≈20% had no other indication for which testing might otherwise be justifi ed (e.g., headache, myalgia). Previous work has shown that relatively few patients with infl uenza virus infection have systemic signs without fever, sore throat, or cough (31). Although changes in CDC recommendations were quickly disseminated to hospital clinicians by management memo, email, or faceto-face meetings, even more rapid communication and follow-up reminders may have enhanced adherence to guidelines.
We found that the dosage and duration of oseltamivir were generally consistent with CDC guidelines in ≈90% of all treated patients, and specifi cally for all outpatients. HUMC required the use of a preauthorization drug form that noted the appropriate age-and weight-based dose; an outpatient prescription for oseltamivir would not have been released without a completed form. Such tools have been shown to limit dosing errors (32,33). Also consistent with the CDC guidelines, >90% of hospitalized patients and patients with severe illness in our study received oseltamivir. Among outpatients, we noted that for ≈50%, an appropriate rationale for not providing oseltamivir was documented in the medical record.
Among the small number of dosing errors identifi ed, >40% were related to inappropriate adjustment for renal insuffi ciency. More than 90% of oseltamivir is metabolized to oseltamivir carboxylate, 99% of which is eliminated by renal excretion, thus requiring dosage adjustment in this setting. Antimicrobial drug dosing errors are common (34,35), and a failure to adjust for renal impairment is a frequent underlying reason (36,37). Although controlled data are not available, oseltamivir has been associated with the development of thrombocytopenia, particularly when renal clearance is artifi cially lowered by concomitant administration of the drug probenicid (38). Attention should be given to patients' renal function, particularly in the elderly (diminished renal clearance) and in those for whom higher doses may be recommended, such as the severely ill or obese (8).
We identifi ed clinical management differences between how clinicians prescribed treatment for adult patients and how they prescribed treatment for children. Children who were inpatients were signifi cantly less likely to have ILI at the time of testing and to receive treatment for ILI. When testing was carried out, children were also more likely to test positive for infl uenza virus than were adults, possibly because of the higher virus load in this population. These data also may refl ect more overall testing of children, particularly young children who are more likely than adults to have nonspecifi c signs and symptoms (lethargy, poor feeding, abdominal pain) (39,40). In addition, infants and young children may not articulate symptoms of ILI (e.g., sore throat), leading to increased nonspecifi c testing and treatment of this population.
The main strength of this study is the comprehensive nature of case ascertainment, which included laboratorybased information and review of all prospectively collected logs for emergency department point-of-care testing. However, some patients who underwent testing for infl uenza virus may not have been noted in the outpatient log system. We appreciate that ICD-9 code data for ILI and LRTI may be nonspecifi c, but our prospectively collected ILI data (albeit for a limited portion of the surveillance period) validated the temporal trends for this diagnosis in the outpatient setting. We also did not include data from medical outpatient (nonemergency department) clinics where other patients with infl uenza may have been identifi ed and treated, perhaps skewing our data to those who were more ill. As a retrospective study, our conclusions depend solely upon information documented in the medical record, which may be incomplete. Also, the use of an antiviral agent authorization form most likely improved the dosing practice, as has been shown in other settings (32,33). Last, our study population includes only a single academic medical center and therefore may not be representative of the region or the nation.
To our knowledge, similar studies of physician behavior with regard to infl uenza disease, and for A(H1N1) pdm09 disease in particular, have not been reported. We have identifi ed variations in clinical practice in relation to national guidelines that suggest potential areas of education for future infl uenza seasons.
This study was supported in part by the Los Angeles Biomedical Research Institute and the Los Angeles County Department of Health Services.
Dr. Vijayan performed this work as a Fellow in Pediatric Infectious Diseases at Harbor-UCLA Medical Center. She is currently an assistant professor of pediatrics at the University of Florida, Gainesville. Her research interests include preventing infections, such as infl uenza and pertussis in mothers and their infants through maternal immunization, and diagnosis and management of travel-and migration-associated disease.