Cameron R. Wolfe

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

BACKGROUND Oseltamivir resistance among 2009 pandemic influenza A (H1N1) viruses (pH1N1) is rare. We investigated a cluster of oseltamivir-resistant pH1N1 infections in a hospital ward. METHODS We reviewed patient records and infection control measures and interviewed health care personnel (HCP) and visitors. Oseltamivir-resistant pH1N1 infections were found with real-time reverse-transcription polymerase chain reaction and pyrosequencing for the H275Y neuraminidase (NA) mutation. We compared hemagglutinin (HA) sequences from clinical samples from the outbreak with those of other surveillance viruses. RESULTS During the period 6-11 October 2009, 4 immunocompromised patients within a hematology-oncology ward exhibited symptoms of pH1N1 infection. The likely index patient became febrile 8 days after completing a course of oseltamivir; isolation was instituted 9 days after symptom onset. Three other case patients developed symptoms 1, 3, and 5 days after the index patient. Three case patients were located in adjacent rooms. HA and NA sequences from case patients were identical. Twelve HCP and 6 visitors reported influenza symptoms during the study period. No other pH1N1 isolates from the hospital or from throughout the state carried the H275Y mutation. CONCLUSIONS Geographic proximity, temporal clustering, presence of H275Y mutation, and viral sequence homology confirmed nosocomial transmission of oseltamivir-resistant pH1N1. Diagnostic vigilance and prompt isolation may prevent nosocomial transmission of influenza.

In Vitro Activity of Amikacin against Isolates of Mycobacterium avium Complex with Proposed MIC Breakpoints and Finding of a 16S rRNA Gene Mutation in Treated Isolates

ABSTRACT Amikacin is a major drug used for the treatment of Mycobacterium avium complex (MAC) disease, but standard laboratory guidelines for susceptibility testing are not available. This study presents in vitro amikacin MICs for 462 consecutive clinical isolates of the MAC using a broth microdilution assay. Approximately 50% of isolates had amikacin MICs of 8 μg/ml, and 86% had MICs of ≤16 μg/ml. Of the eight isolates (1.7%) with MICs of 64 μg/ml, five had an MIC of 32 μg/ml on repeat testing. Ten isolates (2.1%) had an initial amikacin MIC of >64 μg/ml, of which seven (1.5%) had MICs of >64 μg/ml on repeat testing. These seven isolates had a 16S rRNA gene A1408G mutation and included M. avium, Mycobacterium intracellulare, and Mycobacterium chimaera. Clinical data were available for five of these seven isolates, all of which had received prolonged (>6 months) prior therapy, with four that were known to be treated with amikacin. The 16S mutation was not detected in isolates with MICs of ≤64 μg/ml. We recommend primary testing of amikacin against isolates of the MAC and propose MIC guidelines for breakpoints that are identical to the CLSI guidelines for Mycobacterium abscessus: ≤16 μg/ml for susceptible, 32 μg/ml for intermediate, and ≥64 μg/ml for resistant. If considered and approved by the CLSI, this will be only the second drug recommended for primary susceptibility testing against the MAC and should facilitate its use for both intravenous and inhaled drug therapies.

Reversible cardiac dysfunction associated with pandemic 2009 influenza A(H1N1)

Historical influenza A epidemics have carried elevated rates of cardiovascular disease, including transient cardiac dysfunction. Whether such an association holds for the novel influenza A strain, pandemic 2009 influenza A(H1N1) [A(H1N1)], remains unknown. We report an index case of transient cardiac dysfunction associated with A(H1N1) infection. Next, we reviewed 123 sequential cases of patients hospitalized with pandemic A(H1N1) at a single academic medical center in the United States from April 1, 2009, through October 31, 2009. We identified that 4.9% (6/123) of patients had either new or worsened left ventricular dysfunction. These cases ranged in age from 23 to 51 years, and all had preexisting medical conditions. ICU level care was required in 83% (5/6) of the cases. Sixty-seven percent (4/6) of the cases had follow-up echocardiograms, and left ventricular function improved in all four. We conclude that potentially reversible cardiac dysfunction is a relatively common complication associated with hospitalized pandemic A(H1N1) influenza.

Donor-derived transmission events in 2013: a report of the Organ Procurement Transplant Network Ad Hoc Disease Transmission Advisory Committee.

Background The Organ Procurement Transplant Network Disease Transmission Advisory Committee (DTAC), a multidisciplinary committee, evaluates potential donor-derived transmission events (PDDTE), including infections and malignancies, to assess for donor transmitted events. Methods Reports of unexpected PDDTE to Organ Procurement Transplant Network in 2013 were fully reviewed by DTAC. A standardized algorithm was used to assess each PDDTE from a given donor and to classify each individual recipient from that donor. Results Of 443 total PDDTE submitted, 159 were triaged and not sent out to the full DTAC. Of 284 fully evaluated reports, 32 (11.3%) resulted in a proven/probable (P/P) transmission of infection, malignancy or other conditions to 42 recipients. Of 204 infection events, 24 were classified as P/P affecting 30 recipients, with four deaths. Bacteria were the most frequently reported type of infection, accounting for 99 reports but only 12 recipients from 11 donors experienced P/P transmission. There were 65 donors reported with potential malignancy events and 5 were classified as P/P transmissions with 8 affected recipients and 2 deaths. Additionally, there were 16 noninfection, nonmalignancy reports resulting in 3 P/P transmissions to 4 recipients and 1 death. Conclusions There was a 43% increase in the number of PDDTE reported and reviewed in 2013 over 2012. However, the percent with P/P transmission remains low, affecting recipients from 32 donors especially when compared with the more than 14,000 donors recovered annually in the United States. The continued use of the new standard algorithm and triaging process will enhance the reproducibility of DTAC assessments and allow more robust analysis of our aggregate DTAC experience.

Rescue therapy in adult and pediatric patients with pH1N1 influenza infection: a tertiary center intensive care unit experience from April to October 2009.

Objective:Severe respiratory failure is a well-recognized complication of pH1N1 influenza infection. Limited data regarding the efficacy of rescue therapies, including high-frequency oscillatory ventilation and extracorporeal membrane oxygenation, have been previously reported in the setting of pH1N1 influenza infection in the United States. Design:Retrospective, single-center cohort study. Setting:Pediatric, cardiac, surgical, and medical intensive care units in a single tertiary care center in the United States. Patients:One hundred twenty-seven consecutive patients with confirmed influenza A infection requiring hospitalization between April 1, 2009, and October 31, 2009. Interventions:Electronic medical records were reviewed for demographic and clinical data. Measurements and Main Results:The number of intensive care unit admissions appears inversely related to age with 39% of these admissions <20 yrs of age. Median duration of intensive care unit care was 10.0 days (4.0–24.0), and median duration of mechanical ventilation was 8.0 days (0.0–23.5). Rescue therapy (high-frequency oscillatory ventilation or extracorporeal membrane oxygenation) was used in 36% (12 of 33) of intensive care unit patients. The severity of respiratory impairment was determined by Pao2/Fio2 ratio and oxygenation index. High-frequency oscillatory ventilation at 24 hrs resulted in improvements in median Pao2/Fio2 ratio (71 [58–93] vs. 145 [126–185]; p < .001), oxygenation index (27 [20–30] vs. 18 [12–25]; p = .016), and Fio2 (100 [70–100] vs. 45 [40–55]; p < .001). Extracorporeal membrane oxygenation resulted in anticipated improvement in parameters of oxygenation at both 2 hrs and 24 hrs after initiation of therapy. Despite the severity of oxygenation impairment, overall survival for both rescue therapies was 75% (nine of 12), 80% (four of five) for high-frequency oscillatory ventilation alone, and 71% (five of seven) for high-frequency oscillatory ventilation + extracorporeal membrane oxygenation. Conclusion:In critically ill adult and pediatric patients with pH1N1 infection and severe lung injury, the use of high-frequency oscillatory ventilation and extracorporeal membrane oxygenation can result in significant improvements in Pao2/Fio2 ratio, oxygenation index, and Fio2. However, the impact on mortality is less certain.

Two-Phase Hospital-Associated Outbreak of Mycobacterium abscessus: Investigation and Mitigation

Background Nontuberculous mycobacteria (NTM) commonly colonize municipal water supplies and cause healthcare-associated outbreaks. We investigated a biphasic outbreak of Mycobacterium abscessus at a tertiary care hospital. Methods Case patients had recent hospital exposure and laboratory-confirmed colonization or infection with M. abscessus from January 2013 through December 2015. We conducted a multidisciplinary epidemiologic, field, and laboratory investigation. Results The incidence rate of M. abscessus increased from 0.7 cases per 10000 patient-days during the baseline period (January 2013-July 2013) to 3.0 cases per 10000 patient-days during phase 1 of the outbreak (August 2013-May 2014) (incidence rate ratio, 4.6 [95% confidence interval, 2.3-8.8]; P < .001). Thirty-six of 71 (51%) phase 1 cases were lung transplant patients with positive respiratory cultures. We eliminated tap water exposure to the aerodigestive tract among high-risk patients, and the incidence rate decreased to baseline. Twelve of 24 (50%) phase 2 (December 2014-June 2015) cases occurred in cardiac surgery patients with invasive infections. Phase 2 resolved after we implemented an intensified disinfection protocol and used sterile water for heater-cooler units of cardiopulmonary bypass machines. Molecular fingerprinting of clinical isolates identified 2 clonal strains of M. abscessus; 1 clone was isolated from water sources at a new hospital addition. We made several water engineering interventions to improve water flow and increase disinfectant levels. Conclusions We investigated and mitigated a 2-phase clonal outbreak of M. abscessus linked to hospital tap water. Healthcare facilities with endemic NTM should consider similar tap water avoidance and engineering strategies to decrease risk of NTM infection.

High Intensive Care Unit Admission Rate for 2013–2014 Influenza Is Associated with a Low Rate of Vaccination

To the Editor: Influenza causes significant morbidity and mortality (1–3). Effectiveness of the vaccine and severity of the clinical manifestations of infection are highly variable each year. The rate of influenza vaccination in the United States has increased in recent years but remains poor (4, 5). We have previously reported our experience in the intensive care unit (ICU) with influenza A, H1N1 pandemic 2009 virus (pH1N1) (6, 7). We now report our initial observations for the 2013–2014 influenza season. We observe a very high number of otherwise healthy individuals with critical illness requiring care in the ICU. Most patients who required ICU level care were not previously vaccinated. To determine whether patients requiring ICU care have a lower rate of vaccination prior to hospitalization, we reviewed the records of all hospitalized patients who tested positive for the influenza virus by polymerase chain reaction assay at our institution between November 1, 2013, and January 8, 2014. Basic patient demographics and underlying risk factors for severe influenza are provided (Table 1). The median age in our cohort was 28.5 years (range: 2 mo to 101 yr), similar to the age distribution observed during the 2009–2010 influenza season (8). Table 1: Patient Demographics We have observed a dramatic increase in the number of hospitalizations and ICU admissions in recent weeks (Figure 1A). The majority of patients (48/55; 87.3%) were infected with pH1N1, consistent with recent Centers of Disease Control and Prevention (CDC) reporting (9). Only one case of influenza H3 and one case of influenza B were observed. Figure 1. Hospitalized patients with confirmed influenza and vaccination status. (A) We report the number of cases of influenza at a single academic institution by week in non–intensive care unit (ICU) and ICU settings. (B) There was a high number of individuals ... Thirteen of 55 (23.6%) patients were vaccinated against influenza at least 2 weeks prior to the onset of their acute illness. The vaccination rate in hospitalized patients appears lower than the CDC-reported early-season vaccination rate of 36.5% for the 2012–2013 and 39.5% for the 2013–2014 periods (5). Furthermore, the rate of influenza vaccination in patients requiring ICU care was lower than in patients admitted to general wards: 9.1% (2/22) of patients requiring ICU admission were vaccinated, compared with 33.3% (11/33) of patients treated in non-ICU settings (P = 0.053; odds ratio = 5.0 [95% confidence interval (CI), 0.98–25.4]) (Figure 1B). Similarly, 8.7% (2/23) of patients who required either mechanical ventilation or bilevel positive airway pressure were vaccinated, compared with 34.4% (11/32) of patients who did not require positive pressure ventilation (P = 0.051; odds ratio = 5.5 [95% CI, 1.084–27.90]) (Figure 1C). Of the two patients admitted to the ICU who did receive influenza vaccination, one had chronic lymphocytic leukemia and was receiving rituximab, likely impeding an adequate immune response to vaccination; the second patient had hepatitis C and ethanol abuse and was admitted to the ICU overnight for alcohol withdrawal. Of the 11 patients who were treated in the non-ICU setting and received influenza vaccinations, 9 could be considered immunocompromised due to a variety of conditions, including hematologic malignancy, solid organ transplant, liver cirrhosis, renal failure, and use of medications known to suppress the immune system. Together, these observations support that vaccination may provide protection from severe illness requiring hospitalization and is in agreement with previous reports (10, 11). Forty percent (22/55) of patients were admitted to the ICU, 18.2% (10/55) were treated with noninvasive ventilation, and 29.1% (16/55) required mechanical ventilation for respiratory failure. Sixteen of 22 (72.7%) ICU patients developed acute respiratory distress syndrome, and 31.3% (5/16) of those patients required support with extracorporeal membrane oxygenation. Thus far, death occurred in 5.4% (3/55) of all patients; however, 18 patients still remained hospitalized at the time of this initial report. The rate of ICU admission among hospitalized patients infected with the H1N1 virus was 39.6% (19/48), which is 50% greater than the previously reported rate of 20–25% during the 2009 pandemic influenza season (8). We are uncertain whether this high rate of ICU admission and mechanical ventilation represents a diagnosis bias or whether severity of illness being caused by the current H1N1 virus is higher. Because only the critically ill patients routinely receive bronchoscopy with bronchoalveolar lavage (BAL), it is possible that the high rate of patients who are admitted to the ICU reflects underdiagnosis of influenza in the non-ICU patient population, who may have false-negative nasopharyngeal samples. Interestingly, of the 22 patients admitted to the ICU, 31.8% (7/22) patients had previously negative influenza tests, including 4 patients with false-negative rapid influenza antigen tests (RIDTs). Although RIDTs have the advantage of quick turn-around time, their poor performance characteristics were illustrated in a metaanalysis of 159 studies, showing pooled sensitivity of 62.3% (95% CI, 57.9–66.6%) (12). The CDC recommends that antiviral treatment should not be withheld from patients with signs and symptoms suggestive of influenza infection in spite of a negative RIDT (9). Because H1N1 is known to have a high propensity for affecting the lower respiratory tract (1–3, 6, 8), BAL specimens may be more sensitive for H1N1 diagnosis than samples obtained from the upper respiratory tract (13, 14). Antivirals should not be discontinued in patients with an influenza-consistent illness until the lower tract is sampled, even if upper respiratory tract specimens are negative. Treatment with oseltamivir was started in 81.8% (45/55) of patients in our cohort; however, delayed treatment (i.e., ≥24 h after influenza diagnosis was considered) was observed in 33.3% (15/45) of patients. Ten hospitalized patients (non-ICU) never received antiviral treatment for various reasons. The CDC recommends that the decision regarding antiviral treatment of influenza should not await laboratory confirmation and that indications for antiviral treatment include hospitalization, severe complicated and progressive illness, and presence of risk factors for influenza complications, independent of the duration of symptoms (9). Together, our initial observations during this influenza season support a high prevalence of the H1N1 virus affecting young adults who develop severe lung injury requiring ICU care, high false-negative rates of RIDTs, and delay in starting antiviral treatment. We also note very low vaccination rates among both hospitalized and ICU patients, as well as patients requiring positive pressure ventilation. Our observations support encouraging influenza vaccination for all individuals without a contraindication, as this may prevent severe lower respiratory tract complications requiring ICU level care.

Pandemic (H1N1) 2009 and oseltamivir resistance in hematology/oncology patients.

To the Editor: Tramontana et al. (1) recently described characteristics and oseltamivir resistance in hematology and oncology patients infected with pandemic (H1N1) 2009 virus. Such cases merit further study because concurrent medical problems in immunosuppressed patients may obscure and delay diagnosis and management of pandemic (H1N1) 2009 infections. Moreover, severe complications of such infection may be more likely to develop in immunosuppressed patients (2). During the winter of 2009, oseltamivir-resistant pandemic (H1N1) 2009 virus infection was diagnosed for 4 patients at Duke University Medical Center. We describe the clinical features of the infections, the challenges associated with diagnosis of pandemic (H1N1) 2009 virus infection, and the clinical outcome for the infected patients. Four immunocompromised patients who received chemotherapy and immunotherapy for solid-organ and hematologic malignancies were hospitalized at our tertiary care medical center during October–November 2009, a period of peak activity of pandemic (H1N1) 2009 in surrounding communities in North Carolina (3). These 4 case-patients experienced symptoms attributable to pandemic (H1N1) 2009 from 0 to 14 days after hospital admission, and the diagnosis of pandemic (H1N1) 2009 was made 0–28 days after symptom onset. Illness, diagnosis, and treatment of the patients are summarized in the Table. One patient reported contact with a family member who had influenza-like illness. Three other patients likely acquired pandemic (H1N1) 2009 in the hospital. An investigation could not conclusively establish whether transmission of pandemic (H1N1) 2009 occurred between case-patients and healthcare workers or visitors (4). All 4 case-patients ultimately died; 2 patients recovered from pandemic (H1N1) 2009 after antiviral drug therapy but died of underlying disease and subsequent bacterial infections. One case-patient did not receive antiviral drugs because the diagnosis was made posthumously. Table Clinical, diagnostic, and therapeutic patient information for 4 patients hospitalized for hematologic and oncologic conditions, North Carolina, USA, 2009* We learned valuable lessons regarding diagnosis and management of pandemic (H1N1) 2009 in immunocompromised patients. First, pandemic (H1N1) 2009 infection can be difficult to diagnose in immunocompromised hospitalized patients. Such patients do not exhibit consistent symptoms or signs for pandemic (H1N1) 2009. Consistent with Tramontana et al. (1), fever was the most common feature, followed by progressive dyspnea and intermittent cough. None of our patients reported sore throat. Moreover, such nonspecific symptoms may be inadvertently attributed to concurrent medical problems common in immunocompromised patients such as bone marrow suppression, adverse effects of drugs or chemotherapy, recent surgical procedures, opportunistic infections, or line-related bloodstream infections. Second, respiratory viruses may be imported and subsequently transmitted to hospitalized patients despite standard infection prevention measures (5). Clinicians should remain vigilant for hospital-onset respiratory viral infections and have a low threshold for diagnostic testing, particularly during periods of increased influenza or respiratory virus activity in the community. Early suspicion and prompt testing may have reduced the delay in the diagnosis and management of these patients with pandemic (H1N1) 2009. However, the initial nasal wash specimen from patient 1 was negative for pandemic (H1N1) 2009 virus antigen, whereas the initial bronchoscopy and nasal wash specimens from patient 4 also were negative for such antigens on laboratory testing. This underscores the limitations of current testing and that the sensitivity of pandemic (H1N1) 2009 diagnostic testing remains poor and needs further improvement. Thus, in patients suspected of having pandemic (H1N1) 2009 or in those who are critically ill, lower tract respiratory specimens should tested to improve diagnostic sensitivity, and clinicians should consider using immunoassay and culture methods. All 4 patients described in this case series had viral isolates containing H275Y mutation in the neuraminidase gene of pandemic (H1N1) 2009 virus, which is specifically associated with high-level resistance to oseltamivir. Increasing data show that immunocompromised patients are at increased risk for development of drug-resistant influenza infections after oseltamivir prophylaxis or while receiving oseltamivir treatment (6). Fortunately, this resistance trait remains rare. Existing evidence suggests oseltamivir-resistant pandemic (H1N1) 2009 virus is stable and retains similar transmissibility and virulence as the wild-type virus (7). Therefore, in immunosuppressed patients, in which the influenza mortality rate is high, clinicians should also suspect drug-resistant influenza infection if the patient does not improve. Before she died of underlying hematologic illness, patient 2 clinically improved after treatment with intravenous zanamivir (obtained through an emergency application for an investigational–new drug). As reported in other studies, pandemic (H1N1) 2009 virus was found in her nasal washes, 1 week after she received zanamivir for 10 days (8). Some data suggest that pandemic (H1N1) 2009 virus has a predilection to affect the lower respiratory tract and is associated with more illness and death than is seasonal influenza (9). All 4 case-patients with in this series developed dyspnea, and 3 of the 4 ultimately died of refractory respiratory failure. Our observations suggest that oseltamivir-resistant pandemic (H1N1) 2009 virus is also associated with poor prognosis and may retain the same tropism for lower respiratory tract involvement as wild type. These case-patients illustrated the complexity of the diagnosis and management of such infections in hospitalized immunocompromised patients. Vigilance and heightened clinical suspicion are needed to facilitate early diagnosis, treatment and prevention measures to limit transmission of pandemic (H1N1) 2009 virus or similar viral pathogens.

Aerosolized ribavirin: the most expensive drug for pneumonia.

Dramatic, overnight cost increases of important orphan and generic medications have recently come under public and government scrutiny. We highlight the case of aerosolized ribavirin, an important antiviral agent in hematopoietic stem cell transplantation which, because of substantial price increases, may now cost more than the transplant procedure itself.

Disseminated Mycobacterium immunogenum infection presenting with septic shock and skin lesions in a renal transplant recipient.

Mycobacterium immunogenum is a relatively new species within the Mycobacterium chelonae‐Mycobacterium abscessus group of rapidly growing mycobacteria (RGM). M. immunogenum was first characterized in 2001 and, similar to other RGM, is an ubiquitous environmental organism. This organism has most commonly been implicated in cutaneous infection in both healthy and immunosuppressed patients. To our knowledge, this is the first reported case of septic shock in the setting of disseminated M. immunogenum infection. Definitive identification of this organism requires gene sequencing at specialized centers, which may limit its detection. M. immunogenum is resistant to many anti‐mycobacterial agents, and treatment can be especially challenging in transplant patients, given potential drug interactions and added toxicities. It is important to distinguish M. immunogenum from other RGM and determine the susceptibility profile to devise a successful treatment plan, particularly in the transplant population in which it can potentially cause severe, disseminated disease.