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1.  Parainfluenza Virus Type 3 Antibody in Allogeneic Hematopoietic Cell Transplant Recipients: Factors Influencing Post-Transplant Antibody Titers and Associated Outcomes 
Bone marrow transplantation  2014;49(9):1205-1211.
Parainfluenza virus type 3 (PIV-3) can cause severe respiratory illness among hematopoietic cell transplantation (HCT) recipients. Factors associated with PIV-3–specific antibody level, and the association between PIV-3 antibody levels and clinical outcomes in HCT recipients who acquire PIV-3 infection, are unknown. We evaluated PIV-3-specific hemagglutination inhibition antibody levels and clinical outcomes among 172 patients with PIV-3 infection following HCT. In a multivariable linear regression model, high post-transplantation antibody levels were independently associated with higher pre-transplantation recipient titer (mean difference 0.38 [95% CI, 0.26, 0.50], p<0.001). Significant associations between pre-HCT antibody titers in both patients and donors and occurrence of lower respiratory tract disease (LRD) after HCT were not observed. In conclusion, low pre-transplantation titers are associated with low antibody levels after HCT. The relationship between PIV-3 antibody levels and outcomes remain uncertain. Further study is needed to prospectively evaluate the dynamics of PIV-3–specific antibody responses and the relative contribution of PIV-3–specific antibody to protection from infection acquisition and progression to LRD.
PMCID: PMC4332699  PMID: 24978141
parainfluenza virus; hemagglutination inhibition antibody; lower respiratory tract disease; allogeneic hematopoietic cell transplantation
2.  Infectious Causes of Encephalitis and Meningoencephalitis in Thailand, 2003–2005 
Emerging Infectious Diseases  2015;21(2):280-289.
Although many causes were identified, most remain unknown.
Acute encephalitis is a severe neurologic syndrome. Determining etiology from among ≈100 possible agents is difficult. To identify infectious etiologies of encephalitis in Thailand, we conducted surveillance in 7 hospitals during July 2003–August 2005 and selected patients with acute onset of brain dysfunction with fever or hypothermia and with abnormalities seen on neuroimages or electroencephalograms or with cerebrospinal fluid pleocytosis. Blood and cerebrospinal fluid were tested for >30 pathogens. Among 149 case-patients, median age was 12 (range 0–83) years, 84 (56%) were male, and 15 (10%) died. Etiology was confirmed or probable for 54 (36%) and possible or unknown for 95 (64%). Among confirmed or probable etiologies, the leading pathogens were Japanese encephalitis virus, enteroviruses, and Orientia tsutsugamushi. No samples were positive for chikungunya, Nipah, or West Nile viruses; Bartonella henselae; or malaria parasites. Although a broad range of infectious agents was identified, the etiology of most cases remains unknown.
PMCID: PMC4313633  PMID: 25627940
encephalitis; etiology; brain diseases; tropical medicine; Thailand; viruses; bacteria
3.  Respiratory Syncytial Virus Lower Respiratory Disease in Hematopoietic Cell Transplant Recipients: Viral RNA Detection in Blood, Antiviral Treatment, and Clinical Outcomes 
Respiratory syncytial virus (RSV) RNA detection in plasma or serum may be a marker for lung injury and poor outcomes in hematopoietic cell transplant recipients with RSV lower respiratory disease. Treatment with aerosolized ribavirin appeared protective against overall and pulmonary mortality.
Background. Respiratory syncytial virus (RSV) pneumonia after hematopoietic cell transplant (HCT) is associated with severe morbidity. Although RSV RNA has been detected in serum from patients with RSV lower respiratory disease (LRD) after HCT, the association with clinical outcomes has not been well established in multivariable models. Additionally, the role of antiviral treatment in HCT recipients has not been previously analyzed in multivariable models.
Methods. We retrospectively identified HCT recipients with virologically confirmed RSV LRD and tested stored plasma/serum samples by quantitative reverse transcription polymerase chain reaction for RSV RNA. Risk factors for RSV RNA detection and the impact of RSV RNA in serum and antiviral therapy on outcomes were analyzed using multivariable Cox models.
Results. RSV RNA was detected in plasma or serum from 28 of 92 (30%) patients at a median of 24.5 days following HCT and 2 days following LRD. In multivariable models, neutropenia, monocytopenia, thrombocytopenia, and mechanical ventilation increased the risk of plasma/serum RSV RNA detection; lymphopenia and steroid use did not. RSV RNA detection increased the risk of overall mortality in multivariable models (adjusted hazard ratio [aHR], 2.09 [P = .02]), whereas treatment with aerosolized ribavirin decreased the risk of overall mortality and pulmonary death (aHR, 0.33 [P = .001] and aHR 0.31 [P = .003], respectively).
Conclusions. RSV RNA detection in plasma or serum may be a marker for lung injury and poor outcomes in HCT recipients with RSV LRD. Treatment with aerosolized ribavirin appeared to be protective against overall and pulmonary mortality.
PMCID: PMC3840404  PMID: 24065324
respiratory syncytial virus; RSV; hematopoietic cell transplant; antiviral therapy
4.  A phase I dose escalation study of a pharmacobiologically based scheduling of capecitabine and mitomycin C in patients with gastrointestinal malignancies 
Mitomycin C (MMC) produces significant upregulation of thymidine phosphorylase, a principal determinant of the therapeutic index of capecitabine-based treatment, starting 4–6 days after treatment. On the basis of the time-dependency of this upregulation, we performed a phase I dose escalation study of capecitabine and MMC in patients with gastrointestinal malignancies.
A total of 29 patients with advanced gastrointestinal malignancies received MMC at 6 mg/m2 on day 1 and capecitabine escalated in four successive patient cohorts of doses 500–1,000 mg/m2/day twice daily on days 8–21, every 28 days. MMC was capped at 36 mg/m2.
A total of 29 patients were enrolled and 90% had at least one prior treatment in the metastatic setting. There was one DLT, grade 3 hand and foot syndrome, at dose level four. The most common toxicity was fatigue (61%). No patients experienced grade 4 toxicities. Nine patients experienced prolonged stability of disease.
Capecitabine in combination with MMC in the proposed schedule is well-tolerated with evidence of preliminary activity. The recommended dose for phase II studies are MMC at 6 mg/m2 on day 1 of a 28-day cycle with the dose capped at 36 mg/m2, in combination with capecitabine at 1,000 mg/m2 twice daily on days 8–21.
PMCID: PMC4261191  PMID: 19657639
Capecitabine; Mitomycin C; Gastrointestinal malignancies
5.  Home Self-Collection of Nasal Swabs for Diagnosis of Acute Respiratory Virus Infections in Children With Cystic Fibrosis 
Understanding the importance of respiratory viruses in children with cystic fibrosis (CF) has been limited because of challenges using clinic- or hospital-based diagnostic testing. We conducted a pilot study to assess feasibility of home self- (or parent-) collection of nasal swabs (NS).
Cystic fibrosis patients aged 6–18 years with new respiratory illness participated. In clinic, a deep nasal flocked swab was collected by research staff and compared with an anterior foam NS obtained after instillation of saline spray. At home, up to 2 self-collections of paired foam NS (with and without saline) were collected and mailed for real-time polymerase chain reaction (PCR) testing.
Paired swabs were collected from 28 patients: 18 sets in clinic (deep nasal vs saline foam NS) and 43 sets at home (saline vs dry foam NS) with 9 (50%) and 35 (81%) virus detections, respectively. Home-collected NS were obtained closer to illness onset, with a mean difference in symptom days of −2.3 between home and clinic collections (95% confidence interval [CI] −3.5, −1.2; P < .001). Rhinovirus comprised 73% of virus detections; the difference in mean PCR cycle threshold values for rhinovirus between swabs collected at home versus clinic was −3.8 (95% CI −6.8, −0.9; P = .014), indicating significantly higher viral load for home-collected swabs.
Home-collected foam NS had a higher positivity rate compared with clinic-collected swabs, likely because collection was closer to illness onset. Home self-collection is feasible and well tolerated for timely respiratory virus diagnosis and provides a novel approach for clinical diagnostics and surveillance of respiratory virus infections among CF patients.
PMCID: PMC3869469  PMID: 24363931
6.  Outcome of Respiratory Syncytial Virus Lower Respiratory Tract Disease in Hematopoietic Cell Transplant Recipients Receiving Aerosolized Ribavirin: Significance of Stem Cell Source and Oxygen Requirement 
Respiratory syncytial virus (RSV) infection is an important complication after hematopoietic cell transplantation (HCT), and RSV lower respiratory tract disease (LRD) results in substantial early mortality and late airflow obstruction among survivors. Factors associated with poor outcome are unknown. We evaluated the effect of transplant and treatment factors on overall survival, mortality from respiratory failure, and pulmonary function among 82 HCT recipients who had RSV LRD between 1990 and 2011. All patients received aerosolized ribavirin. In multivariable analyses, only the use of marrow or cord blood as graft source (adjusted hazard ratio [aHR] 4.1, 95% confidence interval [CI] 1.8-9.0, P < 0.001) and oxygen requirement (aHR 3.3, 95% CI 1.5-6.7, P=0.003) remained independently associated with overall mortality and death due to respiratory failure (aHR 4.7, 95% CI 1.8-13, P=0.002 and aHR 5.4, 95% CI 1.8-16, P=0.002, respectively). Antibody-based treatments, including intravenous immunoglobulin and palivizumab, were not independently associated with improved outcome and did not alter the associations of the graft source and oxygen requirements in statistical models. In conclusion, use of peripheral blood stem cells as graft source and lack of oxygen requirement at diagnosis appear to be important factors associated with improved survival of HCT recipients with RSV LRD. These results may explain differences in outcomes reported from RSV infection over time, and may guide the design of future interventional trials.
PMCID: PMC3667608  PMID: 23298855
Respiratory syncytial virus; Lower respiratory tract disease; Palivizumab; Pulmonary function; Hematopoietic cell transplantation
7.  Influenza Viral RNA Detection in Blood as a Marker to Predict Disease Severity in Hematopoietic Cell Transplant Recipients 
The Journal of Infectious Diseases  2012;206(12):1872-1877.
Influenza RNA in blood (viremia) was detected in 9 of 79 (11.4%) hematopoietic cell transplant recipients with influenza, and was less frequently observed in patients with upper respiratory tract disease only and more frequently in patients infected with 2009 pandemic influenza A/H1N1 strain (versus seasonal strains). Viremia increased the risk of progression to lower respiratory tract disease (LRD), hypoxemia, respiratory failure, and overall and influenza-related death. Among patients with LRD, viremia was associated with increased hazards of overall and influenza-associated death (hazard ratio 3.5, 1.1–12). Thus, influenza viremia may serve as marker for overall poor outcome.
PMCID: PMC3502377  PMID: 23033148
8.  Self-Collection of Foam Nasal Swabs for Respiratory Virus Detection by PCR among Immunocompetent Subjects and Hematopoietic Cell Transplant Recipients 
Journal of Clinical Microbiology  2013;51(1):324-327.
Self-collected foam nasal swabs (NS) obtained after instillation of saline spray were compared with nasal washes from immunocompetent subjects during 146 upper respiratory infections (URIs); the sensitivities for reverse transcription (RT)-PCR respiratory virus detection were 95% and 88%, respectively (P = 0.06). The sensitivities from NS collected with and without saline spray during 142 URIs from immunocompetent subjects were 96% and 86% (P = 0.004), respectively, and those from 140 URI samples from hematopoietic cell transplantation recipients were 88% and 85% (P = 0.56), respectively.
PMCID: PMC3536199  PMID: 23135933
9.  A dose-finding, pharmacokinetic and pharmacodynamic study of a novel schedule of flavopiridol in patients with advanced solid tumors 
Investigational new drugs  2010;30(2):629-638.
Based on the promising activity and tolerability of flavopiridol administered with a pharmacokinetically-derived dosing schedule in chronic lymphocytic leukemia (CLL), we conducted a phase I study using this schedule in patients with advanced solid tumors.
Experimental Design
Flavopiridol was given IV as a 30-min loading dose followed by a 4-hr infusion weekly for 4 weeks repeated every 6 weeks. Dose-escalation was in cohorts of three patients using the standard 3+3 phase I study design. Blood samples were obtained for pharmacokinetic and pharmacodynamic studies.
Thirty-four eligible patients with advanced solid tumors received a total of 208 doses (median 7, range 1–24). Total doses ranged from 40 – 105 mg/m2. The primary dose limiting toxicity was cytokine release syndrome (CKRS). No antitumor responses were observed. The mean peak plasma concentration across all doses was 1.65 ± 0.86 µM. Area under the concentration-versus-time curve (AUC0–∞) ranged from 4.31 to 32.2 µM·hr with an overall mean of 13.6 ± 7.0 µM·hr. Plasma flavopiridol concentrations and AUC increased proportionally with dose. There was no correlation between cytokine levels and clinical outcomes.
The maximum-tolerated dose of flavopiridol is 20 mg/m2 bolus followed by 20 mg/m2 infusion over 4 hours given weekly for 4 weeks on a 6-week cycle in patients with advanced solid tumors. Flavopiridol PK was notably different, and there was a higher frequency of CKRS, despite prophylactic steroids, seen in this patient group compared to previous studies with CLL using a similar dosing schedule.
PMCID: PMC3486515  PMID: 20938713
Flavopiridol; CDK inhibitor; Phase I trial; Solid tumors
10.  WU and KI Polyomaviruses in Respiratory Samples from Allogeneic Hematopoietic Cell Transplant Recipients 
Emerging Infectious Diseases  2012;18(10):1580-1588.
Routine testing for these viruses in immunocompromised patients is not recommended.
Data are limited regarding 2 new human polyomaviruses, KI polyomavirus (KIPyV) and WU polyomavirus (WUPyV), in immunocompromised patients. We used real-time PCR to test for these and 12 respiratory viruses in 2,732 nasal wash samples collected during the first year after allogeneic hematopoietic cell transplantation from 222 patients. Specimens were collected weekly until day 100; then at least every 3 months. One year after hematopoietic cell transplantation, the cumulative incidence estimate was 26% for KIPyV and 8% for WUPyV. Age <20 years predicted detection of KIPyV (hazard ratio [HR] 4.6) and WUPyV (HR 4.4), and detection of a respiratory virus in the previous 2 weeks predicted KIPyV detection (HR 3.4). Sputum production and wheezing were associated with detection of KIPyV in the past week and WUPyV in the past month. There were no associations with polyomavirus detection and acute graft versus host disease, cytomegalovirus reactivation, neutropenia, lymphopenia, hospitalization, or death.
PMCID: PMC3471632  PMID: 23017213
human polyomaviruses; viruses; WU polyomavirus; WUPyV; KI polyomavirus; KIPyV; hematopoietic cell transplant; immunocompromised patients; respiratory viruses; respiratory samples
11.  Changing Epidemiology of Respiratory Viral Infections in Hematopoietic Cell Transplant Recipients and Solid Organ Transplant Recipients 
Purpose of review
New respiratory viruses have been discovered in recent years and new molecular diagnostic assays have been developed that improve our understanding of respiratory virus infections. This article will review the changing epidemiology of these viruses after hematopoietic stem cell and solid organ transplantation.
Recent findings
Respiratory viruses are frequently detected in transplant recipients. A number of viruses have been newly discovered or emerged in the last decade, including human metapneumovirus, human bocavirus, new human coronaviruses and rhinoviruses, human polyomaviruses, and a new 2009 pandemic strain of influenza A/H1N1. The potential for these viruses to cause lower respiratory tract infections after transplantation varies, and is greatest for human metapneumovirus and H1N1 influenza, but appears to be limited for the other new viruses. Acute and long term complications in hematopoietic and solid organ transplant recipients are active areas of research.
Respiratory viral infections are frequently associated with significant morbidity following transplantation and are therefore of great clinical and epidemiologic interest. As new viruses are discovered, and more sensitive diagnostic methods are developed, defining the full impact of emerging respiratory viruses in transplant recipients must be elucidated by well-designed clinical studies.
PMCID: PMC3210111  PMID: 21666460
Transplantation; human metapneumovirus; bocavirus; coronaviruses; rhinoviruses; polyomaviruses; influenza viruses
13.  Respiratory Virus Pneumonia after Hematopoietic Cell Transplantation: Associations Between Viral Load in Bronchoalveolar Lavage, Viral RNA Detection in Serum, and Transplant Outcomes 
The Journal of infectious diseases  2010;201(9):1404-1413.
Few data exist regarding respiratory virus quantitation in lower respiratory samples and detection in serum from hematopoietic cell transplantation (HCT) recipients with respiratory virus-associated pneumonia.
We retrospectively identified HCT recipients with respiratory syncytial virus (RSV), parainfluenza (PIV), influenza, metapneumovirus (MPV), and coronavirus (CoV) detected in BAL samples, and tested stored BAL and/or serum samples using quantitative PCR.
In 85 BAL samples from 82 patients, median viral load in copies/ml for RSV (n=35) was 2.6×106, PIV (n=35) 4.9×107, influenza (n=9) 6.8×105, MPV (n=7) 3.9×107, and CoV (n=4) 1.8×105. Quantitative viral load was not associated with mechanical ventilation or death. Viral RNA was detected in serum of 6 of 66 patients: 4 of 41 with RSV pneumonia, 1 with influenza B, and 1 with MPV/influenza A/CoV co-infection (influenza A and MPV RNA detected). RSV detection in serum was associated with high viral load in BAL (p=0.05). Detection of viral RNA in serum was significantly associated with death (adjusted RR 1.8, p=0.02).
Quantitative PCR detects high viral load in BAL samples from HCT recipients with respiratory virus pneumonia. Viral RNA is also detectable in serum of patients with RSV, influenza, and MPV pneumonia, and may correlate with disease severity.
PMCID: PMC2853730  PMID: 20350162
Transplantation; Respiratory Virus; Pneumonia
14.  Car seat test for preterm infants: comparison with polysomnography 
To monitor preterm infants in a cot and a car seat and compare an observed car seat trial with polysomnography (PSG).
Non‐randomised controlled trial.
Regional neonatal unit.
Preterm infants before discharge.
Nap PSG respiratory and sleep variables were measured including gastro‐oesophageal pH. Nurse observations included respiratory distress, apnoea measured by apnoea alarm, oxygen saturation and heart rate. Infants were studied supine in a cot and then in a car seat. Nursing observations were compared with PSG during the car seat trial only. Criteria for failure of the PSG and observed tests were predefined.
Main outcome measures
Difference in respiratory instability between cot and car seat. Concurrence regarding failure of the car seat trial between nurse‐observed data and PSG.
20 infants (median gestation 33 weeks (range 28–35 weeks; median postmenstrual age (PMA) at study 36.5 weeks (range 35–38 weeks)) were studied. There were sufficient car seat data on 18 infants for comparison. There were fewer central apnoeas and arousals in the cot than the car seat (p = 0.047 and p = 0.024, respectively). Airway obstruction was not more common in the car seat. Younger PMA at time of study predicted failure in both car seat (p = 0.022) and cot (p = 0.022). The nurse‐observed test had low sensitivity for predicting PSG failure but more accurately predicted airway obstruction on PSG.
Immature infants exhibit respiratory instability in cots and car seats. A car seat test does not accurately detect all adverse events during sleep in the seat.
PMCID: PMC2675396  PMID: 17412748
15.  A Multi-institutional Phase II study of the efficacy and tolerability of Lapatinib in patients with advanced hepatocellular carcinomas 
Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of EGFR and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC.
A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of < 10% and detect a true response rate of ≥30% was utilized. The dose of lapatinib was 1,500 mg/d administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins.
Twenty-six patients with HCC enrolled on this study. 19% had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%) and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease (SD) as their best response including 6 (23%) with SD lasting > 120 days. Median progression-free-survival was 1.9 months and median overall survival 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on >90% of patients. No somatic mutations in EGFR (exons 18–21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT and P70S6K expression did not correlate with survival.
Lapatinib is well-tolerated but appears to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined.
PMCID: PMC2774354  PMID: 19737952
16.  Relating Counselor Attributes to Client Engagement in England 
Client functioning and treatment engagement were examined in relation to staff attributes and organizational climate across a diverse sample of drug treatment and outreach programs in England. Self-rating assessments were obtained from 1,539 clients and 439 counselors representing 44 programs, and results were interpreted using comparable data from studies of treatment programs in the United States. Client scores on treatment participation and counseling rapport in England were directly related to their higher levels of motivation and psychosocial functioning, as well as to staff ratings of professional attributes and program atmosphere. By linking records from English clients with their counselors in each program, findings also indicate these relationships are rooted in the personal interactions between clients and their counselor. Standardized assessments of treatment structure, process, and performance used across therapeutic settings and national boundaries show there is generalizability in the pattern of clinical dynamics, including the relationships between organizational functioning and quality of services.
PMCID: PMC2697954  PMID: 18835675
Treatment process; Client motivation; Client engagement; Counselor rapport; Organizational climate
17.  Role of T Lymphocytes in the Pathogenesis of Chlamydia Disease 
The Journal of infectious diseases  2009;200(6):926-934.
Vaccines are needed to prevent the oculogenital diseases of Chlamydia trachomatis. Infected hosts develop immunity, although temporary, and experimental vaccines have yielded significant protective immunity in animal models, fueling the impetus for a vaccine. Because infections cause sequelae, the functional relationship between infection- and vaccine-induced immunity is unclear. We hypothesized that infection- and vaccine-induced immunity are functionally distinct, particularly in the ability to prevent sequelae. Chlamydia-immune mice, with immunity generated by either a previous infection or vaccination, exhibited a significant degree of protective immunity, marked by a lower-intensity, abbreviated course of infection. However, vaccinated mice were protected from infertility, whereas preinfected mice were not. Thus, infection-induced immunity does not prevent the pathologic process leading to infertility. Furthermore, T cell subsets, especially CD8 T cells, play a major role in Chlamydia-induced infertility. The results have important implications for the immunopathogenesis of chlamydial disease and new vaccine strategies.
PMCID: PMC2847800  PMID: 19656067
18.  Respiratory Viruses Other than Influenza Virus: Impact and Therapeutic Advances 
Clinical Microbiology Reviews  2008;21(2):274-290.
Summary: Though several antivirals have been developed and marketed to treat influenza virus infections, the development of antiviral agents with clinical activity against other respiratory viruses has been more problematic. Here we review the epidemiology of respiratory viral infections in immunocompetent and immunocompromised hosts, examine the evidence surrounding the currently available antivirals for respiratory viral infections other than influenza, highlight those that are in the pipeline, and discuss the hurdles for development of such agents.
PMCID: PMC2292575  PMID: 18400797
19.  Systemic Infection with Enteric Adenovirus in Immunocompetent Child with Haemophilus influenzae Disease 
Emerging Infectious Diseases  2009;15(2):355-357.
PMCID: PMC2657639  PMID: 19193299
human adenoviruses; enteric adenoviruses; species F adenoviruses; adenovirus 40; encephalitis; meningitis; acute CNS illness; immunocompetent child; Thailand; letter
20.  Cardiovascular and Pulmonary Physical Therapy Specialty Practice: Determining the Current Status 
Cardiopulmonary physical therapy was the first recognized clinical specialty within physical therapy in 1978. Since that time, clinical practice in cardiovascular and pulmonary physical therapy has changed dramatically. In order to maintain currency in this field, the American Board of Physical Therapy Specialties requires that a practice analysis be performed at least every 10 years. This paper reports the process of the most recent practice analysis in cardiovascular and pulmonary physical therapy which led to the 2007 version of the Description of Specialist Practice: Cardiovascular and Pulmonary.
PMCID: PMC2845212  PMID: 20467493

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