Delayed Diagnosis of Mycobacteriumbovisbacillus Calmette-Guérin Periprosthetic Joint Infection Following Total Knee Arthroplasty.

Periprosthetic joint infection (PJI) can present challenges in diagnosis and treatment, particularly in the setting of atypical causative organisms such as fungi and mycobacteria. Herein, we present a case and provide a review of the diagnosis and treatment of an unusual PJI caused by bacillus Calmette-Guérin, administered during the treatment of bladder cancer 3 years prior to total knee arthroplasty and subsequent PJI. Although the patient's history of bladder cancer was known, neither his Bacillus Calmette-Guérin treatment nor its potential for distant site spread that could lead to PJI were appreciated, leading to a prolonged diagnostic evaluation and treatment course.

The Shunt of It.

Pulmonary arteriovenous malformations (PAVMs) are rare and most often identified in patients with hereditary hemorrhagic telangiectasia (HHT). We describe a patient with severe hypoxemia and orthodeoxia with imaging findings consistent with PAVMs. Resected lung pathologic findings confirmed the presence of numerous microscopic vascular abnormalities within the right lower lobe that was consistent with diffuse pulmonary arteriovenous shunts. Family history was negative for HHT but was positive for pulmonary arterial hypertension (PAH) in two second-degree relatives. A vascular malformation gene panel was negative for genes that commonly are associated with HHT but identified a pathogenic variant in the gene encoding bone morphogenetic protein receptor-2 (BMPR2 p.Cys123∗). Pathogenic variants in BMPR2 are a well-known cause of hereditary PAH; there have been several reports to date of patients with PAVMs and PAH. However, this is the first patient to be reported with a pathogenic variant in BMPR2 to have PAVMs in isolation.

SARS-CoV-2 innate effector associations and viral load in early nasopharyngeal infection.

COVID-19 causes severe disease with poor outcomes. We tested the hypothesis that early SARS-CoV-2 viral infection disrupts innate immune responses. These changes may be important for understanding subsequent clinical outcomes. We obtained residual nasopharyngeal swab samples from individuals who requested COVID-19 testing for symptoms at drive-through COVID-19 clinical testing sites operated by the University of Utah. We applied multiplex immunoassays, real-time polymerase chain reaction assays and quantitative proteomics to 20 virus-positive and 20 virus-negative samples. ACE-2 transcripts increased with infection (OR =17.4, 95% CI [CI] =4.78-63.8) and increasing viral N1 protein transcript load (OR =1.16, CI =1.10-1.23). Transcripts for two interferons (IFN) were elevated, IFN-λ1 (OR =71, CI =7.07-713) and IFN-λ2 (OR =40.2, CI =3.86-419), and closely associated with viral N1 transcripts (OR =1.35, CI =1.23-1.49 and OR =1.33 CI =1.20-1.47, respectively). Only transcripts for IP-10 were increased among systemic inflammatory cytokines that we examined (OR =131, CI =1.01-2620). We found widespread discrepancies between transcription and translation. IFN proteins were unchanged or decreased in infected samples (IFN-γ OR =0.90 CI =0.33-0.79, IFN-λ2,3 OR =0.60 CI =0.48-0.74) suggesting viral-induced shut-off of host antiviral protein responses. However, proteins for IP-10 (OR =3.74 CI =2.07-6.77) and several interferon-stimulated genes (ISG) increased with viral load (BST-1 OR =25.1, CI =3.33-188; IFIT1 OR =19.5, CI =4.25-89.2; IFIT3 OR =245, CI =15-4020; MX-1 OR =3.33, CI =1.44-7.70). Older age was associated with substantial modifications of some effects. Ambulatory symptomatic patients had an innate immune response with SARS-CoV-2 infection characterized by elevated IFN, proinflammatory cytokine and ISG transcripts, but there is evidence of a viral-induced host shut-off of antiviral responses. Our findings may characterize the disrupted immune landscape common in patients with early disease.

SARS-CoV-2 Innate Effector Associations and Viral Load in Early Nasopharyngeal Infection.

To examine innate immune responses in early SARS-CoV-2 infection that may change clinical outcomes, we compared nasopharyngeal swab data from 20 virus-positive and 20 virus-negative individuals. Multiple innate immune-related and ACE-2 transcripts increased with infection and were strongly associated with increasing viral load. We found widespread discrepancies between transcription and translation. Interferon proteins were unchanged or decreased in infected samples suggesting virally-induced shut-off of host anti-viral protein responses. However, IP-10 and several interferon-stimulated gene proteins increased with viral load. Older age was associated with modifications of some effects. Our findings may characterize the disrupted immune landscape of early disease.

Lung transplantation following coronary artery bypass surgery-improved outcomes following single-lung transplant.

BACKGROUND: Prior coronary artery bypass grafting (CABG) has been a contraindication to lung transplantation (LTx) because of disease severity and technical considerations. Although patients increasingly are being referred for and receiving LTx, whether it should remain a contraindication is unknown. We sought to define the prevalence of LTx after CABG and determine the effect on outcomes. METHODS: The United Network for Organ Sharing Standard Transplant Analysis and Research data set was queried during the period 2004-2013 for adult LTx patients, as prior CABG became a mandatory reporting field in 2004. The primary end-points were 30-day and 1-, 3-, and 5-year survivals. RESULTS: The study cohort included 14,791 patients, of whom 292 patients had previously undergone CABG (single left, n = 68; single right, n = 181; bilateral, n = 43), representing 2% of all transplants. For the entire cohort, 30-day survival was 97%, and survival at 1, 3, and 5 years was 88%, 79%, and 74%. CABG was a predictor of mortality at all time points, with hazard ratios ranging from 1.97 (confidence interval, 1.23-3.16; p < 0.01) at 30 days to 1.38 (confidence interval, 1.12-1.69; p < 0.01) at 5 years. When stratified by type of transplant, CABG strongly predicted mortality at all time points for patients receiving bilateral, but not single, transplants. CONCLUSIONS: Although LTx after CABG is uncommon, it is increasingly performed in the current era. Single right LTx is the most common procedure performed in patients with prior CABG. CABG before LTx is an independent predictor of mortality at all time points and is driven by increased mortality in patients receiving bilateral LTx.

EIF2AK4 mutations in pulmonary capillary hemangiomatosis.

BACKGROUND: Pulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH suggest a heritable cause although the genetic etiology remains unknown. METHODS: We used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n = 1) or sporadic (n = 10) PCH for mutations. RESULTS: Using exome sequencing, we identified compound mutations in eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) (formerly known as GCN2) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identified two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress. CONCLUSIONS: Mutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases.

Pediatric lung transplantation for cystic fibrosis.

Pediatric lung transplantation for cystic fibrosis has uncertain survival effects. Three retrospective studies disagree on survival benefit. The US Lung Allocation Score has changed patient selection for lung transplantation but confounds the analysis of survival outcomes. A prospective trial is needed to resolve clinical equipoise and explore quality-of-life effects.

Lung Transplantation and Survival in Children with Cystic Fibrosis.

BACKGROUND: The effects of lung transplantation on the survival and quality of life in children with cystic fibrosis are uncertain. METHODS: We used data from the U.S. Cystic Fibrosis Foundation Patient Registry and from the Organ Procurement and Transplantation Network to identify children with cystic fibrosis who were on the waiting list for lung transplantation during the period from 1992 through 2002. We performed proportional-hazards survival modeling, using multiple clinically relevant covariates that were available before the children were on the waiting list and the interactions of these covariates with lung transplantation as a time-dependent covariate. The data were insufficient in quality and quantity for a retrospective quality-of-life analysis. RESULTS: A total of 248 of the 514 children on the waiting list underwent lung transplantation in the United States during the period from 1992 through 2002. Proportional-hazards modeling identified four variables besides transplantation that were associated with changes in survival. Burkholderia cepacia infection was associated with a trend toward decreased survival, regardless of whether the patient underwent transplantation. A diagnosis of diabetes before the patient was placed on the waiting list decreased survival while the patient was on the waiting list but did not decrease survival after transplantation, whereas older age did not affect waiting-list survival but decreased post-transplantation survival. Staphylococcus aureus infection increased waiting-list survival but decreased post-transplantation survival. Using age, diabetes status, and S. aureus infection status as covariates, we estimated the effect of transplantation on survival for each patient group, expressed as a hazard factor of less than 1 for a benefit and more than 1 for a risk of harm. Five patients had a significant estimated benefit, 283 patients had a significant risk of harm, 102 patients had an insignificant benefit, and 124 patients had an insignificant risk of harm associated with lung transplantation. CONCLUSIONS: Our analyses estimated clearly improved survival for only 5 of 514 patients on the waiting list for lung transplantation. Prolongation of life by means of lung transplantation should not be expected in children with cystic fibrosis. A prospective, randomized trial is needed to clarify whether and when patients derive a survival and quality-of-life benefit from lung transplantation.

Clinical course and spectrum of intensive care unit patients reactivating herpes simplex-1 virus: a retrospective analysis.

BACKGROUND: Herpes simplex-1 virus (HSV-1) reactivation in the respiratory tract is common in intensive care unit (ICU) patients. However, susceptible ICU populations are poorly defined. Clinical recognition of HSV infection of the respiratory tract is difficult and the impact of such reactivation is not understood. MATERIALS AND METHODS: A retrospective analysis of HSV-1 positive patients encountered over a 5-year period at a multispecialty ICU was carried out. HSV-1 was identified in respiratory secretions using a qualitative polymerase chain reaction (PCR) technique. Patient charts were reviewed for clinical features that would typify HSV-1 respiratory involvement, and the morbidity and mortality risks found with HSV-1 respiratory involvement. RESULTS: A review of 48 HSV-1 positive ICU patients showed that patients reactivating HSV in the respiratory tract fell into one of the three categories: (1) septic elderly patients with and without ARDS, (2) immunosuppressed patients, especially those receiving high-dose steroids, and (3) post-thoracotomy patients. Abnormalities suggestive of HSV-1 reactivation in the respiratory tract included, haemorrhagic or excessive respiratory secretions, concomitant orofacial herpes (42%), and bronchoscopic abnormalities (hemorrhagic ulcers and mucosal friability) (83%). Twenty eight percent of the HSV-1 infected patients experienced postextubation stridor. HSV-1 reactivation was associated with extended ventilator stays, significant mortality (42%), and ventilator-associated pneumonias (52%). CONCLUSIONS: Identification of susceptible populations and definition of clinical features of HSV-1 related respiratory disease can enable diagnosis of HSV-1 infection in ICU patients. Although detection by a PCR technique can rapidly diagnose HSV-1 reactivation, prospective studies are required to clarify HSV disease versus mere shedding, and understand the impact of HSV-1 reactivation in hospitalized patients.

Lung transplantation and survival in children with cystic fibrosis.

BACKGROUND: The effects of lung transplantation on the survival and quality of life in children with cystic fibrosis are uncertain. METHODS: We used data from the U.S. Cystic Fibrosis Foundation Patient Registry and from the Organ Procurement and Transplantation Network to identify children with cystic fibrosis who were on the waiting list for lung transplantation during the period from 1992 through 2002. We performed proportional-hazards survival modeling, using multiple clinically relevant covariates that were available before the children were on the waiting list and the interactions of these covariates with lung transplantation as a time-dependent covariate. The data were insufficient in quality and quantity for a retrospective quality-of-life analysis. RESULTS: A total of 248 of the 514 children on the waiting list underwent lung transplantation in the United States during the period from 1992 through 2002. Proportional-hazards modeling identified four variables besides transplantation that were associated with changes in survival. Burkholderia cepacia infection was associated with a trend toward decreased survival, regardless of whether the patient underwent transplantation [corrected]. A diagnosis of diabetes before the patient was placed on the waiting list decreased survival while the patient was on the waiting list but did not decrease survival after transplantation, whereas older age did not affect waiting-list survival but decreased post-transplantation survival. Staphylococcus aureus infection increased waiting-list survival but decreased post-transplantation survival. Using age, diabetes status, and S. aureus infection status as covariates, we estimated the effect of transplantation on survival for each patient group, expressed as a hazard factor of less than 1 for a benefit and more than 1 for a risk of harm. Five patients had a significant estimated benefit, 283 patients had a significant risk of harm, 102 patients had an insignificant benefit, and 124 patients had an insignificant risk of harm associated with lung transplantation [corrected]. CONCLUSIONS: Our analyses estimated clearly improved survival for only 5 of 514 patients on the waiting list for lung transplantation. Prolongation of life by means of lung transplantation should not be expected in children with cystic fibrosis. A prospective, randomized trial is needed to clarify whether and when patients derive a survival and quality-of-life benefit from lung transplantation.

Lung transplantation for cystic fibrosis.

PURPOSE OF REVIEW: To examine recent publications on lung transplantation for cystic fibrosis for changes in surgical techniques, selection criteria of patients, and impact on quality of life. RECENT FINDINGS: Recent evidence focuses on cystic fibrosis patient subsets enabling better decisions about listing for lung transplantation as a therapeutic option. There is information about Burkholderia cepacia infection, ventilator dependence, young age, and arthropathy. In the US, the United Network for Organ Sharing has addressed perceived inequities in organ distribution by allocating organs by illness severity rather than time on the waiting list. A Lung Allocation Score ranks severity for patients 12 years of age and older for transplantation based on variables including lung function, oxygen and ventilatory needs, diabetes, weight and physical performance. Some recently studied important variables that influence survival in cystic fibrosis and after lung transplantation, including airway infections, pancreatic exocrine function and acute exacerbations, are not included in the Lung Allocation Score. Few publications have examined quality of life after transplantation, and a definitive work has yet to appear. SUMMARY: New information has refined decision-making about lung transplantation for patients with cystic fibrosis. We examine recent findings and make recommendations for patients, families and medical providers.

Pulmonary Langerhans cell histiocytosis: emerging concepts in pathobiology, radiology, and clinical evolution of disease.

Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon disorder of adult smokers associated with a significant morbidity. Arising from the aberrant accumulation of Langerhans and other immune cells, PLCH tends to cause a relatively isolated pulmonary involvement as compared to other forms of Langerhans cell (LC) and histiocytic disorders. Increased knowledge of cytokine triggers, dendritic cell trafficking, and clonality of LC populations in PLCH have resulted in an improved understanding of the pathobiology of PLCH. High-resolution CT (HRCT) of the chest has led to better appreciation of nodular and cystic radiographic abnormalities characteristic of the disease. Correlation of HRCT abnormalities with lung pathologic changes has led to an improved comprehension of clinical evolution of PLCH. Current clinical predictors for PLCH outcomes remain poor, although long-term follow-up and radiologic monitoring may help to define disease progression. This review discusses advances in PLCH emphasizing the etiopathologic bases of the disease and currently available radiologic modalities for monitoring disease progression.

Early experience with sirolimus in lung transplant recipients with chronic allograft rejection.

BACKGROUND: Chronic lung allograft rejection, commonly manifest as obliterative bronchiolitis (OB/BOS), hinders long-term survival after lung transplantation (LT). OB/BOS is traditionally treated with augmented immunosuppression and results in short-term stabilization in pulmonary function for most patients. However, peribronchiolar fibroproliferation and airway obstruction usually recur despite initial improvements seen with increases in immunosuppression. In this observational, uncontrolled study, the effect of sirolimus, a novel immunosuppressant with anti-proliferative activity, was assessed in LT patients with OB/BOS. METHODS: Between June 1999 to November 2000, LT recipients with newly diagnosed or progressive OB/BOS received sirolimus in combination with a calcineurin inhibitor (CI) and prednisone. Pulmonary function, laboratory data and adverse effects were monitored for the first 24 weeks of therapy. RESULTS: Sirolimus was utilized in 12 LT recipients with OB/BOS. After drug initiation, 58% of patients required a reduction in CI dose to maintain appropriate CI trough concentrations. Despite CI dose reduction, serum creatinine rose in 75% of patients. Unexpected adverse effects included anemia of chronic disease (100%), edema (50%) and malignancy (17%). For the group, the rate of change in FEV(1) and FEF(25%-75%) was unchanged with sirolimus, but individual responses varied. CONCLUSIONS: For the group, the decline in pulmonary function was not affected by the addition of sirolimus. However, among individuals with rapidly declining pulmonary mechanics, sirolimus resulted in stabilization or improvement in pulmonary function. Significant adverse effects resulted from combination sirolimus plus CI therapy. Until optimal dosing strategies and a more complete adverse effect profile are established, combination therapy should be utilized cautiously in these patients.

Selection of patients with cystic fibrosis for lung transplantation.

Lung transplantation is the most aggressive therapy available for end-stage lung disease from cystic fibrosis (CF). A new predictive survival model of CF uses demographic, FEV1, nutritional, microbiologic, and acute exacerbation data to produce precise estimates of 5-year survival. The model improves the ability to select patients most likely to have survival benefit from transplantation. We discuss potential application of the survival model to four distinct groups of patients with CF: (1) candidates for cadaveric transplantation, (2) potential living donor recipients, (3) patients infected with multiply-resistant organisms such as Burkholderia cepacia, and (4) patients critically ill and dependent on mechanical ventilation. Measuring the impact of transplantation on quality of life remains a difficult task, and further studies are needed to determine whether lung-transplantation-derived survival benefit implies quality-of-life benefit. However, judicious use of the survival model to select patients for transplantation is likely to improve survival outcomes.