Porcine-derived pancreatic enzyme replacement therapy may be linked to chronic hepatitis E virus infection in cystic fibrosis lung transplant recipients.

OBJECTIVES: In high-income countries hepatitis E virus (HEV) is an uncommonly diagnosed porcine-derived zoonoses. After identifying disproportionate chronic HEV infections in persons with cystic fibrosis (pwCF) postlung transplant, we sought to understand its epidemiology and potential drivers. DESIGN: All pwCF post-transplant attending our regional CF centre were screened for HEV. HEV prevalence was compared against non-transplanted pwCF and with all persons screened for suspected HEV infection from 2016 to 2022 in Alberta, Canada. Those with chronic HEV infection underwent genomic sequencing and phylogenetic analysis. Owing to their swine derivation, independently sourced pancreatic enzyme replacement therapy (PERT) capsules were screened for HEV. RESULTS: HEV seropositivity was similar between transplanted and non-transplanted pwCF (6/29 (21%) vs 16/83 (19%); p=0.89). Relative to all other Albertans investigated for HEV as a cause of hepatitis (n=115/1079, 10.7%), pwCF had a twofold higher seropositivity relative risk and this was four times higher than the Canadian average. Only three chronic HEV infection cases were identified in all of Alberta, all in CF lung transplant recipients (n=3/29, 10.3%). Phylogenetics confirmed cases were unrelated porcine-derived HEV genotype 3a. Ninety-one per cent of pwCF were taking PERT (median 8760 capsules/person/year). HEV RNA was detected by RT-qPCR in 44% (47/107) of PERT capsules, and sequences clustered with chronic HEV cases. CONCLUSION: PwCF had disproportionate rates of HEV seropositivity, regardless of transplant status. Chronic HEV infection was evident only in CF transplant recipients. HEV may represent a significant risk for pwCF, particularly post-transplant. Studies to assess HEV incidence and prevalence in pwCF, and potential role of PERT are required.

A case of hypercalcemia from Pneumocystis jirovecii in an immunosuppressed non-HIV patient.

BACKGROUND: The prevalence of non-HIV related Pneumocystis jirovecii pneumonia (PJP) is increasing with use of immunosuppressive therapies. There are case reports of solid organ transplant recipients on immunosuppressive therapy presenting with mild hypercalcemia, leading to a diagnosis of PJP. Recent studies have shown efficacy of PJP prophylaxis for patients treated with rituximab with a favourable adverse effect profile. CASE PRESENTATION: A 78-year-old male with a history of PR3-ANCA vasculitis, chronic kidney disease and heart failure with reduced ejection fraction presented to our tertiary care hospital with a two-week history of confusion and non-productive cough. Background immunosuppression with rituximab was completed every six months. The patient was found to have hypercalcemia and new infiltrates and ground glass opacities on cross-sectional imaging. Bronchoscopy was performed that was positive for Pneumocystis jirovecii. He was treated with 21 days of trimethoprim-sulfamethoxazole and prednisone with resolution of symptoms and hypercalcemia. CONCLUSIONS: Herein, we present a novel case of PJP in a non-transplant recipient preceded by hypercalcemia. Our case demonstrates the importance for a high suspicion for PJP in chronically immunosuppressed patients on rituximab presenting with PTH-independent hypercalcemia.

Microbial Epidemiology of the Cystic Fibrosis Airways: Past, Present, and Future.

Progressive obstructive lung disease secondary to chronic airway infection, coupled with impaired host immunity, is the leading cause of morbidity and mortality in cystic fibrosis (CF). Classical pathogens found in the airways of persons with CF (pwCF) include Pseudomonas aeruginosa, Staphylococcus aureus, the Burkholderia cepacia complex, Achromobacter species, and Haemophilus influenzae. While traditional respiratory-tract surveillance culturing has focused on this limited range of pathogens, the use of both comprehensive culture and culture-independent molecular approaches have demonstrated complex highly personalized microbial communities. Loss of bacterial community diversity and richness, counteracted with relative increases in dominant taxa by traditional CF pathogens such as Burkholderia or Pseudomonas, have long been considered the hallmark of disease progression. Acquisition of these classic pathogens is viewed as a harbinger of advanced disease and postulated to be driven in part by recurrent and frequent antibiotic exposure driven by frequent acute pulmonary exacerbations. Recently, CF transmembrane conductance regulator (CFTR) modulators, small molecules designed to potentiate or restore diminished protein levels/function, have been successfully developed and have profoundly influenced disease course. Despite the multitude of clinical benefits, structural lung damage and consequent chronic airway infection persist in pwCF. In this article, we review the microbial epidemiology of pwCF, focus on our evolving understanding of these infections in the era of modulators, and identify future challenges in infection surveillance and clinical management.

Potential Contributions of Anaerobes in Cystic Fibrosis Airways.

Cystic fibrosis (CF) is the most common, lethal genetic disease among the Caucasian population. The leading cause of mortality is recurrent acute exacerbations resulting in chronic airway inflammation and subsequent downward progression of pulmonary function. Traditionally, these periods of clinical deterioration have been associated with several principal pathogens. However, a growing body of literature has demonstrated a polymicrobial lower respiratory community compromised of facultative and obligate anaerobes. Despite the understanding of a complex bacterial milieu in CF patient airways, specific roles of anaerobes in disease progression have not been established. In this paper, we first present a brief review of the anaerobic microorganisms that have been identified within CF lower respiratory airways. Next, we discuss the potential contribution of these organisms to CF disease progression, in part by pathogenic potential and also through synergistic interaction with principal pathogens. Finally, we propose a variety of clinical scenarios in which these anaerobic organisms indirectly facilitate principal CF pathogens by modulating host defense and contribute to treatment failure by antibiotic inactivation. These mechanisms may affect patient clinical outcomes and contribute to further disease progression.

Azithromycin and the microbiota of cystic fibrosis sputum.

BACKGROUND: Azithromycin is commonly prescribed drug for individuals with cystic fibrosis (CF), with demonstrated benefits in reducing lung function decline, exacerbation occurrence and improving nutrition. As azithromycin has antimicrobial activity against components of the uncultured microbiome and increasingly the CF microbiome is implicated in disease pathogenesis - we postulated azithromycin may act through its manipulation. Herein we sought to determine if the CF microbiome changed following azithromycin use and if clinical benefit observed during azithromycin use associated with baseline community structure. RESULTS: Drawing from a prospectively collected biobank we identified patients with sputum samples prior to, during and after initiating azithromycin and determined the composition of the CF microbial community by sequencing the V3-V4 region of the 16S rRNA gene. We categorized patients as responders if their rate of lung function decline improved after azithromycin initiation. Thirty-eight adults comprised our cohort, nine who had not utilized azithromycin in at least 3 years, and 29 who were completely naïve. We did not observe a major impact in the microbial community structure of CF sputum in the 2 years following azithromycin usage in either alpha or beta-diversity metrics. Seventeen patients (45%) were classified as Responders - demonstrating reduced lung function decline after azithromycin. Responders who were naïve to azithromycin had a modest clustering effect distinguishing them from those who were non-Responders, and had communities enriched with several organisms including Stenotrophomonas, but not Pseudomonas. CONCLUSIONS: Azithromycin treatment did not associate with subsequent large changes in the CF microbiome structure. However, we found that baseline community structure associated with subsequent azithromycin response in CF adults.

Pulmonary Cryptococcus infections as a manifestation of idiopathic CD4 lymphocytopenia: case report and literature review.

BACKGROUND: Idiopathic CD4 lymphocytopenia (ICL) is a rare clinical disease with relative CD4 deficiency in the absence of HIV infection. The pathogenicity of ICL is poorly understood with an unclear incidence rate in the general population. Sequelae of ICL includes AIDS-defining infections, which most commonly includes Cryptococcus neoformans. Typically, C. neoformans infections present with CNS involvement but rarely with extra-CNS manifestations. Here, we present a rare case of ICL with exclusively primary pulmonary cryptococcus and a review of the literature. CASE PRESENTATION: A 56-year-old female presented to our tertiary care hospital requiring a right hip open reduction intervention. The patient became febrile during admission, prompting a work-up that included a chest X-ray showing a peripheral pulmonary solitary nodule. Transthoracic biopsy revealed encapsulated yeast forms in keeping with C. neoformans. CD4 counts, repeated at least one month apart, were < 200 cells/mm3, with negative HIV testing. Flow cytometry and genetic testing were completed to elucidate the etiology of the immune deficiency, both of which were unremarkable. She was subsequently treated with 12 months of posaconazole with clinical resolution. CONCLUSIONS: Our patient highlights a rare clinical disease, which a review of literature revealed only five cases in the literature with exclusive pulmonary Cryptococcus in ICL/ This case demonstrates the strong clinical acumen required to properly diagnose and ultimately manage the patient.

Another Whipple's triad? Pericardial, myocardial and valvular disease in an unusual case presentation from a Canadian perspective.

BACKGROUND: Whipple's disease is a clinically relevant multi-system disorder that is often undiagnosed given its elusive nature. We present an atypical case of Whipple's disease involving pan-valvular endocarditis and constrictive pericarditis, requiring cardiac intervention. A literature review was also performed assessing the prevalence of atypical cases of Whipple's disease. CASE PRESENTATION: A previously healthy 56-year-old male presented with a four-year history of congestive heart failure with weight loss and fatigue. Notably, he had absent gastrointestinal symptoms. He went on to develop pan-valvular endocarditis and constrictive pericarditis requiring urgent cardiac surgery. A clinical diagnosis of Whipple's disease was suspected, prompting duodenal biopsy sampling which was unremarkable, Subsequently, Tropheryma whipplei was identified by 16S rDNA PCR on the cardiac valvular tissue. He underwent prolonged antibiotic therapy with recovery of symptoms. CONCLUSIONS: Our study reports the first known case of Whipple's disease involving pan-valvular endocarditis and constrictive pericarditis. A literature review also highlights this presentation of atypical Whipple's with limited gastrointestinal manifestations. Duodenal involvement was limited and the gold standard of biopsy was not contributory. We also highlight the Canadian epidemiology of the disease from 2012 to 2016 with an approximate 4% prevalence rate amongst submitted samples. Routine investigations for Whipple's disease, including duodenal biopsy, in this case may have missed the diagnosis. A high degree of suspicion was critical for diagnosis of unusual manifestations of Whipple's disease.

Epidemiological and genomic characterization of community-acquired Clostridium difficile infections.

BACKGROUND: Clostridium difficile infection (CDI) is a major cause of morbidity and mortality in North America and Europe. The aim of this study was to identify epidemiologically-confirmed cases of community-acquired (CA)-CDI in a large North American urban center and analyze isolates using multiple genetic and phenotypic methods. METHODS: Seventy-eight patients testing positive for C. difficile from outpatient clinics were further investigated by telephone questionnaire. CA-CDI isolates were characterized by antibiotic susceptibility, pulsed-field gel electrophoresis and whole genome sequencing. CA-CDI was defined as testing positive greater than 12 weeks following discharge or no previous hospital admission in conjunction with positive toxin stool testing. RESULTS: 51.3% (40/78) of the patients in this study were found to have bona fide CA-CDI. The majority of patients were female (71.8% vs. 28.2%) with 50-59 years of age being most common (21.8%). Common co-morbidities included ulcerative colitis (1/40; 2.5%), Crohn's disease (3/40; 7.5%), celiac disease (2/40; 5.0%) and irritable bowel syndrome (8/40; 20.0%). However, of 40 patients with CA-CDI, 9 (29.0%) had been hospitalized between 3 and 6 months prior and 31 (77.5%) between 6 and 12 months prior. The hypervirulent North American Pulostype (NAP) 1-like (9/40; 22.5%) strain was the most commonly identified pulsotype. Whole genome sequencing of CA-CDI isolates confirmed that NAP 1-like pulsotypes are commonplace in CA-CDI. From a therapeutic perspective, there was universal susceptibility to metronidazole and vancomycin. CONCLUSIONS: All CA-CDI cases had some history of hospitalization if the definition were modified to health care facility exposure in the last 12 months and is supported by the genomic analysis. This raises the possibility that even CA-CDI may have nosocomial origins.

Group B streptococcus (GBS) is an important pathogen in human disease- but what about in cystic fibrosis?

BACKGROUND: Group B Streptococcus (GBS) is a common commensal capable of causing severe invasive infections. Most GBS infections occur in neonates (often as pneumonia). GBS can also cause infection in adults with diabetes and other immunological impairments but rarely leads to pneumonia in adults. GBS has occasionally been found in the sputum of Cystic Fibrosis (CF) patients, an inherited condition known for progressive lung disease. However, the epidemiology and clinical significance of GBS in CF are not understood. METHODS: We retrospectively reviewed a large single-centre adult CF population with an associated comprehensive, prospectively collected bacterial biobank beginning in 1978. We identified all individuals with GBS isolated from their sputum on at least one occasion. The primary outcome was risk of pulmonary exacerbation (PEx) at the time of the first GBS isolate compared to the preceding visit. Secondary outcomes included determining: prevalence of GBS infection in a CF population, whether GBS infections where transient or persistent, whether GBS strains were shared among patients, change in % predicted FEV1 at the time of GBS isolate compared to the preceding visit, PEx frequency after the first GBS isolate, change in % predicted FEV1 after the first GBS isolate, and complications of GBS infection. RESULTS: GBS was uncommon, infecting 3.5% (11/318) adults within our cohort. Only three individuals developed persistent GBS infection, all lasting > 12 months. There were no shared GBS strains among patients. PEx risk was not increased at initial GBS isolation (RR 5.0, CI 0.69-36.1, p=0.10). In the two years preceding initial GBS isolation compared to the two following years, there was no difference in PEx frequency (median 2, range 0-4 vs 1, range 0 to 5, respectively, p=0.42) or lung function decline, as measured by % predicted FEV1, (median -1.0%, range -19 to 7% vs median -6.0%, range -18 to 22%, p=0.86). There were no invasive GBS infections. CONCLUSION: In adults with CF, GBS is uncommon and is generally a transient colonizer of the lower airways. Despite the presence of structural lung disease and impaired innate immunity in CF, incident GBS infection did not increase PEx risk, PEx frequency, rate of lung function decline, or other adverse clinical outcomes.

Prevalence and impact of Streptococcus pneumoniae in adult cystic fibrosis patients: a retrospective chart review and capsular serotyping study.

BACKGROUND: Cystic fibrosis (CF) is a genetic disease characterized by complex polymicrobial communities within the lower respiratory tract. S. pneumoniae, while a well-defined pathogen in the general population, has rarely been identified in CF. Furthermore, prevalence studies on Pneumococcus in CF have predominantly focused on the infant and pediatric populations, and outcome data is lacking. METHODS: Through a review of our comprehensive clinical and microbiologic database from a single adult CF center in Canada from 1978-2013 we sought to determine the incidence, prevalence, serotype and clinical impact of Pneumococcus in adults with CF. RESULTS: Only fifteen of 318 adult CF patients (5%) were ever found to have transient Pneumococcus colonization, and none developed persistent infection although length of carriage varied. As all isolates were stored, capsular serotyping could be performed using a multiplex PCR panel. Capsular serotyping revealed a varied distribution of several serotypes within these isolates. Lung function testing at time of incident Pneumococcus isolation was compared with values before and after isolation and showed no significant reduction in spirometry values, nor was there an increased need for rescue antibacterial therapy. CONCLUSION: Within our center, incident Pneumococcus infection is neither common, associated with a disproportionate clinical deterioration nor results in chronic infection.

Clinical implications and characterization of Group A Streptoccoccus infections in adults with cystic fibrosis.

BACKGROUND: Persistent airway infection is a hallmark feature of cystic fibrosis (CF). However, increasingly it has been observed that non-classical pathogens may transiently infect CF lower airways. Streptococcus pyogenes (Group A Streptococcus; (GAS)) is an uncommon but potentially dangerous cause of community-acquired pneumonia. Our aim was to determine the incidence, natural history, and clinical impact of GAS infections in CF and phenotypically and genotypically characterize the isolates. METHODS: We retrospectively evaluated the Calgary Adult CF Clinic biobank to identify adults with at least one GAS isolate. Patient demographics, medical and pulmonary exacerbation (PEx) histories were evaluated. The primary outcome was PEx occurrence at incident GAS culture. Secondary outcomes evaluated were changes in lung function and PEx frequency following GAS isolation. Isolates were assessed for extra-cellular virulence factor production capacity and ability to produce quorum sensing (AI-2). Isolates were genotyped using pulse-field gel electrophoresis (PFGE). RESULTS: Fifteen individuals who cultured GAS twenty times were identified. At the time of GAS isolation, 47% (7/15) of subjects experienced a PEx and half of these (4/7) were severe. Individuals were more likely to have a PEx at the time of the index GAS isolate compared to the preceding visit (RR = 6.0, 95% CI 0.82-43.0, p = 0.08), particularly if GAS was the numerically dominant sputum pathogen (RR = 6.5, 95% CI 1.00-43.0, p = 0.009). There were no changes in PEx frequency or rate of lung function decline following GAS. None of the patients developed chronic airways infection, bacteremia, necrotizing pneumonia or empyema. Susceptibility was universal to common anti-Streptococcal antibiotics and anti-Pseudomonal antibiotics commonly used in CF, with the exception of azithromycin. GAS isolates varied in their production of protease, DNase, and AI-2 but these did not correlate with PEx, and none produced elastase, chrondrotin sulfatase or H202. One patient had prolonged carriage with the same isolate and two patients had isolates with similar PFGE patterns. CONCLUSIONS: GAS was an uncommon lower respiratory pathogen of adults with CF. Identification of GAS in sputum was frequently associated with PEx, particularly when numerically dominant. However, transient GAS infection did not result in chronic infection nor appreciably change long-term disease trajectory.

A prescription that addresses the decline of basic science education in medical school.

Over 30 years ago a cry rang out through the proverbial halls of academia; "The clinician scientist is an endangered species." These prophetic words have been reverberated in the ears of every specialty and every general medical organization in deafening tones. Why is the role of the clinician scientist or clinician investigator so important that this phrase has been repeated subsequently in medical and educational journals? Simply put, the clinician scientist bridges the ravine between the ever-growing mountain of scientific knowledge and the demanding patient centered clinical care. Here, we describe the current educational model established by the University of Calgary, Leaders in Medicine Program. Our program seeks to train future physicians and clinician scientists by incorporating training in basic science, translational and clinical research with clinical and medical education in a longitudinal program to students of traditional MD/PhD, MD/MSc or MD/MBA stream as well as interested Doctor of Medicine students.

Guideline-Concordant Therapy for Community-Acquired Pneumonia in the Hospitalized Population: A Systematic Review and Meta-analysis.

Background: A commonly used guideline for community-acquired pneumonia (CAP) is the joint American Thoracic Society and Infectious Diseases Society of America practice guideline. We aimed to investigate the effect of guideline-concordant therapy in the treatment of CAP. Methods: We systematically searched MEDLINE, Embase, CENTRAL, Web of Science, and Scopus from 2007 to December 2023. We screened citations, extracted data, and assessed risk of bias in duplicate. Primary outcomes were mortality rates, intensive care unit (ICU) admission, and length of stay. Secondary outcomes were guideline adherence, readmission, clinical cure rate, and adverse complications. We performed random-effect meta-analysis to estimate the overall effect size and assessed heterogeneity using the I2 statistics. Results: We included 17 observational studies and 82 240 patients, of which 10 studies were comparative and pooled in meta-analysis. Overall guideline adherence rate was 65.2%. Guideline-concordant therapy was associated with a statistically significant reduction in 30-day mortality rate (crude odds ratio [OR], 0.49 [95% confidence interval .34-.70; I2 = 60%]; adjusted OR, 0.49 [.37-.65; I2 = 52%]) and in-hospital mortality rate (crude OR, 0.63 [.43-.92]; I2 = 61%). Due to significant heterogeneity, we could not assess the effect of guideline-concordant therapy on length of stay, ICU admission, readmission, clinical cure rate, and adverse complications. Conclusions: In hospitalized patients with CAP, guideline-concordant therapy was associated with a significant reduction in mortality rate compared with nonconcordant therapy; however, there was limited evidence to support guideline-concordant therapy for other clinical outcomes. Future studies are needed to assess the clinical efficacy and safety of current guideline recommendations.

Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response.

Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen capable of exploiting barriers and immune defects to cause chronic lung infections in conditions such as cystic fibrosis. In these contexts, host immune responses are ineffective at clearing persistent bacterial infection, instead driving a cycle of inflammatory lung damage. This review outlines key components of the host immune response to chronic P. aeruginosa infection within the lung, beginning with initial pathogen recognition, followed by a robust yet maladaptive innate immune response, and an ineffective adaptive immune response that propagates lung damage while permitting bacterial persistence. Untangling the interplay between host immunity and chronic P. aeruginosa infection will allow for the development and refinement of strategies to modulate immune-associated lung damage and potentiate the immune system to combat chronic infection more effectively.