Pneumocystis jirovecii Disease: Basis for the Revised EORTC/MSGERC Invasive Fungal Disease Definitions in Individuals Without Human Immunodeficiency Virus.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) causes substantive morbidity in immunocompromised patients. The EORTC/MSGERC convened an expert group to elaborate consensus definitions for Pneumocystis disease for the purpose of interventional clinical trials and epidemiological studies and evaluation of diagnostic tests. METHODS: Definitions were based on the triad of host factors, clinical-radiologic features, and mycologic tests with categorization into probable and proven Pneumocystis disease, and to be applicable to immunocompromised adults and children without human immunodeficiency virus (HIV). Definitions were formulated and their criteria debated and adjusted after public consultation. The definitions were published within the 2019 update of the EORTC/MSGERC Consensus Definitions of Invasive Fungal Disease. Here we detail the scientific rationale behind the disease definitions. RESULTS: The diagnosis of proven PCP is based on clinical and radiologic criteria plus demonstration of P. jirovecii by microscopy using conventional or immunofluorescence staining in tissue or respiratory tract specimens. Probable PCP is defined by the presence of appropriate host factors and clinical-radiologic criteria, plus amplification of P. jirovecii DNA by quantitative real-time polymerase chain reaction (PCR) in respiratory specimens and/or detection of ß-d-glucan in serum provided that another invasive fungal disease and a false-positive result can be ruled out. Extrapulmonary Pneumocystis disease requires demonstration of the organism in affected tissue by microscopy and, preferably, PCR. CONCLUSIONS: These updated definitions of Pneumocystis diseases should prove applicable in clinical, diagnostic, and epidemiologic research in a broad range of immunocompromised patients without HIV.

Characterizing medication management and the role of pharmacists in caring for people living with cystic fibrosis: A work system approach.

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive genetic disease requiring complex, lifelong medication regimens. Given the importance of medication in CF treatment, pharmacists are vital CF care team members in the care of people living with CF (PwCF). OBJECTIVES: This study aimed to (1) define patients' CF medication experiences and educational needs and (2) investigate the CF outpatient clinic and community pharmacist's role in addressing patient challenges. METHODS: A work system approach informed by the Systems Engineering Initiative for Patient Safety (SEIPS) model was used to characterize knowledge and perception of CF medication regimens, educational modalities, and pharmacist interactions for PwCF. Semistructured interviews were conducted with adults living with CF at a CF center clinic. Data analyses identified relationships between the themes in the data and 4 SEIPS work system domains: tasks, tools and technology, person, and environment. RESULTS: Thirty PwCF interviews highlighted 4 themes regarding health care experiences: (1) medication use experience, (2) medication education needs, (3) disease experience, and (4) pharmacist and pharmacy interactions. Patients reported complex medication regimens leading to challenges with medication adherence, although the benefit of treatment was recognized. Although a high level of disease-state knowledge was identified among the participants, PwCF desired to learn about CF medication benefits and adverse effects through credible sources using multiple modalities. Many reported a benefit of pharmacist involvement in their care. CONCLUSION: Pharmacists are well-positioned to support PwCF in adherence, medication regimen management, and medication education. Opportunities exist for growth in these supportive roles of a pharmacist in both community and outpatient clinic settings.

Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.

BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension.

Portopulmonary hypertension (PoPH) refers to pulmonary arterial hypertension associated with portal hypertension with or without evidence of an underlying liver disease. Despite the potential for curing PoPH with liver transplantation, the presence of moderate or severe PoPH is associated with increased morbidity and mortality and is, therefore, a contraindication to transplantation. Previous studies have predominantly used intravenous epoprostenol for treatment in order to qualify patients for liver transplantation. In this retrospective case series, we describe the clinical course of 11 patients whom we successfully treated (predominantly with oral sildenafil and subcutaneous treprostinil) in order to qualify them for liver transplantation. The mean pulmonary artery pressure significantly improved from 44 to 32.9 mm Hg, and the pulmonary vascular resistance decreased from 431 to 173 dyn second cm(-5) . There were significant improvements in the cardiac output and the transpulmonary gradient with these therapies as well. All 11 patients subsequently received liver transplants with a 0% mortality rate to date; the duration of follow-up ranged from 7 to 60 months. After transplantation, 7 of the 11 patients (64%) were off all pulmonary vasodilators, and only 2 patients required transiently increased doses of prostacyclins. In conclusion, an aggressive approach to the treatment of PoPH with sildenafil and/or treprostinil and subsequent liver transplantation may be curative for PoPH in some patients.

High dose atorvastatin decreases cellular markers of immune activation without affecting HIV-1 RNA levels: results of a double-blind randomized placebo controlled clinical trial.

BACKGROUND: 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) exhibit antiviral activity against human immunodeficiency virus type 1 (HIV-1) in vitro and may modulate the immune response to HIV infection. Studies evaluating the antiviral activity of statins have yielded conflicting results. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial to investigate the effect of atorvastatin on HIV-1 RNA (primary objective) and cellular markers of immune activation (secondary objective). HIV-infected individuals not receiving antiretroviral therapy were randomized to receive either 8 weeks of atorvastatin (80 mg) or placebo daily. After a 4-6 week washout phase, participants switched treatment assignments. The study had 80% power to detect a 0.3 log(10) decrease in HIV-1 RNA level. Expression of CD38 and HLA-DR on CD4(+) and CD8(+) T cells was used to measure immune activation. RESULTS: Of 24 randomized participants, 22 completed the study. Although HIV-1 RNA level was unaffected by the intervention (-0.13 log(10) copies/mL; P = .85), atorvastatin use resulted in reductions in circulating proportions of CD4(+) HLA-DR(+) (-2.5%; P = .02), CD8(+) HLA-DR(+) (-5%; P = .006), and CD8(+) HLA-DR(+) CD38(+) T cells (-3%; P = .03). Reductions in immune activation did not correlate with declines in serum levels of low-density lipoprotein cholesterol. CONCLUSIONS: Short-term use of atorvastatin was associated with modest but statistically significant reductions in the proportion of activated T lymphocytes.

Using A Work System Framework to Investigate Pharmacists' Roles in Cystic Fibrosis Management.

OBJECTIVE: Cystic fibrosis (CF) is a genetic disease that requires complex, lifelong treatment regimens to maintain health and reduce disease progression. The aims of this study were 1) to gain the perspectives of multiple health professions to understand medication and well-being challenges of people living with CF; and 2) to apply the Systems Engineering Initiative for Patient Safety (SEIPS) model to further identify opportunities for pharmacists to support people with CF. METHODS: Health care professionals were recruited from a Cystic Fibrosis Center in the Midwest, to participate in audio-recorded semistructured interviews. Topics examined during the interviews included medication education for patients as well as experiences with outpatient, specialty, and community pharmacists. The themes assessed during the pharmacist interviews included support for people living with CF, preferences in conducting medication education, and pharmacist-specific counseling. Interview transcripts were thematically analyzed into categories to determine major themes. Prevalent codes were categorized into 5 major themes guided by the SEIPS model. Interrater reliability was strong (kappa = 0.94). RESULTS: Five major themes were identified: 1) patient tasks; 2) external environment; 3) organizational conditions; 4) patient medication education; and 5) pharmacists' roles and tasks. Professionals identified the importance of the pharmacist on the multidisciplinary CF care team to enhance patient-centered care for people living with CF. CONCLUSIONS: This study highlights health care professionals' views on the unique skillset that pharmacists add to the care team, including a reduction in medication errors, improved adherence, and overall enhanced patient care.

Difficult to Treat Infections in the Burn Patient.

Background: Unusual infections can lead to complications in more severely burned patients and pose major challenges in treatment. Methods: The published literature of retrospective reviews and case series of the uncommon infections of osteomyelitis, polymicrobial bacteremia, recurrent bacteremia, endocarditis, central nervous system (CNS), and rare fungal infections in burned patients have been summarized and presented. Results: When compared with infections occurring in the non-burn population, these infections in burn patients are more likely to be because of gram-negative bacteria or fungi. Because of hyperdynamic physiology and changes in immunomodulatory response secondary to burns, the clinical presentation of these infections in a patient with major burns differs from that of the non-burn patient and may not be identified until the post-mortem examination. Some of these infections (osteomyelitis, endocarditis, CNS, rare fungal infections) may necessitate surgical intervention in addition to antimicrobial therapy to achieve cure. The presence of the burn and allograft can also present unique challenges for surgical management. Conclusions: These difficult and unusual infections in the severely burned patient necessitate an index of suspicion, appropriate diagnosis, identification and sensitivities of the putative pathogen, effective systemic antimicrobial therapy, and appropriate surgical intervention if recovery is to be achieved.

Long-term Outcomes and Survival in Moderate-severe Portopulmonary Hypertension After Liver Transplant.

BACKGROUND: Portopulmonary hypertension is present in an estimated 5.3% to 8.5% of liver transplant candidates. Untreated, 5-year survival is estimated between 14% and 28%. Moderate-severe disease is a contraindication to liver transplant due to the high perioperative mortality, but patients optimized with pulmonary vasodilator therapy can become eligible for transplant. There is minimal data regarding posttransplant outcomes and ability to discontinue pulmonary vasodilator therapy posttransplant. METHODS: We performed a single-center retrospective analysis to evaluate long-term outcomes of patients with moderate-severe portopulmonary hypertension who were optimized with pulmonary vasodilator therapy, became eligible for liver transplant, and subsequently underwent transplant. We identified 24 patients optimized with pulmonary vasodilator therapy who underwent subsequent liver transplantation and 25 patients who were treated with pulmonary vasodilator therapy alone. RESULTS: In the transplanted cohort, 1-year survival from portopulmonary hypertension diagnosis date: 95.8%, 3-year survival: 90.9%, and 5-year survival: 90.9%. Posttransplant; 1-, 3-, and 5-year survival was 86.9%. Among transplanted patients, 41.6% (10/24) were optimized with nonparenteral therapy. Following transplantation, 100% (14/14) of the surviving patients were able to discontinue parenteral therapy; median time: 7.2 months (interquartile range: 5.1-8.9 mo), while 61.9% (13/21) were able to discontinue pulmonary vasodilator therapy altogether; median time: 13.9 months (interquartile range: 5.1-17.6 mo). CONCLUSIONS: Patients who are optimized with pulmonary vasodilator therapy before liver transplant can have excellent long-term outcomes posttransplant. Oral pulmonary vasodilator therapy can be effective treatment to qualify a patient for transplant, and the majority are able to wean from pulmonary vasodilator therapy entirely posttransplant.

Osteonecrosis in HIV-infected persons: radiographic findings delay clinical diagnosis.

Patients with HIV infection demonstrate an unexpectedly high incidence of bone-related disorders, most notably osteonecrosis. We describe 4 HIV-infected patients with osteonecrosis for whom reliance on plain radiographs for establishing the diagnosis was misleading and resulted in a delay in diagnosis. NOne o four patients had significant previously reported risk factors that are associated with osteonecrosis in HIV-infected patients. Osteonecrosis appears to be yet another complication of HIV disease or tis related therapies that has potential for significant morbidity. This disease typically requires surgical intervention for optimal management. Clinicians should maintain a high index of suspicion for osteonecrosis in this patient population in cases of unexplained bone pain or persistent groin pain. Given the high incidence of osteonecrosis in patients with HIV infection, unexplained osteonecrosis should prompt HIV screening, particularly in the absence of identifiable risk factors.

Unusual case of Pneumocystis jiroveci pneumonia during primary HIV infection.

Symptomatic primary HIV infection occurs in an estimated 50% to 90% of patients. A constellation of symptoms that most closely resembles those of acute infectious mononucleosis characterizes the syndrome. On rare occasions, opportunistic infections present simultaneously with primary HIV infection. We describe a patient who presented with an episode of severe Pneumocystis jiroveci pneumonia during what appeared to be a prolonged primary HIV infection. Serological testing demonstrated the progressive development of reactive bands on serial Western blot determinations. This case highlights how primary HIV infection can produce profound immunosuppression through CD4 lymphocytopenia predisposing patients to opportunistic infection.

HIV PrEP in the Military: Experience at a Tertiary Care Military Medical Center.

Objectives: We evaluated human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) administration at the Walter Reed National Military Medical Center (WRNMMC), which serves a geographic area at high risk of HIV infection. Methods: Medical records were reviewed for all patients initiating PrEP at WRNMMC from November 1, 2013, to March 30, 2016. Demographic, laboratory, clinical, and risk exposure characteristics and outcomes were described. Results: One hundred fifty-nine patients received PrEP; 133 (84%) patients were active duty, 95 (60%) patients were over 28 yr old. The majority were non-Hispanic Whites (n = 87, 55%). The median men who have sex with men (MSM) risk index score was 18.0 (IQR 12.0-22.0); 20 patients scored less than 10. One hundred and thirty-one (82%) patients remained on PrEP through the evaluation period. Patients mainly discontinued PrEP for service-related or toxicity reasons. Incident STIs occurred in 31 (19%) patients. No cases of HIV seroconversion were observed. Conclusions: In this first description of PrEP utilization in a U.S. military health care system, a significant number of patients were non-Hispanic Whites, well-educated, were older, or were otherwise at low risk for HIV acquisition. Further effort is needed to enhance PrEP use among the higher risk young African-American MSM population, and further studies are needed to determine the cost-effectiveness of PrEP in individuals who are not categorized as high risk.

Role of pirfenidone in the management of pulmonary fibrosis.

Pulmonary fibrosis is associated with a number of specific forms of interstitial lung disease (ILD) and can lead to progressive decline in lung function, poor quality of life, and, ultimately, early death. Idiopathic pulmonary fibrosis (IPF), the most common fibrotic ILD, affects up to 1 in 200 elderly individuals and has a median survival that ranges from 3 to 5 years following initial diagnosis. IPF has not been shown to respond to immunomodulatory therapies, but recent trials with novel antifibrotic agents have demonstrated lessening of lung function decline over time. Pirfenidone has been shown to significantly slow decline in forced vital capacity (FVC) over time and prolong progression-free survival, which led to its licensing by the United States Food and Drug Administration (FDA) in 2014 for the treatment of patients with IPF. However, pirfenidone has been associated with significant side effects, and patients treated with pirfenidone must be carefully monitored. We review recent and ongoing clinical research and experience with pirfenidone as a pharmacologic therapy for patients with IPF, provide a suggested approach to incorporate pirfenidone into a treatment algorithm for patients with IPF, and examine the potential of pirfenidone as a treatment for non-IPF forms of ILD accompanied by progressive pulmonary fibrosis.

Symptomatic hyperlactataemia precipitated by the addition of tetracycline to combination antiretroviral therapy.

Hyperlactataemia in the setting of combination antiretroviral therapy for HIV infection occurs on a spectrum ranging from common, asymptomatic laboratory abnormalities to rare, potentially life-threatening lactic acidosis. Some other medications, including the biguanides, tetracycline, and even linezolid, have rarely been reported to cause lactic acidosis. Recently, cases of lactic acidosis or hyperlactataemia have been reported in patients receiving combination antiretroviral therapy that have been precipitated by the addition of other medications-eg, metformin or ribavirin. We report a case of symptomatic hyperlactataemia in a patient on combination antiretroviral therapy that was likely precipitated by the addition of tetracycline and discuss the broader implications of other medications with the potential to cause hyperlactataemia in the setting of combination antiretroviral therapy.

Plague.

In the United States, plague poses a threat to humans from the infected animals in the endemic areas of the Western states. Plague may also be used in the near future as an agent of warfare or terrorism. Although the presentation of bubonic plague may be less of a problem, the septicemic and pneumonic forms present challenges to early diagnosis and prompt treatment. The major threat of plague as an agent of terrorism will probably be through the inhalational route. which could result in many cases of the pneumonic form, requiring early recognition and initiation of appropriate therapy. In a mass-casualty scenario, the clinician should be aware of the potential agents of biowarfare and be familiar with the treatment and prophylaxis recommendations outlined by the CDC. It is also prudent to employ universal precautions and respiratory isolation when treating patients with any unknown exposure. In endemic areas, personal protective measures such as use of insecticides, insect repellants, and prompt prophylaxis in cases of exposure to plague are recommended for reducing the incidence of infection. The author also recommends review of CDC website on bioterrorism (http://www.bt.cdc.gov) to keep informed of plague updates.

Defending against viruses in biowarfare. How to respond to smallpox, encephalitides, hemorrhagic fevers.

The threat of bioterrorism with use of viruses is increasing. Smallpox, encephalitis, and hemorrhagic fevers are the most likely diseases to result from viral deployment. It is critical that all healthcare professionals become familiar with the clinical presentation, diagnosis, management, and prevention of these diseases. Awareness and preparedness are instrumental in reducing viral transmission and improving survival of the victims.