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.

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.

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.

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.

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.

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.