Community-acquired Pneumonia Guideline Recommendations-Impact of a Consensus-based Process versus Systematic Reviews.

BACKGROUND: The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) Community-acquired Pneumonia (CAP) guidelines were developed using systematic reviews to inform every recommendation, as suggested by the Institute of Medicine Standards for Trustworthy Guidelines. Recent studies suggest that an expert consensus-based approach, called the Convergence of Opinion on Recommendations and Evidence (CORE) process, can produce recommendations that are concordant with recommendations informed by systematic reviews. PURPOSE: The goal of the study was to evaluate the efficacy of the CORE process had it been used to develop the ATS/IDSA CAP guidelines. METHODS: Experts in CAP who were not on the guideline panel and had no knowledge of the guideline's systematic reviews or recommendations were recruited to participate in the CORE process, addressing the same questions asked by the guideline panel. Recommendations derived from the CORE process were compared to the guideline recommendations. Concordance of the course of action, strength of recommendation, and quality of evidence were determined. RESULTS: Using a threshold of 70% of experts selecting the same course of action to make a recommendation, the CORE process yielded a recommendation for 20 of 31 (65%) questions. Among the 20 CORE-derived recommendations, 19 (95%) were concordant with the guideline recommendations (kappa agreement 0.88, 95% CI .64-1.00). There was less agreement among the strength of recommendations (58%) and quality of evidence (42%). CONCLUSIONS: If the CORE process had been used, 11 systematic reviews would have been necessary rather than 31, with minimal impact on the recommended courses of action.

Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020.

Comprehensive guidelines for treatment of latent tuberculosis infection (LTBI) among persons living in the United States were last published in 2000 (American Thoracic Society. CDC targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-47). Since then, several new regimens have been evaluated in clinical trials. To update previous guidelines, the National Tuberculosis Controllers Association (NTCA) and CDC convened a committee to conduct a systematic literature review and make new recommendations for the most effective and least toxic regimens for treatment of LTBI among persons who live in the United States.The systematic literature review included clinical trials of regimens to treat LTBI. Quality of evidence (high, moderate, low, or very low) from clinical trial comparisons was appraised using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. In addition, a network meta-analysis evaluated regimens that had not been compared directly in clinical trials. The effectiveness outcome was tuberculosis disease; the toxicity outcome was hepatotoxicity. Strong GRADE recommendations required at least moderate evidence of effectiveness and that the desirable consequences outweighed the undesirable consequences in the majority of patients. Conditional GRADE recommendations were made when determination of whether desirable consequences outweighed undesirable consequences was uncertain (e.g., with low-quality evidence).These updated 2020 LTBI treatment guidelines include the NTCA- and CDC-recommended treatment regimens that comprise three preferred rifamycin-based regimens and two alternative monotherapy regimens with daily isoniazid. All recommended treatment regimens are intended for persons infected with Mycobacterium tuberculosis that is presumed to be susceptible to isoniazid or rifampin. These updated guidelines do not apply when evidence is available that the infecting M. tuberculosis strain is resistant to both isoniazid and rifampin; recommendations for treating contacts exposed to multidrug-resistant tuberculosis were published in 2019 (Nahid P, Mase SR Migliori GB, et al. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med 2019;200:e93-e142). The three rifamycin-based preferred regimens are 3 months of once-weekly isoniazid plus rifapentine, 4 months of daily rifampin, or 3 months of daily isoniazid plus rifampin. Prescribing providers or pharmacists who are unfamiliar with rifampin and rifapentine might confuse the two drugs. They are not interchangeable, and caution should be taken to ensure that patients receive the correct medication for the intended regimen. Preference for these rifamycin-based regimens was made on the basis of effectiveness, safety, and high treatment completion rates. The two alternative treatment regimens are daily isoniazid for 6 or 9 months; isoniazid monotherapy is efficacious but has higher toxicity risk and lower treatment completion rates than shorter rifamycin-based regimens.In summary, short-course (3- to 4-month) rifamycin-based treatment regimens are preferred over longer-course (6-9 month) isoniazid monotherapy for treatment of LTBI. These updated guidelines can be used by clinicians, public health officials, policymakers, health care organizations, and other state and local stakeholders who might need to adapt them to fit individual clinical circumstances.

Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children.

BACKGROUND: Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection [LTBI]). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain. METHODS: A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional. CONCLUSIONS: These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.

Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children.

BACKGROUND: Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection [LTBI]). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain. METHODS: A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional. CONCLUSIONS: These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.

Tuberculosis and HIV coinfection.

The human immunodeficiency virus (HIV) pandemic has amplified the global burden of tuberculosis (TB), particularly in sub-Saharan Africa, where 82% of the world's TB/HIV coinfection exists. HIV infection significantly increases the risk of developing and dying from TB and was associated with 350,000 TB deaths in 2010. The diagnosis of HIV-associated TB is often challenging due to atypical clinical and radiographic manifestations, more frequent extrapulmonary disease, and higher rates of smear-negative pulmonary TB. Nucleic acid amplification tests, including the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA), improve our ability to rapidly diagnose both smear-negative and extrapulmonary TB. The standard 6-month anti-TB regimen is usually adequate for HIV coinfected persons, but intermittent dosing in the intensive phase should be avoided because of an increased risk of relapse with acquired rifamycin resistance. The comanagement of HIV and TB is challenging due to drug-drug interactions, overlapping drug toxicities, concerns about adherence, and the immune reconstitution inflammatory syndrome. However, the initiation of antiretroviral therapy (ART) during the course of TB treatment is necessary to improve survival, and the appropriate timing of ART is dependent on the level of immune suppression. Therefore, the management of TB must be well coordinated with HIV resources, prepared to rapidly diagnose HIV, assess immune status, and correctly treat both infections.

Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1-infected men.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1)-infected men are at increased risk for anal cancer. Human papillomavirus (HPV) vaccination may prevent anal cancer caused by vaccine types. METHODS: AIDS Malignancy Consortium Protocol 052 is a single-arm, open-label, multicenter clinical trial to assess the safety and immunogenicity of the quadrivalent HPV (types 6, 11, 16, and 18) vaccine in HIV-1-infected men. Men with high-grade anal intraepithelial neoplasia or anal cancer by history or by screening cytology or histology were excluded. Men received 0.5 mL intramuscularly at entry, week 8, and week 24. The primary end points were seroconversion to vaccine types at week 28, in men who were seronegative and without anal infection with the relevant HPV type at entry, and grade 3 or higher adverse events related to vaccination. RESULTS: There were no grade 3 or greater adverse events attributable to vaccination among the 109 men who received at least 1 vaccine dose. Seroconversion was observed for all 4 types: type 6 (59 [98%] of 60), type 11 (67 [99%] of 68), type 16 (62 [100%] of 62), and type 18 (74 [95%] of 78). No adverse effects on CD4 counts and plasma HIV-1 RNA levels were observed. CONCLUSIONS: The quadrivalent HPV vaccine appears safe and highly immunogenic in HIV-1-infected men. Efficacy studies in HIV-1-infected men are warranted. Clinical trials registration. NCT 00513526.

Hepatic non-Hodgkin's lymphoma with lactic acidosis in HIV-infected patients: report of 2 cases.

We report 2 patients with HIV-associated non-Hodgkin's lymphoma with massive hepatic involvement and lactic acidosis. The lactic acidosis was likely caused by excessive tumor lactate production coupled with impaired hepatic clearance. Although 1 patient died rapidly, the other survived for 7 months after receiving urgent combination chemotherapy. Clinicians should be aware of this condition and the importance of its early diagnosis and treatment.

Prevalence of intestinal microsporidiosis in human immunodeficiency virus-infected patients with diarrhea in major United States cities.

To determine the prevalence of intestinal microsporidiosis in HIV-infected patients, we performed a prospective study of HIV-infected patients with diarrheal illnesses in three US hospitals and examined an observational database of HIV-infected patients in 10 US cities. Among 737 specimens from the three hospitals, results were positive for 11 (prevalence 1.5%); seven (64%) acquired HIV through male-to-male sexual contact, two (18%) through male-to-male sexual contact and injection drug use, and one (9%) through heterosexual contact; one (9%) had an undetermined mode of transmission. Median CD4 count within six months of diagnosis of microsporidiosis was 33 cells/microL (range 3 to 319 cells/microL). For the national observational database (n = 24,098), the overall prevalence of microsporidiosis was 0.16%. Prevalence of microsporidiosis among HIV-infected patients with diarrheal disease is low, and microsporidiosis is most often diagnosed in patients with very low CD4+ cell counts. Testing for microsporidia appears to be indicated, especially for patients with very low CD4+ cell counts.

Prevalence of intestinal microsporidiosis in Human Immunodeficiency Virus-infected patients with diarrhea in major United States cities

To determine the prevalence of intestinal microsporidiosis in HIV-infected patients, we performed a prospective study of HIV-infected patients with diarrheal illnesses in three US hospitals and examined an observational database of HIV-infected patients in 10 US cities. Among 737 specimens from the three hospitals, results were positive for 11 (prevalence 1.5 percent); seven (64 percent) acquired HIV through male-to-male sexual contact, two (18 percent) through male-to-male sexual contact and injection drug use, and one (9 percent) through heterosexual contact; one (9 percent) had an undetermined mode of transmission. Median CD4 count within six months of diagnosis of microsporidiosis was 33 cells/µL (range 3 to 319 cells/µL). For the national observational database (n = 24,098), the overall prevalence of microsporidiosis was 0.16 percent. Prevalence of microsporidiosis among HIV-infected patients with diarrheal disease is low, and microsporidiosis is most often diagnosed in patients with very low CD4+ cell counts. Testing for microsporidia appears to be indicated, especially for patients with very low CD4+ cell counts.

Para determinar a prevalência de microsporidiose intestinal em pacientes infectados pelo HIV foi realizado um estudo prospectivo em três hospitais dos Estados Unidos da América do Norte (EUA) e analizada uma base de dados nacional composta de dados coletados de pacientes infectados pelo HIV em 10 cidades dos EUA. De um total de 737 amostras de fezes de pacientes infectados pelo HIV que apresentavam diarréia, amostras de 11 pacientes (prevalência de 1,5 por cento) foram positivas para microsporídios. Todos os positivos eram do sexo masculino e, entre eles, sete (64 por cento) pacientes adquiriram a infecção pelo HIV através de relação homossexual, dois (18 por cento) através de relação sexual e drogas injetáveis e um (9 por cento) através de contato heterosexual, enquanto que em um paciente o modo de transmissão do HIV não foi determinado. A contagem média de linfócitos CD4 realizada até seis meses do diagnóstico de microsporidiose foi de 33 células/microlitro (3 a 319 células/microlitro). A análise da base de dados nacional (n = 24.098) mostrou uma prevalência de microsporidiose de 0,16 por cento. A prevalência de microsporidiose em pacientes HIV-positivos com diarréia é baixa. Entretando, como a microsporidiose é mais frequentemente diagnosticada em pacientes com contagens de CD4 muito baixas, a indicação de pesquisa de microsporídios é justificada, especialmente para estes pacientes.

An official ATS statement: hepatotoxicity of antituberculosis therapy.

Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop safer treatments for LTBI and for TB disease are presented.

Risk-based human immunodeficiency virus (HIV) testing fails to detect the majority of HIV-infected persons in medical care Settings.

OBJECTIVES: To evaluate opportunities for earlier human immunodeficiency virus (HIV) diagnosis within a comprehensive public health care system. STUDY DESIGN: Retrospective review of newly diagnosed HIV-infected patients between September 2001 and December 2003. RESULTS: One hundred twenty of 348 (34%) newly diagnosed HIV-infected patients had medical care within our system in the 3 years before diagnosis. One hundred five of 120 (88%) patients had at least 1 prior encounter in the emergency department or urgent care center, whereas just 12 (10%) HIV diagnoses were made in these 2 sites. Only 33 (28%) patients previously presented with an HIV clinical indicator condition or sexually transmitted infection. CONCLUSIONS: Although one-third of newly diagnosed HIV-infected patients had clinical visits in the 3 years before diagnosis, few presented with clinical conditions typically associated with HIV infection. Targeted testing based on clinical presentations is not likely to result in substantially earlier HIV diagnosis. Routine screening in high prevalence settings could be more effective.

Factors that complicate the treatment of tuberculosis in HIV-infected patients.

Treatment of tuberculosis (TB) in persons coinfected with HIV has become increasingly complex during the past decade. We describe the factors that complicate anti-TB therapy in a large observational cohort of HIV-infected persons in the United States. Among 367 HIV-infected patients with 372 episodes of culture-confirmed TB, 44.1% had injection drug use as a mode of HIV transmission. Hepatic disease was present at the time of TB diagnosis or during anti-TB therapy for 91 episodes (24.5%). Elevation at least twice the upper limits of normal of aminotransaminases was observed during the first month of anti-TB therapy in 116 (31.2%) of the episodes. The most commonly reported adverse effects occurring during therapy were rash (27.8%), nausea (26.2%), leukopenia or neutropenia (20.2%), diarrhea (19.3%), vomiting (18.5%), and elevated temperature (>101.5 degrees F [38.6 degrees C], 16.9%). Prescription of a rifamycin and a medication known to interact with rifamycins occurred during 270 (72.6%) episodes. Because HIV-infected patients with TB often have underlying complicating conditions, such as hepatic disease, and are treated with medications that may have toxicities and cause drug-drug interactions, we recommend that clinicians pay careful attention to these factors when treating coinfected patients.

Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIV-infected persons: is it different than in HIV-uninfected persons?

BACKGROUND: In 2000, results of a multinational trial demonstrated that a 2-month course of rifampin and pyrazinamide (RZ) was as effective as isoniazid (INH) in reducing tuberculosis in human immunodeficiency virus (HIV)-infected individuals with latent tuberculosis infection (LTBI). After the release of new guidelines, the Centers for Disease Control and Prevention received reports of severe hepatotoxicity associated with the use of the RZ regimen for the treatment of LTBI in the general population. To better understand the occurrence of hepatotoxicity in an HIV-infected population, we conducted a more detailed analysis of the liver function test results obtained in the multinational trial of RZ. METHODS: At study entry, patients were required to have a bilirubin level of < or =2.5 mg/dL and both an aspartate aminotransferase (AST) level and an alkaline phosphatase level of < or =5 times the upper limit of normal. Patients with acute hepatitis were excluded. At months 1 and 2 of the study, all patients had bilirubin and AST levels measured. RESULTS: There was no difference between the RZ and INH groups with regard to AST level or bilirubin level at baseline. An increase in the AST level of > or =40 U/L was associated with the use of INH and older age; and an increase in the bilirubin level of > or =0.5 mg/dL was associated with the use of RZ, male sex, and nonwhite race (P<.05). An absolute AST level of >250 U/L occurred in 12 of 745 INH recipients and in 15 of 721 RZ recipients (P=.56), and an absolute bilirubin level of >2.5 mg/dL occurred in 5 of 743 INH recipients and 13 of 718 RZ recipients (P=.06). CONCLUSIONS: These data demonstrate very little liver injury associated with either INH or RZ in the HIV-infected subjects, leaving unclear the reasons for serious RZ-related liver damage in the general population.

Treatment of latent tuberculosis infection.

Treatment of latent tuberculosis infection (LTBI) is considered an essential component of TB control programs in several industrialized countries and is being used in selected situations in developing countries. In 2000, the American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC) published new recommendations on the diagnosis and treatment of LTBI. These guidelines emphasized targeted tuberculin testing as a means of diagnosis in populations at risk, and expanded the choice of drug regimens to be used for treatment. After the implementation of the recommendations, unexpected and serious hepatic injury with the use of rifampin and pyrazinamide occurred, resulting in a modification of the recommendations. This article reviews the populations who should be considered for targeted tuberculin testing, scientific rationale for the selected treatment regimens, recently completed studies related to rifampin and pyrazinamide, and the prior and updated recommendations for treatment of LTBI.

When to begin highly active antiretroviral therapy? Evidence supporting initiation of therapy at CD4+ lymphocyte counts <350 cells/microL.

We assessed the risk of acquired immunodeficiency syndrome (AIDS)-related opportunistic illness or death among persons first prescribed highly active antiretroviral therapy (HAART) in January 1996 or later in the Centers for Disease Control and Prevention's Adult and Adolescent HIV Spectrum of Disease Project. Patients were included if they were naive to antiretroviral drugs and had no history of AIDS-related opportunistic illness. Risk was assessed as a function of CD4+ lymphocyte count and human immunodeficiency virus load at the time of initiation of HAART in a Cox proportional hazards model. Hazard ratios for AIDS or death were 6.3, 3.5, and 1.7 for persons with baseline CD4+ cell counts of 0-49, 50-199, and 200-349 cells/microL, respectively, compared with the referent (CD4+ cell count > or =500 cells/microL). HAART should not be deferred until the CD4+ cell count reaches <200 cells/microL. The increased hazard associated with CD4+ cell counts of 200-349 cells/microL was modest but supports initiation of HAART at CD4+ cell counts <350 cells/microL, particularly in patients with high virus loads.

HIV transmission risk behavior and its relation to antiretroviral treatment adherence.

BACKGROUND: Rising rates of antiretroviral drug resistance among recently infected persons are evidence of high-risk behavior among persons in HIV care. GOAL: The goal was to determine HIV transmission risk behavior among persons in HIV care and evaluate its association with treatment adherence. STUDY DESIGN: The study involved a structured interview of a random sample of patients in HIV care in an urban public clinic. Participants were categorized by transmission risk: high risk = unprotected anal/vaginal sex and/or needle sharing; low risk = protected anal/vaginal sex, unprotected and/or protected oral sex, no needle sharing; no risk = no sex or needle sharing. RESULTS: Of the 95 participants, 21 (22%) reported high-risk behavior, 36 (38%) reported low-risk behavior, and 38 (40%) reported no transmission risk in the past 3 months. Younger, more educated persons and those with an active substance abuse diagnosis were more likely to have high transmission risk (P < or = 0.05). Patients who engaged in high-risk behavior had equivalent use of antiretroviral therapy (P = 0.80) but lower adherence (P < or = 0.01) and higher median plasma viral loads (P = 0.05). CONCLUSIONS: There was a wide spectrum of transmission risk behavior among persons in HIV care. Persons reporting high-risk behavior were less adherent to antiretroviral therapy, providing a behavioral basis for transmission of drug-resistant HIV.

Infectious diseases detected at autopsy at an urban public hospital, 1996-2001.

Previous studies have demonstrated significant discrepancy rates between clinical and autopsy diagnoses. However, infectious diseases have not received emphasis in these studies. We conducted a study to determine whether the clinical and autopsy diagnoses of infectious diseases are concordant or discrepant and to determine discrepancy rates. Retrospective reviews of the records of 276 patients (adults, 182; fetuses and neonates, 94) who underwent autopsy during the years 1996 through 2001 were performed. Comparison of clinical and autopsy diagnoses was performed using the Goldman classification scheme. Of 182 adult patients, 137 (75.3%) had an infectious disease at autopsy. In 59 (43.1%) of 137 patients, the infectious disease diagnoses were unknown clinically. Of 94 fetuses and neonates, 45 (48%) had an infectious disease at autopsy. In 26 (58%) of 45 patients, the infectious disease diagnoses were unknown before death. There are substantial discrepancies between clinical and autopsy diagnoses of infectious diseases. In adults, acute bronchopneumonia is the infectious disease most often missed clinically; in fetuses and neonates, it is acute chorioamnionitis.