Pneumocystis jirovecii pneumonia in people living with HIV: a review.

Pneumocystis jirovecii is a ubiquitous opportunistic fungus that can cause life-threatening pneumonia. People with HIV (PWH) who have low CD4 counts are one of the populations at the greatest risk of Pneumocystis jirovecii pneumonia (PCP). While guidelines have approached the diagnosis, prophylaxis, and management of PCP, the numerous studies of PCP in PWH are dominated by the 1980s and 1990s. As such, most studies have included younger male populations, despite PCP affecting both sexes and a broad age range. Many studies have been small and observational in nature, with an overall lack of randomized controlled trials. In many jurisdictions, and especially in low- and middle-income countries, the diagnosis can be challenging due to lack of access to advanced and/or invasive diagnostics. Worldwide, most patients will be treated with 21 days of high-dose trimethoprim sulfamethoxazole, although both the dose and the duration are primarily based on historical practice. Whether treatment with a lower dose is as effective and less toxic is gaining interest based on observational studies. Similarly, a 21-day tapering regimen of prednisone is used for patients with more severe disease, yet other doses, other steroids, or shorter durations of treatment with corticosteroids have not been evaluated. Now with the widespread availability of antiretroviral therapy, improved and less invasive PCP diagnostic techniques, and interest in novel treatment strategies, this review consolidates the scientific body of literature on the diagnosis and management of PCP in PWH, as well as identifies areas in need of more study and thoughtfully designed clinical trials.

Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial.

Importance: Extended-spectrum ß-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum ß-lactamase producers. Objectives: To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. Design, Setting, and Participants: Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. Interventions: Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. Main Outcomes and Measures: The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. Results: Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, -∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. Conclusions and relevance: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting. Trial Registration: anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

Determining clinical decision thresholds for HIV-positive patients suspected of having tuberculosis.

Clinical decision thresholds may aid the evaluation of diagnostic tests but have rarely been determined for tuberculosis (TB). We presented clinicians with six web-based clinical scenarios, describing patients with HIV and possible TB at various sites and with a range of clinical stability. The probability of disease was varied randomly and clinicians asked to make treatment decisions; threshold curves and therapeutic thresholds were calculated. Test and treatment thresholds were calculated using Bayes theorem and the diagnostic accuracy of Xpert MTB/RIF. We received 165 replies to our survey. Therapeutic thresholds vary depending on the clinical stability and site of suspected disease. For inpatients, it ranges from 3.4% in unstable to 79.6% in stable patients. For TB meningitis, it ranges from 0% in unstable to 51.4% in stable patients and for pulmonary TB in outpatients it ranges from 29.1% in unstable to 74.5% in the stable patients. Test and treatment thresholds vary in a similar way with test thresholds ranging from 0 in unstable patients with suspected meningitis to 8.2% for stable inpatients. Treatment thresholds vary from 0 for unstable patients with suspected meningitis to 97% for stable inpatients. Therapeutic thresholds for TB can be determined by presenting clinicians with patient scenarios with random probabilities of disease and can be used to calculate test and treatment thresholds using Bayes theorem. Thresholds are lower when patients are more clinically unstable and when the implications of inappropriately withholding therapy are more serious. These results can be used to improve use and evaluation of diagnostic tests.

The Individualised versus the Public Health Approach to Treating Ebola.

Tom Boyles reflects on differing approaches taken for treating patients with Ebola virus disease in low- and high-resource settings.

Blood cultures taken from patients attending emergency departments in South Africa are an important antibiotic stewardship tool, which directly influences patient management.

BACKGROUND: Febrile illness with suspected blood stream infection (BSI) is a common reason for admission to hospital in Africa and blood cultures are therefore an important investigation. Data on the prevalence and causes of community acquired BSI in Africa are scarce and there are no studies from South Africa. There are no validated clinical prediction rules for use of blood cultures in Africa. METHODS: A prospective observational cohort study of patients attending 2 urban emergency departments in Cape Town, South Africa. The decision to take a blood culture was made by the attending clinician and information available at the time of blood draw was collected. Bottles were weighed to measure volume of blood inoculated. RESULTS: 500 blood culture sets were obtained from 489 patients. 39 (7.8 %) were positive for pathogens and 13 (2.6 %) for contaminants. Significant independent predictors of positive cultures were diastolic blood pressure <60 mmHg, pulse >120 bpm, diabetes and a suspected biliary source of infection, but not HIV infection. Positive results influenced patient management in 36 of 38 (95 %) cases with the organism being resistant to the chosen empiric antibiotic in 9 of 38 (24 %). Taking <8 ml of blood was predictive of a negative culture. The best clinical prediction rule had a negative predictive value (NPV) of 92 % which is unlikely to be high enough to be clinically useful. DISCUSSION: Blood cultures taken from patients attending emergency departments in a high HIV prevalent city in South Africa are frequently positive and almost always influence patient management. At least 8 ml of blood should be inoculated into each bottle. CONCLUSION: Blood cultures should be taken from all patients attending EDs in South Africa suspected of having BSI particularly if diabetic, with hypotension, tachycardia or if biliary sepsis is suspected.

The therapeutic threshold in clinical decision-making for TB.

Because TB control is still hampered by the limitations of diagnostic tools, diagnostic uncertainty is common. The decision to offer treatment is based on clinical decision-making. The therapeutic threshold, test threshold and test-treatment threshold can guide in making these decisions. This review summarizes the literature on methods to estimate the therapeutic threshold that have been applied for TB. Only five studies estimated the threshold for the diagnosis of TB. The therapeutic threshold can be estimated by prescriptive methods, based on calculations, and by descriptive methods, deriving the threshold from observing clinical practice. Test and test-treatment thresholds can be calculated using the therapeutic threshold and the characteristics of an available diagnostic test. Estimates of the therapeutic threshold for pulmonary TB from intuitive descriptive approaches (20%-50%) are higher than theoretical prescriptive calculations (2%-3%). In conclusion, estimates of the therapeutic threshold for pulmonary TB depend on the method used. Other methods exist within the field of decision-making that have yet to be implemented or adapted as tools to estimate the TB therapeutic threshold. Because clinical decision-making is a core element of TB management, it is necessary to find a new, clinician-friendly way to unbiasedly estimate context-specific, agreed upon therapeutic thresholds.

Clinical utility of WHO-recommended screening tools and development and validation of novel clinical prediction models for pulmonary tuberculosis screening among outpatients living with HIV: an individual participant data meta-analysis.

BACKGROUND: The World Health Organization (WHO) recommends that outpatient people living with HIV (PLHIV) undergo tuberculosis screening with the WHO four-symptom screen (W4SS) or C-reactive protein (CRP) (5 mg·L-1 cut-off) followed by confirmatory testing if screen positive. We conducted an individual participant data meta-analysis to determine the performance of WHO-recommended screening tools and two newly developed clinical prediction models (CPMs). METHODS: Following a systematic review, we identified studies that recruited adult outpatient PLHIV irrespective of tuberculosis signs and symptoms or with a positive W4SS, evaluated CRP and collected sputum for culture. We used logistic regression to develop an extended CPM (which included CRP and other predictors) and a CRP-only CPM. We used internal-external cross-validation to evaluate performance. RESULTS: We pooled data from eight cohorts (n=4315 participants). The extended CPM had excellent discrimination (C-statistic 0.81); the CRP-only CPM had similar discrimination. The C-statistics for WHO-recommended tools were lower. Both CPMs had equivalent or higher net benefit compared with the WHO-recommended tools. Compared with both CPMs, CRP (5 mg·L-1 cut-off) had equivalent net benefit across a clinically useful range of threshold probabilities, while the W4SS had a lower net benefit. The W4SS would capture 91% of tuberculosis cases and require confirmatory testing for 78% of participants. CRP (5 mg·L-1 cut-off), the extended CPM (4.2% threshold) and the CRP-only CPM (3.6% threshold) would capture similar percentages of cases but reduce confirmatory tests required by 24, 27 and 36%, respectively. CONCLUSIONS: CRP sets the standard for tuberculosis screening among outpatient PLHIV. The choice between using CRP at 5 mg·L-1 cut-off or in a CPM depends on available resources.

Diagnostic options for pulmonary fungal diseases in Africa.

Background: Fungal lung diseases are global in distribution and require specific tests for diagnosis. We report a survey of diagnostic service provision in Africa. Methods: A written questionnaire was followed by a video conference call with each respondent(s) and external validation. To disseminate the questionnaire, a snowball sample was used. Results: Data were successfully collected from 50 of 51 African countries with populations >1 million. The questionnaire was completed by respondents affiliated with 72 health facilities. Of these 72 respondents, 33 (45.8%) reported data for the whole country while others reported data for a specific region/province within their country. In the public sector, chest X-ray and computed tomography are performed often in 49 countries (98%) and occasionally in 37 countries (74%), and less often in the private sector. Bronchoscopy and spirometry were done often in 28 countries (56%) and occasionally in 18 countries (36%) in the tertiary health facilities of public sector. The most conducted laboratory diagnostic assay was fungal culture (often or occasionally) in 29 countries (58%). In collaboration with the Africa Centre for Disease Control and Prevention, regional webinars and individual country profiles provided further data validation. Conclusion: This survey has found a huge disparity of diagnostic test capability across the African continent. Some good examples of good diagnostic provision and very high-quality care were seen, but this was unusual. The unavailability of essential testing such as spirometry was noted, which has a high impact in the diagnosis of lung diseases. It is important for countries to implement tests based on the World Health Organization Essential Diagnostics List.

Guidelines for Diagnosis and Management of Infective Endocarditis in Adults: A WikiGuidelines Group Consensus Statement.

Importance: Practice guidelines often provide recommendations in which the strength of the recommendation is dissociated from the quality of the evidence. Objective: To create a clinical guideline for the diagnosis and management of adult bacterial infective endocarditis (IE) that addresses the gap between the evidence and recommendation strength. Evidence Review: This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In April 2022 a call to new and existing members was released electronically (social media and email) for the next WikiGuidelines topic, and subsequently, topics and questions related to the diagnosis and management of adult bacterial IE were crowdsourced and prioritized by vote. For each topic, PubMed literature searches were conducted including all years and languages. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were crafted discussing the risks and benefits of different approaches. Findings: A total of 51 members from 10 countries reviewed 587 articles and submitted information relevant to 4 sections: establishing the diagnosis of IE (9 questions); multidisciplinary IE teams (1 question); prophylaxis (2 questions); and treatment (5 questions). Of 17 unique questions, a clear recommendation could only be provided for 1 question: 3 randomized clinical trials have established that oral transitional therapy is at least as effective as intravenous (IV)-only therapy for the treatment of IE. Clinical reviews were generated for the remaining questions. Conclusions and Relevance: In this consensus statement that applied the WikiGuideline method for clinical guideline development, oral transitional therapy was at least as effective as IV-only therapy for the treatment of IE. Several randomized clinical trials are underway to inform other areas of practice, and further research is needed.

Outcomes of a model integrating tuberculosis testing into COVID-19 services in South Africa.

The coronavirus disease 2019 (COVID-19) pandemic led to a reordering of healthcare priorities. Health resources were turned to the screening and diagnosis of COVID-19, leading to a reduction in tuberculosis (TB) testing and treatment initiation. An innovative model that integrated TB and COVID-19 services was adopted at primary care facilities in Johannesburg Health District, Gauteng. This short report illustrates results from this model's implementation in two facilities. Patients were screened for COVID-19 at a single point of entry and separated according to screening result. Self-reported human immunodeficiency virus (HIV) status, symptom, and symptom duration were then used to determine TB risk amongst those screening positive for COVID-19. Data from clinical records were extracted. Approximately 9% of patients with a positive symptom screen (n = 76) were sent for a TB test and 84% were sent for a COVID-19 test. Amongst those sent for a TB test, 8% (n = 6) had TB detected, and amongst those sent for a COVID-19 test, 18% (n = 128) were positive. Amongst those with COVID-19-related symptoms, 15% (n = 130) presented with a cough or fever and were known HIV positive and 121 (93%) of these were sent for a COVID-19 test and 31 (24%) were sent for a TB test. Given the HIV prevalence and symptoms in our study, our results show lower-than-expected TB tests conducted.Contribution: Our study documents the outcomes of an innovative way to combine operational workflows for TB and COVID-19. This provides a starting point for countries seeking to integrate TB and COVID-19 screening and testing.

Adherence to a care bundle for Staphylococcus aureus bacteraemia: A retrospective cohort study.

Background: Staphylococcus aureus bacteraemia is associated with high hospital mortality. Improvements in outcome have been described with standardised bundles of care. Objectives: To study the adherence of a standardised bundle of care (BOC) recommendations using a consultation pro forma, for all patients admitted with S. aureus bacteraemia to Groote Schuur Hospital over a year. The study further aimed to describe the 90-day mortality in these patients and to assess for an association between adherence to the bundle of care and outcome. Method: A retrospective audit of all unsolicited infectious disease consultations for patients with S. aureus bacteraemia admitted to Groote Schuur Hospital during 2018. Adherence to recommendations of a standard bundle of care was audited. Results: A total of 86 patients were included in the study: 61 (71%) with hospital-associated infection and 25 (29%) with community-associated infection. Over 80% of adherence to treatment recommendations was achieved regarding antibiotic (including vancomycin) usage, source control and use of echocardiography as required. In-hospital mortality was 16%, while the overall 90-day mortality was 18%, with only age as an independent predictor of mortality. No association between adherence to the bundle of care and outcome was found. Conclusion: Adherence to a simple, structured bundle of care was good when using standardised pro forma as communication tools for advice and a structured antibiotic chart for vancomycin administration. Although adherence was not associated with outcome, the overall mortality for S. aureus bacteraemia was improving in the institution under study. Contribution: Our findings support feasibility and ongoing use of bundles of care for S. aureus bacteraemia in similar settings.

Diagnostic Accuracy of the INSHI Consensus Case Definition for the Diagnosis of Paradoxical Tuberculosis-IRIS.

BACKGROUND: The diagnosis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) relies on characteristic clinical features synthesized as the International Network for the Study of HIV-associated IRIS (INSHI) case definition. There is no confirmatory laboratory test. SETTING: Site B HIV-TB clinic in Khayelitsha, Cape Town, South Africa. METHODS: Using data of participants with HIV-associated tuberculosis starting antiretroviral treatment from a prospective trial evaluating prednisone for TB-IRIS prevention, we applied latent class analysis to model a gold standard for TB-IRIS. The model-predicted probability of TB-IRIS for each participant was used to assess the performance of the INSHI case definition and compare its diagnostic accuracy with several adapted case definitions. RESULTS: Data for this analysis were complete for 217 participants; 41% developed TB-IRIS. Our latent class model included the following parameters: respiratory symptoms; night sweats; INSHI major criteria 1, 2, and 4; maximum C-reactive protein >90 mg/L; maximum heart rate >120/min; maximum temperature >37.7°C; and preantiretroviral therapy CD4 count <50 cells/µL. The model estimated a TB-IRIS incidence of 43% and had optimal goodness of fit (χ2 = 337, P = 1.0). The INSHI case definition displayed a sensitivity of 0.77 and a specificity of 0.86. Replacing all the minor INSHI criteria with objectives measures (C-reactive protein elevation, fever, and/or tachycardia) resulted in a definition with better diagnostic accuracy, with a sensitivity of 0.89 and a specificity of 0.88. CONCLUSION: The INSHI case definition identifies TB-IRIS with reasonable accuracy. Amending the case definition by replacing INSHI minor criteria with objective variables improved sensitivity without loss of specificity.

Consensus study on the health system and patient-related barriers for lung cancer management in South Africa.

BACKGROUND: Lung cancer is the highest incident cancer globally and is associated with significant morbidity and mortality particularly if identified at a late stage. Poor patient outcomes in low- and middle-income countries (LMIC's) might reflect contextual patient and health system constraints at multiple levels, that act as barriers to prevention, disease recognition, diagnosis, and treatment. Lung cancer screening, even for high-risk patients, is not available in the public health sector in South Africa (SA), where the current HIV and tuberculosis (TB) epidemics often take precedence. Yet, there has been no formal assessment of the individual and health-system related barriers that may delay patients with lung cancer from seeking and accessing help within the public health care system and receiving the appropriate and effective diagnosis and treatment. This study aimed to derive consensus from health-system stakeholders in the urban Gauteng Province of SA on the most important challenges faced by the health services and patients in achieving optimum lung cancer management and to identify potential solutions. METHODS: The study was undertaken among 27 participant stakeholders representing clinical managers, clinicians, opinion leaders from the public health sector and non-governmental organisation (NGO) representatives. The study compromised two components: consensus and engagement. For the consensus component, the Delphi Technique was employed with open-ended questions and item ranking from five rounds of consensus-seeking, to achieve collective agreement on the most important challenges faced by patients and the health services in achieving optimal lung cancer management. For the engagement component, the Nominal Group Technique was used to articulate ideas and reach an agreement on the group's recommendations for solution strategies and approaches. RESULTS: Public health sector stakeholders suggested that a lack of knowledge and awareness of lung cancer, and the apparent stigma associated with the disease and its risk factors, as well as symptoms and signs, are critical to treatment delay. Furthermore, delays in up-referral of patients with suspected lung cancer from district health care level were attributed to inadequate knowledge arising from a lack of in-service training of nurses and doctors regarding oncologic symptoms, risk factors, need for further investigation, interpretation of x-rays and available treatments. At a tertiary level, participants suggested that insufficient availability of specialised diagnostic resources (imaging, cytological and pathological services including biomolecular assessment of lung cancer), theatres, cardiothoracic surgeons, and appropriate therapeutic modalities (chemotherapeutic agents and radiation oncology) are the main barriers to the provision of optimal care. It was suggested that a primary prevention programme initiated by the government that involves private-public partnerships may improve lung cancer management nationally. CONCLUSIONS: Considerable barriers to the early identification and treatment of lung cancer exist. Finding solutions to overcome both individual and health-system level obstacles to lung cancer screening and management are vital to facilitate early identification and treatment, and to improve survival. Furthermore, research on inexpensive biomarkers for asymptomatic disease detection, the introduction of diagnostic imaging tools that utilise artificial intelligence to compensate for inadequate human resources and improving clinical integration across all levels of the healthcare system are essential.

Decision-making in the diagnosis of tuberculous meningitis.

Tuberculous meningitis (TBM) is the most devastating form of tuberculosis (TB) but diagnosis is difficult and delays in initiating therapy increase mortality. All currently available tests are imperfect; culture of Mycobacterium tuberculosis from the cerebrospinal fluid (CSF) is considered the most accurate test but is often negative, even when disease is present, and takes too long to be useful for immediate decision making. Rapid tests that are frequently used are conventional Ziehl-Neelsen staining and nucleic acid amplification tests such as Xpert MTB/RIF and Xpert MTB/RIF Ultra. While positive results will often confirm the diagnosis, negative tests frequently provide insufficient evidence to withhold therapy. The conventional diagnostic approach is to determine the probability of TBM using experience and intuition, based on prevalence of TB, history, examination, analysis of basic blood and CSF parameters, imaging, and rapid test results. Treatment decisions may therefore be both variable and inaccurate, depend on the experience of the clinician, and requests for tests may be inappropriate. In this article we discuss the use of Bayes' theorem and the threshold model of decision making as ways to improve testing and treatment decisions in TBM. Bayes' theorem describes the process of converting the pre-test probability of disease to the post-test probability based on test results and the threshold model guides clinicians to make rational test and treatment decisions. We discuss the advantages and limitations of using these methods and suggest that new diagnostic strategies should ultimately be tested in randomised trials.

A Clinical Prediction Score Including Trial of Antibiotics and C-Reactive Protein to Improve the Diagnosis of Tuberculosis in Ambulatory People With HIV.

BACKGROUND: The use of a "trial of antibiotics" as empiric therapy for bacterial pneumonia as a diagnostic tool for tuberculosis in people with HIV (PWH) was removed from World Health Organization (WHO) recommendations in 2007, based on expert opinion. Current guidelines recommend antibiotics only after 2 Xpert MTB/RIF tests (if available), chest x-ray, and clinical assessment have suggested that tuberculosis is unlikely. Despite this, a "trial of antibiotics" remains common in algorithms in low-resource settings, but its value is uncertain. C-reactive protein (CRP), which has been proposed as a "rule-out" test for tuberculosis, may be an objective marker of response to antibiotics. METHODS: We performed a passive case-finding cohort study of adult PWH with a positive WHO symptom screen. All participants received antibiotics at first visit according to the local protocol and were reviewed to ascertain clinical response. Point-of-care CRP was measured at both visits. All patients had sputum tested with Xpert MTB/RIF Ultra (Ultra), and the reference standard was based on 2 sputum mycobacterial cultures. We explored multivariable prediction models (MPM) for tuberculosis based on 1 or 2 visits. RESULTS: Seventy-five of 207 patients (36%) had confirmed tuberculosis. Clinical response to antibiotics after 2 days was a good predictor of disease. An MPM based on 2 visits, without CRP, had acceptable discrimination (c-statistic, 0.75) and calibration (goodness-of-fit P = .07). Addition of CRP after antibiotics improved the model moderately (c-statistic, 0.78). CRP at first visit was not an independent predictor of tuberculosis. CONCLUSIONS: In adult PWH seeking care for symptoms suggestive of tuberculosis, lack of response to antibiotics is a strong predictor of disease and is likely to be useful, particularly when access to Ultra is limited. CRP adds value when measured after antibiotics but is of limited value at first visit.