British HIV Association Guidelines on Pulmonary Opportunistic Infections 2024 PDF

Accepted: 11 March 2024 DOI: 10.1111/hiv.13637 SUPPLEMENT ARTICLE British HIV Association guidelines on the management of opportunistic infection in people living with HIV: The clinical management of pulmonary opportunistic infections 2024 D. H. Dockrell 1,2 | R. Breen 3 |...

Accepted: 11 March 2024 DOI: 10.1111/hiv.13637 SUPPLEMENT ARTICLE British HIV Association guidelines on the management of opportunistic infection in people living with HIV: The clinical management of pulmonary opportunistic infections 2024 D. H. Dockrell 1,2 | R. Breen 3 | P. Collini 4 | M. C. I. Lipman 5,6 | R. F. Miller 5,7,8 1 University of Edinburgh, UK 2 Regional Infectious Diseases Unit, NHS Lothian Infection Service, Edinburgh, UK 3 Forth Valley Royal Hospital, Larbert, Scotland, UK 4 University of Sheffield, UK 5 Royal Free London NHS Foundation Trust, UK 6 University College London, UK 7 Institute for Global Health, University College London, UK 8 Central and North West London NHS Foundation Trust, UK Correspondence Email: [email protected] 1 | INTRODUCTION are low, are also considered. Each section contains spe- cific information about the epidemiology, presentation, With improvements in the human immunodeficiency treatment and prophylaxis of opportunistic infections. virus (HIV) testing and treatment cascade and reductions A simple risk assessment allows the clinician to deter- in the prevalence of advanced HIV, the incidence of mine the likelihood that opportunistic infection is the ‘classic’ pulmonary opportunistic infections is lower, and cause of respiratory disease and that further pathogens so these infections are less frequently encountered by may need to be considered. Relevant factors are listed in physicians. In addition, chronic lung diseases such as Box 1. In particular, lack of viral suppression and low chronic obstructive pulmonary disease (COPD) have CD4 counts increase the likelihood of the opportunistic become more common in people living with HIV taking infections seen commonly in the pre-ART era. Injecting antiretroviral therapy (ART). drug use is associated in particular with increased risk of HIV continues to alter the lung environment bacterial pneumonia and of TB. through the impact of persistent viral replication, Treatment is often started prior to laboratory con- inflammation, oxidative stress, alterations in the firmation of diagnosis. The intensity with which microbiome and the modifiable effects of cigarette investigation is undertaken is usually determined by smoking [1, 2]. This means that the relative contribu- the risk assessment, the severity of the illness and tion of common community-acquired respiratory infec- the resources available locally. While empirical ther- tions is greater and these can present with more severe apy (usually directed against bacterial pathogens) disease necessitating different approaches to preven- may be appropriate for individuals with CD4 counts tion compared with individuals without HIV. Accord- >200 cells/mm3, effort should be made to confirm a ingly, as well as pneumonia caused by Pneumocystis specific diagnosis, particularly in those who are more jirovecii (PCP), in these guidelines we consider bacterial severely immunocompromised. pneumonia and influenza. Fungal pneumonias and As evidence of drug toxicities, drug interactions, preg- cytomegalovirus (CMV), the incidence rates of which nancy safety and cost is constantly evolving, any specific HIV Med. 2024;25(Suppl. 2):3–37. wileyonlinelibrary.com/journal/hiv © 2024 British HIV Association. 3  14681293, 2024, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13637 by Readcube (Labtiva Inc.), Wiley Online Library on [15/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 DOCKRELL ET AL. 2 | METHODS Box 1 Risk factors for pulmonary opportunistic infection. The scope, purpose and guideline topics were agreed by the writing group. The search (population, intervention, comparator and outcome [PICO]) questions were set and Low CD4 T cell count an independent systematic literature review carried out. Detectable viral load The Medline, Embase and Cochrane Library databases Non-adherence to ART or non-retention in were searched and the literature reviewed to address each HIV care question. The PICO questions and search strategies are Non-adherence to opportunistic infection pro- outlined in Appendix 1. phylaxis when indicated Further details of the methodology can be found Neutropenia on the BHIVA website (https://www.bhiva.org/file/5d514ec Use of prolonged courses of immune modulators 9b503d/OI-guidelines-methods-general.pdf), including the (e.g. corticosteroids) use of the Grading of Recommendations Assessment, History of injecting drug use Development and Evaluation (GRADE) system to assess Recent discharge from hospital or current and grade the evidence. Good practice points (GPPs) are hospital admission >5 days (for nosocomial recommendations based on the clinical judgment and expe- infections) rience of the working group. GPPs emphasise an area of important clinical practice for which there is not, nor is there likely to be, any significant research evidence, but drug and vaccine recommendations should be considered where the aspect of care is regarded as such sound clinical in association with the updated summary of product practice that healthcare professionals are unlikely to ques- characteristics for that agent and other relevant sources tion it and where the alternative recommendation is of drug information. Drug interactions are common (for deemed unacceptable. information see ). These guidelines are intended to help physicians investigate and manage people living with HIV with a (suspected) pulmonary opportunistic infection. They 3 | SUMMARY OF are primarily intended to assist practice in the UK RECOMMENDATIONS and related healthcare systems. Their recommenda- tions should be viewed as guidance; they are not From Section 5.3 Diagnosis of PCP designed to be restrictive nor should they challenge research into current practice. Similarly, although the PCP should be considered in any individual living aim of the writing group is to provide guidelines to with HIV who develops new-onset, or worsening optimise treatment, care needs to be individualised. of pre-existing, respiratory symptoms, with an The prophylaxis and management of mycobacterial abnormal chest radiograph (GPP) disease, including Mycobacterium tuberculosis and non- We recommend that PCP should be diagnosed by tuberculous mycobacteria (NTM), and COVID-19 in peo- detection of Pneumocystis by immunofluores- ple living with HIV are not considered here. Tuberculosis cence, histochemistry or PCR of induced sputum (TB) is the focus of separate British HIV Association or BAL (Grade 1A). (BHIVA) guidelines and NTM are reviewed in a sepa- We recommend that people clinically suspected rate chapter of the opportunistic infection guidelines. of having PCP with a negative result from spu- Guidance on vaccination to prevent pneumococcal dis- tum induction for Pneumocystis should be ease and influenza can be found in the BHIVA immuni- referred for bronchoscopy and BAL (Grade 1B). sation guidelines. In symptomatic people with a normal chest radio- Guidance on supporting people living with HIV with graph, thoracic high-resolution computed tomogra- opportunistic infections, including pulmonary opportu- phy (CT) should be performed to assess the nistic infections, can be found on the BHIVA website possibility of early PCP (GPP). (https://www.bhiva.org/file/6225e44b53c49/OI-guidelines- We recommend that the detection of P. jirovecii supporting-patients.pdf). by PCR in respiratory samples, in the absence of A full review of these guidelines is due by 2029, with symptoms or signs of respiratory disease, should interim updates only if recommendations need updating not per se trigger initiation of treatment for PCP in line with new data. (Grade 1B).  14681293, 2024, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13637 by Readcube (Labtiva Inc.), Wiley Online Library on [15/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HIV MEDICINE 5 From Section 5.3.4 Blood tests From Section 5.8.2 Preventing a first episode of PCP (pri- mary prophylaxis) We recommend measurement of serum (1–3)-β-D-glucan for people with suspected PCP We recommend that all adults living with HIV (Grade 1B). with a CD4 count 3 months (Grade 2B). In cases with a compatible clinical syndrome and consistent microbiological or CMV PCR findings From Section 9.3 Diagnosis of aspergillosis in the absence of any other pathogens, we recom- mend that anti-CMV treatment should be consid- We recommend that aspergillosis should be diag- ered (Grade 1C). nosed by a combination of clinical, radiological In individuals co-infected with other pathogens, it and microbiological features. A histological is reasonable to start by treating the co-pathogen  14681293, 2024, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13637 by Readcube (Labtiva Inc.), Wiley Online Library on [15/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 DOCKRELL ET AL. first and to treat the CMV only if there is a failure immunocompromised by HIV infection and other condi- of clinical response (Grade 1C). tions, P. jirovecii causes PCP. P. carinii refers to the spe- We recommend ganciclovir as standard therapy cies of Pneumocystis that causes PCP in rats. Primary for CMV pneumonitis (Grade 1C). infection with P. jirovecii occurs in early life and is either asymptomatic or is associated with mild upper respiratory From Section 10.5 Prophylaxis for CMV tract symptoms [8, 9]. Serological studies show that most healthy children, regardless of HIV status, are exposed to We recommend that valganciclovir may be con- Pneumocystis in the first 6 months of life [7–9]. sidered as primary prophylaxis in selected people It is thought that all individuals are repeatedly with persistent immunosuppression and detect- exposed to Pneumocystis throughout life. Animal studies able CMV DNA, or as secondary prophylaxis in in rats and reports of case clusters in immunodeficient/ those with relapse of CMV pneumonia after immunosuppressed humans suggest air-borne transmis- appropriate primary therapy (Grade 1C). sion of Pneumocystis. Before the widespread use of PCP prophylaxis and ART, PCP occurred in up to 80% of people living with 4 | A U D IT A B L E OU T C O M E S HIV and had a mortality of up to 40% despite treat- ment. Most (but not all) cases of PCP occurred in Proportion of people with suspected PCP, for whom patients with CD4 counts 4.7 kPa PCP in people living with HIV who have respiratory (room air) symptoms and are regarded as having a significant clini- SaO2 (room >92% at rest ≤92% at rest cal risk of PCP. Measuring BDG in BAL fluid has a air) OR OR poor positive-predictive value for the diagnosis of PCP, as Falling on exercise Falling on exercise by oropharyngeal and upper respiratory tract colonisation by 90% for diagnosis of PCP. The diagnostic yield nostic value as elevated levels are not specific to is increased if multiple lobes are sampled, or the proce- PCP [7, 14]. dure is performed at the sites of greatest chest radio- Measurement of serum (1–3)-β-D-glucan (BDG), a graphic abnormality. polysaccharide found in the cell wall of many fungi, is Detection of Pneumocystis using immunofluorescence used increasingly as a diagnostic tool for PCP. Serum (fluorescent, dye-labelled monoclonal antibodies) is more BDG levels are significantly higher in people with PCP, sensitive than using histochemical staining. However, compared to those with a fungal pneumonitis due to immunofluorescence is expensive and accurate interpre- aspergillosis or histoplasmosis, whereas non-fungal pneu- tation is dependent on the training of laboratory staff. monias do not usually cause elevations of BDG. A positive serum BDG is suggestive of PCP when inter- preted in the context of a compatible presentation with 5.3.6 | DNA amplification pneumonitis and consistent imaging findings but should be confirmed with a positive result from a specific Amplification of Pneumocystis DNA by PCR has high Pneumocystis-specific assay (e.g. histochemical or molec- sensitivity for Pneumocystis detection in induced sputum ular detection by PCR in BAL fluid or induced sputum; and BAL fluid, with a sensitivity of 97–99% and speci- see below). ficity of 90–94% [19, 20] for PCP. It is now the investiga- A systematic review and meta-analysis of the use of tion of choice where available. A negative result is likely BDG for diagnosis of PCP in people living with HIV and to exclude PCP (negative predictive value ≥99%). The those without HIV (who had other causes of immunosup- utility of molecular detection techniques is limited as pression) showed that the sensitivity among people living Pneumocystis DNA may be found in respiratory samples with HIV was 94% (95% confidence interval [CI] 91–96%) from some immunodeficient patients who are colonised  14681293, 2024, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13637 by Readcube (Labtiva Inc.), Wiley Online Library on [15/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HIV MEDICINE 11 with Pneumocystis, including some without respiratory Untreated, moderate-to-severe PCP typically pro- symptoms, and others who are symptomatic but who gresses to respiratory failure and death over several days. have a confirmed alternative diagnosis. Additionally, In the first few days of treatment, patients with PCP fre- although Pneumocystis DNA has been detected in sponta- quently experience a paradoxical deterioration in clinical neously expectorated sputum, this has not been prospec- status, with progression of infiltrates on chest radiogra- tively evaluated for diagnosis of PCP. Thus, while PCR phy and reductions in oxygenation. may be replacing immunofluorescence in many clinical laboratories as the primary diagnostic test, results must be interpreted in the context of the clinical picture. Real- 5.4.1 | Prognostic factors time (quantitative) PCR cycle threshold cannot currently be used to differentiate PCP from colonisation; however, Several clinical and laboratory factors are associated with detection of Pneumocystis DNA with a low cycle thresh- a poor outcome. These include, at clinical presentation: a old value (i.e. a higher estimated Pneumocystis load) is patients' lack of knowledge of their HIV infection; older strongly suggestive of PCP. age; second (or subsequent) episode of PCP; poor oxygen- The detection of P. jirovecii by PCR in respiratory ation; marked chest radiographic abnormalities; periph- samples, in the absence of symptoms or signs of respira- eral blood leukocytosis; low haemoglobin or serum tory disease, should not per se trigger initiation of treat- albumin levels; elevated serum LDH levels; and preg- ment for PCP. nancy. Other prognostic factors, identified subsequently, Treatment of suspected PCP should not be deferred in include: CMV or a bacterial or fungal co-pathogen in any individual pending results of sputum induction or BAL fluid; elevated serum LDH enzyme levels that do bronchoscopy with lavage as significant clinical deterio- not normalise despite treatment; pulmonary Kaposi's sar- ration may occur. The diagnostic utility of conventional coma; presence of extrapulmonary comorbidity; ICU staining for P. jirovecii in BAL fluid from individuals with admission; high Acute Physiology and Chronic Health HIV is not impaired for up to 14 days after treatment is Evaluation (APACHE) II score at ICU admission; need started [7, 14]. However, the burden of detectable Pneu- for assisted ventilation; and development of pneumotho- mocystis DNA may fall rapidly in response to starting rax (whether breathing spontaneously or with assisted treatment [22, 23]. ventilation) [26–29]. 5.3.7 | Empirical treatment 5.5 | Treatment of PCP Historically, in people living with HIV this approach was 5.5.1 | General measures associated with higher mortality compared to treatment given for laboratory-confirmed PCP [24, 25]. If empirical Supplemental oxygen given either via a tight-fitting face- therapy is started it may adversely affect subsequent mask or using high-flow nasal oxygen should be given to attempts to establish a laboratory-confirmed diagnosis of hypoxaemic patients with PCP in order to maintain PCP if molecular diagnostic techniques are used, or to SaO2 ≥90% or PaO2 ≥8.0 kPa. If supplemental oxygen identify other pathogens that may have been missed and fails to maintain the SaO2 or PaO2 at these levels, respira- which have temporarily responded to trimethoprim- tory support should be escalated. The patient should be sulfamethoxazole (co-trimoxazole). assessed and transferred to the ICU, if appropriate, for consideration of non-invasive ventilation or endotracheal intubation and assisted ventilation with arterial blood gas 5.4 | Clinical course of PCP monitoring through an arterial line [14, 30]. Assessment of the severity of PCP should be done at initial presentation using SaO2 and arterial blood gas results 5.5.2 | First-line regimens for treatment (see Section 5.3.3). A PaO2 of >9.3 kPa (while breathing of PCP room air) indicates mild-to-moderate PCP, and ≤9.3 kPa indicates moderate-to-severe disease; this approximately Recommendations equates to SaO2 >92% and ≤92% respectively. Using the alveolar–arterial oxygen gradient, the severity of PCP can We recommend trimethoprim-sulfamethoxazole be classified as mild-to-moderate if ≤4.7 kPa or moderate- as the first-line treatment of choice for PCP of to-severe if >4.7 kPa (Table 1). any severity (Grade 1A).  14681293, 2024, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13637 by Readcube (Labtiva Inc.), Wiley Online Library on [15/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 12 DOCKRELL ET AL. We suggest that people who develop PCP despite Cutaneous reactions to trimethoprim-sulfamethoxazole taking trimethoprim-sulfamethoxazole as pro- range from a mild morbilliform rash to life-threatening phylaxis can be treated with standard high-dose ‘skin failure’ syndromes (e.g. toxic epidermal necrolysis or trimethoprim-sulfamethoxazole (Grade 2C). Stevens-Johnson syndrome). In some cases, rash and fever We recommend that treatment should be contin- may resolve spontaneously, or respond to conservative ued in people living with HIV for 21 days measures including antihistamines; however, trimethoprim- (Grade 1B). sulfamethoxazole may need to be discontinued. Oral cortico- We recommend that aerosolised pentamidine steroids can be helpful. Caution is required if desensitisation should not be used in the treatment of PCP is attempted in patients who have experienced cutaneous because of its limited efficacy (Grade 1A). reactions to trimethoprim-sulfamethoxazole. Several alternative regimens can be used for treat- Patients with mild-to-moderate PCP may be treated ment of mild-to-moderate PCP (Table 2). A combination with oral therapy as an outpatient with close clinical of trimethoprim with dapsone, both given orally, has monitoring. Patients with moderate-to-severe PCP been shown to be as effective as trimethoprim- (i.e. PaO2