British HIV Association guidelines on the management of opportunistic infection in people living with HIV: The clinical management of pulmonary opportunistic infections 2024

With improvements in the human immunodeficiency virus (HIV) testing and treatment cascade and reductions in the prevalence of advanced HIV, the incidence of 'classic' pulmonary opportunistic infections is lower, and so these infections are less frequently encountered by physicians. In addition, chronic lung diseases such as chronic obstructive pulmonary disease (COPD) have become more common in people living with HIV taking antiretroviral therapy (ART) [1]. HIV continues to alter the lung environment through the impact of persistent viral replication, inflammation, oxidative stress, alterations in the microbiome and the modifiable effects of cigarette smoking [1, 2]. This means that the relative contribution of common community-acquired respiratory infections is greater and these can present with more severe disease necessitating different approaches to prevention compared with individuals without HIV. Accordingly, as well as pneumonia caused by Pneumocystis jirovecii (PCP), in these guidelines we consider bacterial pneumonia and influenza. Fungal pneumonias and cytomegalovirus (CMV), the incidence rates of which are low, are also considered. Each section contains specific information about the epidemiology, presentation, treatment and prophylaxis of opportunistic infections. A simple risk assessment allows the clinician to determine the likelihood that opportunistic infection is the cause of respiratory disease and that further pathogens may need to be considered. Relevant factors are listed in Box 1. In particular, lack of viral suppression and low CD4 counts increase the likelihood of the opportunistic infections seen commonly in the pre-ART era. Injecting drug use is associated in particular with increased risk of bacterial pneumonia and of TB. Low CD4 T cell count Detectable viral load Non-adherence to ART or non-retention in HIV care Non-adherence to opportunistic infection prophylaxis when indicated Neutropenia Use of prolonged courses of immune modulators (e.g. corticosteroids) History of injecting drug use Recent discharge from hospital or current hospital admission >5 days (for nosocomial infections) Treatment is often started prior to laboratory confirmation of diagnosis. The intensity with which investigation is undertaken is usually determined by the risk assessment, the severity of the illness and the resources available locally. While empirical therapy (usually directed against bacterial pathogens) may be appropriate for individuals with CD4 counts >200 cells/mm3, effort should be made to confirm a specific diagnosis, particularly in those who are more severely immunocompromised. As evidence of drug toxicities, drug interactions, pregnancy safety and cost is constantly evolving, any specific drug and vaccine recommendations should be considered in association with the updated summary of product characteristics for that agent and other relevant sources of drug information. Drug interactions are common (for information see [3]). These guidelines are intended to help physicians investigate and manage people living with HIV with a (suspected) pulmonary opportunistic infection. They are primarily intended to assist practice in the UK and related healthcare systems. Their recommendations should be viewed as guidance; they are not designed to be restrictive nor should they challenge research into current practice. Similarly, although the aim of the writing group is to provide guidelines to optimise treatment, care needs to be individualised. The prophylaxis and management of mycobacterial disease, including Mycobacterium tuberculosis and non-tuberculous mycobacteria (NTM), and COVID-19 in people living with HIV are not considered here. Tuberculosis (TB) is the focus of separate British HIV Association (BHIVA) guidelines [4] and NTM are reviewed in a separate chapter of the opportunistic infection guidelines [5]. Guidance on vaccination to prevent pneumococcal disease and influenza can be found in the BHIVA immunisation guidelines [6]. Guidance on supporting people living with HIV with opportunistic infections, including pulmonary opportunistic infections, can be found on the BHIVA website (https://www.bhiva.org/file/6225e44b53c49/OI-guidelines-supporting-patients.pdf). A full review of these guidelines is due by 2029, with interim updates only if recommendations need updating in line with new data. The scope, purpose and guideline topics were agreed by the writing group. The search (population, intervention, comparator and outcome [PICO]) questions were set and an independent systematic literature review carried out. The Medline, Embase and Cochrane Library databases were searched and the literature reviewed to address each question. The PICO questions and search strategies are outlined in Appendix 1. Further details of the methodology can be found on the BHIVA website (https://www.bhiva.org/file/5d514ec9b503d/OI-guidelines-methods-general.pdf), including the use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to assess and grade the evidence. Good practice points (GPPs) are recommendations based on the clinical judgment and experience 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 where the aspect of care is regarded as such sound clinical practice that healthcare professionals are unlikely to question it and where the alternative recommendation is deemed unacceptable. Pneumocystis is a host-specific opportunistic pathogen found in humans and in many mammals [7]. In humans immunocompromised by HIV infection and other conditions, P. jirovecii causes PCP. P. carinii refers to the species of Pneumocystis that causes PCP in rats. Primary infection with P. jirovecii occurs in early life and is either asymptomatic or is associated with mild upper respiratory tract symptoms [8, 9]. Serological studies show that most healthy children, regardless of HIV status, are exposed to Pneumocystis in the first 6 months of life [7-9]. It is thought that all individuals are repeatedly exposed to Pneumocystis throughout life. Animal studies in rats and reports of case clusters in immunodeficient/ immunosuppressed humans suggest air-borne transmission of Pneumocystis [7]. Before the widespread use of PCP prophylaxis and ART, PCP occurred in up to 80% of people living with HIV and had a mortality of up to 40% despite treatment [10]. Most (but not all) cases of PCP occurred in patients with CD4 counts <200 cells/mm3. In the pre-ART era, other factors were associated with risk of PCP including a previous episode of PCP, unintentional significant weight loss, oropharyngeal candidiasis, CD4 percentage <14% and high plasma HIV RNA levels [11, 12]. Although less often applicable in contemporary care, these factors may still be applicable to some people who are diagnosed late or those not retained in care. The incidence of PCP has fallen markedly with widespread availability and use of PCP prophylaxis and ART. PCP now occurs largely in those who are unaware of their HIV status, who lack access to medical care or who are not taking ART and/or PCP prophylaxis consistently [13]. However, it is important to note that while PCP risk increases with falling CD4 count it can still occur at CD4 counts >200 cells/mm3. The presenting symptoms of PCP [14] are non-specific and have a broad infectious and non-infectious differential diagnosis. The most common presentation is with a subacute onset of progressive breathlessness on exertion, fever and non-productive cough. An inability to inhale deeply, that is not due to chest pain, is frequently reported [14]. Sputum production is rare; haemoptysis is not a feature. Typically, symptoms worsen over 3–8 weeks. In contrast to the presentation of PCP in people without HIV, a rapidly progressive course with deterioration over 7–10 days is rare in people living with HIV [15]. Clinical examination in mild cases of PCP may be normal. With more severe disease, signs of respiratory distress may be observed, with increased respiratory rate and heart rate, use of accessory muscles of respiration and central cyanosis [14]. Examination of the chest is usually normal; in some cases, auscultation reveals fine end-inspiratory crackles. Arterial oxygen saturation (SaO2) may be reduced, or normal in early disease. In people with suspected PCP but minimal symptoms, oxygen desaturation on exercise may indicate significant disease; although not specific for PCP, it is a characteristic feature. Stigmata of immunodeficiency may also be observed, including seborrhoeic dermatitis, extra-genital molluscum contagiosum, cutaneous Kaposi's sarcoma, oral candidiasis and oral hairy leucoplakia [14]. Extra-pulmonary Pneumocystis infection is rare, though can occur in any organ and is associated with advanced HIV infection (low CD4 counts) and use of nebulised pentamidine prophylaxis for PCP [14]. Radiographic abnormalities include bilateral diffuse interstitial infiltrates extending out from the perihilar region, often with subpleural sparing [7, 14]. The chest radiograph may be normal initially, despite progressive respiratory symptoms. More confluent alveolar shadowing ('white out'), with relative sparing of the costophrenic angles and apices, is observed in individuals with rapidly progressive disease or those who present late in the course of their illness [14]. These chest radiograph abnormalities are sensitive for detecting PCP but are non-specific as they are also seen in viral, bacterial, mycobacterial and other fungal infections, as well as in non-infectious conditions including pulmonary Kaposi's sarcoma and non-specific interstitial pneumonitis. Atypical appearances include mediastinal lymphadenopathy, pleural effusion, unilateral infiltrates, cystic air spaces, pneumatoceles, nodules and pneumothoraces [7, 14]. Thoracic high-resolution CT is useful in evaluating immunodeficient people with a pneumonitis and a normal or equivocal chest radiograph. Ground glass opacities, often 'geographic', are typical of PCP but are also observed in pneumonitis caused by viral (e.g. CMV and community-acquired respiratory viruses such as influenza A virus) or fungal (e.g. Talaromyces marneffei) pathogens, as well as in hypersensitivity pneumonitis, occult diffuse alveolar haemorrhage, pulmonary fibrosis and pulmonary oedema [7, 14]. Thoracic high-resolution CT also identifies people with normal lung parenchymal appearances, who are unlikely to have PCP and who can be monitored without starting anti-Pneumocystis treatment. In individuals with PCP, reduced blood oxygenation is a frequent finding [7, 14]. The degree of hypoxaemia (measured as arterial partial pressure of oxygen [PaO2]) or an increased alveolar–arterial oxygen gradient, or low SaO2 measured with a transcutaneous oximeter, is used to evaluate disease severity (Table 1) and monitor progression. Although SaO2 does not always accurately reflect PaO2, there are considerable practical advantages in using this as a first measure of oxygenation rather than an arterial blood gas result. Indications for arterial blood gas measurement include sepsis syndrome, widespread changes on chest imaging and SaO2 <95% at rest while breathing air as well as for individuals who are being considered for referral to the intensive care unit (ICU). Blood gas tensions (room air) PaO2 >9.3 kPa, DA–aO2 ≤4.7 kPa PaO2 ≤9.3 kPa DA–aO2 >4.7 kPa SaO2 (room air) >92% at rest OR Falling on exercise by <3% ≤92% at rest OR Falling on exercise by ≥3% Normal or minor diffuse interstitial shadowing Elevated serum lactic dehydrogenase (LDH) levels, reflecting lung injury, occur frequently but not universally in PCP [16]. Measurement of LDH has limited diagnostic value as elevated levels are not specific to PCP [7, 14]. Measurement of serum (1–3)-β-d-glucan (BDG), a polysaccharide found in the cell wall of many fungi, is used increasingly as a diagnostic tool for PCP. Serum BDG levels are significantly higher in people with PCP, compared to those with a fungal pneumonitis due to aspergillosis or histoplasmosis, whereas non-fungal pneumonias do not usually cause elevations of BDG [17]. A positive serum BDG is suggestive of PCP when interpreted in the context of a compatible presentation with pneumonitis and consistent imaging findings but should be confirmed with a positive result from a specific Pneumocystis-specific assay (e.g. histochemical or molecular detection by PCR in BAL fluid or induced sputum; see below). A systematic review and meta-analysis of the use of BDG for diagnosis of PCP in people living with HIV and those without HIV (who had other causes of immunosuppression) showed that the sensitivity among people living with HIV was 94% (95% confidence interval [CI] 91–96%) and the specificity was 83% (95% CI 69–92%). Among those with other causes of immunosuppression the sensitivity was 86% (95% CI 78–91%), and the specificity was 83% (95% CI 72–90%). A negative BDG result was only associated with a low post-test probability of PCP (5%) when the pre-test probability was low to intermediate (50%). Among individuals with a higher likelihood of PCP, the pooled sensitivity of BDG is insufficient to exclude infection. Based on these findings, a negative BDG result by itself does not 'rule out' a diagnosis of PCP in people living with HIV who have respiratory symptoms and are regarded as having a significant clinical risk of PCP [18]. Measuring BDG in BAL fluid has a poor positive-predictive value for the diagnosis of PCP, as oropharyngeal and upper respiratory tract colonisation with Candida, common in people at risk of PCP, may also give a positive result. As Pneumocystis is rarely identified in spontaneously expectorated sputum [7, 14], this type of sample should not be used to diagnose or exclude PCP. Microscopy of induced sputum, generated by inhalation of aerosolised hypertonic saline, has a moderate-to-high diagnostic yield, ranging from <50% to >90% [7, 14]. People with clinically suspected PCP and a negative result from sputum induction for Pneumocystis should be referred for bronchoscopy and BAL. Fibre optic bronchoscopy with BAL has a diagnostic yield of >90% for diagnosis of PCP. The diagnostic yield is increased if multiple lobes are sampled, or the procedure is performed at the sites of greatest chest radiographic abnormality [14]. Detection of Pneumocystis using immunofluorescence (fluorescent, dye-labelled monoclonal antibodies) is more sensitive than using histochemical staining. However, immunofluorescence is expensive and accurate interpretation is dependent on the training of laboratory staff. Amplification of Pneumocystis DNA by PCR has high sensitivity for Pneumocystis detection in induced sputum and BAL fluid, with a sensitivity of 97–99% and specificity of 90–94% [19, 20] for PCP. It is now the investigation of choice where available. A negative result is likely to exclude PCP (negative predictive value ≥99%). The utility of molecular detection techniques is limited as Pneumocystis DNA may be found in respiratory samples from some immunodeficient patients who are colonised with Pneumocystis, including some without respiratory symptoms, and others who are symptomatic but who have a confirmed alternative diagnosis [21]. Additionally, although Pneumocystis DNA has been detected in spontaneously expectorated sputum, this has not been prospectively evaluated for diagnosis of PCP. Thus, while PCR 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-time (quantitative) PCR cycle threshold cannot currently be used to differentiate PCP from colonisation; however, detection of Pneumocystis DNA with a low cycle threshold value (i.e. a higher estimated Pneumocystis load) is strongly suggestive of PCP. The detection of P. jirovecii by PCR in respiratory samples, in the absence of symptoms or signs of respiratory disease, should not per se trigger initiation of treatment for PCP. Treatment of suspected PCP should not be deferred in any individual pending results of sputum induction or bronchoscopy with lavage as significant clinical deterioration may occur. The diagnostic utility of conventional staining for P. jirovecii in BAL fluid from individuals with HIV is not impaired for up to 14 days after treatment is started [7, 14]. However, the burden of detectable Pneumocystis DNA may fall rapidly in response to starting treatment [22, 23]. Historically, in people living with HIV this approach was associated with higher mortality compared to treatment given for laboratory-confirmed PCP [24, 25]. If empirical therapy is started it may adversely affect subsequent attempts to establish a laboratory-confirmed diagnosis of PCP if molecular diagnostic techniques are used, or to identify other pathogens that may have been missed and which have temporarily responded to trimethoprim-sulfamethoxazole (co-trimoxazole). Assessment of the severity of PCP should be done at initial presentation using SaO2 and arterial blood gas results (see Section 5.3.3). A PaO2 of >9.3 kPa (while breathing room air) indicates mild-to-moderate PCP, and ≤9.3 kPa indicates moderate-to-severe disease; this approximately equates to SaO2 >92% and ≤92% respectively. Using the alveolar–arterial oxygen gradient, the severity of PCP can be classified as mild-to-moderate if ≤4.7 kPa or moderate-to-severe if >4.7 kPa (Table 1). Untreated, moderate-to-severe PCP typically progresses to respiratory failure and death over several days. In the first few days of treatment, patients with PCP frequently experience a paradoxical deterioration in clinical status, with progression of infiltrates on chest radiography and reductions in oxygenation. Several clinical and laboratory factors are associated with a poor outcome. These include, at clinical presentation: a patients' lack of knowledge of their HIV infection; older age; second (or subsequent) episode of PCP; poor oxygenation; marked chest radiographic abnormalities; peripheral blood leukocytosis; low haemoglobin or serum albumin levels; elevated serum LDH levels; and pregnancy. Other prognostic factors, identified subsequently, include: CMV or a bacterial or fungal co-pathogen in BAL fluid; elevated serum LDH enzyme levels that do not normalise despite treatment; pulmonary Kaposi's sarcoma; presence of extrapulmonary comorbidity; ICU admission; high Acute Physiology and Chronic Health Evaluation (APACHE) II score at ICU admission; need for assisted ventilation; and development of pneumothorax (whether breathing spontaneously or with assisted ventilation) [26-29]. Supplemental oxygen given either via a tight-fitting facemask or using high-flow nasal oxygen should be given to hypoxaemic patients with PCP in order to maintain SaO2 ≥90% or PaO2 ≥8.0 kPa. If supplemental oxygen fails to maintain the SaO2 or PaO2 at these levels, respiratory support should be escalated. The patient should be assessed and transferred to the ICU, if appropriate, for consideration of non-invasive ventilation or endotracheal intubation and assisted ventilation with arterial blood gas monitoring through an arterial line [14, 30]. Patients with mild-to-moderate PCP may be treated with oral therapy as an outpatient with close clinical monitoring. Patients with moderate-to-severe PCP (i.e. PaO2 <9.3 kPa at rest breathing room air) should receive intravenous therapy in hospital and can later be switched to oral therapy to complete treatment. Adjunctive corticosteroids are also given to those with moderate-to-severe PCP [31-34]. Benefit has been demonstrated only if corticosteroids are started within 72 hours of initiating specific anti-Pneumocystis therapy [31]. Trimethoprim-sulfamethoxazole is the treatment of choice for PCP of any severity [7, 14, 35, 36] (Table 2). Oral trimethoprim-sulfamethoxazolea (15–20 mg trimethoprim and 75–100 mg/kg/day sulfamethoxazole) in three divided doses, rounded to the nearest 480 mg tablet OR Oral trimethoprim-sulfamethoxazole: two double-strength (960 mg) tablets tds Intravenous trimethoprim-sulfamethoxazolea (15–20 mg trimethoprim and 75–100 mg/kg/day sulfamethoxazole) in three or four divided dosesb,c Oral clindamycin 450 mg qds or 600 mg tds and oral primaquinea 30 mgd od OR Oral dapsonea 100 mg od and oral trimethoprim 15 mg/kg/day in three divided doses, rounded to the nearest 50 mg tablet OR Oral atovaquone 750 mg bd Intravenous clindamycin 600 mg qds or 900 mg tds and oral primaquinea 30 mgd od OR Oral clindamycin 450 mg qds or 600 mg tds and oral primaquinea 30 mgd od OR Intravenous pentamidine isetionate 4 mg/kg od infused over 60 minutes Start oral prednisolone (as soon as possible and within 72 hours of starting treatment for PCP) 40 mg bd: days 1–5 40 mg od: days 6–10 20 mg od: days 11–21 OR Intravenous methylprednisolone at 75% of the prednisolone dose (as above) Mutations in the dihydropteroate synthase (DHPS) gene that confer sulfa resistance in other microorganisms have been described in Pneumocystis [37, 38], but their clinical significance is unclear [38]. People who develop PCP despite taking trimethoprim-sulfamethoxazole as prophylaxis can be treated with standard high-dose trimethoprim-sulfamethoxazole. As with all anti-Pneumocystis drug regimens in people living with HIV, treatment should be continued for 21 days. Adverse reactions to trimethoprim-sulfamethoxazole are common at these high doses and usually begin between 7 and 10 days of starting therapy and may require discontinuation of the drug in up to 50% of cases [7, 14]. Common adverse drug reactions include fever, rash, cytopenias, hyperkalaemia and biochemical hepatitis. Most of these reactions appear to be caused by sulfamethoxazole, but the precise mechanisms are poorly understood. Trimethoprim competitively inhibits potassium excretion in the distal nephron in the same way as the potassium-sparing diuretic amiloride, and this is thought to be the cause of hyperkalaemia. Acute kidney injury and hyperkalaemia associated with trimethoprim-sulfamethoxazole are dose dependent [39]. Adverse effects from trimethoprim-sulfamethoxazole are not reduced in frequency or prevented by the use of N-acetyl cysteine or folinic acid. Additionally, folinic acid may reduce the efficacy of trimethoprim-sulfamethoxazole [40], so should not be co-administered with trimethoprim-sulfamethoxazole. Cutaneous reactions to trimethoprim-sulfamethoxazole range from a mild morbilliform rash to life-threatening 'skin failure' syndromes (e.g. toxic epidermal necrolysis or Stevens-Johnson syndrome). In some cases, rash and fever may resolve spontaneously, or respond to conservative measures including antihistamines; however, trimethoprim-sulfamethoxazole may need to be discontinued. Oral corticosteroids can be helpful. Caution is required if desensitisation is attempted in patients who have experienced cutaneous reactions to trimethoprim-sulfamethoxazole. Several alternative regimens can be used for treatment of mild-to-moderate PCP (Table 2). A combination of trimethoprim with dapsone, both given orally, has been shown to be as effective as trimethoprim-sulfamethoxazole in patients with mild-to-moderate PCP, and is less toxic [35, 41]. Major adverse reactions to dapsone include fever, nausea and vomiting, rash and methaemoglobinaemia. Haemolysis can rarely occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency after dapsone treatment, although this is not a contraindication to the use of dapsone in PCP as benefits are likely to outweigh risks significantly. Caution is advised in administering dapsone to patients who have experienced adverse reactions to sulfonamides or the HIV protease inhibitor darunavir, due to similarities in the sulfa moiety. Several studies have shown that the combination of clindamycin and primaquine has comparable efficacy and toxicity to trimethoprim-sulfamethoxazole [35, 42, 43] and trimethoprim with dapsone [35] in the treatment of mild-to-moderate PCP. Treatment may also be initiated with intravenous clindamycin in those with moderate-to-severe PCP, and then administered orally following clinical recovery. Adverse drug reactions to primaquine are less common when 15 mg, rather than 30 mg, once daily is used and include diarrhoea, fever, methaemoglobinaemia, neutropenia and rash. Atovaquone is less effective than trimethoprim-sulfamethoxazole and shows equivalent efficacy to intravenous pentamidine in the treatment of mild-to-moderate PCP, but it is better tolerated [36, 44]. Adverse reactions to atovaquone include fever, gastrointestinal symptoms, abnormal liver function tests and rash. For moderate-to-severe PCP, based on a retrospective study and a systematic review, the combination of clindamycin and primaquine is the preferred alternative regimen to trimethoprim-sulfamethoxazole. The combination of clindamycin and primaquine was shown to be superior to pentamidine as 'salvage' treatment of PCP in patients not responding to first-line treatment [45, 46]. Clostridioides difficile infections are particularly associated with the use of clindamycin, and clinicians should be alert to the development of diarrhoea in patients receiving the drug. Intravenous pentamidine is almost as effective as trimethoprim-sulfamethoxazole for the treatment of PCP but is less often used due to significant toxicity [45, 47]. Adverse effects from intravenous pentamidine include acute kidney injury, cardiac arrhythmias (e.g. torsades de pointes and ventricular tachycardia), hypotension, pancreatitis, hypoglycaemia and hyperglycaemia, hyperkalaemia, hypomagnesaemia and hypocalcaemia. The mechanism of pentamidine-induced hyperkalaemia is similar to that caused by trimethoprim. Acute kidney injury and hypoglycaemia are associated with high serum pentamidine levels, duration of treatment and cumulative drug dose. Aerosolised pentamidine has no role in the treatment of PCP because of its limited efficacy [48, 49]. Caspofungin is an effective treatment for Aspergillus and Candida infections. Several case series and additional retrospective observational studies have shown that caspofungin may be effective as salvage therapy either as monotherapy or in combination with other agents in patients with PCP who are not responding to, or who are intolerant of, first-line therapy [50]. There have been no prospective evaluations of caspofungin monotherapy compared to trimethoprim-sulfamethoxazole, clindamycin with primaquine, or other regimens as first-line therapy for PCP. Several studies have shown that administration of corticosteroids during the first 72 hours of treatment of HIV-associated PCP can prevent or reduce the decline in oxygenation that is observed in some patients, as well as improving survival [31]. Adjunctive corticosteroids are widely used by clinicians. A systematic review and a more recent meta-analysis support the use of corticosteroids both in reducing mortality and in the need for assisted ventilation [32, 33]. Patients with laboratory proven or clinically suspected PCP and PaO2 <9.3 kPa, or SaO2 ≤92% at rest or falling by ≥3% on exercise, should receive adjunctive corticosteroids as soon as is possible and within 72 hours of starting anti-Pneumocystis treatment for maximal benefit. Treatment failure is defined as a lack of improvement or worsening of oxygenation with/without worsening of chest radiographic appearances between days 4 and 8 of anti-Pneumocystis treatment. Failure attributed to treatment occurs in approximately 10% of patients with mild-to-moderate PCP [45, 46]. There are no robust clinical data on the best management of PCP treatment failure to inform clinicians. Clinicians should wait at least 4 days before switching therapy because of a lack of clinical improvement. An early and reversible clinical deterioration frequently occurs within the first 3 to 5 days of PCP treatment, as discussed in Section 5.4, and is probably a result of the inflammatory response caused by antimicrobial-induced killing of Pneumocystis organisms in the lung. Concomitant infection(s), fluid overload, methaemoglobinaemia and pneumothorax must be excluded as possible causes of clinical deterioration before treatment is changed [14]. Additionally, bronchoscopy (with BAL) should be performed if PCP treatment is being given empirically. Having excluded other causes, any patient not responding between 4 and 8 days should be switched to alternative therapy as shown in Table 2. Treatment failure resulting from treatment-limiting toxicity occurs in more than a quarter of patients. Switching to another regimen is the best management for treatment-related toxicity [45, 46] (see Table 2). When possible, ART should be initiated within 2 weeks of PCP diagnosis [51, 52]. Some clinicians prefer to defer starting ART in patients in the ICU until they no longer require assisted ventilation, given the small risk of ART-induced immune reconstitution inflammatory syndrome (IRIS) provoking a rapid deterioration in respiratory function. IRIS following an episode of PCP is rare and mostly occurs within weeks of the episode. Manifestations include fever and recurrence or worsening of cough and shortness of breath, as well as worsening of previously improving chest radiographic appearance, thus mimicking a relapse of PCP. Management of PCP-associated IRIS is not well defined; some clinicians recommend use of corticosteroids in this setting if other causes have been excluded. Accumulating evidence demonstrates that Pneumocystis is transmissible in experimental animal models and in humans [7]. P. jirovecii has been detected in the air near hospitalised people with PCP [53] and many outbreaks of PCP, each associated with specific genotypes of P. jirovecii, have been reported in kidney