18.4.5 Pulmonary complications of HIV infection 40

18.4.5 Pulmonary complications of HIV infection 4031 Julia Choy and Anton Pozniak

18.4.5  Pulmonary complications of HIV infection 4031 Prevention The World Health Organization has prioritized the eradication of tu- berculosis and set the goal of reducing the incidence of TB to less than one per million population by 2050 in their STOP TB campaign. This requires commitment to finding and treating active cases of tubercu- losis, and also to identifying latent infection. Improving socioeconomic conditions is vital in reducing transmission. There are ongoing studies of new treatments and vaccinations, but the only available vaccine cur- rently is the BCG, which has limited evidence for effectiveness, pro- tecting mainly against miliary disease and meningitis in children. FURTHER READING Campbell I, et al. (2000). Management of opportunistic mycobacterial infections:  Joint Tuberculosis Committee guidelines. Thorax, 55, 210–​18. Griffith D, et al. on behalf of the ATS mycobacterial diseases subcom- mittee (2007). An official ATS/​IDSA statement: diagnosis, treatment and prevention of nontuberculous mycobacteria. Am J Resp Crit Care, 175, 367–​416. Haworth et al. (2017). British Thoracic Society guidelines for the management of nontuberculous mycobacterial pulmonary disease. Thorax, 72, 1–64. Lewinsohn et al. (2016). An official ATS/CDC and IDSA clinical prac- tice guidelines: diagnosis of tuberculosis in adults and children. CID, 64(2), 1–33. Nahid et al. (2016). An official ATS/CDC and IDSA clinical practice guidelines: Treatment of drug-susceptible Tuberculosis. CID, 63, 853–67. NICE Tuberculosis guideline NG33 (2016). Public Health England (2018). Tuberculosis in the UK 2018 report. Public Health England, London. World Health Organization (2006). The stop TB strategy: building on and enhancing DOTS to meet the TB-​related millennium development goals. World Health Organization, Geneva. World Health Organization (2018). Global tuberculosis report 2018. World Health Organization, Geneva. World Health Organization (2019). WHO consolidated guidelines on drug-resistant tuberculosis treatment. World Health Organization, Geneva. 18.4.5  Pulmonary complications of HIV infection Julia Choy and Anton Pozniak ESSENTIALS Most HIV-​positive individuals will experience at least one significant episode of pulmonary disease during their lifetime. The immune status of the HIV-​infected patient is the primary determinant of the risk of developing specific pulmonary diseases: those with advanced immunosuppression are predisposed to opportunistic infections and malignancies; those with mild or no immunosuppression are at greater risk of conditions including community-​acquired pneu- monia, chronic obstructive pulmonary disease, pulmonary hyper- tension, and interstitial lung disease. Pulmonary infections related to HIV infection with severe immuno- suppression include: (1) Pneumocystis jirovecii pneumonia—​typically presents with gradual onset of breathlessness and dry cough, and a chest X-​ray showing diffuse bilateral infiltrates. Diagnosis requires direct visualization of fungal spores in respiratory secretions. First-​ line treatment is with high-​dose trimethoprim/​sulfamethoxazole. (2) Tuberculosis—​is the leading cause of death among people with HIV. Presentation may be nonspecific and atypical, and tissue biopsy may be required for diagnosis. Treatment is as for HIV-​uninfected pa- tients, but great care is needed regarding drug interactions. (3) Fungal infections including aspergillosis and cryptococcosis. Lung malignancies related to HIV infection with severe immuno- suppression include: (1) Kaposi’s sarcoma—​caused by human her- pesvirus (HHV-​8), usually in patients with obvious mucocutaneous lesions and diagnosed by finding of purplish plaques at bronchos- copy; treatment is with systemic chemotherapy. (2)  Lymphoma—​ typically non-​Hodgkin’s B-​cell lymphoma or primary effusion lymphoma (also caused by HHV-​8). Introduction In 2017, 37 million adults were living with HIV, mostly in Low and Middle Income Countries (LMIC). In many countries it is becoming chronic disease with life expectancies approximating normal due to the use of highly active combination antiretroviral therapy (cART). This is testimony to the fact that the risk of developing an opportun- istic infection or malignancy is markedly reduced by being on cART and having an undetectable HIV-​1 viral load. Nevertheless, with un- equal access to diagnostics, treatment, and education worldwide, 1.8 million people are still infected every year and many develop oppor- tunistic infections and HIV-​associated neoplasms leading to almost one million AIDS-related deaths. The lungs are commonly affected in HIV-​positive individuals, 60% of whom will experience at least one significant episode of pulmonary disease during their lifetime. Subsequently, pulmonary disease re- mains a significant cause of morbidity and mortality. A wide range of conditions can occur, ranging from opportunistic infections and tumours to interstitial lung diseases. Available data suggest that both cellular and humoral lung immunity is impaired in HIV and that al- veolar macrophages are an important reservoir for HIV in the lung. This chapter will concentrate on common causes of HIV-​related lung disease and can be divided into: • HIV disease with mild or no immunosuppression (normal or near normal CD4 counts)—​in these patients typical community-​ acquired infections occur at greater frequency than in the general population, and chronic obstructive pulmonary disease (COPD), pulmonary hypertension, interstitial lung disease, and lung can- cers are common, partly related to immune defects and lifestyle factors. • HIV disease with advanced immunosuppression—​in these pa- tients abnormalities of the innate and adaptive lung immunity predispose them to opportunistic infections and opportunistic malignancies.

section 18  Respiratory disorders 4032 Clearly, the differential diagnosis for specific pulmonary diseases in HIV is influenced by the immune status of the HIV-​infected patient, which is the primary determinant for the risk of developing specific pulmonary disease. However, other elements such as demographic factors and the use of prophylactic antibiotics and cART also influ- ence the differential. Epidemiology Immune status In patients with HIV, the occurrence of specific infections/​opportun- istic infections is correlated with the degree of immunosuppression. The CD4 count of an uninfected adult/​adolescent who is gener- ally in good health ranges from 500 cells/​mm3 to 1200 cells/​mm3. There is an increased risk of developing a variety of illnesses when it falls below 350 cells/​mm3, and a very low CD4 count (less than 200 cells/​mm3) is associated with developing opportunistic infec- tions and tumours. The CD4 + lymphocyte count is therefore a useful surrogate marker for immune function in HIV. It provides information about the type of pulmonary disease to which the pa- tient is susceptible and also helps define the stage of HIV, although it should be noted that even at high CD4 counts opportunistic tu- mours and tuberculosis can occur. The Pulmonary Complication of HIV Infection Study Group examined the incidence of pulmonary complications over 5 years. Together with data from the Strategic Timing of Antiretroviral Treatment (START) study, which looked at early versus late initi- ation of HIV treatment, a list of respiratory pathologies based upon HIV disease severity (as indicated by the CD4 + count and whether someone is on antiretroviral therapy) is detailed in Table 18.4.5.1. TB and bacterial pneumonias often occur before subsequent opportunistic infections and neoplasms. With lower CD4 counts there is an increased incidence of all pulmonary pathologies, and different pulmonary infections occur with increasing frequency re- sulting in increased risk of bronchiectasis secondary to recurrent infections over time. The use of cART has dramatically diminished the incidence of all of these complications Demographic factors Injecting drug users are at increased risk of bacterial pneumonias compared to other persons with HIV. In this subgroup bacterial pneumonia is more common than Pneumocystis jirovecii pneumonia (PCP) and fungal pneumonias—​especially invasive aspergillosis—​ are more common. Ethnicity and geography may also influence the risk of developing certain pulmonary diseases in HIV; for example, the risk of tuberculosis (TB) is higher in those living in or coming from developing countries, and those that are black or Hispanic. Conversely, the risk of PCP, HIV malignancies, and cytomegalo- virus disease is higher in the white population. Consequently, there is a higher risk of PCP in Europe and the United States than there is in Africa, where TB is the most common pulmonary complication in HIV. There is a higher incidence of TB in enclosed populations, for example, in prisons and in hostels, and a higher incidence of fungal infections depending on the geographic distribution of en- demic fungi (e.g. histoplasmosis pulmonary infections in HIV-​posi- tive individuals living in the Mississippi Delta or from Africa, and Coccidioidomycosis in California). Prophylactic antibiotics and antiretroviral therapy As described earlier, untreated HIV infection is associated with progressive reduction in cell-​mediated immunity and an increased risk of opportunistic infection. This risk can be decreased by, firstly, starting cART to decrease HIV viral activity which leads to an in- crease in the CD4 count and improved immunity (the incidence of pulmonary opportunistic infection has declined dramatically following the widespread use of cART), and secondly, by putting patients on antimicrobial prophylaxis to decrease the risk of op- portunistic infection at low CD4 counts. The risk of PCP without prophylaxis is 40–​50% per year in those with a CD4 count less than 100: this risk is ninefold lower with the use of antibiotic prophylaxis. Diagnosis of pulmonary disease in HIV infection Patients with HIV-​associated pulmonary diseases often present with nonspecific symptoms such as cough, with or without sputum pro- duction, dyspnoea, and wheezing. The initial diagnostic approach is the same as for any other patient (i.e. history, examination, and appropriate diagnostic tests). However, some specific considerations have to be recognized in the context of HIV. For example, neutro- penia is a recognized complication of HIV, hence if neutropenia is present, empiric therapy covering Pseudomonas aeruginosa may be indicated. Elevated plasma levels of 1-3-beta-D-glucan, a compo- nent of the cell wall of P. jirovecii, have been found in HIV-infected patients with PCP. Lactate dehydrogenase levels may be useful to monitor response to treatment in PCP infection: they are often ele- vated in PCP but are nonspecific. Polymerase chain reaction (PCR) of respiratory fluid, in particular bronchoalveolar lavage (BAL), is increasingly used to make the diagnosis of PCP but cannot distin- guish between colonization and disease. Blood cultures are helpful in the diagnosis of disseminated mycobacteria, fungi, and bacterial Table 18.4.5.1  Respiratory pathologies in HIV infection CD4 + Count (cells/mm3) Pulmonary Disease Any CD4 + count Sinusitis Bronchitis Bacterial pneumonia Tuberculous Kaposi’s sarcoma 100–​≤200 Advanced HIV—​opportunistic infections (opportunistic infection) Pneumocystis (PCP) Fungal Cytomegalovirus (CMV) Primary pulmonary lymphoma ≤100 Late-​stage HIV Non-​TB mycobacteria

350 and viral load (VL) undetectable Well-​controlled HIV Systemic lymphoma (non-​Hodgkin’s lymphoma) Chronic obstructive pulmonary disease Interstitial lung disease Pulmonary hypertension Lung cancers

18.4.5  Pulmonary complications of HIV infection 4033 pneumonia, in particular that due to Streptococcus pneumoniae. Routine collection of expectorated sputum for Gram stain and cul- ture has low sensitivity and specificity in HIV infection, especially after antibiotics have been started. Induced sputum for PCP stain, AFB (acid fast) stain, and culture is the initial test of choice in most centres for diagnosis of Pneumocystis jirovecii, although sensitivity varies widely. This, along with exercise oximetry demonstration oxygen desaturation on exertion, is very useful in diagnosing PCP. If no causative organism is isolated using standard techniques and/​ or the patient has failed to improve on empirical therapy for PCP and bacterial pneumonia, fibreoptic bronchoscopy with bronchoalveolar lavage +/​-​ transbronchial biopsy may be performed. Bronchoalveolar lavage is highly sensitive for the diagnosis of PCP, and Kaposi’s sarcoma is often diagnosed by visualizing the characteristic purple plaques, often without biopsy due to the risk of bleeding. Lung biopsy is likely to be necessary to establish an alternative diagnosis such as cytomegalo- virus, Aspergillus, or lymphocytic interstitial pneumonitis, and video-​ assisted thoracoscopic biopsy can be useful in diagnosis of peripheral nodules or masses not reachable by bronchoscopic. Pulmonary infections The epidemiology of HIV-​related pulmonary infections (Table 18.4.5.2) has changed as a consequence of advances in cART and prophylaxis. However, the most common respiratory infections are: • Community-​acquired pneumonia (CAP) • Pneumocystis jirovecii pneumonia (PCP) • Mycobacterium tuberculosis (TB) In LMICs (e.g. sub-​Saharan Africa), TB remains the most common pulmonary infection in HIV-​infected patients, with CAP second. In resource-​rich countries rates of PCP have decreased considerably with the use of co-​trimoxazole prophylaxis and the introduction of cART. Rates of TB in HIV-​infected patients have also decreased with the introduction of cART and with public health measures, such that bacterial CAP is now the most common pulmonary in- fection in HIV-​infected individuals. Bacterial community-​acquired pneumonia Although HIV affects cell-​mediated immunity most profoundly, ab- normalities in antibody production and (in advanced AIDS) neu- trophil function all contribute to the increased risk of bacterial pneumonia. Bacterial pneumonia is a major cause of pulmonary in- fection in HIV-​infected individuals and can occur at any CD4 count. The annual incidence of CAP in HIV patients is 5.5–​29 per 100, com- pared to 0.7–​10 per 100 in HIV-​negative individuals. Use of cART has resulted in decreased incidence of bacterial pneumonia (from 22.7 to 9.1 episodes/​100 patient years), but this still remains approximately 40 times higher than the risk of age-​matched HIV-​negative adults. The epidemiology of bacterial pneumonia is influenced by both epi- demiologic and immunological factors. Risk factors, apart from HIV infection per se, include CD4 count (<200 cells/​mm3), detectable viral load, neutropenia, not being on cART, having had prior PCP, IV drug abuse, smoking, alcohol abuse and other comorbidities, and steroid use. Aetiology The spectrum of pathogens, in general, does not differ signifi- cantly from those patients who are HIV negative (Table 18.4.5.2). Similarly, the clinical presentation of CAP is very similar to that in HIV-​uninfected patients. Streptococcus pnemoniae, Haemophilus influenza, and Staphylococcus aureus are the most common bac- terial pathogens, often giving a characteristic lobar/​segmental focal consolidative picture on chest X-​ray (Fig. 18.4.5.1), but diffuse bilat- eral infiltrates and cavitation can also occur (Fig. 18.4.5.2). There is a higher rate of bacteraemia in HIV-​infected patients—​HIV-​positive adults are at approximately 40 times higher risk of invasive pneumo- coccal disease compared to age-​matched HIV-​negative adults. Other causative organisms include Gram-​negative pathogens, especially in the context of a low CD4 + count (e.g. Pseudomonas Table 18.4.5.2  Types of pulmonary infection patients with HIV Type of pulmonary infection Species Bacterial community-​acquired pneumonia Streptococcus pneumoniae Haemophilus Staph Aureus Pseudomonas Klebsiella Nocardia Legionella Atypicals Rhodococcus Tuberculosis (TB) Mycobacterium tuberculosis Non-​TB mycobacterium Mycobacterium kansasii, avium, xenopi Fungal PCP Cryptococcus Aspergillus Histoplasmosis (rare in United Kingdom) Viral Cytomegalovirus (CMV) Fig. 18.4.5.1  Chest X-​ray due to Strep pneumonia showing lobar pneumonia.

section 18  Respiratory disorders 4034 aeruginosa and Klebsiella pneumoniae). Atypical pathogens such as Chlamydia, Mycoplasma, and Legionella have been reported, but are relatively uncommon. Other uncommon pathogens causing CAP in HIV patients also include Nocardia asteroids and Rhodococcus equi. Management, prognosis, and prevention Treatment of CAP consists of a β-​lactam plus a macrolide—​ quinolones are avoided due to the risk of quinolone resistant TB. If PCP has been excluded by sputum analysis, commencement of PCP prophylaxis should be considered if the CD4 + count is less than 200 cells/​mm3 or the CD4 percentage is 14% or less. Compared with HIV-​negative adults, HIV-​positive persons show an increased risk of mortality after controlling for age and severity of presentation, and this risk is related to the CD4 cell count. With an increasing proportion of associated comorbidities in ageing HIV-​ positive populations (e.g. cirrhosis, chronic pulmonary disease) case fatality has tended to increase in recent years. Pneumococcal vaccine is recommended for all HIV-​infected people. Two types of pneumococcal vaccine are licensed in the United Kingdom; PPV-​23, the pneumococcal polysaccharide vaccine, and PCV-​13, the pneumococcal protein-​conjugated vaccine. The most ro- bust evidence for the use of pneumococcal vaccines in HIV-​positive adults relates to PCV-​13 use. The conjugated vaccines are immuno- genic and have proven to be clinically effective in randomized con- trolled trials, including one undertaken in HIV-​positive adults with low CD4 counts. Current British HIV Association (BHIVA) and European guidelines recommend that HIV-​positive adults receive a single dose of PCV-​13 irrespective of CD4 cell count, cART use, and viral load. Pneumocystis Pneumocystis jirovecii, formally called Pneumocystis carinii, is the cause of Pneumocystis pneumonia (PCP), a fungal pneumonia. The incidence of PCP has declined dramatically due to cART and PCP prophylaxis in those with low CD4 counts, but it still remains one of the leading opportunistic infections in HIV-​infected persons with low CD4 counts. Most cases occur in those who have undiagnosed HIV, or those who are not receiving or are not engaged in care. Risk factors for PCP include a CD4 + count 200 cells/​mm3 or less, or a CD4% of 14% or less, a previous episode of PCP, a high viral load (>100 000 copies/​ml), and/​or the presence of oral thrush. PCP is unlikely in a patient on cART with a persistently undetectable viral load even with a CD4 count 200 cells/​mm3 or less. Clinical features PCP typically presents with gradually increasing dyspnoea and dry cough with fever over days to weeks. Symptoms are usually gradual in onset (being present on average for 3 weeks), as opposed to CAP. Purulent sputum suggests CAP, although this can be present in one-​ sixth of patients with PCP as a copathogen. The chest X-​ray usually displays diffuse bilateral infiltrates (Fig. 18.4.5.3), which strongly suggests the diagnosis, but sometimes shows nodular opacities, lobar consolidation, or can be normal in up to 25% of patients. Spontaneous pneumothoraces in patients with HIV should prompt the diagnosis of PCP. High resolution computed tom- ography (HRCT) has a high sensitivity for PCP among HIV-positive patients when patchy or nodular ground-glass attenuation are found. A negative HRCT scan makes the diagnosis of PCP unlikely. There are no clinical features specific to PCP, but the diagnosis of PCP may be supported by adjunctive tests. Demonstration of a fall in oxygenation between rest and exercise has been validated as a reason- ably specific test for PCP, but is not reliable enough to make a diagnosis without confirmatory microbiology. Patients with a diagnosis of PCP have significantly higher median 1-3-beta-D-glucan levels than patients without the disease and the test is used in supporting the diagnosis, though it can be positive in other fungal diseases. Lactate dehydrogenase levels are high in 90% of HIV-​infected patients with PCP but have poor sensitivity and specificity diagnostically. A rising lactate dehydrogenase level despite appropriate treatment in PCP is a poor prognostic factor. Microbiological diagnosis PCP is a fungus that cannot be cultured. Diagnosis therefore re- quires direct visualization of the fungal spores in respiratory Fig. 18.4.5.2  Chest X-​ray showing bilateral diffuse infiltrate due to Strep pneumonia, but mimicking Pneumocystis jirovecii pneumonia. Fig. 18.4.5.3  Chest X-​ray showing typical bilateral infiltrates in Pneumocystis jirovecii pneumonia.

18.4.5  Pulmonary complications of HIV infection 4035 secretions by immunofluorescence tests, for which adequate sputum specimens are required. These are most often obtained with induced sputum (sensitivity 50–​90%), which is the least invasive technique. If induced sputum results are negative or inconclusive, then the patient should be assessed for bronchos- copy with bronchoalveolar lavage (diagnostic sensitivity >90%). Endotracheal aspirates and tissue biopsies may also be used in diagnosis. All specimens should be examined for the presence of acid-​fast bacilli, fungi, and viral cellular inclusions, since patients with suspected PCP may have another infection, or may be co-​ infected with other pathogens. Management Treatment is started empirically in a patient with typical clinical and radiographic features and a CD4 less than 200 or 14% and an elevated 1-3-beta-D-glucan level. Pending diagnosis by cytological analysis of induced sputum samples or bronchoalveolar lavage fluid. Indeed, treatment should be started promptly if PCP is suspected, and not delayed for confirmation of the organism. Immunofluorescence tests for Pneumocystis jirovecii will remain positive for several days after treatment is commenced. CART should be started as soon as is practicable and within 2 weeks of PCP diagnosis. Evaluation of the degree of hypoxia through arterial blood gas sampling helps assess the severity of the disease and the need to add glucocorticoids. A PaO2 less than 9.3 kPa on room air indicates se- vere PCP infection and the need for glucocorticoids in addition to antimicrobial agents (Table 18.4.5.3) to suppress the robust inflam- matory response to the Pneumocystis organism. The British HIV Association and American Centre for Disease Control Guidelines recommend high-​dose trimethoprim/​ sulfamethoxazole (TMP-​SMX or co-​trimoxazole) for 21 days as first-​ line treatment for PCP; patients with sulfa allergies require second-​ line regimens. If patients have concurrent gastrointestinal problems affecting swallowing or absorption (e.g. thrush/​diarrhoea), or have moderate or severe disease, then TMP-​SMX should be given intra­ venously rather than orally. Alternative therapies include atovoquone for mild disease and clindamycin-primaquine or IV pentamidine for severe disease. Up to 10% of patients will fail first-​line treatment with TMP-​ SMX (defined as deterioration after 5  days of first-​line therapy) and will have to be switched to second-​line treatments. The use of caspofungin as an adjunct therapy is still uncertain. Prognosis Despite highly active antiretroviral therapy, improvement in diagnos- tics, and the use of antipneumocystis prophylaxis, PCP pneumonia is still the most common cause of respiratory failure and admission to intensive care units in patients with HIV. When treatment is delayed or ineffective, severe PCP—​resembling acute respiratory distress syndrome—​may develop. Progressive respiratory deterioration while on therapy warrants early ICU/​HDU input because acute progression of hypoxia in PCP is associated with high mortality (up to 60%) and morbidity. Other complications of PCP include pneumothorax. Prevention PCP prophylaxis is given to patients with a CD4 count of less than 200 cells/​mm3 who are at greatest at risk of PCP (Table 18.4.5.4). First-​ line choice for prophylaxis is co-​trimoxazole; dapsone, atovaquone, and inhaled pentamidine are alternatives. Prophylaxis can be stopped in patients with an undetectable plasma viral load on cART who have maintained a CD4 count of more than 200 cells/​mm3 for 6 months. Pulmonary tuberculous HIV is a key driver in the global rise in TB cases through both ac- celerated progression of TB after exposure and greatly increased risk of reactivation. Most cases of TB in HIV-​positive individ- uals represent reactivation of latent bacilli. The lifetime risk of developing active TB in an HIV-​uninfected individual with latent TB infection is 10%, compared to 10% per year in an HIV-​infected person not on cART. Active TB can occur at even relatively high CD4 counts (>350 cells/​mm3). Many HIV-​positive patients living in LMICs are exposed to TB due to the nature of their environment, especially overcrowding and poverty. Where the background prevalence of TB is low, the disease is uncommon in HIV-​positive patients unless they can become ex- posed, for instance, through travel. Clinical features and diagnosis Typical clinical features of TB such as a subacute history of a pro- ductive cough, night sweats, and fevers accompanied with weight loss are common to both HIV-​positive and HIV-​negative patients. However, in advanced HIV disease/​CD4 <200, symptoms of TB are often nonspecific and atypical, and many investigations have less diagnostic sensitivity than in an HIV-​uninfected individual with TB (Table 18.4.5.5). Table 18.4.5.3  Treatment of Pneumocystis jirovecii pneumonia Disease severity Mild PaO2 >9.3 kPa Moderate–​severe PaO2 ≤9.3 kPa First choice Co-​trimoxazole Co-​trimoxazole Alternative therapy (second line) Clindamycin-​primaquine or Dapsone with trimethoprim or Atovaquone Intravenous pentamidine or Clindamycin-​primaquine or Dapsone with trimethoprim or Atovaquone Steroids No Yes Table 18.4.5.4  Indications for prophylaxis of Pneumocystis jirovecii pneumonia Primary prophylaxis CD4 ≤200 CD4 count ≤14% of total lymphocyte count Secondary prophylaxis All patients after an episode of PCP Table 18.4.5.5  Features of TB infection in presence and absence of HIV HIV uninfected HIV infected CD4 <200 Symptoms Focal symptoms predominate Nonspecific symptoms predominate Site Pulmonary predominantly Higher rates of extrapulmonary and disseminated disease Sputum smear (AFB) Good yield Low yield Mycobacterial burden (e.g. at biopsy/​autopsy) Low High

section 18  Respiratory disorders 4036 Patients with profound immunosuppression (e.g. CD4 <200 cells/​ mm3) are unable to control TB replication and hence have a greater mycobacterial burden. However, factors associated with reduced sputum smear positivity (e.g. lung cavitation), mean that sputum microscopy has a significantly lower diagnostic yield in HIV/​TB co-​infected patients. In HIV/​TB co-​infection mycobacterial blood cultures and tissue biopsy, for example, from a lymph node (for hist- ology, TB culture, TB-​PCR), may therefore be required to make a positive diagnosis of TB. Patients with advanced HIV infection are more likely to de- velop extrapulmonary TB involving lymph nodes, blood, pericar- dium, lived, bone marrow, or meninges. Extra adjunct tests include adenosine deaminase levels in pleural or ascitic fluid, which are elevated in TB. Immunological tests, such as the tuberculin skin test and ELISpot, performed to assess latent TB infection are often negative in HIV-​ infected individuals if CD4 counts show severe immunosuppres- sion and have poor utility in making a diagnosis of active TB. Radiographic features of TB in HIV-​positive patients with low CD4 counts are different from those in HIV-​negative patients (Table 18.4.5.6). Treatment Empirical TB treatment should start as soon as the diagnosis is confirmed and follows the same guidelines as for HIV-​uninfected patients (i.e. a rifampicin-​based regimen), but there are special considerations in TB/​HIV co-​infection. Firstly, adding cART to TB treatment improves treatment outcome and reduces mortality. Most patients benefit from stating cART within 2 weeks after anti-​TB treatment, especially if CD4 is less than 50 cells/​mm3. For those with higher CD4 counts treatment for HIV can be de- layed, but not beyond 8 weeks. Secondly, while initial TB therapy is empirical, therapy needs to be subsequently tailored to the drug resistance profile of the isolate, given the higher incidence of drug resistant TB in HIV. Thirdly, there should be close monitoring of treatment response and for immune reconstitution syndrome (IRIS), especially if the CD4 is less than 50 cells/​mm3. Lastly, ri- fampicin is a potent inducer of the cytochrome P450 enzyme, hence it interacts with drugs used in cART (especially protease inhibitors) leading to subtherapeutic levels, HIV treatment failure, and HIV drug resistance. A rifabutin-​based regimen, ra- ther than rifampicin, produces less drug-​to-​drug interactions with cART, but careful and expert dose management is required. Careful review for drug interactions is essential when initiating anti-​TB therapy in patients taking cART (see https://​www.hiv-​ druginteractions.org). Fungal pulmonary infections Fungal infections of the respiratory tract are less common than viral or bacterial infections in HIV. However, CD4 cells are critical for antifungal defence, and a decline in CD4 cell numbers and cell func- tion is a risk factor for invasive pulmonary infections in HIV-​infected individuals. Other risk factors include neutropenia, long-​term cor- ticosteroid therapy, intravenous drug use, iatrogenic immunosup- pression after organ transplantation, and abnormal lung architecture. In addition to PCP, the most prevalent pulmonary fungal infections in HIV are Aspergillosis and Cryptococcosis. With the introduction of cART, the prevalence of fungal infections has declined dramatic- ally, but they still substantially contribute to AIDS-​related mortality. Aspergillosis Aspergillosis refers to the illness caused by inhalation of spores of the fungal species Aspergillus from soil or air. Prior to cART, inva- sive aspergillosis was an important cause of death. Today, the infec- tion is rarely seen in patients with HIV, except those with very low CD4 counts (<50 cells/​mm3) +/​–​ other risk factors for fungal dis- ease. US databases have showed that a diagnosis of aspergillosis was found only in 0.43% of HIV-​infected patients. Aspergillus fumigatus is the most common species to cause disease: two clinical entities are recognized. Invasive pulmonary parenchymal aspergillosis—​this accounts for 80% of cases of disseminated aspergillosis in HIV-​infected pa- tients and is often fatal. Cavitating lesions form in the lung par- enchyma, leading to fever, shortness of breath, productive cough, and haemoptysis. Signs of disseminated infection (e.g. neurological signs from brain involvement), may also be present. Imaging may reveal nodular or cavitating lesions on chest radiography. CT images may be may be very helpful in the early diagnosis of aspergillosis if they show a characteristic ‘reverse halo sign’ caused by an area of ground-​glass infiltrate surrounding nodular densities. Tracheobronchial aspergillosis—​the disease site is predomin- ately tracheal and bronchial involvement leading to airway obstruc- tion, audible wheeze, and prominent shortness of breath. As with PCP diagnosis, the rational first step to establishing the diagnosis of invasive Aspergillus involves the use of noninvasive mo- dalities, such as serum biomarkers (galactomannan and β-​D-​glucan assays) and obtaining sputum for fungal staining and culture. If the diagnosis is not made by these methods, then a more invasive approach with bronchoscopy and bronchoalveolar lavage, transbronchial bi- opsy, CT-​guided biopsy, or video-​assisted thoracoscopic surgery is useful for histology, culture, and Aspergillus antigen assay. Treatment of aspergillosis is with voriconazole, although caspofungin is an alternative. Cryptococcosis Infections with the encapsulated yeast Cryptococcus neoformans in the most common fungal infection in HIV-​infected individuals worldwide, but unusual in resource rich countries. Diagnosis of pulmonary cryptococcosis is based on culture of the organism in respiratory secretions or from lung biopsy, and detection of crypto- coccal serum antigen. An HIV-​infected patient is at greatest risk of disseminated extrapulmonary Cryptococcus (e.g. Cryptococcus meningoencephalitis when their CD4 is <100 cells/​mm3). Non-​ specific symptoms such as fever, cough, and shortness of breath Table 18.4.5.6  Chest radiographic features of TB infection in presence and absence of HIV HIV uninfected (typical TB) TB in HIV/​low CD4 counts Upper zone cavitation Pulmonary infiltrates with no particular preference for upper zones or cavitation Bilateral hilar lymphadenopathy Mediastinal lymphadenopathy Pleural effusions

18.4.5  Pulmonary complications of HIV infection 4037 accompany chest radiographic changes including noncalcified pulmonary nodules, predominantly at the bases of the lungs, hilar lymphadenopathy, interstitial infiltrates, and lung masses. Treatment is with liposomal amphotericin (or oral fluconazole if not available) in combination with flucytosine. Lung malignancy Kaposi’s sarcoma and non-​Hodgkin’s lymphoma may involve the lung, and patients with HIV appear to have both increased rates of lung cancer and more aggressive disease compared with uninfected controls. Pulmonary Kaposi’s sarcoma Kaposi’s sarcoma, caused by human herpesvirus (HHV-​8), is the most common malignancy in persons with HIV infection. The skin is the major site of involvement, but visceral involvement with Kaposi’s sarcoma is common in advanced disease, and may involve the airways, lung tissue, mediastinal lymph nodes, and pleura. The lung is the only site of disease in up to 15% of cases. Patients with thoracic Kaposi’s sarcoma usually have obvious mucocutaneous lesions, and a lesion on the palate suggests pul- monary involvement. Lung lesions cause dyspnoea, cough, or haem- optysis, accompanied in severe cases by constitutional symptoms such as night sweats, fevers, and weight loss. The presence of char- acteristic purplish plaque lesions at bronchoscopy is usually con- sidered to be diagnostic. The yield from bronchoscopic lung biopsy, which carries a risk of bleeding, is low, and even open-​lung biopsy is nondiagnostic in about 10% of cases because of the focal distribution of the lesions. Pleural effusions are usually exudative and sanguineous, but cyto- logical examination is nondiagnostic. Closed pleural biopsy speci- mens are rarely positive for Kaposi’s sarcoma due to the focal nature of the pleural lesions and the predominant involvement of the vis- ceral (rather than the parietal) pleura. Radiographic findings are variable, but bronchial wall thickening, Kerley B lines, and nodular infiltrates with peribronchovascular distribution and pulmonary effusions are common (Fig. 18.4.5.4). Treatment is with systemic chemotherapy, namely liposomal anthracyclines plus cART. Lymphoma Non-​Hodgkin’s B-​cell lymphoma is associated with HIV infection and continues to occur despite the use of cART. Although pul- monary involvement is usually clinically asymptomatic the lung is a common site of extranodal disease. Primary effusion lymphoma is most commonly a high-​grade B-​cell tumour associated closely with HHV8 and occurring in the setting of advance HIV infection. Non-​Hodgkin’s B-​cell lymphoma The risk of developing non-​Hodgkin’s lymphoma is 200–​600 times greater in persons with HIV compared with those who are unin- fected. Non-​Hodgkin’s lymphoma associated with HIV infection is most commonly a high-​grade B-​cell tumour and tends to present more commonly with stage IV and extranodal disease. The lung is a site of extranodal disease, but in contrast to non-​AIDS patients, mediastinal and hilar lymphadenopathy is generally not prom- inent. Pulmonary symptoms tend to occur late in the disease and can simulate common opportunistic infections (e.g. lobar consoli- dations, nodules, reticular opacities, and pleural effusions or thick- ening). Airway involvement may cause atelectasis. B-​symptoms may also be present. The diagnosis is established by bronchoscopic or open-​lung/​pleural biopsy, or by cytological analysis of pleural fluid. Bronchoalveolar lavage has a very low diagnostic yield. Primary effusion lymphoma A few lymphomas are associated with HHV8. They present as body cavity lymphomas, causing pleural or peritoneal effusions (primary effusion lymphoma). In almost all cases tumour DNA shows HHV8, which is also the aetiological agent of Kaposi’s sarcoma (as previ- ously described). Non-​small cell carcinoma of the lung It appears that the incidence of non-​small cell lung cancer is in- creased in people living with HIV infection. Whether the increase simply reflects a higher smoking prevalence continues to be debated as there is no association with CD4 count, viral load, or the use of cART. Patients with lung cancer in the setting of HIV infection tend to be relatively young at presentation (mean age 45 years) and have mild or moderate immunosuppression. Most present with stage III or IV disease, and adenocarcinoma is the most common histological type, with its prognosis appearing to be worse in patients with HIV infection. The diagnostic and treatment approaches to HIV-​ associated lung cancer are the same as for those without HIV infec- tion although there is a potential for drug interactions with cART. Other pulmonary conditions In addition infections and malignancies, HIV is associated with an increased risk of other pulmonary diseases such as immune re- constitution inflammatory syndrome (IRIS), pulmonary hyperten- sion, COPD, interstitial lung disease, and lymphocytic interstitial pneumonitis. Immune reconstitution inflammatory syndrome IRIS refers to a disease-​ or pathogen-​specific inflammatory re- sponse in HIV-​infected patients that usually occurs after initiation Fig. 18.4.5.4  CT scan showing nodular infiltrates with peribronchovascular distribution due to Kaposi’s sarcoma.

section 18  Respiratory disorders 4038 or re-​initiation of cART. It has been reported as worsening of symp- toms and signs in those with mycobacterial, fungal, viral, or bacterial infections, and worsening of tumours such as Kaposi’s sarcoma. Most cases occur in patients who have low CD4 counts (usually less than 100 cells/mm3) at the time cART therapy is started and is usually coincident with a rapid increase in CD4 cell count. The time of presentation is usually within the first 8 weeks after starting cART therapy, but has been reported occurred many weeks after initiation. Treatment is with corticosteroids, but the course can be very pro- longed in some. Pre emptive steroids can reduce TB IRIS by 30%. Pulmonary hypertension Pulmonary hypertension is 6–​12 times more prevalent in HIV-​ infected patients compared to the general population. The patho- genesis still remains unclear and some cases are related to prior ARV use with Didanosine. Therapies for HIV-​related pulmonary hyper- tension are nearly identical to those used in non-​HIV patients, ex- cept the use of calcium channel blockers are not recommended. Chronic obstructive pulmonary disease There is high prevalence respiratory symptoms and COPD among HIV-​infected patients. Currently, cigarette smoking and previous bac- terial pneumonia seem to play a significant role in the development of respiratory symptoms and COPD. Smoking cessation is important, and COPD is managed as for the non-​HIV-​infected population. An important consideration is the drug interaction between the antivirals pharmaco boosting agents cobicistat and ritonavir with fluorinated steroids, which can cause Cushing’s syndrome. Asthma/​bronchial hyper-​responsiveness Asthma and airway hyper-​responsiveness may be more common among HIV-​seropositive individuals treated with cART. Again, as with COPD, caution with drug interactions of inhaled fluorinated steroids and antiretroviral therapy is required. Bronchiectasis May result from severe or repeated opportunistic infection, including tuberculosis. In children risk factors include recurrent pneumonia, severe immunosuppression, and lymphoid interstitial pneumonitis. Interstitial lung disease Interstitial pneumonitis and lymphocytic interstitial pneumonitis were frequently described in HIV-​infected adults prior to the use of cART. Post cART, these conditions are less frequent. However, sarcoidosis among HIV-​infected persons is increasingly recog- nized and may represent an immune reconstitution phenomenon. Table 18.4.5.7 compares clinical, radiological, and histo- logical features of the main causes of interstitial lung disease seen in HIV. Table 18.4.5.7  Clinical, radiological, and histological features of the main causes of interstitial lung disease seen in HIV NSIP LIP COP HP Sarcoid Dyspnoea and cough +/​–​ + + + +/​–​ fevers +/​–​ + + -​ +/​–​ Usual CD4 count (cells/​mm3/​μl) <200

350 Any Usually >350 200 Chest X-​ray Interstitial or alveolar infiltrates Normal in up to 50% Reticular or nodular shadowing Consolidation May be normal or diffuse nodules BHL +/​–​
reticulonodular opacities HRCT: Ground-​glass opacification Basal, may be prominent Present Present Diffuse or patchy Occasional diffuse HRCT: Consolidation May be present Not usually a feature Dominant feature Not usually a feature May be present HRCT: Honeycombing Rarely may be present Present in advanced disease Not usually a feature Present in advanced disease May be present if fibrotic disease Other HRCT features Reticular and nodular shadowing Cavitating nodules Mosaic attenuation Adenopathy and nodules on fissures Histopathological features Interstitial infiltrates of lymphocytes, plasma cells/​mm3 and macrophages Interstitial infiltrates of polyclonal lymphocytes, some histiocytes and plasma cells/​mm3 with extension into alveolar septae Organizing pneumonia, intraluminal polyps of granulation tissue Peri-​bronchiolar lymphocytic infiltrates and variable fibrosis in chronic disease Noncaseating granuloma Granulomata Not present Occasionally reported Not present Present Prominent Treatment and prognosis Usually self-​limiting Use of cART leads to improvement in lymphocytic alveolitis May be stable without treatment Some role for steroids and cART Rarely progresses to respiratory failure Responds rapidly to corticosteroids May be self-​limiting on removal of causative agent May require corticosteroids May spontaneously remit May require steroids HRCT, high-​resolution computed tomography; NSIP, nonspecific interstitial pneumonia; LIP, lymphocytic interstitial pneumonia; COP, cryptogenic organizing pneumonia; HP, hypersensitivity pneumonitis and sarcoidosis. Adapted from Clinics in Chest Medicine, 34(2), Doffman SR and Miller RF, Interstitial Lung Disease in HIV, pp. 296–​306, Copyright © 2013, with permission from Elsevier.

18.4.5  Pulmonary complications of HIV infection 4039 FURTHER READING Chu C, Pollock LC, Selwyn PA (2017). HIV-​associated complica- tions: a systems-​based approach. Am Fam Physician, 96, 161–​9. Crothers K, et al. (2011). HIV-​associated lung infections and compli- cations in the era of combination antiretroviral therapy. Proc Am Thorac Soc, 8, 275–​81. Datta S, Mahal S, Ravat V, et al. (2018). Hospitalization outcomes in pneumo- cystis pneumonia inpatient population: A comparison between HIV and Non-HIV patients. Cureus, 10(8), e3082. doi: 10.7759/cureus.3082 George MP, et al. (2009). Respiratory symptoms and obstruction in HIV-​infected subjects in the HAART era. PLoS One, 4, e6328. Gingo MR, et  al. (2010). Pulmonary function abnormalities in
HIV-​infected patients during the current antiretroviral therapy era. Am J Respir Crit Care Med, 182, 790–​6. Grubb JR, et al. (2006). The changing spectrum of pulmonary disease in patients with HIV infection on antiretroviral therapy. AIDS, 20, 1095–​107. Kunisaki KM, et al. (2016). Pulmonary effects of immediate versus de- ferred antiretroviral therapy in HIV-​positive individuals: a nested substudy within the multicentre, international, randomised, con- trolled Strategic Timing of Antiretroviral Treatment (START) trial. Lancet Respir Med, 4, 980–​9. Presti RM, et  al. (2017). Mechanisms underlying HIV-​associated noninfectious lung disease. Chest, 152, 1053–​60. Thao C, Shorr AF, Woods C (2017). Non-​infectious pulmonary dis- orders in HIV. Expert Rev Respir Med, 11, 209–​20. Tornheim JA, Dooley KE (2017). Tuberculosis associated with HIV infection. Microbiol Spectr, 5, doi:  10.1128/​microbiolspec. TNMI7-​0028-​2016.