European Respiratory Society
Pulmonary Complications of HIV

The lung is the most common site of complications resulting from HIV infection. These respiratory conditions may be of infective or noninfective origin, and are associated with considerable morbidity and mortality. The editors of “Pulmonary Complications of HIV” have brought together experts from around the world to discuss this major area. A broad range of topics is covered, from the global epidemiology of HIV to transplantation, and recent advances in HIV infection, complications, treatment and prevention are discussed. The editors hope that books such as “Pulmonary Complications of HIV” will help us move towards achieving more successful therapies for HIV-related pulmonary infectious diseases.

  • European Respiratory Monographs
  1. Page vii
  2. Page ix
  3. Page xii
  4. Page 1
    Abstract
    Correspondence: Willem Daniel Francois Venter, Wits Reproductive Health and HIV Institute (RHI), University of the Witwatersrand, PO Box 2616, Saxonwold 2132, Johannesburg, South Africa. E-mail: fventer@wrhi.ac.za

    HIV arose in Africa and, during the past century, has established itself in very different communities throughout the world. Sexual transmission continues to be the predominant mechanism of transmission, with mother-to-child, intravenous drug use and iatrogenic spread being less common contributors in most settings. Prior to effective ART, the virus placed a huge burden on morbidity and mortality. Although understanding of the transmission of the virus has evolved, there has been continued spread of the virus in the poorer and more marginalised areas of society. Application of new prevention technologies, including the use of antiretrovirals to effectively stop transmission, may be limited by the complex and evolving epidemiology, as well as the cost and political will to tackle affected communities that have historically not had access to healthcare interventions.

  5. Page 12
    Abstract
    Correspondence: Anton L. Pozniak, Dept of HIV Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, 369 Fulham Road, London, SW10 9NH, UK. E-mail: anton.pozniak@chelwest.nhs.uk

    No other area of medicine has progressed as rapidly as HIV. It has now become a chronic disease with on-therapy life expectancies approximating normal. However, there are still important questions that remain unanswered. For example, should all patients start treatment regardless of their CD4+ T-cell count? Are there long term toxicities of therapy? And can patients effectively adhere to lifelong treatment? There is a number of combinations of drugs available for effective therapy that are recommended by international guidelines based on clinical trial data of efficacy and safety. Many of the older drugs have unfavourable side-effect profiles and are currently only used in the developing world, where they are being phased out. Drug–drug interactions with both over-the-counter and prescribed medicines, especially with ritonavir, are a major concern, and physicians and patients have to remain alert to these. International guidelines are helpful in distilling and summarising data but, increasingly, choices are based on tolerability and ease of use, and there is still an important role for the individualisation of therapy.

  6. Page 26
    Abstract
    Correspondence: Julio Ramirez, Division of Infectious Diseases, School of Medicine, University of Louisville, MedCenter One, Suite 120, 501 East Broadway, Louisville, KY 40202, USA. E-mail: j.ramirez@louisville.edu

    Lung immunology is particularly affected in patients with HIV infection. Patients not receiving ART develop immunological and virological failure. In patients with uncontrolled HIV infection, abnormalities of the innate and adaptive lung immunity predispose them to opportunistic infections and opportunistic malignancies. Patients receiving ART have immunological reconstitution, with normal values of CD4+ lymphocytes and control of plasma viraemia. In these patients there is persistent chronic lung inflammation and immune activation, which is associated with accelerated pulmonary ageing. COPD and other chronic pulmonary diseases are more common in this population.

  7. Page 36
    Abstract
    Correspondence: Christian Manzardo, Hospital Clinic/IDIBAPS/University of Barcelona, Infectious Diseases Service, C/Villarroel 170, Barcelona, Catalonia 08036, Spain. E-mail: cmanzard@clinic.ub.es

    Nowadays, in western countries, HIV infection is a chronic disease in patients on effective ART with a life expectancy that is ever closer to that of the general population. However, HIV-infected patients may be at increased risk of infection or experience more severe manifestations following exposure to vaccine-preventable infectious diseases. HIV-infected individuals who travel abroad may require vaccinations against tropical diseases. HIV infection can alter the immune response to vaccination, which varies according to whether patients are receiving effective ART and to the threshold of CD4+ T-cell count. The best serological responses have been obtained in patients who are virologically suppressed and with immune reconstitution on ART, although these responses are generally poorer than in HIV-negative patients. For this reason, vaccination guidelines in HIV-infected patients differ from those of the general population: the vaccine doses often need to be higher, the vaccinations more frequent and regular serology testing is necessary to verify the response to vaccines. However, huge efforts are being made to find HIV preventive vaccines in order to prevent new HIV infections and therapeutic vaccines that provide a “functional cure” for those individuals who are already infected.

  8. Page 60
    Abstract
    Correspondence: Hendrik Suhling, Dept of Respiratory Medicine, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany. E-mail: suhling.hendrik@mh-hannover.de

    In recent years, successful solid organ transplantation in HIV-positive patients has been reported, with early experiences in lung transplantation delivering promising results. Infection rates appear comparable in well-selected patients and drug interactions can be managed with regular immunosuppression monitoring and careful selection of ART. Although increased rejection rates have been reported, outcomes after kidney or liver transplantation are comparable to those of HIV-negative patients.

  9. Page 71
    Abstract
    Correspondence: Mark Fredric Cotton, Division of Paediatric Infectious Diseases, Dept of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Cape Town 7505, South Africa. E-mail: mcot@sun.ac.za

    Better uptake and improved interventions to prevent vertical transmission have reduced the incidence of paediatric HIV infection. Early antenatal identification of maternal HIV status is essential to optimise prevention. Late or missed identification and acute HIV in pregnancy and during breastfeeding increase the risk of transmission. Antiretroviral (ARV) prophylaxis should be initiated by 20 weeks' gestation for maximal efficacy. Partner testing must be encouraged. In high prevalence settings, females initially testing negative should be retested later in pregnancy, during labour and while breastfeeding. Infants at increased risk of transmission require PCR testing and multi-ARV post-exposure prophylaxis as soon as possible after birth. Early infant diagnosis by PCR is less sensitive during infant post-exposure prophylaxis and should be repeated twice between 2 and 8 weeks after cessation. Drug resistance genotyping is important to identify vertically transmitted resistant infections. Infant ARVs should be selected on the basis of maternal ARV exposure and resistance testing results. Finally, HIV-exposed uninfected infants are at greater risk of morbidity and mortality than HIV-unexposed infants.

  10. Page 84
    Abstract
    Correspondence: Robin J. Green, Dept of Paediatrics and Child Health, University of Pretoria, Steve Biko Academic Hospital, Pretoria, South Africa. E-mail: robin.green@up.ac.za

    Pulmonary infectious diseases are common in HIV-infected children and a number of studies have documented both prevalence and aetiology. However, most of these studies highlight a specific disease state. There is no review of the various infectious diseases of the lung that an HIV-infected child may be exposed to over the course of childhood. This review highlights the vast spectrum of pulmonary infectious diseases that impaired immunity makes more probable.

    Although bacterial pneumonia is an important disease entity in HIV-infected children, of equal importance is the contribution viruses and fungi make to lung disease in these children. Severe acute pneumonia in HIV-infected infants is known as PCP. This condition requires paediatric intensive care unit admission for ventilation.

    Admission to hospital is a frequent event for HIV-infected children with pneumonia. The case fatality rate for this condition is high, in both the general ward and paediatric intensive care. Bronchiectasis is the final end to years of recurrent LRTI in HIV-infected children.

  11. Page 98
    Abstract
    Correspondence: Charles Feldman, Division of Pulmonology, Dept of Internal Medicine, University of the Witwatersrand, Medical School, 7 York Road, Parktown, 2193, Johannesburg, South Africa. E-mail: Charles.feldman@wits.ac.za

    Bacterial CAP remains an important cause of morbidity and mortality in HIV-infected patients. Smoking is a major risk factor and daily smoking attenuates the immunological and virological responses to ART by 40%. The bacterial pathogens causing CAP in HIV-infected patients are largely similar to those in HIV-uninfected patients. The clinical presentation in HIV-infected patients is also similar to that of HIV-uninfected patients, although in severely ill HIV-infected patients with bacteraemic pneumococcal CAP, the mortality appears to be higher than in HIV-uninfected patients, with a trend towards increasing mortality in those with lower CD4 cell counts. Empiric antibiotic treatment commonly recommended in HIV-infected patients with bacterial CAP is either a β-lactam/macrolide combination or fluoroquinolone monotherapy. Following recovery from an episode of bacterial CAP, HIV-infected patients may have a worse progression of their HIV disease and permanent declines in lung function. Careful consideration needs to be given to the prevention of CAP in HIV-infected patients, including smoking-cessation strategies and vaccination.

  12. Page 112
    Abstract
    Correspondence: Giovanni Sotgiu, Clinical Epidemiology and Medical Statistics Unit, Dept of Biomedical Sciences, University of Sassari, Research, Medical Education and Professional Development Unit, AOU Sassari, Via Padre Manzella 4, 07100 Sassari, Italy. E-mail: gsotgiu@uniss.it

    TB/HIV co-infection represents a relevant clinical and public health issue. It is estimated that 1.1 million individuals are TB/HIV co-infected. The majority (∼75%) of these patients live in Africa. The annual mortality is estimated to be higher than 300 000 patients. Although a general decrease of the mortality rate has been recorded worldwide, there are several geographical areas where it is highest, particularly in low-income countries. HIV infection is one of the most important risk factors for the development of TB disease: the qualitative and/or quantitative impairment of the immune system caused by the HIV favour mycobacterial replication. TB treatment should be administered early after the diagnosis of the disease. ART should be prescribed within 14 days after the administration of the anti-TB drugs. Several drug–drug interactions have been described, particularly in the case of induction/inhibition of the hepatic cytochromes.

  13. Page 128
    Abstract
    Correspondence: Paula Peyrani, Division of Infectious Diseases, University of Louisville, 501 E Broadway, Suite 120, Louisville, KY 40202, USA. E-mail: paula.peyrani@louisville.edu

    Pulmonary nontuberculous mycobacteria (NTMs) occur in HIV patients when HIV is not well controlled and CD4+ T-cell counts are low. Current ART has changed the disease to the point that lung opportunistic infections are only seen in HIV patients who are not on therapy. The most common NTMs producing lung disease are Mycobacterium avium complex and Mycobacterium kansasii. As NTMs are environmental pathogens that colonise the airway, the differentiation between colonisation and infection is challenging. To address these challenges, we describe a diagnostic algorithm. Current recommendations for therapy of NTMs in HIV patients are based primarily on expert opinion. Therapy should include more than one antimicrobial from the several drugs currently recommended for the NTMs isolated from the patient. Consideration should be given to drug interactions, toxicity and level of immunosuppression. Due to the lack of correlation between in vitro and in vivo activity, a close clinical follow-up is needed to evaluate response and determine whether therapy should be modified.

  14. Page 138
    Abstract
    Correspondence: Alison Morris, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, 628 NW MUH, Pittsburgh, PA 15213, USA. E-mail: morrisa@upmc.edu

    Despite significant advances in ART and prophylactic antibiotics, PCP remains a common opportunistic infection among those with HIV, particularly among persons unaware of their HIV serostatus and in low- and middle-income countries. In high-income countries, PCP is the most common cause of respiratory failure among HIV-infected adults. Clinical, laboratory and radiographic findings in the correct clinical setting may strongly suggest the diagnosis, but confirmation of PCP requires cytological confirmation from a lower respiratory specimen. Noninvasive and non-microscopic methods of establishing the diagnosis, including PCR testing of upper respiratory samples and serum measurements of fungal elements, are active areas of investigation. The backbone of both prophylaxis and treatment of PCP remains TPM-SMX. Identifying persons with HIV and instituting appropriate ART will be key to continuing to decrease the burden of PCP.

  15. Page 153
    Abstract
    Correspondence: Eva Polverino, Respiratory Diseases Dept, Institut Clínic del Tòrax, Hospital Clinic i provincial de Barcelona – IDIBAPS – CIBERES, Calle Villarroel 170 08036, Barcelona, Spain. E-mail: epolveri@clinic.ub.es

    Pulmonary infections are frequent in immunosuppressed adults and are predominantly viral. The advances in molecular diagnostic methods have increased our understanding of the role of viruses in pneumonia. Viral pneumonia is an important cause of morbidity and mortality in the immunocompromised population; however, only limited information is available concerning its impact on patients with HIV infection. In this chapter, we will review the most frequent respiratory viruses that have been implicated in viral respiratory infections and give particular attention to pneumonia in HIV-infected patients. Therefore, we will discuss the epidemiological characteristics, the clinical presentation, and the most appropriate diagnostic approaches and therapies (where available) for these viral infections.

  16. Page 171
    Abstract
    Correspondence: Matthias Stoll, Clinic for Immunology and Rheumatology, Hannover Medical School (MHH), Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail: Stoll.Matthias@mh-hannover.de

    Fungal or protozoan infections of the respiratory tract are less common than viral or bacterial infectious diseases. In the immunocompetent host, most of these infections are rare and predominantly present as mild and self-limiting. Immunocompromised patients, particularly those with T-cellular immunodeficiency or prolonged neutropenia, are at increased risk of opportunistic fungal and protozoan infections and a more severe and prolonged course of disease.

    Whereas candidiasis, cryptococcosis and aspergillosis are prevalent worldwide, other fungal diseases, such as histoplasmosis, coccidioidomycosis, penicilliosis and blastomycosis, are endemic to certain areas, though may also be recognised as imported diseases in nonendemic regions. Although specific and sensitive modern microbiological diagnostic tools and therapeutic options have been established for most diseases, some are either rarely available in low-income/high-prevalence countries or are not often used outside the endemic areas. Hence it is recommended that advice is sought from specialised laboratories and physicians of infectious diseases.

  17. Page 186
    Abstract
    Correspondence: Jean-Paul Sculier, Institut Jules Bordet, Rue Héger-Bordet, 1, B-1000 Bruxelles, Belgium. E-mail: sculier@bordet.be

    Cancer is frequent in patients with AIDS. This chapter deals with three neoplastic diseases that can occur in the thorax: lung cancer, which is the most frequent in western countries; and Kaposi's sarcoma and non-Hodgkin lymphoma, which are two of three cancers that define AIDS. The epidemiology, clinical presentation, treatment and prognosis are reviewed for these three particular tumours in the context of AIDS.

  18. Page 199
    Abstract
    Correspondence: Engi F. Attia, Harborview Medical Center, 325 Ninth Avenue, Campus Box 359762, Seattle, WA 98104, USA. E-mail: eattia@uw.edu

    As ART access expands in low- and middle-income countries (LMICs), HIV-infected individuals are anticipated to experience prolonged survival along with a greater burden of chronic obstructive lung diseases, similar to increases observed among HIV-infected cohorts in high-income nations. COPD related to cigarette smoking is the major aetiology of chronic obstructive lung diseases in adults living with HIV in high-income countries but the pathophysiology of chronic lung diseases is less well understood in LMICs. The distribution of exposure to risk factors for obstructive chronic lung diseases, such as tobacco smoking and other substance use, indoor biomass burning, and occupational and environmental pollutants, varies across LMICs and high-income countries. A better understanding of the risk factors for chronic obstructive lung diseases and their management among HIV-infected populations is critical to inform patient care and improve outcomes.

  19. Page 218
    Abstract
    Correspondence: Rodrigo Cavallazzi, Dept of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Louisville Health Sciences Center, 401 E Chestnut St, Suite 310, Louisville, KY, 40202, USA. E-mail: rcavallazzi@gmail.com

    It has been increasingly recognised that patients with HIV infection are at higher risk of noninfectious lung disorders. Of these, the interstitial lung diseases stand out as an important group of disorders for which the pathogenesis is not fully understood, despite significant advances over the past three decades. Lymphocytic interstitial pneumonitis, nonspecific interstitial pneumonitis, organising pneumonia, follicular bronchiolitis, sarcoidosis and drug-induced interstitial lung disorders have been reported in the setting of HIV infection. With the advent of effective cART, it seems that the epidemiology of these diseases is changing. For instance, the prevalence of LIP appears to be declining while other conditions, such as sarcoidosis, may be on the rise. The immunosuppressed state of HIV-infected patients with interstitial lung diseases often creates a conundrum for the clinician, as some of these conditions are treated with immunosuppressants. There is an enormous need for research in this area, as much of the literature remains anecdotal. This should come in the form of investigations exploring viral–host interactions, as well as carefully designed clinical studies.

  20. Page 232
    Abstract
    Correspondence: Olivier Sitbon, Service de Pneumologie, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France. E-mail: olivier.sitbon@bct.aphp.fr

    PAH is found in approximately 0.5% of patients with HIV infection. The pathogenesis of PAH–HIV is not completely elucidated. It is widely believed that HIV plays an indirect role in the development of PAH–HIV as a result of production mediators, such as cytokines, growth factors or vasoconstrictors. The role of inflammatory mediators is supported by the presence of a marked inflammatory infiltrate in the pulmonary vessels of patients with PAH–HIV. The histopathological and clinical findings in PAH–HIV share many features with the idiopathic form of the disease. Until recently, PAH–HIV was associated with a particularly poor prognosis and patients with the disease tended to die from the effects of PAH rather than as a result of HIV infection. With the availability of ARTs given in combination with PAH-targeted therapies (prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors), the prognosis of the disease has markedly improved in recent years. Therefore, prompt diagnosis and effective treatment of PAH in HIV-infected patients remains essential. Taking into account currently available data and clinical experience, a treatment algorithm based on treatment guidelines for other forms of PAH is suggested.

  21. Page 247
    Abstract
    Correspondence: Montserrat Vendrell, Bronchiectasis Group, IDIBGI, Dr Trueta University Hospital, Avd França s/n (9 planta), 17007 Girona, Spain. E-mail: mvendrell.girona.ics@gencat.cat

    The immune defects associated with HIV infection increase susceptibility to lower respiratory infections and may predispose to the development of bronchiectasis. Bronchiectasis should be considered among the pulmonary manifestations of HIV infection, although the true incidence of bronchiectasis in this population remains to be established. It is especially important to consider the disease in patients with recurrent respiratory infections, a history of mycobacterial disease, or persistent or intermittent productive cough; diagnosis should be made using high-resolution computed tomography. An HIV test should be included as part of the diagnostic work-up both in patients with risk factors for HIV and in those from areas with significant levels of HIV infection. Early diagnosis and assessment in a specialist respiratory medicine unit, particularly in the event of chronic bronchial infection or recurrent exacerbations, may reduce the progression of bronchiectasis. It is probable that bronchiectasis in LIP is a different entity requiring different treatment and management.

  22. Page 253
    Abstract
    Correspondence: David M. Murdoch, Division of Allergy, Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC 27710, USA. E-mail: david.murdoch@duke.edu

    IRIS is an increasingly recognised complication of ART initiation, particularly in HIV patients co-infected with other infectious pathologies. The syndrome is characterised by a clinical picture of an unexpected and often exuberant inflammatory response following ART. Clinically, the syndrome is most commonly classified as an unmasking or paradoxical form. Although these definitions have increased understanding of its pathogenesis and risk factors, the clinical diagnosis of IRIS remains challenging due to its heterogeneous infectious and noninfectious aetiologies, and spectrum of clinical severity. Although IRIS imparts a significant morbidity, including increased hospitalisation rates and diagnostic procedures, direct IRIS-attributable mortality is low. The mainstay of treatment is continuation of ART and, in severe or life-threatening presentations, the administration of nonsteroidal anti-inflammatory drugs and/or systemic corticosteroids. Cessation of ART may also be necessary if inflammation is severe and life threatening, or if the differential includes drug toxicity.

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