Treatment Drugs. Standard \200\230four drug \200\231 treatment with a rifamycin (usually e ither rifampicin or rifabutin), plus isoniazid, pyrazi- namide and ethambutol for two month s followed by con- solidation with rifamycin and isoniazid is the treatment of choice for d rug sensitive disease. Vitamin B6 (10 \200\22325mg once daily) is usually also given to pro tect against isoniazid- induced peripheral neuropathy. Six months \200\231 treatment is adv ocated for most patients; though should be prolonged to nine months in those with cavitator y pulmonary disease, or positive cultures after two months \200\231 treatment where the org anism is known to be drug sensitive and patient adherence is very good. The prolonged durat ion of therapy is designed to reduce the higher risk of relapse that has been reported in t hese sub-groups. Treatment adverse events are common. Moderate to severe rash, hepatotox- i city or gastro-intestinal disturbance occurs in up to 40% of co-infected subjects. This is in part due to the overlapping toxicities with HAART. The best example of this is the perip heral neuropathy that will almost certainly result if isoniazid is given together with the nucleoside reverse transcriptase inhibitor stavudine. Mycobacterium tuberculosis As a genuine and global pathogen, TB can present in all HIV infe cted individuals at any stage of HIV infection. The T cell defects associated with HIV mean that the chance of an individual who has latent TB infection progressing to active clinica l disease is 50 \200\223100 times greater than background rates in HIV negative subjects. T his translates roughly as a reactivation rate of 5% per year compared to a lifetime risk of 5% in HIV-negative individuals. Clinical presentation Patients with higher CD4 counts (>350 cells/ l) present in a similar manner to HIV-negative patients with TB. The immune dysregulation associated with falling blood CD4 counts means that as the CD4 count drops to below 200 cells/ l, patients are mor e likely to have non-pulmonary, disseminated and multi-organ disease. Pulmonary manifes- ta tions are also often different at low blood CD4 counts. \200\230Typical \200\231 chest rad iographic cavitation is replaced by pulmonary in \201 ltration, pleural effusions and medi astinal lymphadenopathy, Table 9.2.4 Treatment schedules for Pneumocystis jirovecii pneumonia Drug Dosage Notes Use in moderate to severe PCP Dilute 1:25 in 0.9% saline infused over 90 \200\223120 minute s Trimethoprim- sulfamethoxazole Trimethoprim 20mg/kg IV q24h and sulfamethoxazole 100mg/kg IV q24h in 2 \200\2233 divided d oses for 3 days then reduced to trimethoprim 15mg/kg IV q24h and sulfamethoxazole 75mg/kg I V q24h in 2 \200\2233 divided doses for 18 further days Same daily doses of trimethoprim-sulphamethoazole PO q24h, in 3 divided doses for 21 days Use in mild to moderate PCP 1920mg (2 trimethoprim-sulphamethoxazole double strength tablets) PO q8h for 21 days Clindamycin- primaquine Clindamycin 600 \200\223900mg IV q6h or q8h IV and primaquine 15 \200\22330mg PO q24h for 2 1 days Methaemoglobinemia Less likely if dose of 15mg PO q24h of primaquine is used Clindamycin 300 \200\223450mg PO q6h to q8h and primaquine 15 \200\22330mg PO q24h for 21 d ays Pentamidine 4mg/kg IV q24h for 21 days Dilute in 250mL 5% dextrose in water and infuse over 60 minutes Trimethoprim- dapsone Trimethoprim 20mg/kg PO q24h in 3 divided doses and dapsone 100mg PO q24h for 21 days Atovaquone 750mg PO q12h for 21 days Give with food to increase absorption Prednisolone 40mg PO q12h, days 1 \200\2235 40mg PO q24h, days 6 \200\22310 20mg PO q24h, days 11 \200 \22321 Start corticosteroid as soon as possible and within 72 hrs of commencing speci \201 c anti -PCP treatment, if PaO2 <9.3 kPa (<70 mmHg) Methylprednisolone IV at 75% of dose given above for prednisolone A DUNLEAVY, M LIPMAN & R MILLER 216 Treatment Treat with either IV liposomal amphotericin and \202 ucyto- sine in meningitis and disseminated disease; or high dose \202 uconazole if there is more limited pulmonary disease. Generally, HAART should be commenced as soon as pos- sible, though IRIS may be mor e likely if HAART is started early. Drug-drug interactions are common in HIV patients with TB. One of the main pharmacokinetic areas of concern is that between rifamycins and antiretroviral drugs. Rifampicin is a poten t inducer of the cytochrome P-450 system. Non- nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PI) are metabolized using cytochrome P-450. Thus reduced concentrations of the NNRTIs and PIs and the development of resistance to HIV can occur if used in combination with rifampicin. Rifabutin is a less potent inducer of the cytochrome P -450 system, but is also a sub- strate of the same enzyme. Hence drugs such as PIs which in hibit the cytochrome P-450 system will lead to increased serum concentrations of rifabutin. Although there are lim- ited clinical trial data with this drug, most clinicians feel that it is as effective as rifampicin when treating TB. Timing of commencing HAART. The \201 rst priority for the TB/HIV co-infected patient is to treat TB. The optimal time to start r emains unclear. A suggested approach is (1) in those with a CD4 count of >200 cells/ l to withhold HAART for the duration of TB treatment; (2) in those with a CD4 count <200 cells/ l but >100 cells/ l to delay HAART until the patient is established on anti-TB therapy (u sually up to two months); (3) to start HAART as soon as possible in those with a CD4 count of <100 cells/ l (usually after about two weeks, based on physician assessment). Drug resi stance is twice as common in HIV co-infected individuals. Multi drug resistance and XDR (ex tremely drug resistant) TB is an increasing global problem. This is likely to be due to rap id progression from latent to active infec- tion combined with delayed diagnosis of disease through atypical presentation. IRIS is commonly associated with TB. Its diagnosis and mana gement is discussed in more detail in the next chapter. Aspergillosis Aspergillosis is relatively rare in HIV-infected individuals compared to thos e with severe immunocompromise from other causes. It is usually seen in the context of prof ound immunosuppression (blood CD4 counts <50 cells/ l). This may also be associated with n eutropenia from drugs such as co-trimoxazole or zidovudine; or the use of systemic glucocor ticoids. Diagnosis rests on the clinical picture plus radiology with or without identi \201 cation of aspergillus from lung specimens. The diagnostic utility of measuring galacto - mannan in blood or lung has not yet been de \201 ned in the HIV-infected patients. Treat ment is similar to that used in other patients, with either voriconazole or liposomal ampho tericin B being \201 rst choice therapies. Candida Candidal infection of the trachea, bronchi and lungs is rare in HIV-infected indivi duals. Although isolation of candida in the sputum is common it usually represents coloniza tion of the oropharynx. Endemic fungi Histoplasma, Coccidioides, Blastomycoses, Paracoccidioides, and Penicillium i nfection are rare in the UK; though should be considered in patients with signi \201 cant immunosuppres- sion who have spent time in parts of the world where these fungi are endemic (see earlier in chapter). The typical presentation is with disseminated disease rather tha n iso- lated pulmonary infection. Just as with cryptococcal infec- tion, patients may have a variety of skin lesions present. These will often be culture positive if biopsied. Treatm ent should be undertaken with specialist input, though in an emergency, IV amphotericin B w ill be effective. Other mycobacterial infections These are generally seen in subjects with blood CD4 <100 cel ls/ l. Isolated pulmonary disease is less common than disseminated infection. It can occur most frequently with Mycobacterium avium-intracellulare complex (MAC), Mycobacterium kansa sii, and Mycobacterium xenopi. Diagnosis is based on a positive culture from a usually ster - ile site (e.g. blood or bone marrow), or multiple positive respiratory samples with consi stent symptoms. Treatment usually consists of a macrolide and ethambutol with or without a rifamycin. Viral infections Community-based viral infections including In \202 uenza A and B occur wi th equal frequency in HIV-infected and non- infected patients. Cytomegalovirus (CMV) Clinical presentation Symptoms are generally quite non-speci \201 c but may mimic PCP. Fungal infections Cryptococcus neoformans Clinical presentation In the lungs infection can present as either primary pulmo- nary cryptococcosis or often as part of a disseminated inf ection complicating cryptococcal meningitis. The former presents in a similar manner to oth er respiratory infections. Diagnosis CMV can be isolated in the BAL \202 uid of up to 50% of patients presenting wit h low CD4 counts but less than 5% of those patients will have a genuine CMV pneumonia. A de \201 nitive diagnosis of CMV pneumonia requires identi \201 a- ble or characteristic int ranuclear and intracytoplasmic inclusions in a lung \202 uid specimen. A high plasma CMV DNA plasma copy (>5000 copies/ml) within the blood increases the risk of future end-organ d isease. Diagnosis Can be made by direct staining for the organism in sputum, BAL or CSF. Cryptococc al antigen (CrAg) in high titres in the blood suggest dissemination but are often negative with primary pulmonary disease, in which case BAL \202 uid CrAg is a reliable test. Treatment Treatment, if required, is with IV ganciclovir or oral valgan- ciclovir. CHAPTER 9.2 Infection in the HIV compromised host 217 Further reading Breen RA, Swaden L, Ballinger J, et al. Tuberculosis and HIV co-infection: a practical therapeutic approach. Drugs 2006; 66(18): 2299 \200\2232308. the Infectious Diseases Society of America. MMWR Recomm Rep 2004; 53(RR-14): 1 \200\22392. Pozniak AL, Miller RF, Lipman MC, Freedman AR, Ormerod LP, Johnson MA, et al. BHIVA treatme nt guidelines for tuberculosis (TB)/HIV infection 2005. HIV Med 2005; 6(Suppl 2): 62 \200 \22383. Lipman MCI, Baker RW, Johnson MA (2004). An Atlas of Differential Diagnosis in HIV Disease, 2nd ed. New York: The Parthenon Publishing Group. The Health Protection Agency. Testing Times - HIV and other Sexually Transmitted Infections in the United Kingdom: 2007. 2007 Nov 23. Lipman M, Breen R. Immune reconstitution in \202 ammatory syndrome UNAIDS/WHO. 2007 AIDS epidemic update. htt p:// w w w . u n a i d s o r g / e n / K n o w l e d g e C e n t r e / HIVData/EpiUpdate/EpiUpdArchive/2007 2007 [cited 2008 Jun 15]; Avail able from: URL: http://www. unaids.org/en/KnowledgeCentre/HIVData/ EpiUpdate/EpiUpdArchive/ 2007 in HIV. Curr Opin Infect Dis 2006;19(1): 20 \200\22325. Miller R, Lipman M. Acquired Immunode \201 ciency Syndrome and the Lung: Pulmonary Infections. Clin Resp Med 2008 433. Mofenson LM, Oleske J, Serchuck L, et al. Treating opportunistic infections among HIV-expos ed and infected children: recom- mendations from CDC, the National Institutes of Health, an d A DUNLEAVY, M LIPMAN & R MILLER 218 9.3 Non-infectious HIV-related lung disease Before the widespread introduction of HAART, reduced patient survival plus the inevitabilit y of acute opportunistic infection meant that chronic, usually non-infectious lung disease was less relevant to HIV and respiratory physicians. This has now changed; and such conditi ons are often encountered in clinical practice. Just as with HIV-related infectious disease s, an individual \200\231s level of immunosuppres- sion (measured by blood CD4 T-cell count and HIV plasma load) provides a useful guide to those illnesses that are likely to occur i n a given clinical setting. For example, pul- monary Kaposi sarcoma (KS) is seen mainly in subjects with very low blood CD4 counts, and is now much less common, therefore, in populat ions using HAART. Conversely, as patients live longer, COPD and lung cancer are more freque ntly encountered, irrespective of CD4 count. Natural history studies pre-HAART reveal a pro gressive loss of pulmonary CD4 T cells and an associated CD8 T-cell alveolitis in the HIV-i nfected lung. The immune dysregulation also involves macrophage activation and widespread c hanges in local cytokine production. pre-requisite for its development; though HIV drives the neoplastic process such that it is approximately 1000 times more frequent in this setting than in HIV-uninfected popu- lation s. It occurs at a considerably greater rate in men who have sex with men, and black African s, than in other HIV positive individuals. It primarily involves muco-cutaneous tissues but is also found at other sites including the lung, lymph nodes and gastro-intestinal tract. Pulmonary KS can involve any of the intra-thoracic structures. Up to one- third of patients with known extra-pulmonary KS will have clinically evident lung involvement. This rises to 50% at autopsy. Clinical features The symptoms and signs associated with pulmonary KS are often non-speci \201 c but gradual-onset breathlessness and cough (with or without haemoptysis) are the mos t com- mon presenting features. Careful examination of skin and mucous membranes, in partic ular, should be undertaken, as often KS involvement will be present at these sites in affec ted individuals. AUTHOR \200\231S TIP Several of the conditions that will be discussed in this chapter are t hought to arise from these particular effects; or, in the case of immune reconstitution in \202 ammatory syndrome (IRIS), when this is reversed by HAART. General approach The clinical approach to the patient is similar to that out- lined in the Chapter 9.2. In those with severe immunocom- promise (essentially a blood CD4 count of <200 cells/ L), opportunistic infections must be considered in the com- mon clinical presentat ions of e.g. breathlessness, sputum production and systemic illness. AUTHOR \200\231S TIP The importance of obtaining tissue or lung \202 uid samples, again, cannot be over-emphasized; and diagnostic proce- dures often required with suspected non-in fectious dis- eases include CT-guided biopsy, VATS or open lung biopsy, and mediastinoscopy /mediastinotomy and biopsy. Transbronchial needle aspiration and endoscopy/bron- choscopic biopsy techniques are also more frequently used as part of the diagnostic work-up Fig. 9.3.1 CT Thorax of Pulmonary Kaposi Sarcoma demonstrating the bronchovascular distribu tion of nodules. Diagnosis Chest radiographic and CT features are variable. These include parenchymal nodule s (often bronchovascular in distribution), consolidation, pleural effusions (which are ofte n haemorrhagic) and intra-thoracic lymphadenopathy. KS lesions are quite distinctive on bro nchoscopy. They are \202 at or raised red or purple plaques. Endobronchial biop- sies are usually not performed as there is a risk of bleeding from these vascular tumors. However a n experienced bronchoscopist may wish to con \201 rm this diagnosis if there is no evidenc e elsewhere for KS. Unexplained pleural disease is probably best assessed using VATS. Non-infectious pulmonary conditions can be broadly clas- si \201 ed as neoplastic, in \202 ammatory (both alveolar and air- way) and vascular. Malignancy and HIV Kaposi sarcoma was the \201 rst malignancy clearly associated with the HIV pandemic. Other important tumors and tumor-like conditions include lymphomas, lung can cer and Castleman disease. KS KS is the most common malignancy seen in HIV-infected individuals. Co-infection with Hum an Herpes Virus 8 (HHV-8, also known as KS Herpes Virus, KSHV) is a Treatment \200 This depends on the degree of cutaneous and visceral involvement; though will always be off ered to patients with pulmonary disease. CHAPTER 9.3 Non-infectious HIV-related lung disease 219 HAART should be given if it is not already prescribed. This will reduce KS lesions in 50 \200\22380% of individuals over a several month period. However IRIS-related worsen- ing of KS has been reported. It is not particularly com- mon, though needs to be considered if th e patient has apparently worsening disease on HAART. Systemic chemotherapy is usually warra nted with lung involvement, especially if the patient is symptomatic, or has rapidly progre ssive disease. Liposomal anthracyclines are most commonly used \200\223 with good results. As in other malignancies, a patient \200\231s performance status and co-morbidities need t o be taken into consideration; though single agent chemotherapy is usually well-tolerated. Current treatments have improved median survival with pulmonary KS from less than six month s to greater than \201 ve years. A worse overall prognosis is associated with hypoxia, pl eural disease and low blood CD4 counts at presentation. three to four times more common in HIV-infected individ- uals than in the general populatio n. The vast majority are cigarette smokers; though they are, on average, younger than other lung cancer patients, with a higher than expected frequency of non-small cell adenocarcino ma tumors. Injecting drug users appear to be particularly at risk \200\223 though this may be confounded by higher smoking rates in this population. Unlike the other malignancies de scribed, there appears to be little association with CD4 counts; and only a modest decrease , if any, in incidence with the use of HAART. This may re \202 ect the different oncogenic process involved in lung cancer development compared to that in KS and lymphomas. Clinical presentation Although symptoms and signs are similar to those in HIV- negative ind ividuals, systemic symptoms including fever are more frequently encountered. Patients also tend to have more advanced disease at diagnosis. Lymphoma and lymphomatous conditions Just as with KS, oncogenic viruses are important in th e pathogenesis of a number of lymphomas. Most non- Hodgkin lymphoma (NHL) is associated wit h Epstein \200\223Barr virus; whilst primary effusion lymphoma (PEL) and multi- centric Cas tleman disease (MCD) are linked to HHV-8. The latter two conditions are rare in non HIV-inf ected sub- jects. PEL (also known as body cavity-associated lym- phoma) presents as an effu sion with no identi \201 able tumor mass. Castleman disease (mult-centric angio-follicular hyperplasia) mimics the features of disseminated mycobac- terial disease or lymphom. In bo th MCD and PEL, the out- look is poor as they are often not considered at an early stage of a patient \200\231s diagnostic pathway. Hodgkin disease also occurs at a greatly increased incidence in HIV-infected populations. Investigation is similar to that for NHL. It is rec ommended that all individuals who are diagnosed with a lymphomatous condition are offered a n HIV test, if this has not been performed recently. Diagnosis Chest radiographs and CT scans are as expected for lung cancer, although the diff erential diagnosis is inevitably more broad in the context of HIV infection and immuno- sup pression. The primary tumor site is often peripheral, and pleural effusions are present in 25% of cases. Assessment and staging is similar to that undertaken in the general populatio n. Treatment There is evidence to suggest that the diagnosis may not be considered at an early enough stage of a patient \200\231s illness. Inevitably investigation may have focused upo n infectious causes of the reported symptoms. As a result, lung cancer can appear to be mor e rapid and less amenable to surgical cure in this population. However, if surgery can be p er- formed, the outcome is no worse for resectable lesions than that seen in HIV negative s ubjects. The majority of individuals, however, are incurable and receive best sup- portive care with symptom control. Median survival is approximately four weeks from diagnosis with nearly 100% mortality at two years in most reported series. NHL NHL is several hundred times more common in HIV- infected subjects. Although its incide nce has decreased by half following the introduction of HAART, it remains a lead- ing cause of mortality; and can occur at any blood CD4 count (though is more common with declining i mmunity). There is a preponderance of high grade, aggressive B cell lymphomas (mainly Burki tt type, centroblastic or immuno- blastic). Pulmonary involvement is either with parenchyma l nodules, pleural effusions or intra-thoracic lymphadenopa- thy. B type symptoms are more frequently seen than in pulmonary KS; and the differential diagnosis often rests between ly mphoma and mycobacterial disease. Clinical features that might suggest lymphoma include ele vated lac- tate dehydrogenase (>1000 IU/L) and lack of lymph node central necrosis on CT sc anning. It should be stressed that these are very insensitive markers, and diagnosis relies upon good quality tissue biopsy. Treatment is with similar regimens to those used in HIV n egative populations. It is clear that the addition of HAART greatly improves outcome (throu gh a reduction in chemo- therapy \200\223 and HIV-related opportunistic infections). Howev er drug-drug interactions are common and need to managed expectantly. Overall median surviv al has risen from less than six months to several years. IRIS Paradoxical symptomatic deterioration following the start of appropriate treatment has been reported by TB physi- cians for over 50 years. The use of HAART, with resultant profo und and rapid changes in immunity, has led to similar clinical events in HIV infected indiv iduals, and been termed IRIS. They are thought to arise from an over-vigorous inter- action between antigen and the host immune response. This typically occurs within a few weeks of starting HAART, though can be up to months later in certain cases. It has been associated w ith a wide variety of organisms as well some apparently non-infectious antigens. However it is most commonly seen in individuals with TB, cryptococco- sis and non-tuberculous mycobac terial infection. Here it has been reported in 15 \200\22335% of HIV-infected patients usin g HAART. Clinical presentation IRIS has two common presentations. Using TB as an exam- ple these are : \200 Paradoxical IRIS \200\223 where the patient is on treatment for active TB, is getting bett er and then starts HAART with a subsequent clinical deterioration. Post-HAART TB-IRIS, wher e an asymptomatic individual starts HAART and develops a rapid-onset and very Lung cancer Although not regarded typically as an HIV-associated malig- nancy, recent data suggest that lung cancer is approximately A DUNLEAVY, M LIPMAN & R MILLER 220 Prevention and treatment \200 (a) Prior to commencing HAART, patients should be screened thoroughly for active opportunistic infection, to minimize the risk of unmasking IRIS. If clinical disease does occur, the rele vant organism should be treated in the usual way. HAART does not normally require dis- cont inuation. In cases of mild, paradoxical IRIS, no treatment may be required other than caref ul observation, as the condi- tion is usually self-limiting. Lymph node disease that is sup purating is often relieved with repeated aspiration. The obtained samples should be culture d, to exclude new or active infection. Corticosteroids are bene \201 cial, though have con siderable adverse effects and should be reserved for more severe manifestations of IRIS. Th ere is no consensus on dose or duration of treatment. Most clinicians would start with arou nd 30 mg prednisolone equivalent (irrespective of concurrent rifamycin use). In severe case s, expert advice should be sought. In general, HAART is not usually stopped, as there is a risk of rapid decline in systemic immunity and opportunistic disease. (b) COPD HIV-infected smokers have an approximately two-fold greater risk of COPD than non-infe cted smokers. Controlling for degree of tobacco exposure, they also appear to have more ana tomical emphysema at presenta- tion. This is further increased in patients who smoke other recreational drugs, in particular crack cocaine. Infection and colonization with bacteria a nd fungi (including Pneumocystis jirovecii) also predisposes to COPD. Symptoms are similar to those of COPD and emphysema in the general population. On chest radiography and CT- scan ning there is an upper lobe predominance of bullous disease and centrilobular emphysema. Tr eatment is in line with COPD guidance, though there are some important interactions between HAART and respiratory medications that should be noted. In particular, the protease inhibi tor ritonavir increases the effective dose of both inhaled and intranasal budesonide and \202 uticasone. Given the increased smoking rates documented in HIV- infected patients, str enuous efforts should be made to encourage smokers to quit. Targeted smoking cessation prog rams are not widely available, and to date have not met with much success. Fig. 9.3.2 Chest radiography before and after commencing TB treatment 35-year-old woman wit h TB-IRIS. The \201 rst chest radiograph (a) was before the initiation off HAART and anti - tuberculosis treatment. The second chest radiograph (b) was taken during the onset of imm une reconstitution and demonstrates increased in \201 ltrates in the left mid-zone. inflammatory episode of TB. This is often termed \200\230unmasking \200\231 of a previousl y unknown and untreated infection. In either case, symptoms and signs are variable, though there is usually a degree of systemic upset. Expansion of intra-cerebral or mediastinal mas ses, or increases in pericardial \202 uid volume may be life-threatening, though this is relatively rare. Alveolitis associated with HIV Patients with HIV-infection can develop a number of sub- acu te or chronic alveolar disorders which are often only distinguished on histo-pathology. The se are lymphoid inter- stitial pneumonitis (LIP), non-speci \201 c interstital pneumoni- t is (NSIP) and organizing pneumonia. All present in a non-speci \201 c manner, often with d ry cough, progressive breathlessness, weight loss and fever. As such they are often mis-dia gnosed clinically as opportunistic infection. Diagnosis often requires a combination of cli nical, radiol- ogy and lung function \201 ndings together with tissue biopsy. Diagnosis There is no laboratory test that helps to distinguish IRIS from other causes of c linical deterioration, such as alterna- tive undiagnosed infection or malignancy; non-adher ence to treatment; drug resistance, malabsorption, hypersensi- tivity or drug-drug interact ion. Hence these should always be excluded before IRIS is con \201 dently diagnosed. It is gen- erally accepted patients with IRIS should have a demon- strable effect of HAART \200 \223 usually a decrease in plasma HIV viral load. Most studies suggest that individuals at greatest risk of paradoxical IRIS following HAART have low baseline blood CD4 counts (<50 c ells/ L) and/or commence antiretrovi- rals within a few weeks of starting speci \201 c op portunistic infection treatment. LIP LIP was initially described in children with HIV infection and slowly progressive breat hlessness and hypoxia. A milder form has been identi \201 ed in adults. This is often asso ciated with CD8 T cell in \201 ltration in other tissue sites including the parotid glands \200\223 and is known as diffuse in \201 l- trative lymphocytosis syndrome (DILS). Featu res on HRCT CHAPTER 9.3 Non-infectious HIV-related lung disease 221 include reticular or nodular opacities, patchy ground-glass attenuation, centri-lobular nod ules and soap-bubble like cysts. HAART is a useful treatment of adult LIP. Symptoms and rad iological abnormalities will often improve without the need to resort to corticosteroids. with exclusion of other known causes of PAH. Investigation should include CT chest with pul monary angiography, as pulmonary embolism is probably also more common in HIV infected subj ects, due to protein C, S and anti-thrombin III de \201 ciencies. Tissue biopsies reveal r emodeling of the pulmonary arterial tree at various levels as well as plexi- form lesions. NSIP Prior to the widespread use of HAART, this disorder was reported relatively frequently in subjects with low CD4 counts presenting with cough, breathlessness and mild fever who w ere had no evidence for infections such as Pneumocystis pneumonia. Diagnosis is based on th e charac- teristic features being present on lung biopsy. These are similar to those of LIP (lymphocytic and plasma cell in \201 ltra- tion) plus also non-speci \201 c alveolar sep tal edema. It is now rarely reported \200\223 which probably re \202 ects the much earlie r use of effective anti-retrovirals in this population. Treatment, if required, is also wit h HAART, if this is not already being taken. Treatment Treatment is broadly similar to that for HIV negative sub- jects with idiopathic PAH. One caveat is that calcium chan- nel blockers are generally contra-indicated as they i nteract with many protease inhibitors, leading to signi \201 cant hypo- tension and decrea sed right heart \201 lling. There is evidence that the use of HAART leads to improvements in symp- toms as well as pulmonary haemodynamics. It also reduces the possibility of furth er respiratory disease, and is there- fore given by most clinicians if primary PAH is eithe r suspected or con \201 rmed. Pulmonary hypertension associated with HIV (PAH) Primary pulmonary arterial hypertension (P AH) is reported to be much more common in HIV infected indi- viduals (six to twelve times t hat of the general population). Its prevalence in some European cohorts is up to 0.5% of th e HIV-positive population. It is diagnosed when an HIV- infected individual develops pulmon ary artery hyperten- sion and no secondary cause can be identified. The etiology is unknown though may be related to associated viral infections such as HHV-8 or HIV itself. Further reading Humbert M, Sitbon O, Chaouat A, et al. Pulmonary Arterial Hypertension in F rance: Results from a National Registry. Am J Respir Crit Care Med 2006; 173(9): 1023 \200 \2231030. Lipman M, Breen R. Immune reconstitution in \202 ammatory syndrome in HIV. Curr Opin Infect Dis 2006; 19(1): 20 \200\22325. Lipman MCI, Baker RW, Johnson MA (2004). An Atlas of Differential Diagnosis in HIV Disease, 2nd ed. New York: The Parthenon Publishing Group. Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconsti tution in \202 ammatory syndrome: case de \201 nitions for use in resource-limited settings. The Lan cet Infectious Diseases 2008; 8(8): 516 \200\223523. Clinical presentation Most affected patients are already known to be HIV infected and prese nt with exertional breathlessness. Given its insidious nature, it is often considered, and therefore diagnosed, late in its clinical course. PAH has no apparent association with an i ndividual \200\231s level of immunosuppres- sion or clinical stage. Ognibene FP, Masur H, Rogers P, et al. Nonspeci \201 c interstitial pneu- monitis without evidence of Pneumocystis carinii in asympto- matic patients infected with human immunode \201 ciency virus (HIV). Ann Intern Med 1988; 109(11): 874 \200\223879. Petrache I, Diab K, Knox KS, et al. HIV associated pulmonary emphysema: a review of the lit erature and inquiry into its mecha- nism. Thorax 2008; 63(5):463 \200\223469. Spano JP, Costagliola D, Katlama C, et al. AIDS-Related Malignancies: State of the Art and Therapeutic Challenges. J Clin Oncol 2008. Diagnosis Diagnosis requires PAH to be con \201 rmed in an HIV infected individual, ideall y by right heart catheterisation; together This page intentionally left blank 223 Chapter 10 Bronchiectasis Chapter contents 10.1 Bronchiectasis (etiology) 224 10.2 Chronic disease management 228 D SMITH 224 10.1 Bronchiectasis (etiology) Overview Bronchiectasis is fundamentally an anatomical diagnosis describing abnormal perman ent dilatation of airways. It may be suspected clinically in patients with chronic cough an d purulent sputum production and con \201 rmed by plain or cross-sectional radiology of th e chest. Radiological bronchiectasis without clinical symptoms is an increasingly common \201 nding of uncertain signi \201 cance. Table 10.1.1 Classi \201 cation of recognized causes and associations of bronchiectasis Causes of bronchiectasis Congenital structural defects Tracheobronchomegaly (Mounier \200\223Khun syndrome) Defective cartilage (Williams \200\223Campbell syndrome) Pulmonary sequestration Elhers \200\223Danlos syndrome Marfan \200\231s syndrome Tracheomal acia Epidemiology No cross-sectional population studies exist but for a DGH population of 250,00 0 about 100 \200\223200 patients could be seen by a respiratory physician with a special in terest. The extent of severe disease in developed countries has declined since the advent o f vaccination programs, the decline in tuberculosis, widespread antibiotic use and improvem ent in living conditions. Balanced against this is an increasing rate of diagnosis of milde r disease consequent on the increasing availability of CT scanning in the last 25 years. Th is has been described as the era of \200\230modern bronchiectasis \200\231. Obstruction Tumor Foreign body External lymph node Impaired mucociliary clearance Cystic \201 brosis Ciliary dyskinesia Young \200\231s syndrome (bronchiectasis, sinusitis and azoospermia) Pathophysiology In the established bronchiectatic airway the key features are those of dila tation with damage to the structural com- ponents of the airway wall (elastin, muscle and c artilage). In addition there is \201 brosis that may extend into the adjacent lung parenc hyma. Chronic in \202 ammation with lymphoid fol- licles in airway walls and neutrophils i n the lumen drives overproduction of abnormally viscid mucus that is poorly cleared, result ing in stagnation and a fertile medium for bacterial colonization and persistence. This in turn encour- ages continued in \202 ammation and cytotoxic damage, a con- tinuing \200 \230vicious circle \200\231. The initial factor beginning the process of chronic in \202 a mmation may vary, for example an exogenous insult such as toxic gas exposure or foreign bod y inhalation or an endogenous defect of host defenses either congenital or acquired. Howeve r, what seems clear is that infection plays a key role both in the development and persiste nce of the disease. Immune de \201 ciency Common variable immunode \201 ciency Selective immunoglobulin de \201 ciency Functional n eutrophil defects Human immunode \201 ciency virus Excessive immune response Allergic bronchopulmonary aspergillosis Lung transplant rejection Chronic graft versus host disease Post-infective Tuberculosis Whooping cough Non-tuberculous mycobacteria Pneumonia Measles Adenovirus Swyer \200\223James syndrome Post- in \202 ammatory pneumonitis Aspiration Inhalation of toxic gasses Miscellaneous Diffuse panbronchiolitis Etiology Although the list of conditions recognized as causing bron- chiectasis is long (se e Table 10.1.1), in clinical practice the majority of cases are of unknown etiology. The mo st commonly identi \201 ed cause is previous severe pulmonary infection, including tubercu losis. Other relatively frequently identi \201 ed causes (up to 10% in some series) includ e ciliary dysfunction, immune deficiency (Stead) and allergic bronchpulmonary aspergillosis (ABPA). Table 10.1.2 shows causes and associations from 2 recent UK studies in tertiary re ferral centers (Pasteur, Shoemark). These results are a consequence of quite intensive inve sti- gation of a selected patient group; \201 ndings in a DGH popu- lation are likely to be different. In practice, investigation into etiology should be limited to identifying cau ses that might lead to speci \201 c therapeutic interventions over and above conventional treatment of the bronchiectasis and/or provide additional prognostic information for the pa tient and their family. Clues as to etiology may come form the history, examination, imagin g and microbiological investigations. Associations Rheumatoid arthritis In \202 ammatory bowel disease Systemic lupus erythematosis Sjogren \200\231s syndrome Ankylosing spondylitis Relapsing polychondritis Yellow nails syndrome (y ellow nails, pleural effusions and lymphoedema) Microbiology Most published studies of non-CF bronchiectasis in adults show similar microbi ological \201 ndings. The most commonly isolated organism is Haemophilus in \202 uenzae. Pseudomonas aeruginosa is present in about a fourth of patients in most series and affects patients with more severe disease. Moraxella catarrha lis and Streptococcus pneumoniae als o appear, as do anaerobic organisms. Staphylococcus aureus is a less common pathogen whose isolation should prompt consideration of CF as a cause. Aspergillus spp. may be cul- tured from some patients and should prompt consideration CHAPTER 10.1 Bronchiectasis (etiology) 225 \200 \200 \200 History of a previous severe infective episode. Family history (including infertility). Sym ptoms of gastro-oesophageal re \202 ux disease. Asthmatic features in the history (ABPA). Table 10.1.2 Frequency of causes and/or associations of bronchiectasis from 2 large UK stud ies (Pasteur, Shoemark) Cause Frequency Many patients will have had symptoms for most of their life that they accept as normal; per sistence in questioning about sputum frequency, volume, color and taste (foul taste suggest ive of anaerobic infection) are important in establishing a baseline. Equally important is an appreciation of the frequency and nature of exacerbations and their response to speci \201 c antibiotics. Past experience of physiotherapy training and the current practice of t he patient are useful to establish at the outset. Some consideration of the impact of disea se on the patient \200\231s quality of life is always worthwhile; many patients curtail soc ial activities because of embarrassment about their cough and sputum. Ideopathic 26-53% Post-infective 29-32% Ciliary dysfunction 1.5-10% Immune de \201 ciency 7-8% Allergic bronchopulmonary aspergillosis 7-8% Aspiration 0-4% Young \200\231s syndrome 3% Cystic \201 brosis 0-3% Rheumatoid arthritis 2-3% In \202 ammatory bowel disease 1-3% Panbronchiolitis <1-2% Examination The majority of patients will have few, if any, physical signs. Crackles and cl ubbing although classical are rare in mod- ern bronchiectasis. Most commonly a few coarse c rackles may be heard over the site of disease. In older patients there may be signs associa ted with previous surgical inter- ventions for the bronchiectasis itself (lung resection) o r for therapy of tuberculosis or other infections. Congenital <1-2% Atypical Mycobacterial 0-2% of ABPA as a causative factor or aspergilloma as a compli- cation. A proportion of patients will not reveal any pathogenic organisms on some samples. Burkholderia cepacia has been re ported in patients with non-CF bron- chiectasis. Isolation requires special culture media a nd should be speci \201 cally requested in patients with unex- plained deterioration. Occa sional samples should also be sent for mycobacterial culture, especially in cases with poor response to conventional antibiotics, haemoptysis or fever. Longitudinal studies suggest t hat, for the majority of patients, sputum isolates show consistent \201 ndings over time. This supports the usefulness of knowing a patient \200\231s microbiological history in pre dicting the likely organism causing an exacerbation.