Approach to the immune compromised patient with pulmonary in \201 ltrates The lung is the organ most commonly affected by compli- cations of immunosuppression. The term \200\230pul monary in \201 l- trates \200\231 can refer to many different disease processes (Table 9.1 .1): although infections are the commonest cause, not all in \201 ltrates are infections, and infection may co-exist with non-infectious processes in this population. When managing an immune compromised patient with lung in \201 ltrates, consider the whole picture, inclu ding risk factors and routes of infection. Many factors contribute to the \200\230net stat e of immune suppression \200\231: \200 The immune defect (due to underlying malignancy, drugs, radiotherapy, autoimmune disease, f unctional defects). Different defects are associated with different complica- tions and inf ections (see Table 9.1.2). Functional defects may not be apparent on simple blood tests. Re cent antimicrobial prophylaxis or treatment. Prophylaxis may defer rather than prevent the development of infection. The patient \200\231s past history: pre-existing lung disease inc reases the risk of infection, and previous complica- tions of immunosuppression may recur. Damage to other host defenses: disruption of skin or mucosal barriers by tumor, mucositis, surgery, intravas- cular devices, catheters, drains. The risk of aspiration, increased by s edation, mucositis, debility and myopathy. Co-infection with immunomodulating viruses (CMV, EBV, HHV 6 \200\2237, HBV, HCV). Comorbidity (e.g. renal failure, malnutrition, ischaemic heart disease, alcoholism, cirrhosis, diabetes). Environmental exposure: consider the geogr aphical prevalence of mycobacteria and endemic fungi (e.g. his- toplasma), other occupation al exposures such as aspergillus, zygomycetes and nocardia in gardeners and farmers, crypto coccus in pigeon breeders. Reactivation of existing infection (CMV, herpes viruses, tubercu losis, aspergillus). Infection from donated transplant organs or blood. Table 9.1.1 Some causes of pulmonary in \201 ltrates in the immune compromised patient Infection (opportunistic or non-opportunistic) \200 Drug-induced lung disease \200 Radi ation pneumonitis \200 Pulmonary oedema \200 Pulmonary embolism \200 Pulmonary hemorr hage \200 ARDS \200 Bronchiolitis obliterans organizing pneumonia \200 Transfusion-as sociated lung injury \200 Diffuse alveolar damage \200 Alveolar proteinosis \200 Post -transplant lymphoproliferative disorder \200 Recurrence of underlying disease in lungs ( e.g. metastatic Clinical features Pneumonia in the immune compromised patient often presents with non-speci \201 c symptoms of fever and malaise. Absence of fever does not exclude infection, and fe ver may be due to malignancy or drugs. Sputum is often not puru- lent, and may be absent. R ate of onset of symptoms may help diagnosis, e.g. acute onset (<24 hours) raises suspicion of oedema, haemor- rhage or embolism. Thorough physical examination is essential. There may be few speci \201 c respiratory \201 ndings, but look for clues such as the absence of crackles despite marked in \201 ltrates and hypoxia in PCP, or squeaks and wheezes in obli terative carcinoma, leukemia, lymphoma) CHAPTER 9.1 Pneumonia in the non-HIV immune compromised patient 203 Transbronchial biopsy (guided by recent CT) may detect malignancy, organizing pneumonia or drug-induced lung disease, and is more sensitive than BAL for invasive infec- tions (e.g. m ycobacteria, aspergillus). It should be consid- ered in all cases when BAL is performed, we ighing the potential bene \201 t against the risk of pneumothorax and bleeding. Percutaneo us lung biopsy under radiological guidance is use- ful in diagnosis of peripheral nodules, and surgical lung biopsy remains the de \201 nitive method to sample the lungs for diffuse or focal processes when the patient \200\231s condition permits. Specimens should be sent for microbiological analysis as well as histopathology. remainder being due to transfusions, drugs or tumor. Sputum production and pulmonary infilt rates may be absent in neutropenic patients with pneumonia. Pathogens The most common infectious complications of neutrope- nia due to chemotherapy are bacterial infections, including gram-positive bacteria (S. aureus, S. epidermidis, strepto - cocci) and Gram-negative bacteria (enterobacter spp., E. coli, Klebsiella, Pseudomonas). Invasive fungal infection with aspergillus, candida or mucor becomes more likely in profoun d, prolonged neutropenia (ANC <0.1). Solid organ transplantation (SOT) Pulmonary complications of lung transplantation are con- sidered elsewhere. Overall approach In all patients the aim should be to obtain a de \201 nitive diag- nosis of infective/non-infective disease as soon as possible, with low thresholds for CT scanning , bronchoscopy and biopsy. Exclusion of infection with BAL allows treatment with corticoste roids for many non-infective pathologies. Delay in diagnosis is associated with markedly wo rse out- come. However, if the patient is unwell or profoundly immunosuppressed, broad-spec trum empirical therapy should be started without waiting for the results of special investi gations. Timing of pulmonary infections after transplantation First month: the risk of infection is due more to surgery and intensive care than to immunosuppressive therapy. Prolonged ventila tion increases the risk of nosocomial pneumonia. Surgery, sedation and pain impair cough an d increase risk of aspiration pneumonia. Nosocomial bacterial infections predominate, e.g. gram negative pathogens (inc. Legionella, Pseudomonas), S. aureus and MRSA. 2nd to 6th mont hs: sustained immunosuppression favors the emergence of opportunistic pathogens (aspergillu s, nocardia, MTB, PCP, listeria), and viruses (most commonly CMV, also EBV and respiratory viruses). After 6 months, if graft function is stable enough to allow reduced immunosuppres sion, community acquired organ- isms cause the majority of respiratory infections (pneumo- coccus, Haemophilus, Legionella, respiratory viruses). Patients who require augmented immun osuppression for graft rejection remain vulnerable to opportunistic patho- gens, particular ly Aspergillus, PCP, Cryptococcus and Listeria. Critical care and non-invasive ventilation The mortality rate in immunosuppressed patients who require invasive ventilation for respiratory failure is very high, approaching 100% in many series. The management of these patients requires honest and careful assessment of the ceiling of treatment, involving discussion with the patient, their family, and intensivist s. Non-invasive face- mask ventilation has been shown to reduce the rate of intubation and hence mortality when applied early, before the onset of hypercapnic respiratory failure. Clinical scenarios Neutropenia Neutropenia is the most important risk factor for pulmo- nar y infection in immune compromised patients. It is a major dose-limiting side effect of cyto toxic chemotherapy, which both decreases neutrophil numbers and causes chemotactic and phag ocytic defects, but it is seen in many other conditions that decrease production or increas e consumption of neutrophils. It is de \201 ned as an absolute neutrophil count (ANC) <1.5 x109/l. The risk of infection increases with: \200 Liver transplantation Liver transplantation involves lengthy surgery in physiolog- ically v ulnerable patients. Prolonged ventilatory support is often required. Most lung problems occ ur within 2 months of transplantation; around half are non-infective. ARDS has an incidence of 5 \200\22315% with 80% mortality after liver transplantation. Risk factors: sepsis, tra nsfusion, aspiration, use of OKT3. Transudative pleural effusions (usually right sided, som e- times bilateral) due to lymphatic disruption are common \200\223 look for an alternativ e cause if not resolved by third week post transplant, or unilateral and left sided. Right- sided diaphragmatic weakness is common, due to phrenic nerve damage, and usually resolves s pontaneously by 9 months. Hepatopulmonary syndrome (hypoxaemia due to intrapul- monary vasc ular dilatation in chronic liver disease) and portopulmonary hypertension (pulmonary hypert ension in advanced liver disease with portal hypertension) are nor- mally diagnosed preoper atively, but are not immediately reversed by transplantation and are associated with reduce d survival. Pulmonary metastatic calci \201 cation: Development of calci- \201 ed pulmon ary nodules after liver and renal transplanta- tion, possibly due to secondary hyperparathy roidism. Degree of neutropenia \200\223 increased risk if ANC <1.0, severe infection probable if AN C <0.1. Duration \200\223 relatively low risk of infection if neutropenia lasts <7 \200 \22310 days (e.g. chemotherapy for solid tumors), high risk after 10 days with risk of mult iple and recurrent new infections. Rate of onset \200\223 risk of infection lower in chron ic neutro- penias (e.g. severe aplastic anemia/idiopathic neutrope- nia) than in patients w ith rapidly declining counts due to chemotherapy. Neutropenic fever is de \201 ned by a single oral temperature >38.3 C (or 38 C over at l east 1 hour). Bacteraemia is documented in 20% of cases of febrile neutropenia. Although no originating site of infection can be determined in 20 \200\22350% of febrile neutropenic c ancer patients, 90% of such patients are likely to have infections, fever in the N BELL & A WHITTLE 204 CXR usually shows single or multiple nodules or airspace opaci \201 cation; calci \201 ca tion is not always apparent on plain \201 lms. CT scanning or technetium bone scanning (d emon- strating tracer uptake in lungs) can con \201 rm diagnosis, and exclude differential diagnoses. Rarely leads to a res- trictive ventilatory impairment; no speci \201 c treatm ent is available. Post transplantation lymphoproliferative disorder (PTLD): see Box 9.1.1. Box 9.1.1 PTLD Lymphoproliferative disorders (usually B cell lines) follow- ing HSCT or SOT range from benign lymphoid hyperplasia to frank malignant lymphoma. They typically occur w ithin 6 months of transplantation (but can be years later), in 4% kidney, 2% liver, and 1 \200\22324% allogenic HSCT (highest with HLA mismatched donors, T-cell depleted donor stem cells, and ATG/monoclonal anti C-cell antibodies used for treat- ment of GVHD). Pre-transpl ant EBV seronegativity is a strong risk factor. PTLD may be asymptomatic or present with fe ver and weight loss, and may cause pulmonary nod- ules or hilar/mediastinal lymphadenopathy . HRCT may show ground glass \200\230halo \200\231 around nodules, interlobular sep- tal t hickening and airspace consolidation, mimicking many infections. Lesions are usually basila r, subpleural and peri- bronchial. Diagnosis is by percutaneous needle or surgical biopsy, occasionally by BAL cytology. PTLD is treated by reducing immunosuppression and giving anti -B cell mono- clocal antibodies, and also (in HSCT) with EBV-speci \201 c cytotoxic T cell s. Prognosis is variable, but poor in HSCT with underlying hematological malignancy. Renal transplantation Around one-third of pulmonary complications after renal transplantati on have a non-infectious etiology. Pulmonary oedema is seen most often in the \201 rst fe w weeks post transplant, due to sodium/water retention with graft dysfunction and over hydr ation. Venous thromboembolism is relatively common, accounting for two thirds of non-infect ious pulmonary complications. Pulmonary metastatic calci \201 cation (as in liver transpla ntation, above) may become apparent or progress after renal trans- plantation, rather than resolving as might be expected. PTLD: see Box 9.1.1. Pre-engraftment phase ( \201 rst 30 days after HSCT): neutrope- nia, mucositis, IV lines a nd impaired mucociliary clearance are the main risk factors for infection. Bacteria (Gram-n ega- tive or Gram-positive organisms) and fungi are the com- monest causes of pulmonary inf ections in this phase. Early post-engraftment phase (days 30 \200\223100 after HSCT): per- sistently impaired cell mediated and humoural immunity. Allogenic HSCT recipients at greate r risk of infection than autologous due to the effects of graft versus host disease (GVHD) and the immunosuppressive drugs used to treat it. The most important pulmonary pathogens ar e fungi Haematopoietic stem cell transplantation (HSCT; bone marrow transplantation) The spectrum o f lung disease following HSCT is very dependent on the time following transplantation: see the \200\230timeline \200\231 in Fig. 9.1.1. Pre-transplant conditioning: myeloablative co nditioning includes high doses of chemotherapy total body irradia- tion (TBI) to ablate bone marrow and destroy tumor cells. Non-myeloablative conditioning uses less toxic regimen s and is associated with fewer pulmonary complications. Fig. 9.1.1 Timeline of pulmonary complications post haematopoietic stem cell transplant. GV HD: graft versus host disease; HSV: herpes simplex virus; CMV: cytomegalovirus; RSV: respir atory syncytial virus; PCP: Pneumocystis jirovecii pneumonia; DAH: diffuse alveolar hemorrh age; PVOD: pulmonary veno-occlusive disease CHAPTER 9.1 Pneumonia in the non-HIV immune compromised patient 205 treatments are available, although some respond to meth- ylprednisolone 1 \200\2232mg/kg/da y; etanercept has been pro- posed as a possible treatment. Obliterative bronchiolitis is a common late complication of allogenic HSCT, associated with chronic GVHD; it is rare after autologous transplants. Risk factors include low FEV1/ FVC pre-HSCT, increasing age, and vi ral chest infection in \201 rst 100 days. The onset is insidious, with dry cough, dysp- n oea and wheezing. Auscultation may find crackles, wheezes, inspiratory squawks or all three . Fever is rare. CXR is usually normal or hyperin \202 ated; HRCT shows mosaic pattern of hyperin \202 ated lobules with reduced vas- cular marking alternating with normal areas, m ost obvious on expiratory \201 lms. Spirometry shows air \202 ow obstruction without bro nchodilator reversibility. Formal diagnosis requires exclusion of infection by BAL. Delayed pulmonary toxicity/restrictive syndrome is late pul- monary injury in autologous HSCT (ori ginally described after high-dose breast cancer chemotherapy) with restric- tive spirometry , impaired diffusing capacity, and ground glass pattern on HRCT. Generally responds to ster oids. Pulmonary veno-occlusive disease occurs rarely after HSCT; it may be due to chemother apy. Patients have dyspnoea, normal lung function, and no infection. Right heart cathe- ter isation shows pulmonary hypertension with no emboli. Lung biopsy con \201 rms the diagnosi s. Treatment with immu- nosuppression and vasodilators is of questionable ef \201 cacy. Po st transplant lymphoproliferative disorder: See Box 9.1.1. Pulmonary lesions may also be du e to relapse of underly- ing malignancy, e.g. lymphoma. Bronchiolitis obliterans organizing pneumonia (BOOP) may follow successful treatment of CMV pneumonitis, be related to chronic GVHD, or be idiopathic. (aspergillus, and in those unable to tolerate prophylaxis, PCP) and viruses (notably CMV, w hich may present much later if prophylaxis used, as well as other respiratory viruses). By the late postengraftment phase (>100 days after HSCT), reconstitution of the immune system is nearly complete in autologous transplants, but allogenic recipients who develop chronic GVHD have persistent defects of cell mediated and humoural immunity and reticuloendothelial function. In these patients, encapsulated bacteria (e.g. H. in \202 uenzae, pneumococcus) and mycobacterial infections are the most important pathogens, in addition to oppor- tunis tic pathogens seen in early postengraftment phase. Non-infectious complications of HSCT Pulmonary oedema (cardiogenic or non-cardiogenic) is a n early complication of HSCT. Cardiac function may be impaired by chemotherapy (e.g. daunor ubicin). Chemotherapy, TBI or sepsis may increase permeability of the alveolar-capillary me mbrane causing non-cardiogenic oedema as seen in ARDS. Treatment is supportive with diu- re tic therapy and treatment of underlying infections. Engraftment syndrome: fever, erythemato us rash and non- cardiogenic pulmonary oedema coinciding with neutrophil recovery after HSC T, which may be more common with use of colony stimulating factors. May respond to steroids , but mortality is high in those who progress to respiratory failure. Diffuse alveolar hemo rrhage is a complication of the pre- engraftment phase with dyspnoea, non-productive cough, fever and hypoxaemia. Haemoptysis is surprisingly rare. CXR shows diffuse in \201 ltrates particularly of the mid/lower zones, sometimes preceding symptoms by several days. BAL sho ws the classic \201 nding of progressively bloodier aliquots of BALF (without organisms). High dose methyl- prednisolone 0.5 \200\2231g/day for several days followed by tapering pr ednisolone over 2 weeks dramatically reduces mortality rates of 50 \200\22380%. Idiopathic pneumonia syndrome: diffuse lung injury occur- ring after HSCT for which an infectious etio logy is not identi \201 ed. Median onset is at 40 days, but it can occur in the pre-engraf tment period or months later. Risk factors include TBI, intensive conditioning regimes, and acute GVHD. Criteria for diagnosis are multilobar in \201 ltrates on CXR or CT, signs and symptoms of pneumonia, and abnormal pulmonary physiology (increased A \200\223a gradient, restrictive pulmonary function tests), plus exclusion of infection with BAL or transbronchi al biopsy. On histology, diffuse mononuclear in \201 ltrate with diffuse alveolar damage i s seen. IPS may progress rapidly to respiratory failure requiring ventilation, with high mo rtality (70%). No speci \201 c Organisms Different forms of immune defect are associated with dif- ferent spectra of patho gens, as summarized in Table 9.1.2. Conventional bacterial infections Common things being common, immunocompromised patients ar e at risk from non-opportunistic bacteria. Organisms are frequently nosocomial and multires istant. Nocardia Nocardia is predominantly an infection of immunocompro- mised subjects, associated with cell-mediated immune defects due to steroid use, hematological malignancy or transpla ntation. Presentation is subacute with fever, dry cough, and weight loss; less commonly dys pnoea, pleuritic pain or haemoptysis. CXR/CT typically shows nodules or Table 9.1.2 Infections associated with different types of immune defect Immune defect Predominant pathogenic organisms Neutropenia or phagocyte defect Bacteria: staphylococci, streptococci, Gram-negative bacilli (enteric and non-enteric), Noc ardia Fungi: Candida, Aspergillus, mucormycosis T-lymphocyte de \201 ciency Viruses: CMV, HSV, VZV, EBV, respiratory viruses Intracellular bacteria: Legionella, mycobacteria, Listeria, Nocardia Fungi: Pneumocystis jiroveci, Histoplasma capsulatum, Cryptococcus neoformans Parasites: Toxoplasma gondii, Strongyloides stercorales B-lymphocyte de \201 ciency, hypogammaglobulinaemia, hyposplenism Encapsulated bacteria: Streptococcus pneumoniae, Haemophilus in \202 uenzae, Neisseria men ingitides N BELL & A WHITTLE 206 masses that may cavitate, but may show parenchymal in \201 l- trates, subpleural plaques o r effusions. It can be compli- cated by empyema (25%), mediastinitis, pericarditis, and sup erior vena cava syndrome. The incidence is reduced by septrin as PCP prophylaxis, but may o ccur after prophy- laxis has ceased. Nocardia are not usually found in the respiratory trac t, so isolation of the \201 lamentous branching gram-positive rods from sputum or BAL is diagnostic. The diagnosis can also be made by aspirating extrapulmonary disease such as ski n abscesses. The laboratory should be warned that nocardia is a possibility, to allow appro priate processing. Tissue biopsies show a mixed cellular in \201 ltrate, rarely with granu - lomata. Treat with sulphonamides for 6 \200\22312 months. for \201 ve days, tapering over two weeks. Expect a response within \201 ve days. The r isk of PCP reduces with use of septrin prophylaxis (from 16% in allogenic HSCT to <0.5%), b ut bone marrow suppression limits tolerability in up to a third; dapsone and nebulised pent amidine are less effective (7% and 3% incidence PCP). Invasive pulmonary aspergillosis Aspergillus infection (most commonly A. fumigatus, also \202 a- vus, niger and >20 other species) is a major cause of disease in the immune comprom ised, associated with prolonged neutropenia, glucocorticoid therapy, HSCT, SOT, HIV, anti- TNFA therapy and chronic granulomatous disease. It is the leading infective cause of death in allogenic HSCT. The symptoms are non-speci \201 c: non-productive cough, fever (may be absent in HSCT), dyspnoea, pleuritic chest pain, haemoptysis (due to angioinvasion & pulmon ary inf- arction), pneumothorax. Disease may progress rapidly over days. CXR may be normal or show peripheral nodules which may coalesce. CT is more sensitive: look for the \200\230 halo sign \200\231 of a ground-glass rim around pulmonary nodules, due to hemorrhage. This is distinct from the \200\230air crescent sign \200\231, which may appear in later stages of invasive aspergil- losis with resorption of necrotic tissue by neutrophils (Fig. 9.1.2). Tuberculosis and other mycobacteria The incidence of TB is increased in all types of immune compromise. The risk is higher in endemic areas, e.g. 0.5 \200\223 2% post-SOT in USA/Euro pe but up to 15% in India. Most infections are due to reactivation of latent disease. It is a late complication of transplantation; fever is the most com- mon symptom. CXR may show f ocal in \201 ltrates, a miliary pattern, effusions, or more rarely (<5%) diffuse interstit ial in \201 ltrates or cavitating lesions. Diagnosis is usually made from sputum or bronch ial washings. Tuberculin skin testing has a high false negative rate in immune suppression; a newly positive skin test suggests active disease, but this is rarely seen. There is litt le data regarding interferon G assays in immune compromised patients. Combination treatment regimes should be used. Isoniazid hepatotoxicity can be problematic in liver transplants. Rifampicin increases clearance of tacrolimus and cyclosporine, increasing risk of rejection , so monitor drug levels closely. Mortality is high (25 \200\22340%) in those who can- not complete the course of treatment. Non-tuberculous mycobacteria (NTM) cause more fre- quent and severe infections in the immune compromised. There are many NTM species: refer to curre nt guidelines for management. Prolonged treatment is required and mortality is high; contro l rather than eradication of infec- tion may be the best achievable outcome. Fungi Pneumocystis pneumonia (PCP, Pneumocystis jirovecii) Risk factors for PCP include pro longed glucocorticoid use, malignancy (esp. hematological, and with use of purine analogs e .g. \202 udarabine) and transplant. Defective cell- mediated immunity probably leads to r eactivation of latent disease. It presents with dry cough, dyspnoea and usually fever; the onset is often more rapid in non-HIV than in HIV. Clinical examination is often normal, wit h no crackles. There is marked arterial oxygen desaturation on exertion. CXR (and HRCT) may show bilateral perihilar alveolar in \201 ltrates (less commonly isolated nodules, lobar consoli- dation, cavities/cysts, pneumothorax); CXR is normal in up to 30%. WCC is usually normal, LDH may be raised. Diagnosis is usually by identi \201 cation of the organism (e.g . direct immuno \202 uorescence) in induced sputum or BAL \202 uid: sensitivity is lower than in HIV (60%) as the burden of infection is usually lower. If clinical suspicion is hi gh and sputum/BAL is negative, consider transbronchial or open lung biopsy. If the patient is unwell, begin empirical treat- ment: BAL remains positive for at least a week. Treat wit h high-dose septrin for 14 \200\22321 days, or iv pentamidine, dapsone+trimethoprim, clinda mycin+primaquine or atovaquone if intolerant. If unwell, add high dose steroids Fig. 9.1.2 Nodule (arrow) caused by Aspergillus infection, illustrating both the halo and a ir crescent signs. The diagnostic gold standard is isolation of the organism on culture of tissue from lung bi opsy. Culture is required to distinguish Aspergillus from other fungi. Aspergillus in spu- tum or BAL \202 uid can represent colonization or contamina- tion rather than invasive in fection, and BAL sensitivity is low (30 \200\22350%). However, if aspergillus is isolated i t is usually treated, if the clinical scenario suggests a high risk of infection. ELISA for serum galactomannan (a fungal wall component released in invasive aspergillosis, often bef ore radiographic change) is sensitive and speci \201 c in HSCT and haematologi- cal malign ancy, less so in SOT. Beta-lactam antibiotics can cause false positives; antifungal treatme nt reduces sensitivity. CHAPTER 9.1 Pneumonia in the non-HIV immune compromised patient 207 Treatment: reduce immunosuppression if possible. Voriconazole shows a higher response, lowe r mortality and fewer adverse reactions than liposomal amphotericin B; caspofungin is an al ternative if other drugs are not toler- ated. Treatment should continue for at least 2 week s after clinical/radiological appearances have resolved, which may take months. The conditi on may relapse if neutropenia recurs. is itself immunomodulatory and predisposes to PCP, Aspergillus infection and graft rejectio n. CMV pneumonia commonly presents with \202 u-like symp- toms, low grade fever, dyspnoea , dry cough and hypoxia, progressing to respiratory failure. Blood tests may show leucopeni a, thrombocytopenia, hepatitic liver function. CXR appearances are variable, classically bi lateral subtle diffuse in \201 ltrates, sometimes lobar consolidation or small nodules. HR CT shows ground glass opacities or small cen- trilobular nodules. The gold standard for dia gnosis is demonstration of \200\230owl \200\231s eye \200\231 viral inclusion bodies on lu ng biopsy, but this is frequently impractical. Serology is useful to determine past infecti on status but not as a test for acute infection unless seroconversion is demonstrated in a suggestive clinical context. CMV antigenaemia and quantitative blood PCR testing are rapid and speci \201 c; a rise in values may prompt pre-emptive treatment before disease is appa rent. BAL cytology (visualization of nuclear/cytoplasmic inclu- sion bodies) is speci \201 c but insensitive. Conventional cul- ture takes weeks, replaced by shell-vial assay (early antigen detection using immuno \202 uorescence with monoclonal antibodies to CMV) which t akes 2 \200\2233 days and is more sen- sitive, but not speci \201 c. Culture of CMV in BAL \202 uid de \201 nes systemic infection but not necessarily pneumonia. CMV PCR on BALF is being evaluated. Treatment of may be started pragmatically on basis of compatible clinic al/radiological features, preferably with detection of CMV on BAL. Treat with IV ganciclovi r for 2 \200\2234 weeks, plus CMV-specific immune globulin in severe cases. Mortality is hi gh, up to 85%, with relapse in up to a third. Cryptococcus neoformans (cryptococcal pneumonia) Risk factors: impaired cellular immunity i ncluding HIV, malignancy (esp. lymphoma), transplantation, corticoster- oids, cirrhosis, re nal failure, diabetes, chronic lung disease, TNFA antagonists. It presents acutely or insid iously with cough, dyspnoea, fever and other non-speci \201 c symptoms. CXR/CT commonly sh ows peripheral nodules, sometimes cavitating, less commonly lobar in \201 ltrates, adenopa thy, effusions. Diagnosis: identi \201 cation of the organism (Indian ink stain) in sputum or BALF is speci \201 c, as it is a rare contaminant. Serum cryptococcal antigen is posit ive in 70% non-HIV patients with cryptococcal pneumonia and suggests aggres- sive disease; it can be used to monitor disease. Pleural \202 uid and BAL cryptococcal antigen may als o be helpful. Most patients with pneumonia also have extrapulmonary dis- ease: consider CT head/LP to exclude cryptococcal menin- goencephalitis. Treat with amphotericin and \202 u cytosine for 14 \200\22321 days followed by \202 uconazole PO for 6 \200\22312 months. Candida pneumonia The signi \201 cance of Candida isolated from the respiratory tract is o ften debated because of the frequency of oral contamination, but true Candida pneumonia is a severe complication of immunosuppression or critical illness, with a poor prognosis. It m ay follow aspiration or candidaemia, and often causes high fever. Radiological \201 nding s include nodules and consolidation; Candida may also cause empyema. Because of the risk of contamination of sputum/ BALF, de \201 nitive diagnosis requires lung biopsy. Treat with amphotericin or \202 uconazole. Other respiratory viruses RSV and in \202 uenza are epidemic in winter/spring, adenovi- ru s and parainfluenza occur throughout year. In SOT recipients, LRTI from these viruses is mo re common than in the general population, manifest as fever, dyspnoea, cough and wheezing n ormally in 2nd \200\2236th months post-transplant. RSV pneumonia after HSCT causes bilatera l interstitial in \201 ltrates and high mortality. RSV also causes otitis media and sinusi tis. Ribavirin may help if given early enough. Adenovirus infection may cause fatal pneumon ia 2 \200\2233 months post-HSCT, as well as pharyngitis, tracheitis, bronchitis, enteritis, cystitis, or disseminated disease. It can be cul- tured from pharynx, respiratory secretio ns or urine. There is no proven effective prophylaxis or treatment. HSV, since aciclovir pr ophylaxis, is now a rare cause of pneumonitis in preengraftment phase of HSCT. It is due to reactivation, so only seropositive patients are at risk. HHV-6 has been reported to cause pulmonary in \201 ltrates after HSCT, and may account for some cases diagnosed as IPS. Par ain \202 uenza is a cause of URTI, laryngotracheitis, bronchi- olitis, and pneumonia after HSCT. URTI precedes LRTI: nasopharyngeal lavage may allow diagnosis before pneu- monia (cu ltures positive 9 days after symptoms). Fatal once respiratory failure occurs; there are re ports of bene \201 t from ribavirin. Human metapneumovirus is a recently described and som e- times fatal cause of lung disease after HSCT. Pulmonary zygomycosis (including mucormycosis) The zygomycetes are ubiquitous fungi in soil or decaying vegetation; Mucor spp. are most familiar, but Rhizopus spp. are commoner patho gens. Lung infection is due to inhala- tion; risk factors include neutropenia, diabetes, IV DU, mal- nutrition, trauma/burns, steroids, hematological malignancy, transplant, and iron overload treated with des- ferrioxamine. Infection causes rapid onset of fever, cough, dysp noea and haemoptysis (may be massive, due to angioinvasion). The pneumonia is diffuse with infarction and necrosis; CXR/CT may show cavitation with air crescent sign, nodules, or eff u- sions. BAL sensitivity is low, the gold standard is lung biopsy tissue culture. Treat wi th amphotericin; consider surgical resection if planning HSCT as the risk of recurrence is high. Viruses Cytomegalovirus (CMV) pneumonia Clinical CMV infection may be due to reactivation o r to transmission from seropositive transplant or blood donors. The main risk factor is def ective cell-mediated immunity, especially in allogeneic HSCT. The risk depends on the infec tion history of donor and recipient, so is lowest when both are seronegative. Ganciclovir p rophylaxis is effective, but its tolerability is limited by neutropenia; disease may occur 1 \200\2234 months after stopping prophylaxis. CMV infection N BELL & A WHITTLE 208 Further reading Abramson S. The Air Crescent Sign. Radiology 2001; 218: 230 \200\223232. Ko the H, Dalhoff K. Pneumonia in the immunocompromised Ra a A, Agust a C, Jimeneza P, et al. Pulmonary in \201 ltrates in non-HIV immunocompr omised patients: a diagnostic approach using non-invasive and bronchoscopic procedures. Tho rax 2001; 56: 379 \200\223387. patient. Eur Respir Mon 2006; 36: 200 \200\223213. Shellito J. Symposium: The Compromised Host. Proc Am Thoracic Kotloff RM, Ahya VN, Crawford SW. Pulmonary Complications of Solid Organ and Hematopoietic Stem Cell Transplantation. Am J Resp Crit Care Med 2004; 170: 22 \200\22348. Soc 2005; 2: 397 \200\223460. Pizzo PA. Fever in Immunocompromised Patients. New Engl J Med 1999; 336: 309 \200\223316. This page intentionally left blank A DUNLEAVY, M LIPMAN & R MILLER 210 9.2 Infection in the HIV compromised host Since the \201 rst, consistent reports of HIV infection in the early 1980s, the speed at which advances in our under- standing of this condition have taken place is unparalleled in medicine. The introduction of HAART in 1995, plus effective chemoprophylaxis against oppor tunistic infec- tions, has transformed the natural history of HIV infection from one with a uniformly gloomy outlook to a condition with an associated life-span perhaps not much less than that of the general population in the developed world. Despite this it remains a huge global health problem. For respiratory physicians this is important as the lungs are the s ite most commonly affected by opportunistic infections (OI). The UNAIDS estimated that in 2 007, 33.7 million individu- als were living with HIV infection. Two-thirds of these are wit hin sub-Saharan Africa. Approximately 21.5 million peo- ple have died since 1990 as a resul t of HIV infection. Possibly up to 50% of these have been due to TB. In the US there are ab out 1 million infected individuals; whilst the UK has around 72,000. Survey data suggest th at almost one third of these people do not know they are infected. Thus it is depressingly common to see patients presenting in extremis with undiagnosed HIV infection and opportun- istic disease. The major groups of affected individuals within the UK are men who have sex with other men (MSM) (40% of cases), heterosexual women (30%), heterosexual men (20%) and i njecting drug users (<5%). New cases are more frequently heterosexual than MSM; and are fou r times more likely to be black-African than any other ethnic group. This chapter describes respiratory infections in individuals with known or suspected HIV infection. It provides a gen- eral approach to assessment, and then covers speci \201 c, important pulmonary infec tions relevant to UK practice. Table 9.2.1 Causes of pulmonary infection in the HIV compromised Bacterial Streptococcus pneumoniae Haemophilus in \202 uenzae Staphylococcus aureus Pseudo monas aeruginosa Escherichia coli Mycobacteria Mycobacterium tuberculosis Mycobacterium avium-intracellulare complex Mycobact erium kansasii Other non-tuberculous mycobacteria Fungi Pneumocystis jirovecii Cryptococcus neoformans Histoplasma capsulatum Penicillium mar neffei Aspergillus spp. Coccidioides immitis Blastomycetes dermatitidis Parasites Toxoplasma gondii Strongyloides stercoralis Viruses Cytomegalovirus Adenovirus Herpes simplex is >200 cells/ l, bacterial pneumonia and TB are most likely. At lower CD4 counts, PCP, fu ngal and non-tuberculous mycobacterial infections are additional possibilities. It should b e remembered that PCP can occur at higher CD4 counts (especially in people with physical in dicators of immune suppression such as oral thrush; or very high HIV plasma loads). It may also be seen occasionally during acute (primary) HIV infection when there is a profound, tr ansient fall in systemic immunity. Blood CD4 counts may \202 uctuate on a day to day basi s; and it can be helpful to also know either the CD4:CD8 ratio or CD4 percentage (of all T and B lymphocytes), which are rather more stable measures. The latter can be related to blo od CD4 absolute counts if one remembers that a CD4 of 200 cells/ l is usually 14%, and CD4 of 400 cells/ l is roughly double that at 27%. General approach to the HIV patient with pulmonary infection The immune dysregulation assoc iated with HIV means that a wide spectrum of organisms may be responsible for pul- monary i nfection (Table 9.2.1). However, it is important to remember that Pneumocystis jirovecii pn eumonia (PCP) and bacterial pneumonia are the commonest causes of acute, life-threatening H IV-related respirator y disease. Mycobacteria (and in particular TB) should not be forgot- ten; nor that more than one pathogen can be demon- strated in up to 20% of cases. Although there may be helpful pointers in the history, examination and initial sim- ple investigatio ns, often the decision needs to be taken to start empiric therapy prior to obtaining a de \201 nitive diagno- sis. This is discussed in more detail later in this chapter. Important points in assessment The degree of immunosuppression It is possible to map speci \201 c respiratory conditions to the level of an individual \200\231s immuno-suppression. This is most easily assessed using blood CD4 T-lymphocyte counts, which generally are inver sely related to the degree of immune dysfunction. In an HIV-uninfected individual the norma l absolute CD4 count is between 500 \200\2231500 cells/ l. During the course of untreated HIV infection this will almost certainly fall to near undetectable levels after sev- eral y ears. Different organisms should be considered depending on the blood CD4 count. When the C D4 count Patient medication history Patients who are using effective HAART (sustained sup- pression or near-suppression of plasma HIV load for at least 3 months) have a greatly reduced (50 \200\22380%) risk of severe respiratory illness. This is particularly the case for PCP and TB; though rather less so with bacterial pneumo- nia. The use of speci \201 c OI prophylax is (such as PCP proph- ylaxis with co-trimoxazole taken at an effective dose for at least 2 weeks) is also relevant; as this may suggest alterna- tive diagnoses (than in this example , PCP) or raise the pos- sibility of the development of resistance to the prophylactic agen ts. Medication (e.g. the antiretroviral, zidovudine or CHAPTER 9.2 Infection in the HIV compromised host 211 Investigations Serology. Pneumococcal urinary antigen is helpful in sus- pected bacterial p neumonia. It has a similar sensitivity (approaching 80%) and speci \201 city (approximatel y 95%) in HIV infected and uninfected individuals. Urine testing for Legionella antigen may also be of value; whilst in appropriate cases, urine and blood Histoplasma polysaccharide antigen tests have good sensitivity; although false positives can occur in Blastomyces and Coccidioides spp. infected individu- als. Serum cryptococcal antigen has excellent speci \201 city; though is less sensitive in local (e.g. pulmonary) cryptococ- cal infection than in disseminated disease, where crypoto- coccaemia is more likely to be present (e.g. >90% positive in cryptococcal meningitis). Serology (acute and convales- cent) can be sent for a typical organisms such as Legionella pneumophila, Mycoplasma pneumonia and Chlamydia spp. L actate dehydrogenase (LDH) is elevated in up to 90% of patients with PCP; however it is als o increased in several other infections (in particular mycobacterial disease and histoplasm osis) as well as lymphoma and lymphocytic interstitial pneumonitis (LIP). As such it lacks diagnostic speci \201 city. prolonged use of antibiotics such as rifabutin) can lead to neutropenia and a subsequent in creased risk of systemic bacterial infections and invasive fungal infections