Neoplastic complications Immunosuppression impairs T-lymphocyte mediated tumor surveillance , predisposing patients to malignancy. Tumors tend to be more aggressive than is seen in th e general population. The commonest tumor is PTLD. Other tumors include Kaposi \200\231s sa rcoma and cancers involving the skin, lung, pros- tate, colon, head and neck and kidneys. P TLD is a non Hodgkin \200\231s lymphoma predominantly of B cell type whose proliferation is driven by EBV. The risk of PTLD is highest in EBV seronegative recipients who receive an E BV positive graft. Most PTLD occurs in the \201 rst year after transplant and involves th e allograft with pulmonary nodules and possible mediastinal lymphadenopathy. Disease presen ting later tends to be more disseminated and carries a worse prog- nosis with an overall mo rtality of 40 \200\22350%. Diagnosis of PTLD is best achieved by tissue biopsy. Pa- tients are staged by CT scanning. The main treatment is a signi \201 cant reduction in immunosupp ression to restore some host immunity to EBV. If this fails, other options in- clude surgic al resection of localized disease and chemo- therapy/radiotherapy in refractory cases. Chem otherapy is poorly tolerated, infectious complications are frequently seen as a result of t he additional immunosuppression. Fungal infection Routine trimethoprim-sulfamethoxazole prophylaxis has reduced Pneumocystis carinii infection rates from 70% to virtually zero. Other fungi causing infections in lung transplant recipients include Cryptococcus, Candida species and Aspergillus. Aspergillus i s a ubiquitous environmental fungus that is common in lung transplant recipients, affecting 30 \200\22350%. Despite this only 3% develop invasive disease that presents as pneumonia o ccasionally complicated by systemic dis- semination with mortality rates as high as 60%. Tr eatment is with intravenous or nebulised amphotericin or oral voriconazole and surgical res ection of affected areas in refractory cases. Renal disease Chronic kidney disease (CKD) is common after transplant, eventually affecting up to 90% of patients. Deterioration in S PARKER & A FISHER 424 Gastrointestinal complications Gastrointestinal problems, mainly due to immunosuppres- sive drug toxicity, are common (incidence of up to 50%) in lung transplant recipients, the majo rity are self-limiting and respond to conservative management. Complications include: pepti c ulcer disease, gastritis, gas- troparesis, pseudomembranous colitis, and CMV infection. B owel perforation in an immunosuppressed patient carries a particularly high mortality of up to 75%. Table 17.2.1 International Society of Heart and Lung Transplantation scoring criteria Grade Histology A0 (no rejection) No signi \201 cant abnormality A1 (Minimal) Infrequent perivascular mononuclear cell in \201 ltrates around venules A2 (Mild) More frequent in \201 ltrates, more than a few cells thick, involving veins and arteries. A3 (Moderate) More exuberant mononuclear cell in \201 ltrates from the perivascular space into the alveo lar interstitium. KEY FACT Gastroesophageal re \202 ux disease appears to be a partic- ular problem after lu ng transplant and has been linked to the development of BOS. A4 (Severe) In \201 ltrates extend into the alveolar space with pneumocytes damage: there may be necro sis of vessels and lung parenchyma. Neurological complications Most non-infectious neurological complications are due to calcin eurin inhibitor side effects. Manifestations are usually mild and include tremor, headaches and paraesthesia. Drug-induced leukoencephalopathy is a more serious problem, manifesting as a wide range of possible symptoms including confusion, coma, seizures, cortical blindnes s and quadriplegia. Occipital lobe involvement is common with CT scans showing non-enhancin g areas of reduced attenu- ation in the cerebral white matter. The cause of the injury is n ot clear and may relate to either a direct toxic effect of the drug or possible vasospasm a nd consequent ischaemic injury. Dose reduction or withdrawal of the offending drug is usual ly results in a substantial improvement. small and medium sized airways airways with connective tissue. OB is a histological diagnos is obtained from lung biopsy but patchy distribution of disease results in a low diagnos- t ic sensitivity (15 \200\22328%). This lead to the use of a clinical correlate, the \200 \230bronchiolitis obliterans syndrome \200\231 (BOS) based on the development of air \202 ow limitation with de- cline in FEV1 and reduced FEF25 \200\22375, from a stable post trans plant baseline value. Staging of the disease (BOS level 0 \200\2233) depends on the magnitu de of the decrease in FEV1. The loss of function was considered to be irreversible (present >3 weeks) and requires exclusion of other condi- tions that can alter allograft function s uch as infection or acute rejection. BOS is variable in its clinical presentation and natur al history. Initial symptoms are often non speci \201 c or absent. As the disease progress es patients develop exertional dys- pnoea, cough, and wheezing and can suffer frequent resp i- ratory tract infections. Acute rejection Acute rejection of the transplanted lung affects up to 40% of patients in t he \201 rst 30 days after transplant and its inci- dence markedly declines after 6 months . Acute rejection presents with non speci \201 c symptoms such as fever, cough, breathless ness and malaise and may be as- sociated with in \201 ltrates or pleural effusions on the CXR. Rejection may be clinically silent, particularly later on and as many as 20% of cases are picked up unexpectedly during surveillance transbronchial biopsy. Bronchoscopy and tran sbronchial biopsy is required for diagnosis. Histologically it is characterized by perivasc ular and interstitial mononuclear cell infiltrates that may extend into the alveolar septae and affect the airway depending on severity. Acute rejection is graded according to an ISH LT formulation from A0 (no evidence of rejec- tion) to A4 (severe acute rejection). Early a cute rejection is treated with pulsed IV methylpred- nisolone followed by an augmented dose of oral corticos- teroids tapered over the course of a month. Most patients respond rapidl y with improvements seen as early as 24 hours after treatment is commenced. Acute rejection occurring after the \201 rst month can be adequately treated with augmented oral cortico steroids The frequency and severity of acute rejection episodes are recognized as predispos ing to BOS, the principal cause of late mortality. Table 17.2.2. BOS Scoring System (Estenne, 2002) BOS 0 FEV1 >90% of baseline and FEF25 \200\22375% >75% of baseline FEV1 81 \200\22390% of baseline and/or FEF25 \200\22375% <75% of baseline BOS 0 p ( \200\230potential \200\231 BOS) FEV1 66 \200\22380% of baseline FEV1 51 \200\22365% of baseline FEV1 <50% of baseline BOS 1 BOS 2 BOS 3 The median time from transplantation to initial diagnosis is 16 \200\22320 months, yet the range is very wide. The disease is progressive with a poor long-term survival rate of 30 \200\22340% at 5 years. Progression of BOS tends to follow one of three patterns: \200 Su dden onset of symptoms with a rapid decline in lung function. Insidious onset and slow progression over time. \200 Initial rapid decline followed by a period of stable lung function. BOS impacts on quality of life; patients have less energy, more depressive symptoms and imp aired functional capacity compared to those who are BOS-free. Worse outcomes are seen with acute onset, female gender, single lung transplant and pretransplant diagnosis of idiopathi c pulmonary \201 brosis. The bronchiolitis obliterans syndrome (BOS) Diagnosis and clinical features of BOS Oblitera tive bronchiolitis (OB) is the pathological manifes- tation of chronic allograft dysfunctio n in the transplanted lung with affected individuals showing obliteration of the CHAPTER 17.2 Complications after lung transplantation 425 Retransplantation is a controversial issue. Outcomes compare favorably with primary lung tr ansplant in highly selected individuals and rates of BOS recurrence are not increased. Most centers will consider patients on a case by case basis but the lack of suitable donor orga ns has resulted in this procedure only being performed in exceptional cases. Treatment of BOS Most treatments for BOS are disappointing and the disease remains the majo r barrier to long-term survival after transplant. Most therapies seem to work by an anti- i n \202 ammatory rather than anti \201 brotic effect and therefore early detection and pre vention of BOS should be emphasized. Augmentation of immunosuppression with antilymphocyte antibodies, cyclophosphamide, methotrexate and total lymphoid irradiation has shown only mo dest success. These therapies may slow progression but offer little chance to reverse disea se. Altering immunosuppressive therapy from ciclosporine to tacrolimus may have some bene \201 t but there is concern that this effect may not be speci \201 c. The macrolide antibi otic azithromycin seems to partially reverse air \202 ow obstruction seen in some patients with established BOS. Currently placebo controlled randomized trial are not available but are awaited. Gastroesophageal re \202 ux disease has been implicated in the etiology of BO S and intervention with early gastric fundoplication may offer some protection. Further reading Alexander BD, Tapson VF. Infectious complications of lung transplantation. Transpl Infect Dis 2001; 3: 128 \200\223137. Boehler A, Estenne M. Post transplant bronchiolitis obliterans. Eur Resp Monograph 2003; 26: 158 \200\223178. Kotloff RM, Ahya VN. Medical complications of lung transplantation. Eur Resp J 2004; 23: 334 \200\223342. Perrot M, Mingyao M, Waddell TK, et al. Ischaemia-reperfusion- induced lung injury. Am J Re sp Crit Care Med 2003; 167: 490 \200\223511. Studer SM, Levy RD, McNeil K, et al. Lung tran splant outcomes: a review of survival, graft function, physiology, health related qual- ity of life and cost effectiveness. Eur Resp J 2004; 24: 674 \200\223685. van der Bij W, Speic h R. Infectious complications after lung transplantation. Eur Resp Monograph 2003; 26: 193 \200\223207. S PARKER & A FISHER 426 17.3 The care of lung transplant candidate or recipient Clinical updates Once a patient has been accepted as a suitable lung trans- plant candidate and is placed on an active waiting list it is essential that they remain in the best possi ble condition. It is important that lung transplant candidates remain under the care of the ir referring respiratory physician while on the transplant waiting list and are regularly r eviewed at least every 3 months, and in many cases monthly would be more appropriate. Copie s of clinic let- ters should be sent to the transplant team and any change in the patient \200\231s condition should be communicated to the transplant center immediately. Non-invasive ventilatory support (NIV) however is to be encouraged in patients with progres sive hypercapnic respiratory failure on the transplant waiting list as it allows the patien t to maintain their level of \201 tness for possible transplant. Palliative care The widening gap between the demand for lung transplan- tation and the shor tage of donor organs accounts for a waiting list mortality of approximately 30 \200\22340%. As a result it is not infrequent for patients to die while waiting for a suitable donor lu ng. It is important to identify when a lung transplant candidate has moved beyond the trans plant window and has become too sick to survive the transplant surgery. There should be no reluctance to commence palliative care in such individuals as being on the transplant waiti ng list should not exclude giving appropriate palliative care to patients with end-stage di sease. The decision to switch to a purely palliative approach and remove a patient from the lung transplant waiting list can be traumatic for both patient and their next of kin. Such decisions should be made in conjunction with the transplant center. Use of antibiotics Although many patients with COPD or pulmonary \201 brosis may become a ccustomed to regular use of antibiotics be- fore referral for lung transplantation, once on the waiting list antibiotic use should be kept to a minimum. Over zeal- ous use of antibio tics is associated with the emergence of more resistant bacterial species such as Pseudomon as spp. This can also produce fungal contamination which may be problematic after transplan tation due to the powerful im- munosuppression used. It is recommended therefore that antib iotics are reserved for microbiologically proven and clinically relevant infections only. P atients with cystic \201 brosis however, will have complex anti-microbial regimens and wi ll likely need ongoing courses of antibiotics while waiting for lung transplant. Use of pow - erful combinations of antibiotics for atypical mycobacteria or resistant fungi or mold in fections must be discussed with the transplant center. Many of these treatments may need to be reserved for the post-transplant period where they would have much more chance of penet rating lung tissue if there is any recurrence of these infections. The lung transplant recipient Sudden changes in clinical condition The \201 rst 6 months and especially the \201 rst 3 months after lung transplantation represents the time of hi ghest risk for the development of acute rejection of the transplanted lungs. This is also a key period when a number of transplant- associated infections are common. The symptoms, si gns and investigation \201 ndings shown in Table 17.3.1 can be caused by both acute rejec tion and infection. Clearly rejection and infection will require very different interventio ns and so the presence these indicators warrant immediate further investi- gation and discu ssion with the transplant center. Ventilation Some patients awaiting lung transplantation will deterio- rate either acutely d ue to an exacerbation of their disease or slowly due to progressive respiratory failure. Th e ques- tion as to whether individuals with end-stage lung disease should be intubated and ventilated is made more com- plicated when the patient is actively waiting for a lung trans plant. Table 17.3.1 Changes in condition Symptoms Investigations Fall in FEV1 of greater than 15% New pleural effusion New or worsening cough Breathlessness Persisting fever New pulmonary in \201 ltrate General malaise KEY POINT Currently in the UK, no lung transplantations are per- formed on patients who are mechanically ventilated. This is because the outcomes from this group are very poor compar ed to non-ventilated patients. The high risk of acute rejection during this period means an urgent transbronchial lung bio psy is indicated. This is best carried out at the transplant center where specialist transp lant histopathologists are available to interpret the potentially dif \201 cult histologic al appearances. At the same time detailed microbiological evaluation of bronchoalveo- lar l avage (BAL) can be performed. If a patient is too unwell to be transferred to the transplan t center then a manage- ment plan should be agreed with the transplant team and there shoul d be daily communication about progress. It is important to note that the risk of acute rej ection is most marked in the \201 rst month following transplantation and the risk reduce s each month until after 6 months, after which it is quite rare for patients to have an epi sode of acute rejection. In essence therefore, intubation and ventilation should be avoided in virtually all patient s on the lung transplant wait- ing list as it is likely to be a futile intervention which w ill render the individual non-transplantable. If the cause of an acute deterioration is fel t to be highly reversible then it maybe justi \201 able to intubate and venti- late the pa tient. They would however need to demonstrate survivability and a capability to rehabilitat e from the epi- sode before they would become active on the transplant waiting list again. CHAPTER 17.3 The care of lung transplant candidate or recipient 427 Fig. 17.3.1 Patient presenting 2 months \202 owing bilateral lung transplant with severe acute rejection. Plain CXR shows diffuse alveolitic shadowing in both lung \201 elds and small lung volumes. CT chest images demonstrate the extent of the alveolitis and also the p resence of large bilateral pleural effusions not seen on the plain CXR. Immunosuppression The immunosuppression regimen used by an individual recipient will have b een tailored to their speci \201 c needs by the transplant center. In general this will co mprise a triple drug approach with a calcineurin inhibitor either ciclosporin or tacrolimus , corticosteroids and a cell cycle inhibitor such as azathioprine or mycophenolate mofetil. Other agents such as methotrexate or sirolimus may be used in addition. The transplant cen ter will assume responsibility for appropriate dosing of immunosuppression and for any chan ges in the immunosuppression regimen. In order to do this it is necessary to monitor the se rum level of immuno- suppressive drugs as well as liver and renal function. These will be c hecked every time the patient attends the trans- plant clinic but it will be necessary to c heck these bloods at least every 6 weeks. It is essential that the immuno- suppression is n ot stopped or changed without prior consultation with the transplant team. identify the cause and to control the vomiting with appro- priate anti-emetics. Missing one or two doses of immuno- suppressive medication is unlikely to cause any problems and it is important to exclude toxic levels of ciclosporin or tacrolimus as causes for the vomiting. If this is excluded and if control of the vomiting is unsuccessful then immunosup- pressio n can be given intravenously and an appropriate regime should be discussed with the transpl ant center. Dehydration in the presence of only moderately elevated serum concentrations of the calcineurin inhibitors can pre- cipitate renal failure and care must be made to avoid dehy- dration in the vomiting lung transplant patient. In such cir- cumstances daily measur ements of serum drug levels may be necessary to aid prescribing. Seizures A new lung transplant recipient who experiences a seizure shortly after discharge from the transplant center may have developed leuco-encephalopathy as a result of their imm unosuppressive drugs. Warning signs of this complica- tion include prior visual disturbance , hypertension and a low serum magnesium level. Patients who have seizures usually do so wi thin the \201 rst week or two following commencement of immunosup- pression though rarely it may occur in the \201 rst month, which might include after discharge from the transpl ant center. Initial management should be as for any other patient with a seizure and the tr ansplant center should be informed as soon as possible. MRI scanning of the brain is the mo st useful investigation in determining the presence of leuco-encephalopathy. CT scanning of the brain will not diagnose this condition but may be useful in excluding other intra-cran ial pathology. If a CT scan is performed as an initial investigation then it should be done with intravenous contrast. If boluses of diazepam are unable to control the seizures or th ere is a need to give anti-convulsant therapy then sodium valproate is the anticonvulsant o f choice because it will not interact with the patient \200\231s immunosuppression. The danger of drug interactions There are many interactions between immunosuppressive drugs and other medications in common use. Extreme care should be exercised whenever a new medic ation is pre- scribed to ensure that it will not decrease or signi \201 cantly increase se rum levels of immunosuppression and either expose the patient to the risk of rejection or t o drug toxicity. The British National Formulary provides a comprehensive list of important interactions. For example, the macrolide anti- biotics clairthromycin or erythromycin must not be given without a signi \201 cant reduction in the dose of ciclosporin or tacrolimus and preferably they should be avoided altogether. This is because these drugs will increase signi \201 cantly the area under the serum concentration curve for these drugs and may le ad to marked renal dysfunction and in severe cases haemolytic uraemic syndrome. The vomiting lung transplant recipient If a lung transplant recipient presents with prolong ed vom- iting they may not be able to take or be absorbing suf \201 cient immunosuppressio n. Every effort should be made to S PARKER & A FISHER 428 Blood pressure and renal function Hypertension and renal dysfunction are very common in lun g transplant recipients. This is due to side effects of their immunosuppressive therapy and as the two complications are interrelated it is important that careful attention is paid t o both. Blood pressure should be controlled within standard guideline limits in an attempt to preserve good renal function and reduce other cardiovascular risks. The calcineurin inhi bitors have potent nephrotoxic side-effects due to their vasoconstrictive actions on renal arterioles. Excellent blood pressure control, diabetes control and reducing levels of immun suppression can help improve or stabilize renal function for many years. However in some pa tients renal dysfunction will progress despite these measures and may require renal replace ment therapy and consideration for renal transplant. The balance between the level of immun osuppression and its evidence on renal function will depend on the rejection history of the recipient and recent allograft biopsies. In recipients with stable lung function and a low risk of rejection ciclosporin or tacrolimus levels can be reduced signi \201 cantly to pr otect renal function. Any change to a patients immunosuppression regime must be made in con - sultation with the transplant center. If there is dif \201 culty in controlling seizures then phenytoin can be given but this wi ll interact and dose changes in immunosuppression will be required. The calcineurin inhibit ors (ciclosporin or tacrolimus) should be stopped until seizure activity is controlled. Infections in the lung transplant recipient Although lung recipients are at increased risk of opportun- istic infections, it is much more frequent for them to present with common vir al or bacterial infections than an opportunistic pathogen. These infections may, however, b e more severe than in an immunocompetent patient. It is important to note that lung transpl ant recipients are rarely neutropenic and therefore it is unnecessary to commence high dose broad spectrum antibiotics immediately on pres- entation with a fever or other clinical si gns of infection. However a recipient presenting very unwell with signs suggestive of sepsi s should receive appropriate broad spectrum antibiotics as per any acutely unwell patient. Appropriate sampling: \200 blood cultures; \200 urine cultures; \200 sputum cultures or BAL culture. In many cases identi \201 cation of causative organisms can be made on cul ture allowing more targeted antibiotic therapy is commenced. Lung recipients will receive p rophylaxis against speci \201 c opportunistic infections, such as pneumocystis and herpes virus infection. Prophylaxis against pneumocystis should be continued lifelong with the sta ndard regimen of co-trimoxazole 480mg daily or an alternative if necessary. pneumocystis in fection is vanishingly rare in patients on prophylaxis. This therapy therefore should not b e stopped without consultation with the transplant center. Herpes virus prophylaxis is prov ided by oral acyclovir which can be stopped after 3 \200\2236 months when levels of immunos uppres- sion are lowered. Cytomegalovirus (CMV) infection is an important cause of disease in lung transplant recipients. CMV may present with generalized malaise and \202 u-like s ymptoms or with spe- ci \201 c gastrointestinal symptoms or respiratory symptoms. When the re is a mismatch between the donor and recipi- ents CMV status the risk of CMV disease is m uch higher. In these cases prophylactic treatment against CMV is given for the \201 rst 3 months with an anti-viral agent such as oral val- ganciclovir when the risk of developing CMV disease is at its highest. Other patients will be under surveillance for a rise in CMV activity using a PCR-based assay of viral load meas- ured on a weekly basis. In these patie nts viral load will in- crease before symptoms develop allowing pre-emptive treatment with valganciclovir before a full blown CMV syn- drome develops. If CMV disease is suspected the n early discussion with the transplant center should occur. Some recipients may also be rec eiving nebulised anti-infec- tive agents such as anti-pseudomonal antibiotics and/or anti-f ungal therapy on the basis of organisms they were culturing pre-transplant or guided by pos itive cultures from pre-discharge bronchoalveolar lavages. These should be continued until reassessed by the transplant center and may be required lifelong. Increased cancer risk Lung transplant recipients have an increased risk of cancer as a resu lt of their immunosuppression. Skin cancers are particularly common and recipients are advi sed to avoid excessive periods in the sun or to use very high factor sun protection. Recipi ents should be advised to be vigilant for new skin lesions and report them immediately. The risk of solid organ cancers is also increased. Any patient presenting with tonsil enlargem ent, peripheral lymph nodes, recurrent abdominal pain suggestive of intus- suception, bowel obstruction, perforation or the presence of pulmonary nodules on CXR may have developed po st transplant lymphoproliferative disease (PTLD). Rarely, a patient with PTLD may present w ith perforation or bowel obstruction and will require emergency surgery. In such cases biop sies of any lymph nodes and abnormal tissue should be taken for frozen section as well as p laced in formalin so that appropriate molecular typing can be undertaken. PTLD is usually a n Epstein \200\223Barr virus-driven B-cell prolif- erative process that responds in a major ity of cases to a reduction in immunosuppression. Such patients should not therefore be fas t-tracked into local lymphoma services to receive chemotherapy. It is very important that t he transplant team is informed immediately should a recipient present in this way so that a management plan can be formulated. Ideally Patients presenting in an emergency situation w ith nodules or lymph nodes including tonsillar enlargement should be referred back to the t ransplant center for investigation and subsequent management. Lung transplant recipient needing routine surgery Lung transplant recipients may require ro utine surgery and advice may be sought from local respiratory physicians by surgeons or ane sthetists. CHAPTER 17.3 The care of lung transplant candidate or recipient 429 Special attention should be given to maintain good hydra- tion, monitor renal function and serum levels of immuno- suppressive drugs. Immunosuppression can be omitted the morning of surgery and restarted when the recipient is safely passing urine again usually within 24 ho urs. If a patient will be unable to take oral medication for some time a treatment regimen should be agreed with the trans- plant center in advance. KEY POINT A lung transplant recipient with stable and adequate lung function has no excessi ve risk associated with routine surgery. There is no need to give prophylactic antibiotics to lung recipients speci \201 cally unless they would normally be used for that procedure anyway. A MILLAR 430 17.4 Acute respiratory distress syndrome Pathophysiology ARDS is characterized by evidence of alveolar in \202 amma- tion and injur y leading to breakdown of the alveolar- capillary membrane and resultant pulmonary capillar y permeability. It involves through exudative, in \202 ammatory, and \201 broproliferati ve processes which are not sequential. ARDS is the most extreme manifestation of acute lung injury (ALI). This condition can devel op as the result of a wide range of both direct and indirect insults. Prevention is the bes t strategy in that the outcome is usu- ally dependent on prompt identi \201 cation and man agement of the precipitating cause which is a key role for the respi- ratory team. Presentation \200 <50% of patients with acute lung injury present either with acute lung injury or full-blown ARDS, which may have prognostic seem to develop ARDS within three days of admission to an intensive care unit. De \201 nition of ALI/ARDS Radiology: new, bilateral, diffuse pulmonary in \201 ltrates o n CXR consistent with pulmonary oedema. Oxygenation: PaO2:FiO2 ratio of <40kPa (acute lung injury); PaO2: FiO2 ratio of <26kPa (acute respiratory dis- tress syndrome). No clinical ev idence that heart failure, \202 uid overload, or chronic lung disease are responsible for the in \201 ltrates; or pulmonary artery occlusion pressure of <18mmHg. The advantages of this de \201 nition are that it is simple to apply in the clinical setting, it recognizes that the spectrum of lung injury severity and also attempts to exclude cardio- genic pulmo nary oedema and chronic lung disease. It has limitations \200 No account of the amount of PEEP applied, which may profoundly affect oxygenation or lung compliance the cause of ARDS or consideration of different pathophysi- ology according to the site of the original inju ry. Most patients present clinically with dyspnoea, which may be masked by symptoms of the prec ipitating condition. Differential diagnosis \200 Cardiogenic pulmonary oedema: excluded by using echocardiography. Acute interstitial pneumonia: rapidly progressing form of lung injury. BAL characteristical ly shows both eosino- phils and neutrophils. AUTHOR \200\231S TIP Prognostic factors predicting death at the time of diag- nosis include chronic liver disease, nonpulmonary organ dysfunctions, sepsis and age. Oxygenation (PaO2/ FiO2) is not a prognostic factor at onset of ARDS but 24 \200\22348 hours later predicts ou tcome. Presence of multiorgan dysfunction and the radiographic \201 ndings are not speci \201 c. Diffuse alveolar hemorrhage: seen at bronchoscopy (post-intubation). Diagnostic haemosideri n laden macro- phages appear after 48 hours. AUTHOR \200\231S TIP The de \201 nition does not demand the automatic mesure- ment of PAOP . It can be elevated over 18 mmHg in ARDS patients particu larly if volume overloaded or wi th high intrathoracic pressures. Idiopathic acute eosinophilic pneumonia: raised eosino- phils (typically 40%) are seen in t he BAL \202 uid and usually in the blood. Lymphangitis carcinomatosis: bronchoscopy with BAL (and biopsy) aids diagnosis. Epidemiology Using the 1994 consensus de \201 nition the reported inci- dence has varied f rom 13.5 per 100,000 to 75 per 100,000. Ongoing prospective studies using the 1994 consensu s de \201 nition will clarify this issue. The number of patients at risk of ARDS is unknow n. The proportion of those which develop ARDS varies with the etiology from 2% following ca rdiopulmonary bypass to 35% following aspiration. In the critically ill an incidence of 16 \200\22318 % is reported. Investigation These will depend on the mode and severity of presentation. The respiratory t eam will be involved both with patients at risk of developing ARDS (e.g. those with pneumon ia) also with management and investigation of patients on ITU with the condition. \200 Ra diology: CXR and CT to exclude other diagnoses. \200 Physiology: blood gasses will establ ish severity of respira- tory failure. Bronchoscopy and BAL, will be useful both diagnostically (especially in the immunocom promi sed) and therapeuti- cally to remove mucus plugs. Risk factors \200 Direct injury: pneumonia, aspiration, pulmonary contu- sion, fat emboli, near-drowning, inhalational injury. Indirect injury: sepsis, trauma, cardiopulmonary by pass, drug overdose, acute pancreatitis , massive blood transfusion. AUTHOR \200\231S TIP Sepsis is the factor most associated with development of ARDS (40% of cases) and the presence of multiple pre- disposing factors substantially increases the risk . CHAPTER 17.4 Acute respiratory distress syndrome 431 Mechanical ventilation is discussed in detail in Chapter 17.6. Low tidal volumes have been shown to be protec- tive but can result in reduced carbon dioxide clearance. Permissive hyp ercapnia is acceptable as long as oxy- genation is not compromised and the pH is maintained above 7.2. The use of positive end expiratory pressure (PEEP) and prone ventilation are ot her techniques which may be helpful. Corticosteroids: these drugs remain controversial and no clear cut advantage has been shown by Cochrane review. \200 Inhaled nitric oxide: an improvement in oxygenation occurs in 6 0% of patients but the effect is transient (48 hours) and does not improve mortality. Nebulised prostacyclin: this is another vasodilator with similar physiological effects to n itric oxide. When nebu- lised, it has an equivalent effect on pulmonary vasodi- lation and oxygenation but is easier to administer, and requires no special monitoring. Outcome \200 Most studies until recently have reported a mortality rate of 40 \200\22360%. Death occurs mainly due to sepsis or multiorgan dys- function and not respiratory failure. The therapeutic success of low tidal volume ventilation in the ARDS Network Trial indicates some deaths are directly related to lung injury. Some data suggest mortality is falling. Possible reasons for this include improved treatmen t of sepsis, better ventilation strategies and improved supportive care. \200 Pulmonary f unction in most survivors returns to normal Fig. 17.4.1 A typical CXR of ARDS showing widespread diffuse alveolar shadowing. or near-normal levels by 6 months. Mild restriction, reduced, bronchial hyper-reactivity and air trapping can persist. AUTHOR \200\231S TIP ARDS survivors may have a persistent extrapulmonary functional disabil ity 12 months after discharge mainly due to muscle wasting and weakness with minimal lung f unction changes. Further reading Bernard GR, Artigas A, Brigham KL, et al. The American-European consensus c onference on ARDS. De \201 nitions, mechanisms, rele- vant outcomes, and clinical trial co ordination. Am J Respir Crit Care Med 1994; 149: 818 \200\223824. Fig. 17.4.2 A CT scan showing widespread ground glass showing with areas of consolidation a nd some areas of more normal appearance. Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute resp iratory distress syndrome. N Engl J Med 2006; 354: 1775 \200\2231786. Treatment Treatment is essentially supportive ventilation with aggres- sive management of t he precipitating condition. Nutritional support and tight glycaemic control are essential C omplica- tions include the exacerbation of lung injury, multiple organ system failure, noso comial pneumonia, deep vein thrombosis, and gastrointestinal bleeding must be minimized. Peter JV, John P, Graham PL, et al. Corticosteroids in the prevention and treatment of acut e respiratory distress syndrome (ARDS) in adults: meta-analysis. BMJ 2008; 336: 1006 \200 \2231009. Useful Website: NHLBI Acute Respiratory Distress Syndrome network for trial details and results. www.ardsnet.org S POUTANEN 432 17.5 Severe acute respiratory syndrome Epidemiology \200 SARS was \201 rst recognized i n Guangdong Province, Chi- na in November 2002 and spread to 26 countries over the subseque nt 9 months. Clinical course Clinical presentation \200 Clinical presentation ranges from asymptomatic disease to mild respiratory symptoms to the severe acute respira- tory syndrome after whic h the virus was named. 8098 infected people and 774 deaths were reported to the World Health Organization before t he outbreak was declared over in July 2003. Typical SARS presents with fever, chills, malaise, head- ache, and myalgia; non-productive cough, dyspnoea, and sometimes watery diarrhea seen 3 to 5 days later. \200 If infants an d children acquire the infection (rare), they Four isolated cases of SARS with no associated trans- mission were identi \201 ed in China in December 2003 and January 2004. Two isolated cases and a cluster of 11 cases (one death ) were identi \201 ed in South-East Asia related to breaches in biosafety practices in lab oratories culturing SARS-CoV. follow a milder course frequently with rhinorrhea. Routine laboratory investigations \200 Normal total white blood cell count, lymphopenia, increased lactate dehydrogenase and creatinine kinase levels are typical. Whether or not a large-scale re-emergence of SARS will occur is debatable. Laboratory abnormalities progress and peak at/just after Etiology \200 SARS Coronavirus (SARS-CoV) was identi \201 ed in 2003. \200 SARS-CoV li kely evolved from animal SARS-like CoV (found most frequently in Himalayan civet cats and b ats in China). the second week of disease. Chest radiography \200 75% of patients have uni- or bilateral in \201 ltrates on CXR at the time of presentation. If CXR clear, ground glass opacities often detectable on SARS-CoV, like other coronaviruses, is an enveloped non-segmented, single-stranded, positiv e sense, RNA virus. HRCT or will progress to develop CXR in \201 ltrates. Typically see air-space opacities with ill-de \201 ned margins in a predominant peripheral location progressing from unilateral focal involvement to unilateral or bilateral multifoc al involvement. Incubation period \200 Based on the 2003 outbreak, the typical incubation period for SARS is 2 to 10 days (mean of 4 to 6 days). A small proportion of cases may have incubation per iods as short as 1 day and as long as 14 days. CXR opacities peak between 8 and 10 days after illness onset and then improve. Progressive radiographic deterioration may occur asso- ciated with a more protracted clinical course. SARS is not communicable prior to symptom onset but transmission may occur soon after. Risk of transmission increases as symptoms progress, peaking during the second week of illness corresponding to peak viral load. Most countries considered patients to be potentially infe ctious and kept them in isolation precautions un- til 10 days after resolution of fever and signs of clinical improvement. There was no evidence of transmission from anyone treated i n this manner, and it is possible that isolation for a shorter period of time may be suf \201 cient. Cavitation, lymphadenopathy, and pleural effusions are not typically seen. Pneumothoraces h ave been found in critically ill patients receiving mechanical ventilation. Prognosis \200 20% of patients develop worsening respiratory distress requiring intensive care. Approximately 10% of patients die from progressive respiratory distress or complications of their hospital admission, typically during the third or fourth week of symptomatic illness . Increased risk of death with age (50% mortality if >60 years), co-morbidity, elevated lacta te dehydrogenase, elevated CRP, and elevated neutrophil counts.