calcium; 2 encouraging physical activities; and 3 management of pulmonary exacerbations. Randomized controlled trials have con \201 rmed that a combi- nation of oral vitamin D, oral calcium and bisphosphonate are effective in the management of reduced bone mineral density. These s tudies included organ transplant recipients. The effects are similar are for either intrave nous pamidro- nate or oral alendronate. For patients who are likely to remain on glucocorti coids for a lengthy duration, for example those with allergic broncho-pulmonary aspergillos is, bisphosphonate should start with or shortly after the introduction of glucocorti- coids . Table 11.5.4 outlines the indications for administration of bisphosphonate in CF patients with reduce BMD. Fig. 11.5.5 A 22-year-old patient who underwent a liver transplant. The patient has percuta neous enterogastric (PEG) feeding with a tube in situ. Survival rate for liver transplantation is favorable with one year survival reaching 82% an d 10 year survival of over 60%. The status of the lungs and microbiology are carefully asse ssed for liver transplant recipients. Contraindications of liver transplant include: \200 \200 Severe ventilatory failure with impaired gas exchange, Pulmonary infection with the epidemi c strains genomovar III of Burkhuldria cepacia (also known as Cenoce pacia,) and Psychosoci al status deemed to influence adherence to life-long administration of cytotoxic agents use d to prevent graft rejection and of follow-up in specialist clinic. Table 11.5.4 Indications of bisphosphonate treatment Reduced Z score on DEXA scan below \210\2222.0 despite optimal treatment Reduced Z score b elow \210\2221.5 in organ transplant candidates or recipients Patients likely to have a le ngthy course of glucocorticoids Patients sustained stress fractures Patients with failure t o increase weight, body mass index less than 17 and a Z score of less than \210\2221.5 \200 \200 Paradoxically the lungs often improve after liver transplant. Possible reasons for this are : 1 reduced intra-pulmonary shunt; 2 probable anti-in \202 ammatory properties of the cyto toxic Bisphosphonate is usually a life-long treatment. Musculoskeletal pain is a recognized occas ionally associ- ated with the use of bisphosphonate. The mechanism is not established. Howe ver, treatment with a short course of prednisolone prior to IV pamidronate suggests an in \202 am- matory mechanism for the pain. agents; and 3 improved nutritional status and increased body mass index which tends to occur following liver transplantation. Reduced bone mineral density BMD (osteomalacia and osteoporosis): Reduced BMD is now a reco gnized, preventable and treat- able CF complication. Possible reasons are outlined in Table 11.5.3: The upper airways in CF patients It is reasonable to regard the respiratory tract as a pass age starts at the nostrils and ends at the alveoli. This fact is true N JARAD 256 in CF where impaired CFTR in the upper airway is mani- fested with life long incurable dise ases. Sinusitis and nasal polyps In the author \200\231s unit, over 75% of patients admitte d to chronic nasal symptoms and 62% are aware of having chronic sinusitis with acute \202 are up. Mucosal in \202 ammation results in narrowing and blockage of the nasal outlets o f the maxillofacial and frontal sinuses. This leads to under-developed facial sinuses seen in CF patients. Nasal polyps are probably an exaggerated manifestation of in \202 amed muc osa. They are histologically different from allergic nasal polyps. Symptoms of rhino-sinusi tis start during childhood with the triad of runny nose, nasal congestion, and post-nasal d rip. Acute on chronic sinusitis often precede symptoms of pulmonary exacerbations. Most pat ients interpret this as a viral disease (cold) followed by respiratory symptoms In chronically infected patients, swabs from sinus secre- tions often grow Pseudomonas aeru ginosa and Haemophillus in \202 uenzae which are implicated in the pathogenesis. Management Acute sinusitis responds well to antibiotics provided for pulmonary exacerbation s. Oral antibiotics typically with quinolones help with isolated episodes of sinusitis. Nas al corticosteroids reduce the nasal in \202 ammatory proc- ess. Systemic corticosteroids a re useful in reducing the size of nasal polyps. Nasal decongestants are useful symptomatic management during the acute phase, but should be used only for a short period of time to av oid vasomotor disease which is a phe- nomenon in which the nasal vessels do not constrict a fter prolong use of decongestant. Surgical management consists of resection of nasal polyps . Irrigation of the sinuses has also a short symptomatic bene \201 t AUTHOR \200\231S TIP A careful history which rules out viral nasal symptoms in the patients surrounding or when nasal symptoms occur outside the cold season suggest that the patient suffers from acute CF sinusitis. The reproductive system and pregnancy Several surveys showed that CF patients of both gende rs felt that adequate information about sexual functions and reproduction have not been pro vided during repeated consultations. Male CF patients Almost 97% of male CF patients are infertile due to azoospermia. This is b ecause of bilateral absence of vas deferens and atrophy of the seminal vesicle, ejaculary d uct and body and tail of epidydymis. The testicles are normal in architecture and histology and able to produce active sperms. Sexual potency is not affected. With the increase survi val and improved quality of life, male patients are increasingly seeking fertility assistan ce. Combining sperm harvesting with intra-cytoplasmic sperm injection (ICSI) are the standa rd methods. The conception rate is variable. Female CF patients The fallopian uterine ducts are patent, but the mucous is more viscous a nd less well hydrated than in normal females. Delayed puberty and abnormal menarche are wel l recog- nised in CF female The reported rate of fertility in female CF patients varies. A conception rate after 2 years of active sexual contact ranged from 20 \200\22375%. We advis e that all female CF patients should regard them- selves to be fertile and if they do not w ish to they should take similar birth control precautions as non CF persons. AUTHOR \200\231S TIP Almost all male CF patients are azoospermic. Conversely, all female CF patients should be regarded as fertile and should be given a proper contraception advise i f they do not wish to conceive. CF and pregnancy Retrospective studies showed no adverse outcome on the mother or the child when FEV1 was over 50% of predicated values. During a consultation on pregnancy, the discu ssion should be supportive and sensitively tailored according to the general performance an d FEV1 of the patient. The following areas need to be discussed. 1 The effect of late stage s of pregnancy on lung function Fig. 11.5.6 MRI of facial sinuses. The right side shows thickened mucosa in both sides with reduced air space in the maxillofacial sinuses. On the left side, there are absent air spa ces with obvious bilateral large nasal polyps (white arrow). Facial X ray should no longer be used to make a diagnosis of sinusitis. Facial CT scan or p referably MRI scan (Fig. 11.5.6) are the investigations of choice. The radiolo- gical featu res are those of thickened mucosa and reduced or absent air spaces. especially for those with advanced lung disease. CHAPTER 11.5 Extra-pulmonary manifestations of cystic \201 brosis 257 2 The effect of CF and the CF drugs on pregnancy and the higher rate of miscarriage, extra- uterine pregnancy and pre-term delivery compared to non-CF persons. King LJ, Scurr ED, Murugan N et al. Hepato-biliary and pancreatic manifestations of cystic fibrosis: MR imaging appearances. Radiographics 2000; 20: 767 \200\223777. Kopleman H, Corey M, Gaskin K, et al. Impaired chloride secretion, as well as bicarbonate s ecretion, underlies the \202 uid secretory defect in the cystic \201 brosis pancreas. G astroenterology 1988; 95: 349 \200\223355. 3 The higher probability of the child having CF. We advise that the partner seeks counselin g and provide blood samples for detection of CF genetic pro \201 le. 4 We would seek the views about the patients \200\231 ability to Kotlof RM, FitzSimmons SC, Feil SB. Fertility and pregnancy in patients with cystic \201 brosis. Clin Chest Med 1992; 13: 623 \200\223635. Laang S, Thorsteinsson B, Pociot F et al. Diabetes Mellitus in cystic \201 brosis: genetic and immunological markers. Acta Paediat r 1993; 82:150 \200\223154. care for a toddler. Further reading Colombo C, Castellani MR, Balistriri WF et al. Scintigraphic docu- mentatio n of an improvement in hepatobiliary execretory func- tion after treatment with ursodeoxych olic acid in patients with cystic \201 brosis and associated liver disease. Hepatology 19 92; 15: 677 \200\223777. Marshall BC, Butler SM, Stoddard M, et al. Epidemiology of cystic \201 brosis-related diabetes. J Paediatr 2005; 146: 681 \200\223687. Raj P, Stableforth D, Morgan DW. A prospective study of nasal dis- ease in adult cystic \201 brosis. J Laryngol Otol 2000; 114: 260 \200\223263. Ramsey B, Richardson MA. Impact of sinusitis on cystic \201 brosis. Conway SP, Morton AM, Oldroyd B et al. Osteoporosis and osteo- penia in adults and adolesce nts with cystic \201 brosis: prevalence and associated factors. Thorax 2000; 55: 798 \200 \223804. J Allergy and Immunol 1992; 90: 547 \200\223552. Rolon MA, Benali K, Munck A et al. Cystic \201 brosis-related diabetes mellitus: clinical impact of pre-diabetes and effects of insulin therapy. Acta Paediatr 2001; 50: 1336 \200 \2231343. Edenborough FP, Mackenzie WE, Stableforth DE. The outcome of 72 pregnancies in 55 women wit h cystic \201 brosis in the United Kingdom 1977 \200\2231996. Br J Obstet Gynaecol 2000; 107: 254 \200\223261. Sawyer SM. Reproductive and sexual health in adolescents with cystic \201 brosis. BMJ 1996; 313: 1095 \200\2231096. Elkin SL, Vedi S, Bord S et al. Histomorphometric analysis of bone biopsies from the iliac crest of adults with cystic \201 brosis. Am J Respir Crit Care Med 2002; 166: 1470 \200 \2231474. The Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenoty pe in patients with cystic \201 brosis. N Engl J Med 1993; 329: 1308 \200\2231313. Haworth CS, Selby PL, Adams JE et al. Effect of intravenous pamid- ronate on bone mineral d ensity in adults with cystic \201 brosis. Thorax 2001; 56: 314 \200\223316. The UK CF Trust bone mineralization document. Cystic Fibrosis Trust Publication 2007. www.cftrust.org.uk. Van de Meeberg PC, Houwen RH, Sinaasappel M et al. Low-dose versus high-dose ursodeoxycholi c acid in cystic \201 brosis choles- tatic liver disease: results of randomized study wit h 1 year follow- up. Scand J Gastroenterol 1997; 32: 369 \200\223373. Jarad NA, Higgs S, Giles K. Factors associated with reduced FEV1 in adult patients with cys tic \201 brosis in a relatively af \202 uent area. Chronic Resp Dis 2005; 2: 133 \200 \223137. Jarad NA, Giles K. Factors associated with increased rate of pulmo- nary exacerbations. Chronic Resp Dis 2008; 5: 1 \200\2235. This page intentionally left blank 259 Chapter 12 Pulmonary vascular problems/issues Chapter contents 12.1 Pulmonary embolism 260 12.2 Pulmonary hypertension 264 12.3 Pulmonary vasculitis and h emorrhage 272 A FENNERTY 260 12.1 Pulmonary embolism Epidemiology \200 The incidence of pulmonary emboli (PE) increases expo- nentially with a ge from 5:100,000 in children increasing to 400:100,000 in the over eighties. Table 12.1.1 Major risk factors for venous thrombosis (Continued) Reduced mobility \200\223 major illness with prolonged bed rest Age >70 years The mortality rate in a clinically stable patient presenting with a PE is 1 \200\2232%. Mor tality increases with age and co-morbidity. The overall mortality rate which includes patie nts with signi \201 cant co-morbid conditions is 12 \200\22315%. \200 60 \200\22380% of deaths due to PEs are undiagnosed in life, despite post-mortem evidence of earlier \200 \230sentinel \200\231 emboli. \200 Post-mortem studies consistently show that PEs are res ponsible for 10% of all hospital deaths, highlighting the importance of thromboprophylaxis in hospital patients. Thrombophilias: Antithrombin de \201 ciency Protein S de \201 ciecy Protein C de \201 ciency Antiphospholipid antibodies Diagnosis \200 Pulmonary embolism presents with non-speci \201 c symp- toms and signs (T able 12.1.2) and is therefore considered in the differential diagnosis of many patients pre senting to an acute unit. Etiology \200 Venous thromboembolic disease is a multifactorial con- dition, resulting fr om an interaction of genetic factors (known and unknown), external factors and age. It is important to select only those patients who have a reasonable chance of a PE for further investigation. The major risk factors individually increase the risk of a A full history, examination and routine tests, which should include a CXR, an ECG and a ful l blood count, will help rule out PE in patients with alternative diag- noses such as infec tion, ischaemic heart disease or chest wall pain. PE by a factor of 5 or more (Table 12.1.1). The minor risk factors increase the risk of a PE by a factor of 2 \200\2233 and include the oral contraceptive pill, hormone replacement therapy and long distance travel (travel grea ter than 8 hours). These factors are more likely to cause disease when combined with geneti c or other external factors, and they are not usually considered when assessing the clinica l probability of a PE (see later). The classic ECG \201 ndings of right ventricular hypertrophy and strain, or CXR findings of the peripheral wedge shaped infarct or areas of hypoperfusion are rare. Thrombophilias Thrombophilia is a generic term for conditions in which venous thromboses oc cur inappropriately. These condi- tions may be inherited or acquired. Up to 20% of patients with venous thromboembolism will have a recognized ge- netic clotting abnormality. It is l ikely that these abnormali- ties only give rise to problems when combined with one or more additional genetic defects or when interacting with external risk factors. \200 For pract ical purposes it is not worthwhile to routinely test for thrombophilias. Affected patients are no more likely to suffer a repeat event once anticoagulation is stopped than someone no t affected, so the result will not alter management. Table 12.1.2 Clinical presentation of pulmonary emboli Dyspnoea \200\223 73% Pleuritic chest pain \200\223 66% Tachypnoea \200\223 70% Crackles \200\223 51% Cough \200\223 37% Tachycardia \200\223 30% Haemoptysis \200\223 13% Pleural rub \200\223 3% Presenting signs and symptoms of patients with a proven PE in the PIOPED study Screening patients who might be at risk, such as patients wanting the oral contraceptive pi ll, is not cost effective. Thrombophilia testing is recommended in: In a proportion of patients no clear alternative diagnosis can be made and the diagnosis of PE then becomes a rea- sonable possibility. The patient now enters the clinical algo- rith m for the diagnosis of PE a) Patients under the age of 40 with recurrent throm- boembolic events and a strong family history of thromboembolic disease in \201 rst degree relatives. In such patients combinat ions of defects or the more serious, but rarer, single defects (Table 12.1.1) are more like ly. (However, even a strong family history is a poor indicator of an underlying thrombophil ia.) b) Patients who might have disease associated with the Clinical probability The next step is to assess the clinical probability of the patient hav ing a PE \200 The positive and negative predictive value (PPV, NPV) of a test depends on the prevalence of the condition being tested for in the population under investigation. acquired anti cardiolipin antibody. The NPV of a test increases when the prevalence is low and decreases when it is high. (To p ut it another way, you are more able to trust a negative test if the diagnosis was unlikely in the \201 rst place!) The reverse applies to the PPV. \200 The purpose of the clinic al probability is to help the clini- cian decide on the likely prevalence of a PE in a grou p of patients presenting with the same clinical features as their patient. Table 12.1.1 Major risk factors for venous thrombosis Major surgery Orthopedic surgery to lower limb/lower limb trauma History of venous thrombos is Cancer Pregnancy/puerperium \200 \200 \200 \200 CHAPTER 12.1 Pulmonary embolism 261 The clinical probability will determine which test you do next and importantly how you inte rpret all subsequent tests. The D-dimer is not sensitive enough to be used in patients with a high clinical probability. A wide range of conditions is associated with increased Several scoring systems, of varying objectivity, have been developed to assess clinical pro bability. The BTS score is the least well validated but has the bene \201 t of being simpl e and easy to remember. levels of D-dimer D-dimer levels increase with age and this should be consid- ered when dealing with borderli ne results in the elderly. \200 If used appropriately a negative D-dimer can effectively rule out the diagnosis of PE in about 30% of patients. Clinical probability scoring systems Revised Geneva Score Age > 60 years Previous VTE Surge ry/fracture lower limb in last month Active malignancy Unilateral lower limb pain Haemoptys is Heart rate 75 \200\22394 D-dimer can be raised in \200 Venous thromboembolic disease. \200 Increasing age. \200 Cancer. \200 Infection. \200 Haematoma. \200 Post operative. \200 In \202 ammati on. \200 Pregnancy. \200 Peripheral vascular disease. \200 Liver disease. If the diag nosis of PE cannot be ruled out by the D-dimer, or if the clinical probability is high, the n proceed to imaging to con \201 rm the diagnosis. Points 1 3 2 2 3 2 3 5 >95 Pain on lower limb deep venous palpation and unilateral oedema 4 Clinical probability Low Intermediate High Total points 0 \200\2233 4 \200\22310 >10 Imaging \200 Multidetector CT pulmonary angiography (CTPA) is the imaging modality of choice for the diagnosis of PE. Modi \201 ed Wells score Symptoms & signs of a DVT Alternative diagnosis less likely Heart rate > 100 Immobilization >3 days or surgery Points 3.0 3.0 1.5 The PIOPED 2 study showed that CTPA has a sensitivity of only 85% (96% when the scan con \201 rmed the clinical probability eg. a positive scan in a high clinical probability patie nt). Large outcome studies show that less than 2% of patients with a negative CTPA suffer a subs equent venous throm- boembolic event if left untreated. This would suggest that any missed PEs are not clinically important. in the previous month 1.5 1.5 1.0 1.0 Previous VTE Malignancy Haemoptysis In the uncommon event of a negative CTPA in a high clinical probability patient, further in vestigations might be appropriate. Score 4 or less: PE unlikely (equivalent to low probability) This scheme is designed for us e with low sensitivity D-dimmer tests eg, SimpliRED, in patients with a low clinical probab ility. If the diagnosis is in doubt, investigation of the leg veins is sometimes advocated, since this is where most emboli arise. Thrombi are only found in 35 \200\22345% of patients with a known PE (using Doppler ultra sound or CT venogra- phy respectively). If thrombi are seen it is reasonable to assume that the patient has had a PE and will need treat- ment. If neg ative, this may be because the thrombus has detached completely and gone to the lung, and t here is a small risk (less than 5%) of the patient having a further VTE. Further investigat ions are unlikely to be helpful. \200 One large study has shown that there is nothing to be gained from doing routine leg ultrasound with a CTPA. \200 It is worth noting that PIO PED 2 also showed a substan- tial false positive rate in patients with a low clinical prob- ability. In this situation the diagnosis should be reviewed, especially if only a small is olated PE is seen. BTS Score Is a PE a reasonable diagnosis? Is an alternative diagnosis less likely? Is a maj or risk factor present? Points 1 1 1 1 point: low clinical probability 2 points: intermediate clinical probability 3 points: hig h clinical probability The D-dimer \200 The D-dimer test is useful for ruling out a PE. \200 Tests have a high sensitivity (a low false negative rate, particularly when the clinical probability is low) , but a poor speci \201 city (high false positive rate) which can lead to a lot of unneces sary investigations when the test is used inappropriately. The ventilation perfusion isotope lung scan is only useful if reported as \200\230normal \200\231 or \200\230high probability \200\231, in the former case an alternative diagnosis is sought or in the latter case the patient is treated. Unfortunately these outcomes only occur in 30% of cases, and in the remaining 70% a PE can- not be ruled in or out, and furth er tests will be required. \200 The echocardiogram can detect right heart strain and an i ncrease in pulmonary artery pressure in the case of a large PE, but further objective tests are required to con \201 rm the diagnosis. Tests with a high sensitivity (>95%) have a very high NPV (few false negatives) in patients with a low or intermedi- ate clinical probability. Most, but not all, of the rapid ELISA k its can be used in these patients. Tests with a lower sensitivity can only be used in patients with a low clinical probability , as they have an unaccepta- bly poor NPV (too many false negatives) in other patients. The widely used SimpliRED test falls into this category. A FENNERTY 262 Treatment \200 Low-molecular-weight heparin (LMWH) should be started Pulmonary embolism and pregnancy \200 Diagnosis of PE in pregnancy can present a challeng e. Symptoms and signs can be dif \201 cult to interpret, the D-dimer is often elevated in the absence of PE and there are concerns regarding fetal exposure to radiation when imaging is required. Given that PE is the second most common cause of death in pregnancy, accurate diagnosis is essential. as soon as PE is considered a reasonable diagnosis. When the diagnosis is con \201 rmed on CTPA warfarin is started and the heparin continued until the INR is in the target range of 2 \200\2233, at which point, if clinically stable, the heparin is stopped and the patient is usually discharged home. This is one situation where isotope scanning may be appropriate. The CTPA exposes the fetus to less radia- tion than an isotope scan, but exposes the maternal breasts to signi \201 cantly more, at a time when they are particularly vulnerable, increasing the risk of breast can- cer in the future. There is a background recurrence rate after an idiopathic PE of about 5% per year (25% at 4 years) once anticoagu- lation is stopped. The risk of a major hemorrhage on long-term warfarin is in the region of 1% per year in pat ients under 75 years and 5% when older. A half dose perfusion scan, to further minimize the risk to the fetus, in the absence of an y active lung disease, has been advocated If the scan is indeterminate then the options are to proceed with a CTPA or rely on further non- invasive tests such as Doppler ultrasound o f the leg veins. The patient and doctor should consider this risk- bene \201 t pro \201 le when discussing how long to anticoagulate. Anticoagulation for 3 months is the minimum treatment period, and little is to be gained by continuing beyond this unless opting for lifetime treatment. Once con \201 rmed, LMWH is used throughout the preg- nancy. Warfarin has adverse effects on fetal develop- ment. Warfarin can be started in the post-partum period, if wished. Life long therapy should be considered after a life- threatening idiopathic PE, in patients with severe cardio- respiratory disease, after a second event or in the event of an ongoin g major risk factor. Caval \201 lters \200 Filters are considered when a patient suffers recurrent PEs despi te adequate anticoagulation or when anticoag- ulants are contraindicated. Is PE a reasonable diagnosis? Filters undoubtedly prevent PEs though there is no evi- Yes dence that they affect mortality. If left in situ they are associated with a signi \201 cant rise in the incidence of deep v ein thrombosis, and thus require ongoing anticoagulation. Assess the clinical probability of a PE Filters can only be used short term in patients who have contra-indications to anticoagulat ion and in these patients only removable \201 lters should be used. Clinical probability Thrombolysis \200 Thrombolysis is the treatment of choice for acute mas- sive PE. This is recognized by cardiovascular collapse in a patient with a known or suspected PE or, more c om- monly, in a patient known to be at risk. Some form of objective test, which in this sit uation would include an echocardiogram, should be undertaken to con \201 rm the diagnosis. Unfortunately there is often little time for this. \200 First-line treatment is thrombol ysis with alteplase 50mg Low/Intermediate * High D-dimer Negative Positive IV bolus. If thrombolysis fails to restore the circulation various techniques using percutaneous cath eters to remove or ablate the embolus have been affective, and in some centers surgical rem oval might be attempted. Both techniques carry a high mortality rate. CTPA No treatment The role of thrombolysis in less severe PEs remains unclear. In so called sub-massive embol i, characterized by right ventricular strain and an increase in pulmonary artery pressure, thrombolysis may improve recovery time but has no effect on mortality. Negative Positive Cancer There is a high recurrence rate of PE in patients with can- cer, even when adequatel y anticoagulated. The rate can be halved using LMWH instead of warfarin and this is now reg arded as the treatment of choice in this situation. It would be reasonable to allow for pat ient choice however, and use warfarin if preferred, converting to long-term LMWH in the eve nt of a recurrence. No treatment Treat Fig. 12.1.1 Diagnostic algorithm for suspected pulmonary embolism. Low sensitivity D-dimer test are only used in patients with a low clinical probability, hig h sensitivity tests can be used in patients with both a low and an intermediate clinical pr obability CHAPTER 12.1 Pulmonary embolism 263 Baglin T, Luddington R, Brown K, et al. Incidence of recurrent venous thromboembolism in re lation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 3 62: 523 \200\223526. Le Gal G, Righini M, Roy PM, et al. Prediction of pulmonary embo- lism in the emergency department: The revised Geneva score. Ann Intern Med 2006; 144:165 \200 \223171 AUTHOR \200\231S TIPS \200 The D-dimer test should not be used as a screening test. Only consider testing patients with a reasonable possibility of a PE, after a full history, examination and routine investigations. Perrier A, Bounameaux H. Accuracy or outcome in suspected pul- monary embolism. N Eng J Med 2006; 354:2383 \200\22384. If used appropriately, the D-dimmer can rule out the Scarsbrook AF, Gleeson FV. Investigating suspected pulmonary diagnosis of PE in 30% of suspected cases. embolism in pregnancy. BMJ 2007; 334: 418 \200\223419. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the model \200\231s utility with th e SimpliRED D-dimer. Thromb Haemost 2000; 83:416 \200\223420. Further reading British Thoracic Society guidelines for the management of sus- pected acute pulmonary embolism. Thorax 2003; 58: 470 \200\223484. N MORRELL 264 12.2 Pulmonary hypertension De \201 nition The normal pulmonary circulation is a low press ure, high \202 ow system that delivers the output of the right ventricle to the alveolar capillary network during each cardiac cycle for the purposes of gas exchange. Pulmonary hyp ertension is de \201 ned as a sustained elevation of mean pulmonary arterial pressure to g reater than 25mmHg at rest, or 30mmHg on exercise. Many diseases can lead to an eleva- tion of pulmonary arterial pressure. Therefore, the term pulmonary hypertension is not a \201 nal diagnosis, but a start- ing point for further investigation. In general terms the main causes of pulmonary hypertension are (i) a narrowing or obstruction of the precapillary pu lmonary arteries, (ii) an increase in pulmonary venous pressure, or (iii) a persistent elev ation of pulmonary blood \202 ow. Table 12.1.1 (Continued) Clinical classi \201 cation of pulmonary hypertension (Venice 200 3) 5. Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, \201 brosing mediastinitis) 1. Type Simple Atrial septal defect (ASD) Ventricular septal defect (VSD) Patent ductus art erious Total or partial unobstructed anomalous pulmonary venous return Combined Describe combinati on and de \201 ne prevalent defect if any Complex Truncus arteriosus Single ventricle with unobstructed pulmonary blood \202 ow Atrioventricular septal defects Classi \201 cation Table 12.2.1 shows the latest World Health Organization (2003) classi \201 cation of pulmonary hypertension as deter- mined by an international panel of experts. The grouping of causes in this classi \201 cation takes into account similarities in etio logy, pathology, and haemodynamic assessment at right heart catheterisation. The classi \201 cation is a useful framework to consider the various causes of pulmonary hypertension, described in more detail below. 2. Dimensions Small (ASD \211 2.0cm and VSD \211 1.0cm) Large (ASD >2.0cm and VSD >1.0cm) 3. Associated extracardiac abnormalities 4. Correction status Noncorrected Partially corrected (age) Corrected: spontaneously or sur gically (age) Table 12.1.1 Clinical classi \201 cation of pulmonary hypertension (Venice 2003) 1. Pulmonary arterial hypertension (PAH) 1.1. Idiopathic (IPAH) 1.2. Familial (FPAH) 1.3. A ssociated with (APAH): Guidelines for classi \201 cation of congenital systemic-to-pulmonary shunts Epidemiology Pulmonary arterial hypertension is broadly divided into idiopathic PAH (previo usly known as primary pulmonary hypertension), and PAH found in association with other cond itions. Idiopathic PAH is further divided into familial and sporadic disease. Approximately 10% of patients with idiopathic PAH have an affected relative. Idiopathic PAH is a rare di sorder with an estimated incidence of 1 \200\2232 per million per year. It is more common i n women (F:M sex ratio = 2.3:1). The disease can occur at any age but most commonly between the ages of 20 and 45. Pulmonary arte- rial hypertension, pathologically indistinguishable from the idiopathic form, can occur in a range of associated condi- tions (Table 12.2.1). Of the connective tissue diseases, the most common association is with systemic sclerosis, where PAH can complicate the clinical course in 15 \200\22320% of patients, in the absence of interstitial lung disease. Other associated conditions include mixed connective tissue d isease and systemic lupus erythematosis, and more rarely, rheumatoid arthritis, dermatopoly myositis and primary Sjogrens \200\231 sysndrome. There is a well recognized associa- tion of PAH with congenital heart disease causing left to right shunts. Overall the prevalence o f PAH is 15 \200\22330%, but varies depending on the nature of the underlying cardiac defec t. Portal hypertension, usually associated with cirrho- sis, is associated with PAH in less than 5% of patients. There is an unusually high prevalence of PAH (0.5%) in patients with HIV infection. Epidemiological studies have con \201 rmed the association of PAH with amph etamine-like diet pills. In the 1970s increased numbers of patients with PAH were found to have been exposed to Aminorex. In the 1990s, further studies confirmed an assocation of 1.3.1. Collagen vascular disease 1.3.2. Congenital systemic-to-pulmonary shunts** 1.3.3. Po rtal hypertension 1.3.4. HIV infection 1.3.5. Drugs and toxins 1.3.6. Other (thyroid disord ers, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemo globinopathies, myeloproliferative disorders, splenectomy) 1.4. Associated with signi \201 cant venous or capillary involvement 1.4.1. Pulmonary veno-occlusive disease (PVOD) 1.4.2. Pulmonary capillary hemangiomatosis ( PCH) 1.5. Persistent pulmonary hypertension of the newborn 2. Pulmonary hypertension with left heart disease 2.1. Left-sided atrial or ventricular hea rt disease 2.2. Left-sided valvular heart disease 3. Pulmonary hypertension associated with lung diseases and/or hypoxemia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Sleep-disord ered breathing 3.4. Alveolar hypoventilation disorders 3.5. Chronic exposure to high altitu de 3.6. Developmental abnormalities 4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease 4.1. Thromboembolic obstruction of proximal pulmonary arteries 4.2. Thromboembolic obstruct ion of distal pulmonary arteries 4.3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign material) CHAPTER 12.2 Pulmonary hypertension 265 PAH with appetetite suppressant drugs of the fen \202 uramine and dexen \202 uramine grou p. An epidemic of PAH also oc- curred in Spain in 1980s following the ingestion of con- tam inated rape seed oil. Other more rarely associated conditions are listed in Table 12.2.1. T he classi \201 cation of PAH includes two other rare pulmonary vascular diseases, pulmonar y veno-occlusive disease and pulmonary capillary haemangiomatosis. Both are more rare than idiopathic PAH, though the true prevalence is unknown. Persistent pulmonary hypertension of the newborn is a disorder characterized by a failure of vascular transition from fetal to a neonatal circulation and is estimated to affect 0.2% of live-born term infants. Pulmonary and pleural lymphatics are dilated and long- standing venous hypertension may lea d to oedema and \201 brosis. A further distinct pathological entity is pulmonary capillar y haemangiomatosis (PCH), characterized by the presence of numerous foci of proliferating, congested, thin- walled capillaries, which invade alveolar tissue, as well as pleura, bronc hial and vascular tissue. Clinical features Symptoms The three main presenting symptoms are dyspnoea, chest pain and syncope. The severity of symptoms is related to prognosis. Unexplained breathlessness on ex ertion should always raise the possibility of pulmonary arterial hyperten- sion, particular ly in the setting of conditions known to be associated with pulmonary hypertension (Table 1 2.2.1). The condition may have an insidious onset. Frequently there is a delay of up to thr ee years between the \201 rst symptoms and diagnosis. Syncope is an ominous sign, usu- al ly re \202 ecting severe right ventricular dysfunction. Other symptoms include lassitude, abdominal swelling from ascites and ankle swelling. Small haemoptysis may occur at later st ages. Genetic factors Familial PAH is a rare autosomal dominant condition with reduced penetrance . It is indistinguishable on clinical or pathological grounds from idiopathic PAH. In 2000, hetero- zygous germline mutations were identi \201 ed in the gene encoding the bone morph ogenetic protein type II receptor (BMPR-II), located on the long arm of chromosome 2 (2q33) . BMPR-II is a receptor for bone morphogenetic pro- teins (BMPs). BMPs are members of the t ransforming growth factor- (TGF- ) superfamily. Mutations in BMPR- II have now been iden ti \201 ed in over 70% of cases of familial PAH. Similar mutations are also found in 15 \200\22326% of patients thought to have sporadic or idiopathic disease. BMPR-II mutations h ave been identi \201 ed in most of the 13 exons of the BMPR2 gene. The majority (70%) of m utations are non- sense or frameshift mutations. Approximately 30% of the mutations are mis sense mutations. These cause retention of mutant protein within the endoplasmic reticulum o r affect important functional domains of the receptor, such as the ligand binding domain or the kinase domain. Muta- tions in BMPR-II have also been found in a small proportion (10%) of patients with PAH associated with appetite sup- pressants and in children with complica ted PAH associated with congenital heart disease. Mutations in another TGF- receptor, ALK -1, have also been reported is association with PAH. ALK-1 mutations are usually found in f amilies with hereditary haemorrhagic telangiectasia, though occa- sionally some family memb ers develop severe PAH. These \201 ndings have highlighted the central role of the TGF- signaling pathway in the pathogenesis of PAH. Clinical signs Tachypnoea may be present, even at rest. Peripheral cyano- sis is common due to a low cardiac output. Central cyano- sis occurs later as pulmonary gas exchange deterio rates or right to left shunting occurs through a patent foramen ovale. The jugular venous p ulse may be elevated with a prominent \200\230a \200\231 wave, re \202 ecting the increas ed force of atrial contraction, or, if tricuspid regurgitation is present, there may be a l arge \200\230V \200\231 wave. There may be a right ventricular heave and a pulsatile liver . On auscultation, forceful closure of the pulmonary valve leads to an accentuated pulmonar y arterial component of the second heart sound. There is often a third and fourth right hea rt sound. The murmurs of tricuspid regurgitation (systolic) or pulmonary regurgita- tion (d iastolic) may be heard. Jaundice, ascites and periph- eral oedema may be present at advance d stages of the disease. Cyanosis may be present, though profound cyano- sis may indicate t he presence of a right to left shunt. Differential diagnosis If the symptoms and clinical signs suggest pulmonary hy- pertension, the differential diagnosis should be considered with reference to the classi \201 cation in Table 12.2.1. Most importantly the presence of left heart disease, parenchy- mal lung di sease or congenital heart disease should be excluded. Pulmonary hypertension due to chronic throm- boembolic disease is important to detect because speci \201 c surgical treatment i s available. Idiopathic PAH remains a diagnosis of exclusion.