He had been diagnosed with follicular lymphoma 4 years previously, and had received extensi ve chemotherapy, as well as chest radiotherapy, a year later. One year after that, and 2 ye ars prior to this presentation, he underwent an allogeneic bone marrow transplantation (BMT , sibling donor), which had been complicated by development of chronic graft-versus-host di sease affect- ing his eyes and mouth. He had never smoked and there was no prior history of any lung disease. His current medications included prednisolone 10mg once a day, cyclosporin 50mg twice a day , penicillin V 250mg twice a day, acyclovir 200mg twice a day, fluconazole 50mg once a day, co-trimoxazole 960mg 3 times a week, alendronic acid 70mg weekly, and omeprazole 20mg once a day. Becotide 200 g 2 puffs twice a day had been started by the referring team with lit tle impact on his symptoms. On examination his oxygen saturation was 97% on room air and he had scattered wheezes and squawks on auscultation. Investigations \227\206 FBC, U&Es and LFTs were all within normal limits \227\206 CXR and pulmonary function tests are shown in Fig. 10.1 and Table 10.1 . CASE HISTORIES IN RESPIRATORY MEDICINE 76 Fig. 10.1 CXR. Table 10.1 Pulmonary function tests Measured % Predicted FEV1(L) 2.4 65 FVC(L) 4.6 100 FEV1/FVC ratio (%) 53 VA(L) 5.4 77 TLCO(mmol/min/kPa) 6.05 58 KCO(mmol/min/kPa/L) 1.47 75 CASE 10 77 Questions 10a) What does (i) the CXR and (ii) the pulmonary function testing show? 10b) What is the likely diagnosis? What differential diagnoses would you consider? 10c) How would you manage this patient? CASE HISTORIES IN RESPIRATORY MEDICINE 78 Answers 10a) What does (i) the CXR and (ii) the pulmonary function testing show? The CXR shows hype r-inflation together with para-mediastinal fibrotic change in keeping with his previous rad iotherapy exposure. Bi-apical pleural thickening and a tented right hemi-diaphragm are also present. (ii) His lung function tests show moderate airflow obstruction with reduced gas t ransfer. 10b) What is the likely diagnosis? What differential diagnoses would you consider? The likely diagnosis is chronic pulmonary graft-versus-host-disease (GVHD) with bronchiolit is obliterans (also called obliterative bronchi- olitis), mainly suggested by the obstructi ve defect and clinical context. The differential diagnosis might include adult onset asthma or other causes of bronchioliti s. These are clearly less likely than chronic GVHD with pul- monary involvement, resulting in symptomatic airflow obstruction. The occurrence of bronchiolitis obliterans (BO) is not limited to those who develop chronic GVHD; it is also seen in some BMT patients without sig - nificant GVHD, and other lung insults, such as infection and irradiation, are thought to contribute. GVHD is usually associated with a severe form of BO which is very similar to th at seen in lung transplant recipients. The following points should be borne in mind: \227\206 Minor asymptomatic decrements in lung function are common post- BMT, and a histor y of acute or chronic GVHD, older recipient age and early respiratory viral infection post- transplant are recognized risk factors. \227\206 Symptomatic airflow obstruction post-BMT is more common in adults than children a nd occurs more frequently following allogeneic BMT. The exact pathogenesis remains elusive and disease is mild in most cases. \227\206 Chronic (>100 days post-BMT) GVHD arises in up to 50% of patients who survive 6 m onths, and direct pulmonary involvement is com- mon. The risk of other non-infectious pulmo nary complications (see Table 10.2 ) is also increased by chronic GVHD, which itself is ass oci- ated with marked immunosuppression, made worse by the drugs used to treat it. Clinical ly dyspnoea, a non-productive cough and wheeze (+/ \200\223 crackles and squawks) are seen at a median post-transplant time of 5 months. The CXR may be normal, but lung function indi cates airway obstruction unresponsive to bronchodilators. Histologically, CASE 10 79 Table 10.2 Other pulmonary complications occurring late (>100 days) post-BMT Infection Risk is reduced with prophylaxis with antibiotics Idiopathic pneumonia syndrome Diagnosis of exclusion with associated high mortality Diffuse alveolar hemorrhage Underlying infection common, mortality high Secondary alveolar proteinosis Reported following transplantation for acute leukemia. BAL positive for lipoproteins Secondary malignancies Underlying malignancy may relapse. Epstein-Barr virus related lymphoma can involve the lung Radiation pneumonitis Radiation induced pulmonary fibrosis, may take 6 \200\22324 months to develop and can devel op in areas not irradiated Pulmonary veno-occlusive disease Rare. Patients dyspnoeic but lung function normal with no signs of infection. Right heart c atheterization shows pulmonary hypertension and lung biopsy confirms the diagnosis pulmonary GVHD may manifest as diffuse alveolar damage, lym- phocytic interstitial pneumoni a (LIP), lymphocytic bronchitis or bronchiolitis obliterans. \227\206 Bronchiolitis obliterans may produce severe symptomatic airflow obstruction in be tween 2% and 14% of patients post-allogeneic BMT. Histologically the small airways are dest royed; fibromyxoid granula- tion tissue causes this small airway obliteration. It is almost exclusive to recipients with chronic GVHD, which has led to the hypothesis that the small airway obliteration is a pulmonary manifestation of GVHD (with bronchiolar epithelial cells targeted by cytotoxic donor T lymphocytes). The exact pathophysiology, however, is unknown ; other factors postulated to mediate persistent small airway inflamma- tion include viral infections, inadequate immunosuppression, low serum IgG, and gastro-oesophageal reflux. 10c) How would you manage this patient? Management should include: \227\206 Augmentation of immunosuppressive therapy (guided by the refer- ring hematology team) Increase in oral prednisolone dose (this is often tried first line) Increase dose of other immunosuppressive agents CASE HISTORIES IN RESPIRATORY MEDICINE 80 Methotrexate, cyclosporin and azathioprine may be used in addi- tion to prednisolone Thalidomide, methylprednisolone, hydroxychloroquine, tacrolimus and TNF antagonists have also been studied \227\206 Optimization of bronchodilator medication Long-acting bronchodilators High-dose inhaled corticosteroids \227\206 Exclusion of concomitant infection \227\206 Prompt treatment of infection (to avoid decline in airflow obstruction and bronchiectatic exacerbations) \227\206 High-resolution CT scan to confirm likely diagnosis and exclude alternatives \227\206 Surveillance with monitoring of lung function/symptoms \200\224the sever- ity and progression of chronic GVHD related airflow obstruction is best assessed by regular monito ring of FEV 1 . There are no prospective studies to guide the definitive treatment of post-BMT airway obstr uction. Most treatment approaches address underlying chronic GVHD with corticosteroids the mainstay of treat- ment for BO. Unfortunately BO is often poorly responsive to therapy. Progress Combination therapy (long-acting bronchodilators and inhaled corticosteroid) was commenced but, despite this, the FEV 1 fell from 2.4 to 1.9. A thoracic CT was performed ( Fig. 10.2 ). Questions 10d) What does the CT show? 10e) What would you do next? 10f ) What other treatment strategies could be considered? CASE 10 81 (a) (b) Fig. 10.2 Two slices from CT chest. CASE HISTORIES IN RESPIRATORY MEDICINE 82 Answers 10d) What does the CT show? His CT reveals para-mediastinal radiotherapy change with mild bron- chiectasis. A mosaic pa ttern of attenuation, consistent with areas of air-trapping, and subtle paucity of peripher al vascularity is seen. 10e) What would you do next? The clinical and radiological picture is consistent with bronchiolitis obliterans and open lung biopsy for histological confirmation is not required. However, concomitant infection s hould be excluded as it is a common precipitant of symptomatic and spirometric deterioratio n (death due to severe chronic GVHD is usually a consequence of infectious complications). Bronchoscopy with broncho-alveolar lavage (specimens sent for micro- scopy, culture for bac teria, mycobacteria and fungi, and cytology) should be performed next. Transbronchial biops y for tissue histology is an option, but diagnostic sensitivity is limited as small airway involvement is often patchy. 10f) What other treatment strategies could be considered? Other treatments to be considered include azithromycin. The anti- inflammatory action of ma crolide antibiotics is well established, although the mechanism is poorly understood. Use o f azithromycin has been shown to improve airflow limitation in patients with BO following B MT (although most evidence is available from patients with BO post-lung transplantation). T he majority of responders will do so after three months of treatment. Hepatic impairment is a recognized complication of macrolides and liver function monitoring is advised. Identification and treatment of gastro-oesophageal reflux, which may contribute to decline in lung function. Patients are at higher risk of reflux due to oesophageal involvement with GVHD and with the use of systemic corticosteroids. All patients should receive annual infl uenza vaccination. CASE 10 83 Progress Pseudomonas species <10 4 organisms/ml were cultured from the BAL and a course of ciprofloxacin eradication therapy was completed. Azithromycin was started (250mg thrice wee kly). Despite a period of stability, after 6 months his exercise tolerance fell (from 300 t o 50 yards) and his FEV 1 dropped further. His prednisolone dose was increased to 30mg dail y with little impact on his respiratory symptoms; ocular and mucosal symptoms remained unde r control. Questions 10g) What would you do next? 10h) What is his prognosis? CASE HISTORIES IN RESPIRATORY MEDICINE 84 Answers 10g) What would you do next? \227\206 A therapeutic trial of higher dose azithromycin (250mg daily) can be considered \227\206 Case reports of successful lung transplantation in selected patients with BO asso ciated with chronic GVHD following allogeneic BMT, and refractory to conventional immunosup pressive therapy, have been published. 10h) What is his prognosis? The prognosis of BO is poor, with an overall mortality of 65% at 3 years post-BMT. For pati ents with airflow obstruction per se , reported mortality rates of 9% at 3 years and 18% at 10 years; in those with chronic GVHD, rates of 22% at 3 years and 40% at 10 years have bee n noted (Chien et al . 2003). Some patients with chronic pulmonary GVHD exhibit a fluctuating course with a remitting or relapsing pattern similar to other autoimmune diseases. A more progressive decline is usual ly seen in patients with BO with development of hypercapnic respiratory failure and death. Early detection of airflow decline is important to allow prompt adjust- ment of immunomodul atory regimens and identification and treatment of exacerbating factors (e.g. infection and reflux) if present. Unfortunately, in spite of such focused approaches, the prognosis rema ins poor. Further reading Chien JW , Martin PJ , Gooley TA , Flowers ME , Heckbert SR , Nichols WG et al. ( 2003 ). Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation . Am J Respir Crit Care Med ; 168 : 208 \200\223 214 . Dudek AZ , Mahaseth H ( 2006 ). Hematopoietic stem cell transplant-related airflow obstruction . Curr Opin Oncol ; 18 : 115 \200\223 119 . Khalid M , Al Saghir A , Saleemi S , Al Dammas S , Zeitouni M , Al Mobeireek A et al. ( 200 5 ). Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a p reliminary study . Eur Respir J ; 25 : 490 \200\223 493 . Case 11 A 53-year-old social worker was referred with a 2-year history of daily cough productive of small amounts of clear sputum. He had been given antibiotics every 3 months or so for epis odes of increasing sputum purulence. He had no haemoptysis, exercise limitation or wheeze. Past history was of severe sinusitis in childhood requiring surgery, but he denied any chil dhood respiratory prob- lems. At age 21 he had severe pneumonia and since then described co lds \200\230going to his chest \200\231 in winter time but, until the last 2 years, had be en well in-between these episodes. He was an ex-smoker of 10 years with a prior 25-pack yea r his- tory. Systemic enquiry revealed no current upper airway or GI symptoms (e.g. bloatin g, fatty stools or difficulty maintaining weight) but he had intermittent arthralgia affect ing his wrists, elbows and shoulders. He had 2 children and denied any family history of re spiratory disease. On examination he weighed 91.7kg, BMI 29, there were some course crackle s in the right base, but otherwise was completely normal. Investigations \227\206 Hb 13.8g/dL, WCC 9.33 \227 10 9 /L, platelets 404 \227 10 9 /L \227\206 ESR 22 mm/h, CRP 6mg/L, U&E, glucose, LFT normal \227\206 Sputum culture, no growth \227\206 Pulmonary function (Table 11.1). Table 11.1 Pulmonary function tests Measured % Predicted FEV1(L) 2.7 73 FVC(L) 4.8 102 FEV1/FVC(%) 53 FRC(L) 5.5 151 RV(L) 3.9 171 TLC(L) 9.0 123 VA(L) 5.9 81 TLCO(mmol/min/kPa) 9.44 90 KCO(mmol/min/kPa/L) 1.6 112 CASE HISTORIES IN RESPIRATORY MEDICINE 86 Fig. 11.1 CXR. CASE 11 87 (a) (c) (b) (d) Fig. 11.2 Four slices from HRCT thorax. Questions 11a) Interpret the lung function tests. 11b) Interpret the CXR. 11c) Interpret the HRCT images. 11d) What is the differential diagnosis? 11e) What key part of the history has to be clarified to aid a clinical diagnosis? 11f ) What further investigations are needed? CASE HISTORIES IN RESPIRATORY MEDICINE 88 Answers 11a) Interpret the lung function tests. The lung function (Table 11.1) shows airflow obstruction, and static lung volumes show hype rinflation and air trapping. Reversibility testing has not been performed. 11b) Interpret the CXR. The CXR shows mildly hyperinflated lung fields. There is bronchial wall thickening througho ut both lung fields. 11c) Interpret the HRCT images. The HRCT slices (Fig. 11.2) show features of generalized bronchiectasis, with dilated airwa ys, bronchial wall thickening and mucous plugging. 11d) What is the differential diagnosis? Differential diagnosis includes the causes of generalized bronchiectasis: \227\206 Immune deficiency \200\224primary (e.g. hypogammaglobulinaemia, com- mon variable immunodeficiency) or secondary (HIV, CLL) \227\206 Post-infective (whooping cough, TB, severe pneumonia; although these often produce more patchy, or localized, bronchiectasis) \227\206 Mucociliary clearance abnormalities \227\206 Primary ciliary dyskinesia \227\206 Young \200\231s syndrome \227\206 Cystic fibrosis \227\206 Connective tissue disease (RA, SLE, Sj gren \200\231s syndrome) \227\206 Inflammatory bowel disease \227\206 Yellow nail syndrome \227\206 Idiopathic. 11e) What key part of the history has to be clarified to aid a clinical diagnosis? The family history must be clarified. Males with CF are infertile, but the patient has 2 ch ildren. On revisiting this issue it transpired that the patient \200\231s children had been adopted because he was infertile. Furthermore, his younger sister had died at the age of 5 with an unknown, undiag- nosed illness associated with severe pneumonia and malabsorption. His mother died from breast cancer in her 50s and his father died aged 62 following an MI. This makes cystic fibrosis a likely cause for his bronchiectasis. CASE 11 89 11f) What further investigations are needed? With knowledge of the full family history, investigations can be targeted at confirming the diagnosis of CF. Other investigations, looking for other underlying causes of generalized bronchiectasis (such as immunoglobu- lins, auto-antibody screen), are not essential at pres ent. CF must be con- sidered in all adults presenting with otherwise unexplained generalize d bronchiectasis. The most appropriate initial investigation would be genotyping for the common CF mutations. Over 1000 different mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene are recog- nized to cause clinical disease, with homozygosity for \224F508 muta tion the most common (approximately 67%). Genotyping revealed our patient to be a compound heterozygote for \224F508 and R117H. The clinical spectrum for this mutation is highly variable but usually mild, with some adult pa tients asymptomatic (detected by screening following a sibling diagnosis of CF). Other pres entations include mild cough, through to clinical bronchiectasis as demonstrated here, to r arely more severe fatal disease. Returning to our patient \200\231s family history, this ra ises intriguing questions about his sister \200\231s genotype. \224F508 homozygosity invar iably causes malabsorption, whereas the R117H and most other mutations permit partial CFTR function and are only rarely associated with pancreatic insufficiency. If she had the same genotype as our patient, her malabsorption would not have been due to CF. For this she woul d have had to be homozygous for \224F508 and therefore one of her parents would have to ha ve been a compound heterozygote \224F508/R117 (and apparently asymptomatic) and the other a simple carrier of the \224F508 mutation (frequency in the general popula- tion 1/25). Al ternatively, our patient \200\231s sister could have died of other causes. In the clinical context of our patient, if genotyping studies for common mutations had been negative, other supporting evidence for a clinical diagnosis of CF would be sought. Here a sweat test could be helpful, but results in adults are more likely to be borderline, as th e reference ranges for normal sweat concentrations are wider and higher. A repeatedly posit ive test would, however, be diagnostic (chloride sweat concentra- tion of >60 mmol/L). Some CF mutations associated with milder disease may produce a near normal, or even normal, swe at test. False-negatives are thus possible (although less common than false-positives) and the test should be repeated in a patient with a phenotype suggestive of CF. CASE HISTORIES IN RESPIRATORY MEDICINE 90 He has the clinical triad of Young \200\231s syndrome (bronchiectasis, sinusitis and infert ility). Separating this from CF requires normal sweat chloride level and pancreatic functio n; and from primary ciliary dyskinesia (PCD) by normal ciliary ultrastructure. The cause of Young \200\231s syndrome is unknown, but the respiratory secretions are excessively viscid leading to prolonged mucociliary transportation. Another diagnosis to consider in this context, had the genotype been negative, would be pri mary ciliary dyskinesia (PCD) which is characterized by bronchiectasis, chronic sinusitis a nd middle ear disease (although patients are not invariably infertile). When PCD is associa ted with dextro- cardia (50% of cases) it assumes the eponym Kartagener \200\231s syndrome. Ciliary function can be assessed by light microscopy (beat frequency) and electron microsc opy (ultrastructure) of a nasal brush biopsy (only available in specialist centers). An alt ernative is to perform a saccharin test, where a small (0.5mm) particle from a saccharin ta blet is placed 1cm behind, or under, the front edge of the inferior turbinate. The patient sits quietly, should not sniff, looks down and reports when sweet- ness is tasted. Beyond 3 0 minutes is considered abnormal. Further reading Massie RJ , Poplawski N , Wilcken B , Goldblatt J , Byrnes C , Robertson C ( 2001 ). Intron -8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C . E RJ ; 17 : 1195 \200\223 2000 . Wilson R ( 2003 ). Bronchiectasis . In: Gibson GJ , Geddes DM , Costabel U et al . (eds) Re spiratory Medicine ( 3 rd edn). Saunders , London , chapter 49 , pp. 1445 \200\2231464. Hod son M , Geddes D , Bush A (eds) ( 2007 ). Cystic Fibrosis ( 3 rd edn). Hodder Arnold , London . Case 12 A 53-year-old lady presented to her GP with a lower respiratory tract infection following a holiday in Spain. Two courses of antibiotics produced little response. Because she was whe ezing, and had a history of exercise wheeze in the past, she received beclomethasone and sa lbutamol inhalers; in addition, her atenolol for hypertension was stopped. This produced a short-lived improvement but wheezing and intermittent dizziness continued, despite various changes in asthma therapy. Finally, despite a normal peak flow, she received a course of or al steroids pending referral to the clinic. In clinic she brought a peak flow chart showing values varying between 400 and 500 L/m, but with no hint of morning dipping. She had never smoked, had a past history of sinus problem s, had no children (but several miscarriages) and was divorced. She slept well. Recent rout ine hematology and biochemis- try (including thyroid function) were normal. On examination She appeared anxious and was tachypnoeic at rest. Resting arterial SaO 2 was 99%. Examinati on was otherwise normal. She was exercised by stepping up and down a 9in block; she immedia tely became breathless, managing only 8 steps, and her breathing was irregular throughout. Her SaO 2 remained at 99% during and after the exercise. Doing spirometry made her dizzy, T able 12.1. Table 12.1 Pulmonary function tests Measured % Predicted 2.9(l) 110% FEV1 FVC 3.2(l) 108% Investigations CXR and ECG normal. Questions 12a) What is the most likely diagnosis? 12b) What test would be appropriate next? CASE HISTORIES IN RESPIRATORY MEDICINE 92 Answers 12a) What is the most likely diagnosis? Given the normal lung function and normoxia, the degree of dyspnoea was out of proportion, particularly on mild exercise, when the dyspnoea became acutely worse before any significan t energy expenditure. The supra-normal SaO 2 (>98%) is perhaps of interest too. This raises the possibility of psychogenic dyspnoea (dysfunctional breathing, or hyper- ventilation sy ndrome, all these terms are used interchangeably). This is both a diagnosis of exclusion, a s well as requiring the presence of a likely explanation for this psychological response. 12b) What test would be appropriate next? As a diagnostic test, some recommend asking the patient to deliberately hyperventilate to s ee if they develop the same symptoms, such as dizzi- ness, numbness and tingling of the lip s and extremities, and a sense of impending doom. This does not always work. Arterial blood gasses at rest can be very useful. They showed the following: \227\206 pH, 7.48 \227\206 PaCO 2 (kPa), 3.62 \227\206 PaO 2 (kPa), 15.1 \227\206 [HCO 3 ] (mmol/L), 21.7 \227\206 Base excess (mmol/L), \200\2233.3. CASE 12 93 Questions 12c) What do the blood gasses tell you about the degree of over (or under) ventilation, and for how long it might have been going on? 12d) What is this patient \200\231s alveolar to arterial gradient for oxygen? 12e) Do these blood gas results support the diagnosis of hyperventilation syndrome? 12f) What theories are there as to the cause of this syndrome? 12g) What are the important alternative diagnoses to exclude, and why do they not seem likely in this lady? 12h) What approaches are available to manage this syndrome? CASE HISTORIES IN RESPIRATORY MEDICINE 94 Answers 12c) What do the blood gasses tell you about the degree of over (or under) ventilation, and for how long it might have been going on? The PaCO 2 is low, and therefore there is alveolar hyperventilation; there is not a low PaO 2 (in fact slightly high), so t hat hypoxia is not the cause of the hyperventilation. There is a small base deficit suggest ing a renal metabolic compensation for the respiratory alkalosis, indicating some chronicit y to the hyperventilation. 12d) What is this patient \200\231s alveolar to arterial gradient for oxygen? The alveolar to arterial gradient is normal at 0.4kPa. In young people up to 2kPa is consid ered normal, and up to 3kPa in the elderly. The alveolar to arterial gradient for oxygen is essentially how much the arterial PaO 2 is less than it ought to be, given the alveolar PO 2 , which is predicted from the PaCO 2 (i.e . the more you ventilate, the lower the PaCO2 and the higher the PaO 2 ought to be). Theref ore, it is calculated by first correcting the PaCO 2 for the respiratory quotient (CO 2 pro - duced, divided by oxygen consumed, usually 0.8), subtract it from the inspired oxygen pre ssure (less water vapor pressure, about 1kPa) and then subtract the actual PaO 2 from it. T hus in this case: A \210\222 a gradient = ( 20 \210\222 3.62 / 0.8 ) \210\222 15.1 = 0.4 kPa . 12e) Do these blood gas results support the diagnosis of hyperventilation syndrome? This indicates there are no low V/Q units, indicating neither areas of lung with relative u nderventilation compared to perfusion, nor right-to- left shunting. This, together with the low PaCO 2 , strongly supports hyperventilation with no intrinsic lung abnormality. 12f) What theories are there as to the cause of this syndrome? The explanations for hyperventilation syndrome are varied. It appears to be one of several symptom complexes reflecting anxiety and panic attacks, sometimes called somatization. Thes e include diarrhea and abdominal pain, episodes of sharp chest pain, palpitations, sweating , headaches and so on. A significant proportion of patients with agora- phobia have hyperve ntilation syndrome. Once established, fears of seri- ous underlying disease seem to maintai n it. In the respiratory version, some preceding respiratory event, such as a chest infecti on, or episode of asthma, generates breathlessness and anxiety which persists after the ori ginal problem has resolved. CASE 12 95 The hyperventilation and consequent alkalosis generate a variety of symp- toms that concern the patient (dizziness from the cerebral vasoconstric- tion, general tiredness and weaknes s, numbness and tingling, dyspnoea), which produce more hyperventilation and more anxiety. The hypocapnia is said to sometimes cause wheeziness. Functional laryngeal dysfunction can occur, with inspiratory stridor. Occasionally the episodes may be self-terminated by loss o f consciousness from the hypocapnia-induced cerebral vasoconstriction. It can exist in an e pisodic form, or more chronically when dyspnoea occurs most of the time, and a base deficit develops. This case is more at the chronic end of the spectrum. It is more common in women , and usually occurs between the ages of 15 and 55. This patient had a history of respirato ry symptoms and a more recent acute event. She had no demonstrable objective abnormalities (apart from persistently high SaO 2 ), a bizarre breathing pattern, and no exer- cise desat uration. 12g) What are the important alternative diagnoses to exclude, and why do they not seem likely in this lady? It is important not to miss other diagnoses that present with few clues (and no fall in SaO 2 on exercise to the point of breathlessness) when making a diagnosis of hyperventilation syndrome, e.g. \227\206 Very mild asthma \227\206 Thyrotoxicosis \227\206 Primary pulmonary hypertension \227\206 Early interstitial lung disease with a normal CXR \227\206 Early heart failure \227\206 Pulmonary emboli. The last four, however, would normally be expected to produce a fall in SaO2 following suff icient exercise to provoke breathlessness. Thus an HRCT might be indicated, but unnecessary investigations will increase the patient \200\231s view that \200\230the doctors think so mething is wrong \200\231. Calcium levels should be checked, as hypocalcaemia may cause similar symptoms to alkalosis: weakness, carpopedal spasm, and parasthesiae. Early interstitial lung disease is unlikely here, given the supranormal spirometry; asthma seems unlikely given the normal FEV 1 /VC ratio and unconvincing peak flow chart. Primary p ulmonary hyperten- sion seems unlikely given the normal ECG and no exercise hypoxia. Heart failure seems unlikely with normal sleep and an uncharacteristic Table 12.1 Nijmegen score. A score over 22 is highly suggestive of hyperventilation syndrom e Before treatment Never 0 Rarely 1 Some- Often 3 Very times 2 often 4 \234\223 Chest pain \234\223 Feeling tense \234\223 Blurred vision \234\223 Dizzy spells \234\223 Feeling confused \234\223 Faster/deeper breathing \234\223 Shortness of breath \234\223 Tight feeling in the chest \234\223 Bloated feeling in the stomach \234\223 Tingling fingers \234\223 Unable to breath deeply \234\223 Stiff fingers or arms \234\223 Tight feeling around mouth \234\223 Cold hands or feet \234\223 Heart racing (palpitations) \234\223 Feeling anxious Total score = 34 After treatment Never 0 Rarely 1 Some- times 2 Often 3 Very often 4 \234\223 Chest pain \234\223 Feeling tense \234\223 Blurred vision \234\223 Dizzy spells \234\223 Feeling confused \234\223 Faster/deeper breathing \234\223 Shortness of breath \234\223 Tight feeling in the chest \234\223 Bloated feeling in the stomach \234\223 Tingling fingers \234\223 Unable to breath deeply \234\223 Stiff fingers or arms \234\223 Tight feeling around mouth \234\223 Cold hands or feet \234\223 Heart racing (palpitations) \234\223 Feeling anxious Total score = 4 CASE 12 97 pattern of dyspnoea. The immediate dyspnoea on attempting exercise, and the irregular patte rn during it, suggest a psychogenic origin. 12h) What approaches are available to manage this syndrome? Treatment can be difficult with great resistance to accepting that there is nothing physica lly wrong, and accepting that not reacting to stress with hyperventilation will help. Somet imes, firm reassurance that nothing is structurally amiss, and a careful explanation as to how hyperventilation syndrome comes about, will work. The explanation needs to acknowl- edg e that there is a problem, which is not \200\230all in the mind \200\231, and that it has arisen from real pathology, which has resolved, but that the body is now reacting inappropr iately. More formally, this could be delivered as cog- nitive behavior therapy. Some will use a short course of sedatives to demonstrate to the patient that it can be stop ped, which may help convince the patient of its origins. Physiotherapists have developed useful approaches to helping patients focus their anxiety a way from their breathing. Examples include: breath- ing slowly through the nose, using the diaphragm rather than the upper chest; avoiding sighing and yawning; trying specific relaxa tion tech- niques; and placing the hands over the cheeks during attacks (the cold clammy ha nds are thought to inhibit inspiration via the diving reflex \200\224 stimulation of the tr igeminal area with cold). The Nijmegen score ( Table 12.1 ) can be useful to follow patients, assess their responses to treatment and as a patient education tool. This patient was treated by a physiotherapist skilled in this area, and the patient \200\231s score sheets, before and after treatment, are shown in Table 12.1 . Further reading www.physiohypervent.org (accessed 1st September 2009) Case 13 A 31-year-old man presented to the emergency department with dyspnoea, slowly progressive o ver a period of 3 months, associated with fatigue, anorexia and 2-stone weight loss. One we ek before presentation he developed night sweats. He was otherwise fit and well, with no re levant past medical or family history. He was Indian and had moved to the UK 5 years previo usly. On exam- ination he was febrile, tachypnoeic (20/min) with oxygen saturations of 96% on room air, and signs of a large left pleural effusion. A BCG scar was present in the righ t deltoid area. Investigations \227\206 Mild leukocytosis \227\206 Raised inflammatory markers (CRP = 98mg/L, ESR = 66mm/h) \227\206 CXR, Fig. 13.1. Fig. 13.1 CXR. Questions 13a) Provide a differential diagnosis for this presentation. 13b) What is the most appropriate next diagnostic step? CASE HISTORIES IN RESPIRATORY MEDICINE 100 Answers 13a) Provide a differential diagnosis for this presentation. Differential diagnosis of massive effusion. Although heart failure may present with unilate ral effusion, it is unlikely to cause an effusion of this size. The main differentials to c onsider are, therefore: \227\206 TB pleuritis \200\224in an Indian presenting with progressive symptoms, large eff usion and systemic illness, this is the most likely diagnosis. TB pleuritis is usually asso ciated with small to moderate sized collections but large effusions may occur. TB pleuritis is the result of an immuno- logical reaction in the pleural space to mycobacteria, and sho uld not be confused with TB empyema \227\206 Malignancy \200\224around 70% of massive (>2/3 hemithorax) effusions are due to p rimary or secondary malignancy. Tissue types to be considered in this age group include lym phoma, germ cell tumors and testicular cancer. A systemic inflammatory reaction is not unco mmon \227\206 Parapneumonic effusion/empyema \200\224the prolonged (3-month) his- tory of sympt oms does not rule out pleural infection (especially with anaerobic organisms), which may ru n an indolent course. Such a mas- sive effusion is against the diagnosis of frank empyema ( the patient would be likely to be much more unwell). \227\206 Acute trauma and haemothorax may cause a massive effusion, but the history is too prolonged. 13b) What is the most appropriate next diagnostic step? Diagnostic pleural aspiration is the next step to narrow the differential. With a large eff usion, the initial attempt can be made \200\230blind \200\231. If pleural fluid is not obt ained at the first attempt (by an experienced operator), image guidance is required. Progress Diagnostic pleural aspiration was undertaken. Investigations \227\206 Appearance: straw-colored, no odor \227\206 Biochemistry: pH 7.43 Glucose 3.3mmol/L CASE 13 101 Protein 53g/L LDH 431IU/L (serum normal 13 \200\223250) \227\206 Cytology: Benign reactive mesothelial cells Few mature lymphocytes No malignant cells seen \227\206 Microbiology: Gram stain negative ZN stain negative. Questions 13c) Comment on the pleural fluid biochemical parameters. 13d) Comment on the pleural fluid microbiology and cytology results in terms of differential diagnosis. 13e) What is the next stage in diagnosis / management? CASE HISTORIES IN RESPIRATORY MEDICINE 102 Answers 13c) Comment on the pleural fluid biochemical parameters. Pleural fluid biochemistry: \227\206 Exudate on the basis of Light \200\231s criteria (see case 22) (assuming serum pr otein and LDH to be normal). In this situation this does not aid in narrowing the different ial diagnosis, as the main differentials are exudates. \227\206 Suggestive of an inflammatory exudate (high LDH indicative of high cell turnover). \227\206 Normal pH and glucose are strong indicators that this is not due to bacterial pleural infection. \227\206 Pleural fluid pH of <7.2 and a glucose of around 1mmol/L are usual for complicate d parapneumonic effusion or empyema (also seen in some cases of malignancy, oesophageal per foration, rheumatoid dis- ease and systemic lupus erythematosis). \227\206 Glucose level of 3.3mmol/L (low-normal) would be typical of TB pleuritis. 13d) Comment on the pleural fluid microbiology and cytology results in terms of differential diagnosis. Pleural fluid microbiology and cytology: \227\206 Negative Gram and ZN stains do not rule out bacterial or mycobacte- rial infectio n, as effusions may be mainly reactive to the presence of a few bacteria. \227\206 Up to 40% of empyemas are Gram and culture negative. \227\206 Only the minority of TB effusions are ZN positive. \227\206 Absence of malignant cells does not rule out malignancy (40% cytology negative on first aspiration). \227\206 TB pleuritis typically associated with a lymphocyte predominant cell population; up to 10% of cases are polymorph predominant. 13e) What is the next stage in diagnosis / management? Management: \227\206 The diagnosis is not established and there is no gross respiratory embar- rassmen t, therefore complete drainage of pleural fluid (as was done here) is unnecessary and makes subsequent pleural biopsy hazardous. \227\206 There are no biochemical parameters (pH <7.2, glucose <2mmol/L) indicating pleural infection requiring drainage. CASE 13 103 \227\206 Draining a limited amount of pleural fluid for patient comfort would be reasonable. \227\206 Pleural biopsy (non-image guided, e.g. Abram \200\231s, image guided or tho- raco scopic) or contrast enhanced thoracic CT (to highlight the pleural surfaces) would be the n ext step. \227\206 Given the high likelihood of TB pleuritis, closed (e.g. Abram \200\231s) pleural biopsy would be reasonable (overall sensitivity of ZN stain or culture and histology of 80 %), although trial evidence suggests that thora- coscopy has a far higher sensitivity (appr oaching 100%). Fig. 13.2 CXR post drainage. CASE HISTORIES IN RESPIRATORY MEDICINE 104 Progress The patient was started on broad-spectrum antibiotics, a chest drain was inserted and the e ffusion freely drained for presumed pleural infection. Twenty-four hours after drain insert ion, a CXR was performed ( Fig. 13.2 ). Five days later the patient was afebrile and clinically improved. Blood cul- tures and pleu ral fluid cultures were negative and he was discharged home with out-patient follow-up in 4 weeks. One week after discharge, he was admitted to the respiratory unit with an acute illness characterized by high fevers, sweats and malaise. Investigations \227\206 White cell count, 28 \227 10 6 /ml, 90% neutrophils \227\206 Raised inflammator y markers (CRP >160mg/L, ESR, 13mm/h) Fig. 13.3 Repeat CXR. CASE 13 105 Fig. 13.4 Septated collection. \227\206 Pleural fluid parameters at this stage: Appearance, turbid Biochemistry, pH 6.9 Glucose, 1.0mmol/L Protein, 50g/L LDH 5467IU/L \227\206 Thoracic ultrasound: see Fig. 13.4 . Questions 13f) Comment on the post drainage CXR ( Fig. 13.2 ). 13g) What is the most likely diagnosis for this second presentation? 13h) Give the most important immediate steps in management. CASE HISTORIES IN RESPIRATORY MEDICINE 106 Answers 13f) Comment on the post drainage CXR ( Fig. 13.2 ). Shows a chest drain in situ in the left low er zone, some left basal consolida- tion and pleural reaction, and a bulky left hilar/aorto - pulmonary window area suggestive of lymphadenopathy. 13g) What is the most likely diagnosis for this second presentation? The most likely diagnosis for this second presentation is pleural infection (possibly iatro genic given the previous chest drain), consistent with the: \227\206 Pleural fluid biochemistry (suggestive of complicated para-pneumonic effusion) \227\206 Appearance (turbidity suggestive of above) \227\206 Radiology (septations on ultrasound). 13h) Give the most important immediate steps in management. Management of pleural infection: \227\206 Broad-spectrum antibiotics to cover likely pathogens, i.e. Gram-positive, Gram-ne gative and anaerobic bacteria, including cover in this situation for possible MRSA \227\206 Same-day chest drainage (image guided, if necessary) \227\206 TB pleuritis was not excluded on the previous admission, therefore obtaining pleural tissue should now be considered.