Authors:- Matthew Hind FRCP
- Simon Jordan FRCS
- David Hansell FRCR
- Andrew G Nicholson FRCPath
- Guy Neild FRCP
- Michael Polkey FRCP
Information about Interactive Grand Round- Interactive Grand Round is an educational interactive feature, which follows a case from a collaborating hospital. The format is similar to the proceedings of hospital teaching meeting; a patient's history and examination are revealed in stages, and questions are asked based on the information provided. As in real life, not all cases have a concrete diagnosis, and some patients whose cases are presented are still being followed up. However, the cases have been chosen for their interest and learning points, rather than to highlight an unusual final diagnosis, or the diagnostic prowess of the authors.
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History- A 73-year-old man, originally from Pakistan, was referred to our institution in 2007, with type II respiratory failure for consideration of home ventilation. He reported a 4 year history of respiratory symptoms, presenting initially with relatively rapid onset of worsening breathlessness, orthopnoea, and morning headache.
- Exercise tolerance was reduced to just 5 m on flat terrain limited by dyspnoea. He was sleepy during the day, with frequent morning headaches and unable to leave his house.
- Before referral, he had been admitted on two occasions for treatment of right upper lobe pneumonia. He had commenced a long-acting β agonist and inhaled corticosteroid for a diagnosis of chronic obstructive pulmonary disease (COPD) with little noticeable improvement in symptoms.
- He was an ex-smoker with a 15 pack-year history.
- He lived with his wife who was well.
Past Medical HistoryPast medical history:- 1987: Bladder carcinoma cystectomy and ileal conduit
- 2002: Chronic pancreatitis, biliary stricture, and malabsorbtion
- 2002: Atrial fibrillation requiring cardioversion and ablation
- 2005: Renal impairment
- 2005: Previous right upper lobe pneumonia, consolidation on CT, inflamed mucosa at bronchoscopy, negative washings for cytology, routine and mycobacterial culture
Drug history:- Aspirin 75 mg once daily
- Frusemide 40 mg once daily
- Alfacalcidol 0·5 microgram once daily
- Effervescent calcium 1·25 g twice daily
- Aledronate 70 mg once weekly
- Warfarin as per INR
- Creon 25 000 3 tablets three times daily
- Sodium bicarbonate 2 g mane, 1·5 g nocte
Social history:Born in Pakistan, childhood in Kenya, been in UK for many years.
Ex-smoker, 15 pack-year history. No known contact with tuberculosis. No relevant occupational or exposure history. Physical examination- Clinical assessment revealed he was sleepy. There was bilateral parotid enlargement, reduced chest wall expansion, and paradoxical abdominal movement during respiration. His chest was clear with reduced breath sounds throughout. There were shotty inguinal lymph nodes and symmetrical, proximal limb muscle weakness, MRC grade 4/5.
- Resting oxygen saturations on air were 92%.
- The remainder of the examination was unremarkable.
| Arterial blood gas breathing air | MEASURED | RANGE | | pH | 7·4 | 7·35–7·45 | | PaO2 (kPa) | 8·6 | 10–14 | | PaCO2 (kPa) | 8·4 | 4·5–6·0 | | BE (mEql/L) | 10·7 | –2 to +2 mEql/L | | HCO3- (mmol/L) | 34 | 22–26 |
| CHEMISTRY | MEASURED | RANGE | | Na (mmol/L) | 135 | 135–145 | | K (mmol/L) | 4·3 | 3·5–5·1 | | Urea (mmol/L) | 23·2 | 2·1–7·1 | | Creatinine (μmol/L) | 203 | 60–120 | | CRP (mg/L) | 12 | 0–5 |
QuestionWhat is the physiological abnormality demonstrated on the arterial blood gas sample? QuestionWhat is the physiological abnormality demonstrated on the arterial blood gas sample? Answer- Chronic or compensated respiratory acidosis. The arterial blood gas demonstrates normal pH, mild hypoxia, but elevated PaCO2 and HCO3- suggesting renal compensation and a degree of chronicity.
- The cause of ventilatory failure should be identified. Type II respiratory failure can result from abnormalities from the respiratory system, central and peripheral nervous system, the respiratory muscles, and the chest wall. Arterial blood gas analysis is required in all patients who are seriously ill or in whom ventilatory failure is suspected. A chest radiograph is essential, and pulmonary function tests are very useful. ECG and echocardiography are often helpful.
Radiology 1: The plain chest radiographThe plain chest radiograph demonstrates contraction of the right hemithorax with extensive patchy consolidation predominantly in the right upper zone. Less dense consolidation is also seen at the right base and left mid zone. There is elevation of the right hemidiaphragm and generalised bronchial wall thickening. Radiology 2 – High resolution chest CTThe CT scan confirms localised consolidation in the right upper lobe and some nodular opacities in the left upper lobe with some bronchial wall thickening. QuestionWhat is the most likely diagnosis based on the radiological findings? QuestionWhat is the most likely diagnosis based on the radiological findings? Answer- Organising pneumonia is the most likely diagnosis based on the radiology.
- Tuberculosis is less likely because there is no necrosis or cavitation with no evidence of overspill (tree-in-bud).
- The consolidation is localised and in the wrong distribution for amyloidosis with no ancillary features such as calcification.
- Neoplastic disease is unlikely in the absence of a centrally obstructing tumour; however, a lymphoproliferative disorder remains a possibility based on the imaging.
Further investigations- Sputum microbiology unremarkable; acid fast bacilli smear negative.
- Mantoux negative.
- Serum angiotensin-converting enzyme normal.
- Tuberculosis interferon-gamma release assay (Elispot) negative.
- HIV negative, autoimmune profile negative.
- Bronchoscopy: performed on the Intensive Care Unit (ICU) for safety. Poorly tolerated. Washings, bacterial, fungal, and tuberculosis smear negative. Cytology: mixed inflammatory cells with abundant neutrophils. No malignant cells seen.
- Lung function: patient had difficulty with tests. FEV1 0·89 L (40%), FVC 1·53 L (52·5%), TLCO 38% predicted, KCO 79% predicted.
- Sleep study: mean overnight transcutaneous CO2 7·5 kPa on non-invasive ventilation (NIV), with significant oxygen desaturations.
- Respiratory muscle tests: Twitch Pdi 3·9 cm H20 (normal >20 cm H20), sniff Pdi 9 cm H20 (normal >80 cm H20).
QuestionWhat is the likely dominant cause of ventilatory failure in this man? QuestionWhat is the likely dominant cause of ventilatory failure in this man? Answer- The correct answer is respiratory muscle weakness
Respiratory muscle pump capacity- Hypercapnia arises when the load on the respiratory muscle pump exceeds its capacity (see figure, right).
- Patient has normal oxygen on room air, suggesting parenchymal lung disease not main problem.
- TLCO (transfer factor of the lung for carbon monoxide) and KCO (transfer coefficient): suggests respiratory muscle weakness in the absence of chest wall problems.
 Pathway to ventilatory failure Testing phrenic nerve function Sniff pressure measured at the nose reflects intrathoracic pressure  1 Hz Phrenic nerve stimulation in a healthy man (Thorax 1994: 49: 1234)  Phrenic nerve stimulation in diaphragm paralysis (AJRCCM 1997: 155: 1565) - Respiratory muscle weakness measured as maximal sniff nasal pressure (non-invasive).
- Diagnosis confirmed by magnetic stimulation of the phrenic nerve roots (invasive).
Further investigations- ECG and echocardiogram were unremarkable.
- Both parotids grossly enlarged on ultrasound, but are of normal texture.
- Renal ultrasound: normal left and right kidney size and morphology.
- Total IgG elevated: 32·6g/L (6–15g/L).
- Serum protein electrophoresis—polyclonal increase in IgG.
- CT imaging including abdomen and pelvis was arranged to exclude malignancy/lymphoma.
CT PelvisThe CT pelvis confirms the small volume inguinal lymphadenopathy (1·5 cm) highlighted by the arrow. Clinical summary to date- An elderly man is in type II respiratory failure with respiratory muscle weakness, parotid enlargement, chronic pancreatitis, chronic renal impairment with persistent right upper lobe consolidation, and enlarged inguinal lymph nodes.
- The clinical suspicion at this point was of an underlying lymphoproliferative disorder.
Further investigations- Ultrasound of the right groin showed three enlarged lymph nodes. Needle aspiration of largest node is non-diagnostic.
- A surgical biopsy of the right groin lymph node was done.
- Histology showed a partial effacement of lymph node architecture with expansion of paracortex by lymphocytes, plasma cells, eosinophils. Possible lymphoma.
Progress- Postoperative confusion.
- Recurrent hyperkalaemia, worsening renal failure.
- Multiresistant Escherichia coli in urine culture. Intravenous antibiotics.
- Despite supportive medical treatment with NIV, oxygen, and empirical antibiotics there was progressive deterioration and he required intubation and ventilation and transfer to ICU.
- The working differential diagnosis included underlying lymphoma.
- Day 49: A diagnostic investigation was done.
QuestionWhich investigation would you do next? QuestionWhich investigation would you do next? Answer- The correct answer is surgical lung biopsy
Lung biopsy histologyThe histology demonstrates a fibroinflammatory process involving both the alveolar spaces with organising pneumonia and abnormal interstitium (A), rich in plasma cells (B), with many staining for IgG4 (C) QuestionWhat is the unifying diagnosis? QuestionWhat is the unifying diagnosis? AnswerDiagnosis IgG4-related lung and mediastinal disease with probable phrenic nerve involvement IgG4-related disease- IgG4-related disease is a recently recognised, multisystem, immune-mediated disorder that often mimics malignancy and infection; it was first reported in the context of sclerosing pancreatitis in 1995.
- IgG4-related disease presents to a variety of different specialties with diverse synonyms depending on the location and organ involved; examples include sclerosing siliadenitis, retroperitoneal fibrosis, Riedles thyroiditis, fibrosing or sclerosing pancreatits, sclerosing cholangitis, and inflammatory aneurysm of the aorta .
- Lung disease is well described, (reviewed in: Ryu JH, Sekiguchi H and Yi ES. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. ERJ. 2012; 39: 180-186) but probably underreported.
- Most patients have elevation of serum IgG4 (70–90%). The role of IgG4 in the pathogenesis of the disease is currently unclear.
- The pathology is characterised, as illustrated by this case, of a lymphoplasmatytic infiltrate with immunohistochemistry demonstrating numerous IgG4 positive plasma cells. Resolution of the lesions may result in dense fibrosis.
- IgG4-related disease should be considered in the differential diagnosis in a variety of fibroinflammatory diseases of the chest.
PodcastDr Hind discusses IgG4-related disease in the chest Progress- Prolonged postoperative ITU stay and respiratory wean.
- Pulsed with intravenous methylprednisolone, then prednisolone 40 mg once daily.
- Serum IgG4 concentration elevated, confirming diagnosis and subsequently used as biomarker to assess disease response.
- Recurrent episodes of sepsis, atrial fibrillation, hyperkalaemia, and renal failure.
- Discharge delayed by aspiration and PEG insertion, rehabilitation, instigation of multidisciplinary care package.
- Excellent and rapid clinical response to immunosuppression; initially intravenous methylprednisolone, subsequently oral prednisolone 20 mg once daily and azathioprine.
- Discharge daytime arterial blood gasses on air, with overnight respiratory support with NIV, PaO210·60 kPa, PCO2 6·39 kPa, HCO3- 36·2 mmol/L.
CT on discharge- Resolving of right upper lobe consolidation with residual fine reticular pattern denoting minor fibrosis.
- Contrast-enhanced CT section through the lower zones showing a plaque of soft tissue density along the right mediastinal surface. Although non-specific, in the clinical context this finding would be consistent with localised fibrosing mediastinitis. The right phrenic nerve runs caudally over this part of the mediastinum and thus may be involved.
Summary- This case shows the investigation and management of a patient with type II respiratory failure presenting with lung and mediastinal IgG4-related disease. The patient died 6 months after discharge following a further probable aspiration event.
- IgG4-related disease is a recently recognised chronic inflammatory condition that can affect many organs often with different synonyms.
- IgG4-related disease is characterised histologically by lymphoplasmacytic infiltrate with IgG4-positive cells often resulting in dense fibrosis on resolution.
- The incidence and prevalence of lung and mediastinal IgG4 -related disease is currently unknown.
Further reading:- Neild GH, Rodriguez-Justo M, Wall C, Connolly JO. Hyper-IgG4 disease; report and characterisation of a new disease. BMC Medicine 2006 4: 23.
- Ryu JH, Sekiguchi H, Yi ES. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. Eur Respir J 2012; 39: 180–86.
- Khosroshahi A, Wallace ZS, Crowe JL, et al. Second International Symposium on IgG4-Related Disease International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis Rheumatol 2015; 67: 1688–99.
- Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet 2015; 385: 1460–71.
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