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Clinical Meetings at RH Year 2002

2002 Mar - A Young Gentleman With An Unsual Lung Mass

Dr Dominic Choy, Dr David Hui; Department of Medicine, Prince of Wales Hospital

Case Report
The patient was a 36-year-old man with a smoking history of 15 pack-years. He was a non- drinker and worked as a van driver delivering chicken. He enjoyed good past health and gave no recent traveling history. He first became unwell in Jan 2001 when he noted increasing lethargy, headache, jaw numbness and dry cough. He saw various GPs without improvement and was eventually admitted into a HA hospital on 13/1/2001 with worsening jaw pain and a cough which was now productive of bloodstained sputum. He had a low-grade fever on admission. His admission CXR showed a huge left upper lobe mass and right upper lobe nodules (Fig 1). A CT thorax confirmed a necrotic lung mass with mediastinal lymphadenopathies (Fig 2). Bronchoscopy was performed via the oral route due to nasal congestion and there was complete occlusion of his left upper lobe orifice with nodular mucosa in the right upper and middle lobes. The endoscopic diagnosis was carcinoma of the lung but both the histology of the bronchoscopic biopsy and a subsequent fine needle aspiration of the lung lesion yielded necrotic material only. He was treated with antibiotics and analgesics for presumed chest infection but his condition deteriorated with increasing respiratory distress.

On 24 January 2001, he was transferred to 8t Paul's Hospital in a critical condition with high fever and oxygen requirement. He was noted to have an inflamed oropharaynx. Due to his critical condition with no definite diagnosis, he was commenced on the combination of chemotherapeutic agents including carboplatin, etoposide and taxol, immunosuppresives including prednisolone and methotrexate, and anitibiotics including rifampicin, ofloxacin and septrin. Remarkably, his condition improved with resolution of the fever and he was weaned off oxygen. A repeat bronchoscopy showed inflamed mucosa with whitish patches in the trachea and main bronchi. Histology revealed severe squamous metaplasia with atypical cells. The provisional diagnosis was an 'endobronchial infection with extensive pneumonitis and abscess formation in the left upper lobe... .heading towards a sqamous cell carcinoma'.

On 7 February 2001, he was transferred to Prince of Wales Hospital under the cardiothoracic surgeons for further management of the lung lesion. He was well on admission other than complaints of left sided pleuritic chestpain. He had mild conjunctival injection but there were no oral ulcers. His blood results were as follows:

Hb 10.5 PLT 829 WCC 13.7
Na 131 K 4.3 Ur 7.8 Cr 105
TP 63 alb 18 bili 7 ALP 253 ALT 14
Ca/P04 nonnal
ESR 129 CRP 265
Urine analysis: +ve alb/RBC
Fresh urine: dysmorphic RBCs <5 phpf, no casts

At PWH, a repeat bronchoscopy with biopsy and trucut biopsy again yielded necrotic material. His medications from St Paul's hospital were stopped -with a plan for excisional biopsy of the lung lesion.

On 10 February 2001, he developed sudden onset retrostemal chestpain with shortness of breath. He became hypotensive, tachycardic and febrile. ECG showed anterior ST elevation. The diagnosis of acute myocardial infarction vas confinned by a +ve TNT, an elevated CPK and echocardiogram showing a hypokinetic apical wall. A cardiac catheterisation showed an occluded distal LAD artery. He was treated with a combination of low-molecular weight heparin, aspirin and clopidegrel. However, his condition deteriorated with high fever and hypotension. Intravenous ceftazidime and metronidazole were commenced for presumed chest infection as pseudomonas was isolated on sputum culture. He was eventually admitted to ICU with increasing respiratory distress, sepsis and renal impainnent. At this stage, oral ulcers had developed over his soft palate (Fig 3). ENT surgeons were consulted for biopsy of the lesions but this was thought to be too hazardous as he was on antiplate!et agents and anticoagulants. Likewise, a renal biopsy was thought to be prohibitive. His ANA and ANCA titres were checked on admission (when he was still on steroids) but were negative.

Despite the negative results of the immune markers, vasculitis was thought to be the most likely underlying cause of his illness and he was commenced on intravenous hydrocortisone at a dose of 100 mg 6-hourly. Intravenous septrin was also commenced to cover the possibility of an undiagnosed nocardia lung abscess. ANCA was repeated prior to recommencement of steroids and the repeat test was now positive for C-ANCA at a titre of 1:160 with an anti..PR3 of >200RU/ml. He also developed a vasculitic lesion on his right big toe. Biopsy of the lesion confinned a leucocytoclastic vasculitis (Fig 4). A diagnosis of Wegener's granulomatosis was therefore made on the basis of the presence of nasopharyngeal ulcers, lung nodules, episcleritis. vasculitic skin lesions and +ve C-ANCA/PR-3.

He was treated with pulse methyprednisolone with a plan for maintenance steroids and cyclophosphamide. He developed clinical improvement initially but developed rapid deterioration on the third day of pulse steroids with hemoptysis and whitening of his lung fields. Despite empirical broad spectrum antibiotics, antifungals, antivirals and IVIG, he succumbed rapidly to respiratory failure.

Discussion
Wegener's granulomatosis (WG) is a clinical syndrome consisting of a necrotising granulomatous vasculitis involving the upper and lower respiratory tract and glomerulonephritis. It is a mutisystem disease which may also affect the eyes, ear, heart, skin, joints and nervous system. WG is a rare disease with a prevalence of 3/100,000 in the USA. It affects male and females equally with the mean age of onset being 40-55 years of age. The disease is thought to be even rarer in SE Asia (1). The etiology of the disease remains unknown although infection (especially with Staph aureus) is believed to be an important contributor (2).

More than 90% of cases present with upper and/or lower airways symptoms (3). Upper tract symptoms include rhinorrhoea, oral/nasal ulcers, nasal perforation, saddle-nose deformity, earache and hearing loss. Hoarseness and stridor may signify subglottic stenosis, present in 20% of patients. Lower airway involvement may produce cough, hemoptysis, dyspnea and pleuritic chestpain, although up to 1/3 of cases may be asymptomatic. Radiological features include nodules (50% cavitating), infiltrates including alveolar hemorrahage, segmental atelectasis and pleural effusions. The most frequent physiological abnormality is airflow obstruction with a reduced DLCO although a restrictive pattern may also result from diffuse interstitial involvement. A rapid progression to renal failure may occur in the absence of symptoms. Vigilance is essential as renal impairment is present at diagnosis in only 20% but develops in 80% eventually (4). Ocular involvement may result in conjunctivitis, episcleritis and uveitis. Nervous system involvement produces mononeuritis, cranial nerve lesions and CNS mass lesions. Skin lesions may be vesicular, purpuric, ulcerative or hemorrhagic. Cardiac involvement may give rise to pericarditis, myocarditis, conduction system abnormalities and coronary arteritis (as in the current case report). Limited WG is a term used when the clinical findings are limited to the respiratory tract. However, many such patients may develop systemic disease subsequently.

The diagnosis of WG is usually made on the basis of a compatible clinical setting, tissue biopsy demonstrating granulomatosis and vasculitic inflammation, and a positive ANCA. The sensitivity of ANCA is related to the severity and activity of the disease at the time of sampling and ranges from 28-92% (3). A positive ANCA per se does not confirm the diagnosis. In a local study, the positive predictive value of ANCA for WG was only 22% (5).

Without treatment, median survival is only 5 months and 90% of patients will die within 2 years from respiratory or renal failure. Prednisolone will extend the median survival to 12.5 months (3). Long-lasting remissions can be induced when prednisolone (I mg/kg/day) is combined with Cyclophosphamide (2mg/kg/day) (6). Despite addition of cyclophosphamide, 50% will suffer a relapse and 42% will experience drug-related toxicity. Drug toxicity can be reduced by intermittent dosing but this may be associated with a higher relapse rate (7). The use of low dose methotrexate (20-25mg weekly) and steroids have been shown to produce satisfactory results in patients without life-threatening disease or who developed toxicity to cyclophosphamide (8). This combination is associated with fewer side effects. Azathioprine is not effective at inducing remission but may prove useful as maintenance therapy in patients who develop cyclophosphamide toxicity (9). Septrin may be useful in isolated upper airway disease (10). The addition of plasmapheresis may be beneficial in patients who are initially dialysis-dependent and who develop life-threatening pulmonary hemorrhage. The role of IVIG however remains controversial. Patients with fulminant renal or respiratory disease should be given pulse methyprednisolone (250-1000mg) IVI for 3 days.

Figure 1: Initial CXR


Figure 2: CT Thorax


Figure 3: Oral Ulcers


Figure 4: Skin Biopsy


References
  1. Aozasa K, Ohsawa M, Tajima K, Sasaki R, et al. Nation-wide survey study of lethal mid-line granuloma in Japan: frequencies of Wegener's granulomatosis, polymorphic reticulosis, malignant lymphoma and other related conditions. Int J Cancer 1989; 44:63-66.
  2. van Putten JW, van Haren EH, Lammers JW. Association between Wegener's granulomatosis and Staphylococcal aureus infection? Em Respir J 1996; 9:1955- 1957.
  3. Langford CA, Hoffman GS. Wegener's granulomatosis. Thorax 1999; 54:629-637.
  4. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener's granulomatosis: an analysis of 158 patients.Ann Intern Med 1992; 116:488-494.
  5. Lee S, Lawton JW. Heterogeneity of anti-PR3 associated disease in Hong Kong. Postgrad Med J 2000;76:287-288.
  6. Hollander D, Manning RT. The use of alkylating agents in the treatment of Wegerner's granulomatosis.Ann Intern Med 1967; 67:393-398.
  7. Hoffman GS, Leavitt RY, Fleisher TA, et al. Treatment of Wegener's granulomatosis with intermittent high-dose intravenous cyclophosphamide. Am J Med 1990; 89:403-410.
  8. Hoffman GS, Leavitt RY, Kerr GS, et al. The treatment of Wegener's granulomatosis with glucocorticoids and methotrexate. Arthritis Rheum 1992; 35:1322-1329.
  9. Fauci AS, Haynes SF, Katz P, et al. Wegener's granulomatosis:prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983; 98:76-85.
  10. sreal HL. Sulfamethoxazole-trimethoprin therapy for Wegerner's granulomatosis. Arch Intern Med 1988; 148:2293-5.
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