Pyrexia of unknown origin and pulmonary fibrosis as a presentation of MPO-ANCA associated vasculitis

Abstract

The authors report the case of a 72-year-old man presenting with chronic dyspnoea and pyrexia of unknown origin (PUO). After extensive investigation, he was found to have pulmonary fibrosis with usual interstitial pneumonia pattern on high-resolution CT imaging and positive myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) with no infectious cause or other evidence of vasculitis organ involvement. His pyrexia and symptoms settled with oral systemic corticosteroid treatment. To the authors’ knowledge this is the first case of MPO-ANCA positive vasculitis presenting as PUO and pulmonary fibrosis alone. The authors review the recent literature regarding the association of pulmonary fibrosis with ANCA-positive vasculitides with regards to pathogenesis, prognosis and treatment.

Background

Microscopic polyangiitis (MPA) is a multisystem, small vessel necrotising vasculitis classically associated with perinuclear antineutrophil cytoplasmic antibodies (pANCA), which target myeloperoxidase (MPO) as their antigen.¹ The condition typically presents with renal impairment due to progressive glomerulonephritis, while the lungs are the second most commonly involved organ. This is most commonly due to diffuse alveolar haemorrhage,² but more recently an association with idiopathic pulmonary fibrosis (IPF) has been recognised.³ The mainstay of treatment is systemic corticosteroids and immunosuppressants. Pyrexia of unknown origin (PUO) has previously been described as a presenting feature of MPA but in all cases on further investigation multiple end-organ involvement is discovered.^{4 5}

We herein present the case of a man with an acute pyrexial illness on the background of chronic dyspnoea. After extensive investigation, he was found to have a characteristic usual interstitial pneumonia (UIP) pattern on high-resolution CT (HRCT) imaging and positive MPO-ANCA titres without any further cause for pyrexia. There was no evidence of further end-organ involvement suggestive of ANCA associated vasculitis. The patient was managed successfully with resolution of pyrexia and stabilisation of lung function with oral systemic corticosteroids.

To the authors’ knowledge this is the first case of MPO-ANCA positive vasculitis presenting as PUO and pulmonary fibrosis alone. We discuss the newly recognised association of pulmonary fibrosis with MPO-ANCA positive vasculitis and the suggestion that this may be an early precursor for more extensive multi-organ involvement of MPA.

Case presentation

A 72-year-old man presented with a 3-week history of acute daily pyrexia associated with occasional non-drenching night sweats. He was originally of Pakistani descent and had recently returned from a trip to Pakistan 1 month previously, but had been a resident in the UK for 40 years. He was a life-long non-smoker, worked within an office with no occupational or recreational exposures of note and lived in an urban setting with a wife and two children with no pets. He had no existing medical comorbidities and had no recent unwell contacts. During his visit to Pakistan, he had only stayed with family in an urban location. No malarial prophylaxis was taken.

On further questioning, the patient revealed a 3-month history of gradually increasing breathlessness and decreased exercise tolerance associated with a mildly productive cough of yellow sputum and mild weight loss of 4 kg. Respiratory examination revealed fine bilateral end-inspiratory crepitations but no other positive findings of note.

Investigations

Initial investigation revealed raised blood inflammatory markers (C reactive protein – 124 mg/l, erythrocyte sedimentation rate – 107 mm/h) and white cell count (15.9×10⁹/l) and chest radiograph in keeping with bibasal pulmonary fibrosis. Despite a 14-day course of broad-spectrum antibiotics, the patient continued to be pyrexial between 38°C–39°C on a daily basis.

A PUO screen was then performed. Blood, sputum and urine cultures and bronchoscopy washings did not reveal any microbiological growth and tuberculosis smears and cultures were negative. An Elispot and Mantoux test, malaria film and antigen testing and an extensive tropical disease serological panel were negative. Immunoglobulins and total IgE level were within normal range. Trans-thoracic echocardiography did not reveal any valvular lesions and CT imaging of sinuses, chest, abdomen and pelvis did not reveal any collections, lymphadenopathy or focus of infection. HRCT imaging revealed bilateral peripheral reticular changes and early honeycombing consistent with UIP (figure 1). Pulmonary function testing revealed a mild restrictive spirometry pattern with a forced expiratory volume in 1 s (FEV1) of 71% predicted and a reduced carbon monoxide diffusing capacity (DLCO) of 67% predicted. Subsequent positron-emission tomography imaging did not reveal any areas of high FDG (¹⁸Fluorodeoxyglucose) avidity suggestive of a focus of infection.

Figure 1.

High-resolution CT scan showing classical features of usual interstitial pneumonitis with subpleural basal interlobular septal thickening and early honeycombing.

A comprehensive vasculitis screen was sent which revealed an isolated positive MPO-ANCA of 150 U/ml (134 on repeat testing) with the normal range being 0–25 U/ml. Urine dipstick and microscopy did not reveal any microscopic haematuria, red cell casts or proteinuria and a thorough rheumatological and skin examination did not reveal any arthritis, arthralgia or connective tissue disease features.

Differential diagnosis

This combination of clinical and laboratory findings pointed towards an ANCA-associated vasculitis with no features to suggest an infectious cause or alternative connective tissue disorder.

Treatment

After all infectious causes had been excluded, the patient was started on a course of oral prednisolone starting at 0.5 mg/kg/day.

Outcome and follow-up

One month later, his pyrexia had resolved, he had gained weight and his respiratory symptoms had improved with stabilisation of his lung function. Azathioprine (gradual dose increments to reach 3 mg/kg/day) and N-acetylcysteine (600 mg tds orally) have been added to his treatment regimen for pulmonary fibrosis and his steroid dose is being tapered with close monitoring. Repeat MPO-ANCA titres following corticosteroid administration showed gradual decline with eventual negative ANCA screening after 2 months of treatment.

Discussion

PUO is a diagnostic challenge frequently presenting itself to physicians. Petersdorf and Beeson originally defined it in 1961 as a recurrent fever greater than 38.3°C during at least 3 weeks of illness and without a firm diagnosis after a week of inpatient investigations.⁶ Recent studies suggest that inflammatory conditions account for 33% of cases with infections being the next most significant group at 30%.⁷ Inflammatory illnesses such as MPA are usually managed with immunosuppressive therapy and before commencing it is essential to rule out latent or existing infections, which may be reactivated.⁸

ANCA-associated vasculitis may present as PUO with subsequent investigation highlighting often multiple organ involvement.^{4 5} However this case, is the first to the authors’ knowledge of pulmonary fibrosis as the sole other presenting feature of MPO-ANCA positive vasculitis. The association between idiopathic IPF and ANCA positive vasculitis is newly and increasingly recognised.^{3 9} IPF is an inflammatory, destructive condition resulting in reduced lung volumes and gas exchange, with restrictive spirometry. The diagnosis is based on a UIP pattern on histology. However, with the advance of high-resolution imaging, if a characteristic pattern is seen on CT a histological diagnosis is rarely sought.¹⁰ The presentation of IPF is usually with a gradual onset of dyspnoea and cough with only low-grade pyrexia being rarely reported previously as a feature.¹⁰

In a recent case series of 33 patients with biopsy proven MPA by Tzelepis et al,¹¹ the frequency of pulmonary fibrosis was found to be 38% with UIP the most common radiological and histological appearance. In the majority of cases pulmonary fibrosis predated the diagnosis of MPA. In patients diagnosed with IPF, a study by Shiraki et al¹² of 69 patients showed an MPO-positive ANCA frequency of 7.2%. These are sometimes thought to be transiently produced in the context of superimposed infection, and without any other stigmata of vasculitis are often assumed to be incidental findings.¹³ However, recent studies suggest that as many as 40% of these patients will develop MPA over time⁹ and additionally the higher the ANCA titre the more likely MPA will develop.¹⁴ In this study by Nozu et al,¹⁴ IPF patients with a high titre of MPO-ANCA (>50 U/ml) had a worse prognosis than ANCA negative patients, and were additionally more likely to develop MPA suggesting a causative role. It would also appear that the subset of MPA patients first presenting with pulmonary fibrosis have a worse prognosis than other presentations of MPA.¹⁵ It is not yet clear whether making the diagnosis and instituting treatment early has any impact on survival, however there is some evidence that reducing ANCA titres with corticosteroid therapy may prevent development of MPA.¹⁴ Practically, this data implies at the importance of screening for ANCA antibodies in patients presenting with IPF.

The presence of MPO-ANCA has been postulated to have a pathological role in the development of IPF, with theories ranging from recurrent occult haemorrhages stimulating fibrotic change, or the MPO-ANCA antibodies having a pro-fibrogenic effect.¹⁶ Subclinical alveolar haemorrhage is often detected in patients with ANCA-associated vasculitidies and pulmonary involvement with fibrosis can develop in a similar manner to that in idiopathic haemosiderosis.¹⁷ MPO-ANCA antibodies have also been suggested to cause direct tissue injury by release of products of activated neutrophils with subsequent fibrosis developing as a cause of a reparative process of chronic lung injury.^{16 18} Alternatively, given that in the majority of cases IPF predates the development of MPA, the possibility of IPF inducing MPO-ANCA antibodies and MPA cannot be discounted.

We speculate that in our case, given the high MPO-ANCA titre, the presentation of PUO may have been an early manifestation of MPA with IPF clearly symptomatically predating its development. It remains to be seen whether treatment with systemic corticosteroids will prevent progression and induce remission, however initial symptom resolution is promising. In summary, we present a case with a unique presentation of an intriguing association; however further research is required to fully understand its pathological and prognostic significance.

Learning points.

• ▶PUO may be due to inflammatory conditions in a third of cases.
• ▶MPO-ANCA titre positivity is a newly described association with IPF.
• ▶PUO and pulmonary fibrosis may be a presenting feature of ANCA-positive vasculitis in the absence of other end-organ involvement.
• ▶High level MPO-ANCA titre positivity with IPF may be a early precursor of microscopic polyangitis.