Granulomatosis with polyangiitis in an adolescent male with chronic cough and pulmonary nodules

Background

Chronic cough is a frequent patient complaint in all age groups. While common causes need to be considered first, it is important to include unusual or sinister aetiologies in the right circumstances. Our patient’s chronic cough was misdiagnosed for months and ineffectively treated with steroid inhalers and antibiotics. A key lesson of his case is to ensure that there is ongoing re-evaluation of patient symptoms, particularly for unusual features or red flags, and initiating further investigations, as appropriate. In our adolescent patient, granulomatosis with polyangiitis (GPA) was the cause of the chronic cough. While GPA is rare, especially in paediatrics, it is a diagnosis that can be easily missed if not considered in the right context.

GPA is a small to medium vessel vasculitis that likely has an autoimmune basis. The reported prevalence of GPA across all age groups ranges from 2.3 to 146 cases per million people,1 and much rarer in children. In paediatrics, the median age of diagnosis is about 14 years and the median time-to-diagnosis, from symptom onset, is approximately 3 months. The typical clinical presentation includes a triad of upper airway, lower respiratory tract and renal manifestations, but symptoms generally are insidious and can be non-specific, such as dyspnoea, chronic cough and constitutional symptoms (ie, fever, malaise, fatigue, weight loss). In some cases, the clinical presentations can be much more striking with pulmonary haemorrhage, upper airway obstruction and/or renal failure.

In this case report, the reader will gain an appreciation for the patient’s clinical presentation, the diagnostic workup and treatment, and patient response. We will also provide a topical overview of the common GPA presentation, classification criteria and management.

Case presentation

An adolescent male presented to a community hospital’s emergency department with a progressively worse dry cough over the last year, post-tussive emesis, malaise and new-onset fevers and night sweats. Weight loss (approximately 20 pounds over 1 year) and intermittent epistaxis were also noted. He had travelled to South Asia 2 years prior, but there were no known tuberculosis (TB) contacts. His medical history included asthma, anaphylaxis to peanuts, eczema, psoriasis and environmental allergies. In the last year, he was prescribed inhaled fluticasone and salbutamol, as well as montelukast, with minimal benefit; he had also been treated with a course of antibiotics previously without effect.

On physical examination, he had a temperature of 37°C, heart rate of 68 beats per minute, respiratory rate of 18 breaths per minute, oxygen saturations of 100% on room air and blood pressure of 97/62 mmHg. Head and neck examination was unremarkable, including no evidence of lymphadenopathy or stridor. There were no signs of respiratory distress or abnormal breath sounds on respiratory examination. The remainder of the physical examination was unremarkable. A chest X-ray (CXR) showed pulmonary nodules and a cavitary lesion (figure 1). Based on these findings, he was was subsequently transferred to our institution for further workup and management.

Investigations

A chest computerized tomography (CT) scan confirmed multiple nodules, adding that some were cavitary lesions (figure 2). Bloodwork showed a mild normocytic anaemia, leucocytosis, neutrophilia, slightly elevated International Normalized Ratio (INR) and high C-Reactive Protein (134.5 g/L). The remainder of the bloodwork and urinalysis were unremarkable. Infectious workup included nasopharyngeal viral polymerase chain reaction (PCR) swab, throat swab culture, TB gastric aspirate cultures and a Mantoux test, which were all negative. Bronchoscopy and broncho-alveolar lavage (BAL) were unremarkable with normal airway anatomy and no evidence of pulmonary haemorrhage or infection. Allergy skin prick testing (including aspergillus) was negative. Vasculitis panel revealed cytoplasmic pattern Antineutrophil Cytoplasmic Antibody (cANCA) positivity (>8.0 AI units). Ultrasound guided transthoracic needle biopsy was done and showed evidence of diffuse interstitial reactive fibrosis with fibroblastic nodules, patchy necrosis, fibrin and abscesses with poorly formed granulomatous reaction.

Differential diagnosis

The differential diagnosis for chronic cough is broad but is a bit more focused once pulmonary nodules are discovered. Generally speaking, one can approach the differential diagnosis from a systems-based perspective, considering infectious, inflammatory, congenital, vascular, malignant, benign and other causes, as summarised in (table 1). In this case, infectious aetiologies were ruled out with nasopharyngeal viral PCR swab, bacterial throat culture, TB gastric aspirate cultures, BAL culture and Mantoux skin test. Malignant causes were not likely based on the pattern on CT imaging, Complete Blood Count results and history. Congenital causes were also ruled less likely based on a lack of symptoms as an infant/young child and appearance/location of the lesions on CT imaging. The autoimmune bloodwork and histopathology helped to finalise the cause as inflammatory rather than benign or malignant lesions.

Treatment

A diagnosis of GPA was made using the new American College of Rheumatology and the European Alliance of Associations for Rheumatology (ACR/EULAR) criteria (see table 2) and the patient was started on induction therapy. His regimen included pulsed corticosteroids and rituximab. Subsequently, for maintenance, he was initiated on high-dose oral corticosteroids with a tapering protocol and rituximab. In the literature, there are other therapeutic options that could be considered for induction (eg, cyclophosphamide) and maintenance (eg, azathioprine, mycophenolate and methotrexate). However, these other options may not be well tolerated or be less efficacious, leading to our decision to use corticosteroids and rituximab.

If untreated, the prognosis of GPA is almost universally fatal and the long-term morbidities, even in treated GPA, may include persistent airway obstruction and renal insufficiency, emphasising the importance of early diagosis and treatment. Therapeutic options are typically based on disease severity with severe disease defined as having any life or organ threatening manifestations, such as alveolar haemorrhage or glomerulonephritis. Treatment is often subdivided into phases: induction and maintenance. For induction, the current guidelines recommend rituximab and corticosteroids, and for maintenance, rituximab is preferred±low-dose steroids or steroid-sparing agents, such as low-dose methotrexate, azathioprine or mycophenolate mofetil.2

Outcome and follow-up

The patient responded well to induction therapy with no significant side effects and initial improvement of his symptoms within a few weeks. While on maintenance therapy, a follow-up CXR was completed and showed improvements in the pulmonary nodules and cavitary lesions (figure 3). Over about 2 months, he became fully asymptomatic, returning to full activity, such as playing basketball, essentially at the level prior to the onset of his illness. He continues to be followed in a specialised respiratory/rheumatology vasculitis clinic with good control of his disease. He is in the process of weaning the maintenance corticosteroids slowly; of note, he has experienced some side effects of chronic steroid use, such as striae and weight gain.