An Unusual Cause of Fever, Bilateral Ear Discharge, Lung Nodules, and Polyuria in a Young Male Post Coronavirus Disease 19

Abstract

We present a case of a young male with pyrexia of unknown origin, bilateral ear discharge, lung nodules and polyuria within four weeks of recovering from a moderate Coronavirus disease-19 infection. To the best of our knowledge, this is the first case of post- Coronavirus disease-19 Granulomatosis with Polyangiitis with overlapping large vessel vasculitis with a favorable outcome.

Introduction

Granulomatosis with polyangiitis (GPA)is a small vessel vasculitis, classified under the broad heading of anti-neutrophilic cytoplasmic antibodies (ANCA) associated vasculitis (AAV), as per the 2012 Modified Chapel Hill Consensus Committee classification [1]. GPA is characterized by granulomatous necrotizing vasculitis predominantly involving the upper and lower respiratory tract, along with renal involvement in the form of glomerulonephritis. Worldwide, the prevalence of GPA varies between 2.3–146 cases per million population, with an annual incidence of 0.4—11.9 cases per million [2]. Off late, there have been a few case reports of GPA following coronavirus disease -19 (COVID-19) infection [3–5]. Here, we present a case of GPA that manifested post-moderate COVID-19 infection and had rare clinical manifestations in the form of an overlap with large vessel vasculitis and occurrence of central diabetes insipidus, who showed an excellent response to treatment with steroids and Cyclophosphamide. To the best of our knowledge, this is the first Case of post-COVID-19 GPA and overlapping large vessel vasculitis with a favorable outcome.

Case Presentation

Our patient was a 32 years old male initially admitted to a peripheral hospital with complaints of fever and cough of five days duration. He was subsequently diagnosed with a case of moderate COVID-19 infection based on positive COVID Real-Time Polymerase chain reaction and high-resolution computerized tomography (HRCT) chest showing bilateral ground glass opacities in both lung fields with CT severity score of 12/25. He was managed with oxygen, oral glucocorticoids, and low molecular weight heparin resulting in a complete recovery.

He was readmitted after four weeks at the same hospital with symptoms of bilateral ear discharge. He was managed as a case of acute otitis media with broad-spectrum antibiotics and analgesics, with minimal relief. An otorhinolaryngeal examination revealed an erythematous bulging tympanic membrane, for which he underwent a myringotomy. Post myringotomy, he had mild relief in symptoms. However, within a few days, he developed severe vertigo and bilateral sensory neural hearing loss (SNHL). Suspecting an inner ear involvement, he was transferred to our center.

At our center, he was evaluated by the otorhinolaryngology team and managed with vestibular sedatives, a short course of oral glucocorticoids in the form of Tab Prednisolone 80 mg once daily for seven days, along with bilateral grommet insertion and discharged. After five weeks, he was readmitted with complaints of fever of two weeks duration, otalgia and vertigo. Subsequently in hospital he developed left VII nerve palsy of lower motor neuron type, along with an episode of hemoptysis. A clinical diagnosis of pyrexia of unknown origin was established. A whole body ¹⁸Fluorodeoxyglucose positron emission tomography (WB ¹⁸FDG-PET) was done as part of PUO work up, which revealed an increased FDG activity in the segment of the abdominal aorta and arch of the aorta (Fig. 1a & 1b), suggesting a large vessel vasculitis(LVV).

Fig. 1.

A and B: Whole body ¹⁸ FDG PET revealed increased FDG activity in the segment of the abdominal aorta and arch of the aorta, as depicted by the red arrows. C and D: Repeat whole body ¹⁸ FDG PET after therapy revealed resolution of previously seen metabolic activity in the arch of aorta, and the segment of the abdominal aorta

HRCT temporal bone was done which revealed bilateral oto-mastoiditis with bony rarefaction and erosion of the footplate of the left stapes. The patient underwent cortical tympanotomy; histopathology examination revealed granulation tissue, and the patient was started on provisional anti-tubercular treatment without any relief in his symptoms.

A rheumatology consult was sought after one week because of non-resolving otitis media and extreme prostration and WB ¹⁸FDG-PET suggesting increased FDG activity in the segment of the abdominal aorta and arch of the aorta. Because of persistent chronic otitis media, SNHL, and vertigo, along with possible lower respiratory tract involvement in the form of hemoptysis, a possibility of systemic vasculitis of small vessel type overlapping with LVV was considered. Salient investigations revealed thrombocytosis, elevated acute phase reactants, elevated anti-Proteinase 3 levels of 37.9 IU/L(Normal range < 20 IU/L) and presence of 10 dysmorphic RBC per high power field in urine morning sample. A contrast-enhanced computed tomography (CECT) chest revealed bilateral nodular opacity with ground glass opacities (GGO) (Fig. 2).

Fig. 2.

Contrast-enhanced computed tomography of the chest, The red arrows show nodular opacities, and the yellow arrows show bilateral ground glass opacities

At this stage, we established the diagnosis of GPA (as per American College of Rheumatology- European Union League against Rheumatology criteria- 2021) and managed him with intravenous pulse methylprednisolone 1 g for three days followed by tab prednisolone 50 mg daily. His computed tomographic (CT) angiography was normal. He was managed as a case of GPA with overlapping large vessel vasculitis (unspecified) and initiated on injection Cyclophosphamide as per European Union Vasculitis (EUVAS) regime (Intravenous Injection Cyclophosphamide 750 mg every two weeks). His Birmingham vasculitis activity score for Wegener's Granulomatosis (BVAS-WG) on initiation of treatment was 27. On two consecutive days, the patient was subsequently noticed to have polyuria (Urine volume- 5 L in 24 h).

Evaluation for pituitary dysfunction was carried out and is depicted in Table 1. Further evaluation revealed evidence of secondary central diabetes insipidus (CDI), with imaging evidence in the form of loss of pituitary bright spot, on the MRI brain. The desmopressin suppression test was positive. An endocrinology consult was taken, and he was managed with the initiation of desmopressin.

Table 1.

Pituitary function test

Name of assay	Patient value	Reference range
Insulin-like growth factor1	163 ng/ml	46–212 ng/ml
Follicle-stimulating hormone	15.18 mIU/ml	1.27–19.26 mIU/ml
Luteinizing hormone	7.15 mIU/ml	1.24–8.62 mIU/ml
Prolactin	7.65 ng/ml	2.64–13.13 ng/ml
Thyroid-stimulating hormone	2.5 mIU/L	0.4–4.0 mIU/L

He received three further doses of Cyclophosphamide and subsequently was initiated on maintenance immunosuppression with mycophenolate mofetil and continued on tapering doses of oral glucocorticoids. A repeat WB-18FDG PET revealed the resolution of large vessel vasculitis (Fig. 1c, d). A repeat review after six months showed a mild residual SNHL, with complete resolution of left VII nerve paresis. His repeat investigations revealed normal Anti Proteinase 3 levels and normalization of quantitative C- reactive protein values. His BVAS-WG score on follow-up was four, and his vasculitis damage index score was 1.

Discussion

Incidences of GPA following COVID-19 infection have been seldom reported in the literature and have been summarized in Table 2.[3–5] Large vessel vasculitis (LVV) in GPA is rare, with around 40 cases reported so far [6]. As per a hospital-based study, the observed prevalence has been about 5% in patients with AAV [7]. Coattrenac et al. published observational data on the prevalence of LVV in AAV between 2006 and 2016 in their hospital [7]. Their single-center study comprised 101 patients with small vessel vasculitis, including GPA (n = 58), EGPA (n = 28), and MPA (n = 15), and LVV was detected in 5/101 patients (prevalence- 5%). Skeik et al, report ten cases of aortitis related to AAV and suggested using rituximab for treatment [8]. 16 GPA patients with aortitis, aortic dissection, and/or aneurysm have also been reported in a recent study from China [9]. Our case similarly presented with ear, renal, neurological and pulmonary involvement and showed evidence of LVV in the form of an increased FDG uptake in the wall of the abdominal aorta and aortic arch and showed favorable response to Cyclophosphamide with complete resolution of FDG avidity on WB ¹⁸FDG PET scan. A comparative analysis of our cases with other similar reported cases is shown in Table 3.

Table 2.

Comparison of case reports of GPA post-COVID-19

S No	Age (Year)	Sex	COVID RT PCR	Delay in symptoms post COVID	Severity & Management of COVID 19	Organ Involvement in GPA	Management of GPA
Selvaraj V et al. [3]	60	Female	Positive	04 weeks	Moderate management with Colchicine	Lung and Kidney	Plasma exchange & steroids
Bressler MY et al. [4]	46	Male	Negative	Not known	Nil	Lung, Kidney, and Cutaneous	Steroid + Rituximab
Lind E et al. [5]	40	Male	Positive	Two months prior	Nil	Musculoskeletal, Lung	Steroid + Rituximab
Present Case	32	Male	Positive	04 weeks	Moderate management with steroids	ASOM, lung, kidney, pituitary, cranial nerve, and large vessels	Steroid + Cyclophosphamide

Table 3.

Comparison of cases of ANCA-associated vasculitis overlapping with large vessel vasculitis

Characteristics	Patient 1 [7]	Patient 2 [7]	Patient 3 [7]	Patient 4 [7]	Patient 5 [7]	Our patient
Age (years)	66	52	76	63	46	32
Sex	Female	Female	Female	Male	Female	Male
ANCA associated vasculitis	GPA	GPA	GPA	GPA	GPA	GPA
Large vessel vasculitis	Aortitis	Temporal arteritis	Temporal arteritis	Temporal arteritis	Aotitis	Aortitis Arch and abdominal
Clinical manifestation
ENT	Sinusitis	Sinusitis	NCD, SGS	Crusts, OPT	Nasal Polyp	Otitis media, hearing loss
Renal	–	Hematuria	Hematuria	–	–	Hematuria
Pulmonary	Nodules/ infiltrate	–	Nodules	Nodules	–	Infiltrate
Neurologic	–	Pachymeningitis	–	–	–	VII cranial nerve palsy
Joints	Arthritis	–	–	–	–	–
Laboratory
ANCA	cANCA-PR3	cANCA-PR3	pANCA-MPO	cANCA-PR3	cANCA-PR3	cANCA-PR3
ESR mm/hr		85	67			84
CRP mg/l		176	120			28.7
Treatment	Corticosteroid + Cyclophosphamide	Corticosteroid + Rituximab	Corticosteroid + Methotrexate	Corticosteroid + Methotrexate	Corticosteroid + Cyclophosphamide	Corticosteroid + Cyclophosphamide

GPA: Granulomatosis with polyangiitis, NCD: nasal cartilage destruction, SGS: subglottic stenosis, OPT: orbit pseudotumor

The gold standard for diagnosing LVV remains the biopsy; however angiography, CT, MRI and positron emission tomography with 18F-Fluorodeoxyglucose are widely accepted as complementary tools to assess vascular involvement at first diagnosis [10]. 18-FDG PET can facilitate an early diagnosis due to the fact that the increased metabolic activity caused by the inflammation of the vascular wall precedes the morphological changes in the arterial wall [11]. In our patient also WB-18FDG PET initially showed increased uptake in the abdominal aorta and arch of aorta and complete resolution after treatment.

Pituitary involvement in GPA is also a rarity, with a total of 51 cases (2 case series and 26 case reports) reported to the best of our knowledge. CDI was the most frequent endocrine abnormality. However, endocrine abnormalities improved in only a minor subset of patients, including a decrease in urine volume. Our patient was a male, who presented with pituitary involvement after other organs like ENT and lung, was anti PR3 positive, manifested with loss of pituitary bright spot on MRI, and showed good response to Cyclophosphamide with a reduction in urine volume. Pituitary involvement can occur any time during the illness, before or after other organs are involved. Polydipsia and polyuria are usually the first symptoms, as in our case.

Clinically differentiating GPA from TB can be challenging due to the overlapping manifestations. There is a paucity of data on rarer manifestations of GPA from India and South Asia, which may be attributed to the considerable overlap between GPA and Tuberculosis (TB). It is further compounded by the radiological similarity of lung imaging and the fact that auto-antibodies routinely used to diagnose GPA may also be positive in TB.

Conclusion

To conclude, GPA is a multisystem disorder that may be a great masquerader. Symptoms of GPA may range from something as trivial as otitis media to something as sinister as CDI. To add to this diagnostic dilemma is the association with COVID-19 infection, which may result in confounding clinical manifestations. However, an early clinical suspicion followed by prompt management can lead to good treatment outcomes, as was evident in our case.

Author Contributions

AH, RA, KU, AJ, VV, MS and VM conceptualized the study. AH, RA, KU and MS performed clinical studies, data collection. VM and AH was involved in statistical analysis. The first draft was written by AH and VM. All authors approved the final manuscript.

Funding

All the authors declare that no funds were received for the diagnosis and management of this case.

Declarations

Conflict of interest

All authors declare that there is no conflict of interest.

Consent for Publication

The authors certify that they have obtained all appropriate patient consent. In the consent form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published, and that every effort will be made to conceal his identity, but anonymity cannot be concealed.

Ethics Approval

Our institute does not require ethics approval to publish individual case reports.

Informed Consent

Informed written consent was taken from the patient before submitting this manuscript.