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\begin{document}

\title{Title: Granulomatosis with Polyangiitis Mimicking COVID-19 Pneumonia: A
Case Report}



\author[1]{Arjun Basnet}%
\author[1]{Sajog Kansakar}%
\author[2]{Nava Sharma}%
\author[1]{Sudarshan Gautam}%
\author[3]{SARAL LAMICHHANE}%
\author[1]{Kripa Tiwari}%
\author[4]{Madalasa Pokhrel}%
\author[1]{Sehajpreet Singh}%
\affil[1]{Maimonides Medical Center}%
\affil[2]{Manipal College of Medical Sciences}%
\affil[3]{Gandaki Medical College}%
\affil[4]{Montefiore New Rochelle Hospital}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\textbf{Title: Granulomatosis with Polyangiitis Mimicking COVID-19
Pneumonia: A Case Report}

\textbf{Abstract}

Granulomatosis with polyangiitis (GPA), formerly known as Wegener's
granulomatosis, is a necrotizing vasculitis characterized by small to
medium-sized vessel involvement and the presence of antineutrophil
cytoplasmic antibodies (ANCA). We present a case of a 26-year-old Asian
female who was transferred to our center from a nearby hospital, where
she presented with shortness of breath, tested positive for COVID-19,
and was being managed for COVID-19 pneumonia. She also had hemoptysis,
skin lesions, and left foot numbness. Serological markers and
VATS-guided lung biopsy confirmed the diagnosis. Treatment with
methylprednisolone and rituximab led to stabilization, despite
complications of subcutaneous emphysema and lower extremity neuropathic
symptoms. Early recognition and appropriate management of GPA are
crucial for optimal outcomes.

\textbf{Keywords:}

granulomatosis with~polyangiitis, ANCA-associated vasculitis, COVID-19

\textbf{Introduction}

Granulomatosis with Polyangiitis (GPA) is a small-medium vessel
necrotizing vasculitis and is a component of Anti-Neutrophil Cytoplasmic
Antibody (ANCA) Associated Vasculitides\textsuperscript{1}. It has a
peak incidence at 64 to 75 years of age and is commonly reported in
Caucasians without sex predilection\textsuperscript{2}. Although almost
any organ can be involved in GPA, the upper respiratory tract, lower
respiratory tract, and kidneys are commonly affected\textsuperscript{3}.
The severity of the disease can be heterogeneous. We report a unique
case of granulomatosis with polyangiitis (GPA) in a 26-year-old Asian
female who was initially transferred from an outside hospital due to
shortness of breath presumed to be caused by COVID-19 pneumonia.
However, further evaluation led to the diagnosis of GPA highlighting the
importance of considering GPA in the differential diagnosis, even in
younger individuals and those presenting with respiratory symptoms
suggestive of COVID-19.

\textbf{Case Presentation}

A 26-year-old Asian female with a medical history of migraine was
transferred to our center from a nearby hospital, where she presented
with shortness of breath, tested positive for COVID-19, and was being
managed for COVID-19 pneumonia. In the outside center, she was being
managed with supplemental oxygen, Remdesivir, Dexamethasone, and
Levofloxacin to cover community-acquired pneumonia (CAP). During the
hospitalization, she developed hemoptysis. The tuberculosis workup was
negative. She was started on Baricitinib and transferred to our center
for specialized care and further workup, given worsening symptoms
despite standard treatment.

At the presentation to our center, she complained of chest pain. A
review of systems was notable for paresthesia on the dorsal aspect of
the left foot. She was tachycardic and required a high-flow nasal
cannula to maintain oxygen saturation \textgreater{}92\%. Physical
examination revealed diffuse bilateral crackles on lung auscultation and
nodular non-blanching violaceous skin lesions on bilateral legs, which
she attributed to shaving her legs. A patchy area of numbness was
appreciated on the dorsal surface of the left leg. Initial laboratory
results were significant for leukocytosis, elevated lactate
dehydrogenase (LDH), procalcitonin, erythrocyte sedimentation rate
(ESR), and C-reactive protein (CRP), as summarized in Table 1. Severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected on
polymerase chain reaction (PCR). Electrocardiogram (EKG) revealed sinus
tachycardia.

\textbf{Table 1: Initial laboratory values}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Tests} & \textbf{Result} & \textbf{Reference
Range}\tabularnewline
\midrule
\endhead
Sodium, serum & 137 mmol/L & 135-149 mmol/L\tabularnewline
Potassium, serum & 4.5 mmol/L & 3.4-4.8 mmol/L\tabularnewline
Chloride, serum & 99 mmol/L & 93-105 mmol/L\tabularnewline
Bicarbonate, serum & 27 mmol/L & 23-32 mmol/L\tabularnewline
Blood Urea Nitrogen, serum & 16.0 mg/dL & 7-21 mg/dL\tabularnewline
Creatinine, serum & 0.6 mg/dL & 0.3-1.1 mg/dL\tabularnewline
White blood count & 10.4 k/uL & 4.8-10.8 k/uL\tabularnewline
Hemoglobin & 10.5 g/dL & 12-16 g/dL\tabularnewline
Platelets & 512 k/uL & 150-450 k/uL\tabularnewline
lactate dehydrogenase & 482 IU/L & 108- 199 IU/L\tabularnewline
C-Reactive Protein & 13.624 mg/dL & 0.0-0.9 mg/dL\tabularnewline
Erythrocyte Sedimentation rate & 45 mm/hr & 0-20 mm/hr\tabularnewline
\bottomrule
\end{longtable}

The patient's urinalysis showed trace protein, moderate hemoglobin, and
urine red blood cell (RBC) count of 25-50 per high power field (HPF).
Chest X-ray (CXR) revealed extensive opacity in the right lung and mid
to lower lung opacity on the left as shown in Figure 1. Computed
Tomography (CT) chest showed dense consolidation in the entire right
lung and peripheral infiltrates in the left lung as shown in Figure 2.
The patient was admitted to the intensive care unit for COVID-19
treatment. Rheumatology consultation was sought due to hemoptysis, skin
lesions, and numbness in the left foot. Laboratory tests revealed an
elevated rheumatoid factor, positive cytoplasmic C-ANCA antibody, high
C-ANCA titer, and elevated PR-3 antibody, raising suspicion of
granulomatosis with polyangiitis (GPA) rather than COVID-19 pneumonia
with associated neuropathy and rash.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1: Chest X-ray showing extensive right lung opacity and left mid
to lower lung opacity.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2: Computed Tomography (CT) chest showing dense consolidation of
the entire right lung and peripheral infiltrates in the left lung.

To confirm the diagnosis, a Video-assisted thoracoscopic surgery
(VATS)-guided lung biopsy was performed, showing characteristic
histological features of ANCA-associated vasculitis, including fibrin
and blood filling the alveolar space, inflammatory infiltrate with
neutrophils, scattered areas of necrosis, endothelial damage, and
necrotizing vasculitis as shown in Figure 3 and Figure 4. Despite the
absence of well-formed granulomata, the findings supported the diagnosis
of GPA. Treatment with methylprednisolone and rituximab led to medical
stabilization, although the patient experienced complications of
subcutaneous emphysema and progressive lower extremity neuropathic
symptoms.

Following successful stabilization, the patient was discharged home with
a walker due to foot drop and was scheduled for outpatient neurology and
rheumatology follow-up.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure 3: VATS guided biopsy showing diffuse alveolar hemorrhage.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Figure 4: Video-assisted thoracoscopic surgery (VATS)-guided lung biopsy
showing necrotizing vasculitis.

\textbf{Discussion}

GPA, previously known as Wegener's granulomatosis, is the most common
pulmonary vasculitis and is associated with anti-neutrophil cytoplasmic
antibodies (ANCA) to proteinase 4 (PR3). Microscopic polyangiitis (MPA)
and eosinophilic granulomatosis, and polyangiitis (Churg Strauss
syndrome) are also associated with ANCAs, often against myeloperoxidase
(MPO), and are grouped within ANCA-associated
vasculitis\textsuperscript{4}. GPA is a rare disease with an estimated
incidence of 0.4-11.9 cases per 1 million person-years predominantly
affecting populations of European descent, while MPA predominates in
Asian populations\textsuperscript{5}. The typical age of onset is 45-65
years with no sex predilection. Our patient was a 26-year-old Asian
woman, demonstrating that any age group and ethnicity might be affected.

GPA is heterogeneous in its spectrum and severity of presentation. Up to
80\% of patients present with prodromal clinical features of systemic
inflammation, such as fever, weight loss, fatigue, myalgia, and
arthralgia\textsuperscript{4}. Rarely, patients may present more acutely
over days. It commonly affects the upper respiratory tract (e.g.,
sinuses, nose, ears, pharynx, trachea), lower respiratory tract, and
kidneys. A varying degree of disseminated vasculitis can occur that can
affect any organ. Pulmonary involvement is seen in 50-90\% of
cases\textsuperscript{6}. It can manifest as cough, dyspnea, and a wide
variety of imaging abnormalities such as single or multiple nodules,
cavitation, ground-glass opacities, consolidation (reflecting
inflammation or alveolar hemorrhage), effusions, stenosis of trachea and
bronchi, and rarely fibrosis\textsuperscript{6,7}. Glomerulonephritis
occurs in 70-85\% of patients, with the characteristic lesion being a
segmental focal glomerulonephritis, with rapidly progressive
glomerulonephritis (RPGN) seen in fulminant cases\textsuperscript{4}.
The onset and course are variable, and ESRD develops in 11-32\% of the
patients\textsuperscript{8}.

Our patient developed sudden onset of respiratory symptoms without any
prodrome, which is uncommon. Imaging revealed dense consolidation of the
entire right lung and peripheral infiltrates in the left lung, and she
tested positive for SARS-CoV-2. This clinical picture resembled COVID-19
pneumonia very closely. No upper-respiratory tract involvement was seen,
and microscopic hematuria was seen, which is non-specific. As a result,
she was initially managed with therapy directed towards COVID-19
pneumonia. The lack of improvement with COVID-19-directed treatment, the
nodular non-blanching violaceous skin lesions on bilateral legs, and
left foot numbness (that eventually progressed to distal sciatic
neuropathy) raised suspicion for GPA in this case. Skin involvement can
present as palpable purpura, nodules, ulcers, and maculopapular rashes
and can correlate with active disease. A biopsy can demonstrate
leukocytoclastic vasculitis or granulomatous vasculitis, which are not
specific to GPA\textsuperscript{9}. Nervous system involvement is less
common but presents most commonly as mononeuritis multiplex, as seen in
our case. Other reported manifestations to include cerebral infarction
or bleeding, seizures, cranial nerve palsies, altered mental status,
meningismus, quadriparesis, or paraparesis\textsuperscript{10,11}.

A biopsy was pursued to confirm the diagnosis in our case. A VATS-guided
biopsy of the lung was performed rather than a kidney biopsy, as the
yield was likely to be low in the presence of only microscopic
hematuria. Histopathological features of GPA described in the literature
include necrotizing vasculitis involving venules, arterioles, and
capillaries, granulomatous inflammation with/without parenchymal
necrosis, micro-abscesses, and fibrosis\textsuperscript{4}.
Histopathological examination of the lung specimen of our patient
revealed alveolar hemorrhage, micro-abscesses, and necrotizing
vasculitis consistent with GPA, even in the absence of granulomas.

Treatment of GPA is divided into the induction phase, to achieve
remission in 3 months, and the maintenance phase, to maintain remission.
Glucocorticoids, along with either cyclophosphamide or rituximab, are
the standard of care for inducing remission in severe diseases, such as
in our case\textsuperscript{12}. Rituximab is becoming preferred with
growing evidence supporting its efficacy and benefits, such as fertility
preservation, superiority in PR3- ANCA positive patients, and relapsing
disease\textsuperscript{5}. Thus, rituximab was preferred over
cyclophosphamide in our patient with subsequent stabilization of her
condition over several days.

\textbf{Conclusion}

This case emphasizes the importance of considering GPA in the
differential diagnosis, particularly in younger patients with
respiratory symptoms. Early recognition and accurate diagnosis are
crucial for appropriate management and improved outcomes in GPA. Further
studies are needed to explore the potential association between GPA and
COVID-19, as well as to better understand the heterogeneous nature of
the disease.

References:

1. Lee SW, Park YB. Classification of Antineutrophil Cytoplasmic
Antibody-associated Vasculitis. \emph{Journal of Rheumatic Diseases} .
2019;26(3):156. doi:10.4078/jrd.2019.26.3.156

2. Ntatsaki E, Watts RA, Scott DGI. Epidemiology of ANCA-associated
Vasculitis. \emph{Rheumatic Disease Clinics of North America} .
2010;36(3):447-461. doi:10.1016/j.rdc.2010.04.002

3. Greco A, Marinelli C, Fusconi M, et al. Clinic manifestations in
granulomatosis with polyangiitis. \emph{Int J Immunopathol Pharmacol} .
2016;29(2):151-159. doi:10.1177/0394632015617063

4. Lynch J, Derhovanessian A, Tazelaar H, Belperio J. Granulomatosis
with Polyangiitis (Wegener's Granulomatosis): Evolving Concepts in
Treatment. \emph{Semin Respir Crit Care Med} . 2018;39(04):434-458.
doi:10.1055/s-0038-1660874

5. Kitching AR, Anders HJ, Basu N, et al. ANCA-associated
vasculitis.\emph{Nat Rev Dis Primers} . 2020;6(1):71.
doi:10.1038/s41572-020-0204-y

6. Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinary
approach to the care of patients with Wegener's granulomatosis:
long-term outcome in 155 patients. \emph{Arthritis Rheum} .
2000;43(5):1021-1032.
doi:10.1002/1529-0131(200005)43:5\textless{}1021::AID-ANR10\textgreater{}3.0.CO;2-J

7. Lee K, Kim T, Fujimoto K, et al. Thoracic manifestation of Wegener's
granulomatosis: CT findings in 30 patients. \emph{Eur Radiol} .
2003;13(1):43-51. doi:10.1007/s00330-002-1422-2

8. Aasar\selectlanguage{ngerman}ød K, Bostad L, Hammerstrøm J, Jørstad S, Iversen BM. Renal
histopathology and clinical course in 94 patients with Wegener's
granulomatosis. \emph{Nephrology Dialysis Transplantation} .
2001;16(5):953-960. doi:10.1093/ndt/16.5.953

9. Barksdale SK, Hallahan CW, Kerr GS, Fauci AS, Stern JB, Travis WD.
Cutaneous pathology in Wegener's granulomatosis. A clinicopathologic
study of 75 biopsies in 46 patients. \emph{Am J Surg Pathol} .
1995;19(2):161-172.

10. Murphy JM, Gomez-Anson B, Gillard JH, et al. Wegener granulomatosis:
MR imaging findings in brain and meninges. \emph{Radiology} .
1999;213(3):794-799. doi:10.1148/radiology.213.3.r99dc11794

11. Higuera-Ortiz V, Reynoso A, Ruiz N, Delgado-Hernández RD,
Gómez-Garza G, Flores-Suárez LF. Pachymeningitis in granulomatosis with
polyangiitis: case series with earlier onset in younger patients and
literature review. \emph{Clin Rheumatol} . 2017;36(4):919-924.
doi:10.1007/s10067-016-3520-6

12. Hellmich B, Sanchez-Alamo B, Schirmer JH, et al. EULAR
recommendations for the management of ANCA-associated vasculitis: 2022
update. \emph{Ann Rheum Dis} . Published online March 16,
2023:ard-2022-223764. doi:10.1136/ard-2022-223764

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