An unusual cause of fever of unknown origin with enlarged lymph nodes—relapsing polychondritis: A case report

Abstract

Introduction:
Fever of unknown origin (FUO) is a common initial presentation leading to a diagnostic challenge.

Patient concerns:
A 3-month history of moderate-to-high fever was reported in an otherwise healthy 54-year-old man. Enhanced computed tomography (CT) scans of his chest showed a remarkable progressive enlargement of bilateral cervical, supraclavicular, hilar, and mediastinal lymph nodes within 2 weeks. Bronchofibroscopy manifested obvious luminal stenosis with swelling, thick pale mucosa, and disappearing of structures of trachea cricoid cartilage, followed by a 18F-fluorodeoxyglucose positron-emission tomography-computed tomography (18F-FDG PET/CT) with intense symmetric FDG uptake in larynx, tracheobronchial tree, and hilar, mediastinal, and axillary lymph nodes being demonstrated.

Diagnosis:
A diagnosis of relapsing polychondritis (RP) was finally reached.

Interventions:
The patient received methylprednisolone 40 mg daily with a gradual tapering in a 4-month follow-up.

Outcomes:
The patient experienced no relapse of fever and lymph nodes enlargement in the 4-month follow-up.

Lessons:
Even though long-term fever with multiple lymphadenectasis usually lead to a diagnosis of lymphoma, the bronchoscopic features and evidence from 18F-FDG PET/CT in this case were much more approximate to RP, indicating an importance of a sensible differential diagnosis of RP in patients who present with nonspecific features such as FUO and lymph nodes enlargement. Keeping a high index of clinical suspicion in these patients can help recognize uncommon of RP and promote diagnosis and treatment. Our case highlights the significance of 18F-FDG PET/CT in helping reaching the diagnosis of RP in this condition. This report provides new data regarding the diagnostic difficulties of this rare type of autoimmune disease, and further investigations are needed as cases accumulate.

Full text

An unusual cause of fever of unknown origin with
enlarged lymph nodes—relapsing polychondritis
A case report
Wei Liu, MD, Hongli Jiang, MD
∗
, Han Jing, MS, Bing Mao, MD
Abstract
Introduction: Fever of unknown origin (FUO) is a common initial presentation leading to a diagnostic challenge.
Patient concerns: A 3-month history of moderate-to-high fever was reported in an otherwise healthy 54-year-old man. Enhanced
computed tomography (CT) scans of his chest showed a remarkable progressive enlargement of bilateral cervical, supraclavicular,
hilar, and mediastinal lymph nodes within 2 weeks. Bronchofibroscopy manifested obvious luminal stenosis with swelling, thick pale
mucosa, and disappearing of structures of trachea cricoid cartilage, followed by a 18F-fluorodeoxyglucose positron-emission
tomography–computed tomography (18F-FDG PET/CT) with intense symmetric FDG uptake in larynx, tracheobronchial tree, and
hilar, mediastinal, and axillary lymph nodes being demonstrated.
Diagnosis: A diagnosis of relapsing polychondritis (RP) was finally reached.
Interventions: The patient received methylprednisolone 40 mg daily with a gradual tapering in a 4-month follow-up.
Outcomes: The patient experienced no relapse of fever and lymph nodes enlargement in the 4-month follow-up.
Lessons: Even though long-term fever with multiple lymphadenectasis usually lead to a diagnosis of lymphoma, the bronchoscopic
features and evidence from 18F-FDG PET/CT in this case were much more approximate to RP, indicating an importance of a sensible
differential diagnosis of RP in patients who present with nonspecific features such as FUO and lymph nodes enlargement. Keeping a
high index of clinical suspicion in these patients can help recognize uncommon of RP and promote diagnosis and treatment. Our case
highlights the significance of 18F-FDG PET/CT in helping reaching the diagnosis of RP in this condition. This report provides new data
regarding the diagnostic difficulties of this rare type of autoimmune disease, and further investigations are needed as cases
accumulate.
Abbreviations: 18F-FDG PET/CT =18F-fluorodeoxyglucose positron-emission tomography–computed tomography, FUO =
fever of unknown origin, RP =relapsing pholychondritis.
Keywords: differential diagnosis, fever of unknown origin, lymphadenectasis, relapsing pholychondritis
1. Introduction
The term of fever of unknown origin (FUO) was coined in the
1960s to define a body temperature above 38.3°C for >3 weeks
without diagnosis, despite a comprehensive physical examination
together with exhaustive laboratory tests.
[1]
It was recorded that
no etiology could be determined in 10% to 32% of fever cases.
[2]
As fever could be an atypical presentation of frequent clinical
pictures, identifying the etiological diagnosis for FUO is a great
challenge for the clinicians. Although the majority cases with
FUO are progressing favorably, about 5% patients have a final
ominous prognosis with a neoplastic diagnosis, establishing the
importance of cautious differential diagnosis for FUO. During
the process of etiological diagnosis for FUO, it is significant to
carry out a systematic workup following a logical order to
promote the diagnosis and treatment. Some physical signs would
present concomitantly with long-term fever, such as lymph
nodes enlargement, which may help reach a diagnosis, but not
always.
Relapsing polychondritis (RP) is an uncommon multisystem
autoimmune disorder, characterized by recurrent episodes of
cartilaginous inflammation and subsequential destruction, with
etiology and pathophysiology remaining unknown. Although
auricular and nasal cartilages are usually the first to be affected at
the onset of RP, airway cartilage abnormality may also be the sole
presentation recognized in 10% of the patients during the early
stages,
[3]
which will present in up to 50% in the course of the
disease and is generally considered a major cause of morbidity
and mortality.
[4,5]
No matter which system is involved, RP rarely
presents as FUO.
[6]
Here, we report a case of RP with FUO
and progressive enlargement in multiple lymph nodes as initial
presentations.
Editor: N/A.
The authors have no funding and conflicts of interest to disclose.
Division of Respiratory Medicine, Department of Integrated Traditional Chinese
and Western Medicine, West China Hospital, Sichuan University, Chengdu,
Sichuan, People’s Republic of China.
∗
Correspondence: Hongli Jiang, Division of Respiratory Medicine, Department of
Integrated Traditional Chinese and Western Medicine, West China Hospital,
Sichuan University, 37 Guoxue Street, Chengdu, Sichuan, People’s Republic of
China (e-mail: doc_jhl@163.com)
Copyright ©2017 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows
others to remix, tweak, and build upon the work non-commercially, as long as
the author is credited and the new creations are licensed under the identical
terms.
Medicine (2017) 96:46(e8734)
Received: 5 October 2017 / Received in final form: 20 October 2017 / Accepted:
23 October 2017
http://dx.doi.org/10.1097/MD.0000000000008734
Clinical Case Report Medicine®
OPEN
1

2. Case report
A 54-year-old man with a 3-month history of moderate-to-high
fever (38.5°C–39.4°C) was referred to West China Hospital of
Sichuan University (Chengdu, China) in April 2017. The fever
arose without a trace and spiked 3 to 4 times per day with mild
headache and dry cough, no chills, notable sweats, sore throat,
hoarseness, stridor, arthralgia, dyspnea, nausea, vomiting,
abdominal pain, diarrhea or urinary frequency, and urgency
were complained. Investigations at another hospital failed to
identify the cause. He had no response to any antipyretics and
empiric antibiotics for suspected infections. The fever could be
relieved by steroid but recurred. He lived in a rural area, worked
as a peasant. History of contacts with animals (cows, sheep,
insects, etc.), filthy water or food, and people with infectious
diseases were denied. Upon admission, the patient was
febrile (38.4°C) and diaphoretic. Percussion and auscultation
of the lungs reveal no significant abnormality. The remainder
of the physical examination was otherwise unremarkable.
Comprehensive diagnostic workup were continued during
hospitalization and revealed evidence of increased erythrocyte
sedimentation rate (63 mm/h, reference range [RR] <21 mm/h),
mild anemia (hemoglobin 11.1 g/dL, [RR] 13–17.5 g/dL), mild
hypoalbuminemia (ALB 38.5 g/L, [RR] 40.0–55.0 g/L), throm-
bocythemia (391 10
9
/L, [RR] 100–300 10
9
/L), high level of
procalcitonin (0.24 ng/mL, [RR] <0.046 ng/mL), C-reactive
protein (10.7 mg/dL, [RR] <0.5 mg/dL), and interleukin-6
(44.12 pg/mL, [RR] 0.00–7.00 pg/mL). White blood cell count,
tumor biomarkers investigation, serology detections on viral
infections (HIV, syphilis, hepatitis viruses, influenza viruses, PIV,
ADV, CMV, BOV, RHV, RSV, EBV, metapneumovirus, and
coronavirus), and zoonoses (tuberculosis, Brucella spp., Rickett-
sia spp., Coxiella burnetii, Leishmania spp., Clonorchis sinensis,
plasmodiosis, schistosomiasis japonica, Echinococcosis, Chla-
mydiosis, MPP, toxoplasmosis, and leptospirosis), complements
3 and 4, rheumatoid factor, autoimmune antibodies (antinuclear
antibody, antidouble-strand DNA antibody, anti-RNP antibody,
anti-SM antibody, anti-SSA/B antibody, anti-SCL-70 antibody,
anti-Jo-1 antibody, anti-RIB antibody, and antineutrophil
cytoplasmic antibodies) all yielded normal results. No bacterial
and fungal pathogens were cultured from blood, sputum, bone
marrow, or bronchial alveolar lavage fluid. Bone marrow biopsy
and aspiration gave negative results in cytological smear and flow
cytometry. Interferon-gamma-release assay (IGRA) testing for
tuberculosis was also negative. His abdomen was innocent.
Enhanced computed tomography (CT) of the chest showed
intumescence of bilateral cervical and right supraclavicular
lymph nodes, and pulmonary emphysema with bilateral multiple
small nodules (0.3–0.5 cm) (Fig. 1). Biopsy specimens taken from
the right supraclavicular lymph node for histopathological study
showed nonspecificinflammation with cellular infiltrates of
lymphocytes and plasma cells.
Empiric treatment with moxifloxacin hydrochloride was
initiated considering occult bacterial infections. However, the
patient experienced a deterioration of fever (spiked more with
temperature >39°C) with chills and a worsening productive
cough. The patient had mild tachypnoea with the presence
of sonorous rhonchi. Besides, anemia and thrombocythemia
developed during this period with a weight loss of 5 kg. In
addition, thickening of the tracheal wall, more remarkable
lymphadenectasis, and lumen deformity were monitored by the
review of lung CT scans (Fig. 1). Transbronchial needle
aspiration of enlarged mediastinal lymph nodes was performed
by endobronchial ultrasound (EBUS), and showed fibrinous
inflammation with fibroplastic proliferation. Bronchofibroscopy
was conducted and manifested obvious luminal stenosis with
swelling, thick and pale mucosa, and, most strikingly, loss of
trachea cricoid cartilage (Fig. 2), which led us to the consideration
of RP, and the diagnosis of RP was confirmed by an 18F-FDG
PET/CT with intense symmetric FDG uptake in larynx,
tracheobronchial tree, and hilar, mediastinal, and axillary lymph
nodes being demonstrated (Fig. 3).
The patient was treated with methylprednisolone 40 mg daily
with rapid improvement in his symptoms. His body temperature
returned to normal and the cough resolved. ESR, PCT, and CRP
began to subside and the patient was discharged from the
hospital. Tapering of his methylprednisolone dose without
Figure 1. CT scans show dynamic increase of hilar/mediastinal lymph nodes, thickening of the airway wall, lumen stenosis, and deformity. CT scan conducted in
March 9, 2017 (left, A and B), and April 28, 2017 (right, C and D).
Liu et al. Medicine (2017) 96:46 Medicine
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combination of any immunosuppressive agent was conducted in
a 4-month follow-up, during which no subsequent flare-up of RP
was noticed. A repeat of the chest CT scans at 3 months revealed
no enlargement in hilar/mediastinal lymph nodes, but a
progression of airway wall thickening and luminal stenosis,
predicting a poor outcome.
3. Discussion
In clinical practice, causes of FUO are usually being explored
from 4 main etiological possibilities: infections, neoplasms,
noninfectious inflammatory diseases (NIID; e.g., connective-
tissue diseases, vasculitis), and miscellaneous conditions.
[7,8]
In
our case, negative results in detailed medical history review,
repeated physical examinations, and comprehensive serological
tests and culture studies, as well as nonresponse to antibiotic
therapy all excluded the infectious, NIID, and neoplastic
identifications. Although bilateral small nodules revealed by
chest CTs indicated minor inflammation, it was unlikely to
explain the long-term high fever. Fever accompanied by lymph
nodes enlargement without obvious infectious signs usually lead
to a potential diagnosis of lymphoma; however, unspecific
inflammatory findings that revealed by the biopsy of the right
superclavical and mediastinal lymph nodes, as well as the typical
signs of tracheobronchial cricoid cartilage disappearance, airway
wall thickening, tracheal stenosis, and deformity in this case
made the diagnosis of RP much more likely than lymphoma. On
closer examination by PET-CT, along with an increased degree of
clinical suspicion, a diagnosis of RP was eventually reached. In
parallel, fever subsided immediately after administration of
corticosteroids, so did the cough and abnormal pulmonary signs,
which was another indication for a nonmalignant cause of fever.
Figure 3. PET-CT fusion images of: trachea (A) and bronchus, hilar and mediastinal lymph nodes (B). Coronal images show moderate FDG accumulation in the
laryngeal cartilages, tracheobronchial tree, and the hilum and mediastinal lymph nodes (C).
Figure 2. Fiber bronchoscopic image shows loss of cricoid cartilage: (A) trachea; (B) carina of trachea; (C) the opening of upper and lower lobe bronchus of left lung;
(D) the opening of upper and middle lobe bronchus of right lung.
Liu et al. Medicine (2017) 96:46 www.md-journal.com
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More importantly, the absence of lymph nodes enlargement after
corticosteroids therapy alone in this case further confirmed the
diagnosis of RP rather than lymphoma.
RP is an uncommon connective tissue disease that can involve
multiple organ systems, mostly the ears, joints, eyes, nose, larynx,
and tracheobronchus,
[9–12]
with the presenting manifestations
highly variable. Usually, auricular chondritis, polyarthritis, nasal
chondritis, and/or ocular inflammation often inaugurate the
disease. Therefore, although airway involvement by RP is not
uncommon, extra pulmonary manifestations are almost always
the key to the diagnosis. According to the McAdam’s criteria,
establishing the diagnosis requires the fulfillment of 3 or more
clinical manifestations.
[5]
However, chondritis is absent initially
in nearly half of the cases with some general and unspecific signs
as the presenting symptom long before cartilaginous inflamma-
tion begins, which complicate the diagnosis. In our case,
unexplained prolonged fever accompanied by multiple enlarged
lymph nodes were the unspecific presentations that may confuse
the clinical decision-making. The relationship between these
atypical features and RP is still unknown. We consider that the
fever and lymph nodes enlargement may be related to the
potential release of inflammatory substances from tissue affected,
and subsequent systematic inflammation overflow during the
process of RP. Although histological proof remains the gold
standard to confirm the diagnosis, it is not always readily
accessible especially in cases like this. First, tracheal and
bronchial cartilage was already disappeared. Second, the biopsy
collection might induce a high risk of a worsening of edema,
bronchospasm, bleeding, and respiratory failure as his airway
collapsed easily without the support of cartilaginous structure.
In our present case, the only specific symptom of cough,
although, indicates the possible involvement of lungs but is far
too away from a diagnosis confirmation. Our step-by-step
diagnostic process was fundamental in concluding the correct
diagnosis, in which CTs disclosed respiratory tract involvement,
bronchoscopy detailed the absence of cricoid cartilages and
initiated suspicion for RP, and PET-CT finally established the
diagnosis. Until now, no abnormalities in eyes, ears, nose, or
joints developed in this patient. Although commonly seen in
almost half of patients with RP, airway involvement as a unique
manifestation is rarely reported.
It has been demonstrated that RP with airway involvement can
be debilitating and life threatening even diagnosed early.
Cricoarytenoid chondritis may be presented by odynophagia,
hoarseness of voice, dysphonia, respiratory distress, and
recurrent pneumonias, which may result in a dynamic airway
collapse, causing respiratory failure and sudden death. Even
though early medical intervention can be helpful,
[13]
the airway
cartilage collapse is irreversible. Patient in this scenario did not
develop severe dyspnea, so he was treated with only steroid
without any immunosuppressive agent. Although the patient did
not develop any further symptoms during the follow-up, the
radiographic evidence indeed indicates a progression of his
disease.
4. Conclusions
We presented a case with unexplained fever that was later
determined to be an early manifestation of RP with chondritis
restricted in airways. In this case, cervical, supraclavicular, hilar,
and mediastinal lymph nodes enlargement were present along
with FUO, indicating systemic inflammatory manifestations of
RP in addition to the local inflammation in cartilaginous tissues.
Many aspects of RP remain inconclusive due to its rarity. Our
case highlights a differential diagnosis of RP in patients with
abnormal features such as FUO and multiple lymph nodes
enlargement to improve the likelihood of a timely therapeutic
intervention. The significance of 18F-PET/CT in RP diagnosis
was proved again in this case.
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