Case Sharing of Granulomatous Vasculitis "Unconventional"

Author: Li Yunan, Tianjin Medical University General Hospital Airport Hospital; Hong Yunchuan, Tianjin Medical University General
Hospital
Case Review A 57-year-old female patient complained of "low-grade fever, polydipsia, polydipsia, and polyuria for 3 weeks in the afternoon".
The admission time was October 19, 2020
.

History of present illness: 3 weeks before admission, low fever in the afternoon after catching cold, initial body temperature 37.
6 ℃, accompanied by polydipsia, polydipsia, polyuria, fond of drinking warm water, and nighttime, accompanied by fatigue, double temporal tightness
.

No cough, sputum, hemoptysis; no chest tightness, suffocation; no muscle pain, joint pain, dry eyes, hair loss, Raynaud's phenomenon, etc.
, went to a local clinic, and received symptomatic antipyretic treatment, and the body temperature can be reduced to normal
.

After still repeated afternoon low fever
.

He went to the local hospital again, and chest CT showed infectious lesions in both lungs (see Figure 1); PPD, sputum acid-fast staining, X-pert negative, RF (+), CRP 79 mg/L; moxifloxacin, imipeptide Nanxistatin infection, the treatment effect is not good, 1 week later chest CT showed that the lesions progressed (see Figure 2)
.

The patient is now admitted to our department for further diagnosis and treatment
.

Since the onset of the disease, the patient has been in good spirits, with decreased appetite, poor sleep, normal bowel movements, significantly increased urine output, and a weight loss of 2 kg
.

Past history: left ear cholesteatoma more than 10 years ago, left ear hearing loss; left breast cancer for 8 years, left mastectomy, postoperative chemotherapy, no recurrence after follow-up; uterine fibroids 8 years ago Laparoscopic myomectomy
.

Denied a history of asthma, sinusitis, etc.

.

History of allergy to "doxofylline"
.

Personal history: Denied smoking and drinking history
.

Family History: Sister cervical cancer
.

Figure 1 2020.
10.
6 chest CT plain scan in a foreign hospital, multiple lumps and small nodules in both lungs, and infectious lesions were consideredFigure 2 2020.
10.
13 After 1 week of anti-infective treatment, the chest CT plain scan in the other hospital was reviewed, and the bilateral lung lesions were higher than before Progress admission examination body temperature 36.
5 ℃, pulse 95 times/min, respiration 20 times/min, blood pressure 111/55mmHg
.

Conscious and autonomous
.

Calm face, no pale or yellowish skin and mucous membranes
.

The superficial lymph nodes of the body were not enlarged
.

Hearing loss in left ear
.

Pharynx is not red, tonsils are not large
.

The trachea was in the middle, the shape of the thorax was normal, the left breast was absent, the breath sounds were thick in both lungs, and no wet or dry rales were heard
.

The heart sounds are fine, the rhythm is uniform, and there is no pathological murmur
.

Abdominal soft, no tenderness, rebound tenderness and muscle tension
.

Both lower extremities are not swollen
.

The patient was in good general condition when admitted to the hospital.
Strong antibiotics were given in other hospitals to cover common pathogens of community-acquired pneumonia, but the treatment was ineffective
.

Therefore, there was a tendency to be non-infectious diseases at that time, and it was necessary to exclude the possibility of infection by special pathogens
.

Auxiliary examination after admission to the hospital, a complete chest CT scan showed that the bilateral lung lesions had progressed compared with the previous ones, and some lesions had cavitary changes (see Figure 3)
.

Blood gas analysis: oxygen concentration 29%, pH 7.
461, pCO2 44.
8mmHg, PO2 90.
0mmHg
.

Blood routine: WBC 7.
47*10^9/L, RBC4.
12*10^12/L, HB 120g/L, PLT 356*10^9/L↑, N70.
6%, L 18.
6%
.

Coagulation function: FIB 8.
22g/L↑, DD 1319ng/ml↑
.

Biochemistry: normal renal function and electrolytes; liver function: globulin 43g/L↑, albumin 28g/L↓
.

Fasting blood sugar: 6.
0mmol/L, random blood sugar 6.
3mmol/L
.

Anti-cancer + lung tumor markers: ferritin 318.
28ng/mL↑, CA125 59.
70U/mL↑
.

Infection indicators: CRP 10.
50mg/dl↑, ESR 60mm/h↑, PCT < 0.
05ng/mL
.

Cryptococcus capsular polysaccharide antigen negative
.

Aspergillus IgG antibodies were normal
.

G test, T-SPOT, and hemorrhagic fever antibody IgM were all negative
.

Urine routine: urine glucose -, urine ketone body -, urine occult blood -, urine specific gravity 1.
004↓, uric acidity 6.
50, urine albumin -
.

Taking into account the 24h intake and output, the patient's urine output increased significantly, more than 5000ml per day (see Figure 4)
.

Routine examinations do not give valid clues to the diagnosis
.

Next, we hope to get some clues by further improving bronchoscopy, bronchoalveolar lavage fluid, biopsy and rheumatism-related examinations
.

Bronchoscopy: Microscopically normal
.

Alveolar lavage fluid flow: macrophages, squamous epithelial cells and other 80.
08%, lymphocytes 2.
94%, neutrophils 16.
11%, eosinophils 0.
87%
.

Bronchoalveolar lavage fluid: X-pert, GM test, bacteria, and fungal cultures were negative
.

ROSE: "Inflammatory Changes"
.

Pathology of TBLB: (subsegmental lung biopsy of the posterior segment of the left upper lobe) The specimens are small airway mucosa and peripheral lung tissue.
In the small airway mucosa, a large number of acute and chronic inflammatory cell infiltration, focal fibrous tissue hyperplasia, and a small amount of mild extrusion are seen.
Atypical glands; immunohistochemical staining showed extruded glands were positive for CK, CK7 and TTF-1
.

(Brush film of the sub-subsegment of the posterior basal segment of the left lower lobe) No tumor cells were seen
.

Immunocompletion + rheumatic antibody + ANCA: IgA 595.
00mg/dl↑, RF 190.
00IU/ml↑, C-ANCA positive↑, anti-PR3 (ELISA) 195.
53RU/ml↑
.

At the same time, according to the patient's polyuria, considering that diabetes insipidus cannot be excluded, a water deprivation pressure test (see Figure 5) was performed, and the result suggested that it was central diabetes insipidus
.

To further improve the head MRI (see Figure 6), suggesting hypophysitis
.

And then improve the relevant examination to evaluate the anterior pituitary function
.

Six items of free thyroid function, growth hormone, insulin-like growth factor-I, and sex hormone were normal
.

Adrenal function: Cortisol >50.
0ug/dL ↑, ACTH 39.
40pg/mL
.

Urinary cortisol: 24-hour urine volume was 5200ml, and the calculated result of urinary cortisol was 381.
16ug/24h ↑
.

Low-dose dexamethasone overnight test suggests ACTH-dependent hypercortisolism
.

Fig.
3 The multiple clump shadows in both lungs of our hospital on 2020.
10.
21 on chest CT plain scan were larger than before, and some were accompanied by cavitary changesFig.
4 The fluid intake and output of the patient after admissionFig.
5 The result of the patient's water deprivation and compression testFig.
6 Picture A: Pituitary MRI plain scan, picture B is a half-dose enhanced MRI of the pituitary, suggesting that the pituitary is enlarged, the coronal median height is about 9.
1mm, uneven enhancement, and the pituitary stalk is thickened, which is consistent with the manifestations of hypophysitis.
Finally, after multidisciplinary consultation and discussion, granulomas were considered.
Vasculitis involving both the lungs and pituitary gland
.

The final diagnosis was: ANCA-associated vasculitis, granulomatous vasculitis, hypophysitis, central diabetes insipidus, and hypercortisolism
.

High-dose corticosteroids, intravenous methylprednisolone 120 mg/d, combined with intravenous cyclophosphamide when the dose is reduced to 40 mg/d, and oral desmopressin for diabetes insipidus, starting with low doses, according to urine output Adjust dosage
.

After 2 weeks of treatment, the patient's symptoms were significantly relieved, and the anti-PR3 (ELISA) showed a downward trend in re-examination.
The chest CT scan and pituitary MRI lesions were significantly smaller than before (see Figure 7)
.

Figure 7 The left side shows the chest CT and pituitary MRI before treatment, and the right side shows the chest CT and pituitary MRI after treatment
.

Figure 8 Discussion of the 2017 EULAR-ACR provisional classification criteria Granulomatosis with vasculitis (GPA, formerly known as Wegener's granulomatosis) is an autoimmune small-vessel vasculitis closely associated with anti-neutrophil cytoplasmic antibodies (ANCA)
.

The global annual incidence of GPA is approximately 10-20 cases per million, with approximately the same incidence in men and women [1]
.

The typical triad of GPA is: necrotizing granulomatous inflammation of the upper and lower airways (sinusitis, crusted rhinitis, saddle nose, otitis media, mastoiditis, hearing loss, pulmonary nodules, alveolar hemorrhage), systemic necrotizing vasculitis and necrotizing glomerulonephritis
.

According to the 2017 EULAR-ACR interim classification criteria (see Figure 8), a total score of 9 items greater than or equal to 5 can be classified as GPA
.

GPA can also affect other systems, including the joints, eyes, skin, nervous system, cardiovascular, and gastrointestinal tract
.

Nervous system involvement occurs in 22% to 54% of cases, often manifesting as peripheral neuropathy and cranial nerve palsy, central nervous system involvement is rare, accounting for about 10% of patients with GPA, and pituitary dysfunction is more rare, accounting for about 10% of patients with GPA.
1%[2]
.

The clinical manifestations of pituitary dysfunction are diabetes insipidus, secondary hypogonadism, central hypothyroidism, and secondary adrenal insufficiency
.

Pituitary dysfunction can accompany the entire course of the disease
.

The imaging features are a mass in the sella area with a central cystic lesion with homogeneous enhancement around it [3]
.

According to the 2020 Dutch consensus statement on the diagnosis and treatment of ANCA-associated vasculitis, induction therapy with intravenous glucocorticoids combined with cyclophosphamide or rituximab is recommended for patients with systemic multisystem involvement or life-threatening disease.
Relief after 3-6 months
.

Such as the use of cyclophosphamide induction therapy recommended low-dose corticosteroids plus azathioprine maintenance therapy to prevent recurrence, such as the use of rituximab induction therapy without maintenance therapy [4]
.

GPA responds well to treatment and has a good prognosis
.

The treatment response rate is above 90%, and the 10-year survival rate is 40% with renal involvement and 60-70% without renal involvement [5]
.

A Chinese retrospective study found that in 60 patients with impaired pituitary function, when the systemic remission rate was 70%, the recovery rate of anterior and posterior pituitary function was only 16.
7% and 21.
7%
.

The recovery of pituitary function is not ideal, which may be due to permanent pituitary damage due to necrotizing granulomatous inflammation of the gland [6]
.

Thinking Granulomatous vasculitis is a systemic disease that can involve multiple organs such as the respiratory tract, kidneys, nervous system, cardiovascular, and gastrointestinal tract
.

For patients with atypical clinical manifestations at the same time, it is necessary to actively give systematic examination and evaluation, and try to use "monism" to explain the occurrence and development of the disease
.

Multidisciplinary consultation and discussion are very important for the diagnosis and treatment of complex and difficult diseases
.

1.
Garlapati, P.
and A.
Qurie, Granulomatosis with Polyangiitis, in StatPearls.
2021, StatPearls Publishing Copyright © 2021, StatPearls Publishing LLC.
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De Parisot, A.
, et al.
, Pituitary Involvement in granulomatosis with polyangiitis: report of 9 patients and review of the literature.
Medicine (Baltimore), 2015.
94(16): p.
e748.
3.
Esposito, D.
, et al.
, Pituitary dysfunction in granulomatosis with polyangiitis.
Pituitary, 2017.
20(5): p.
594-601.
4.
Dirikgil, E.
, et al.
, A Dutch consensus statement on the diagnosis and treatment of ANCA-associated vasculitis.
Neth J Med, 2020.
78(2): p.
71-82.
5.
Greco, A.
, et al.
, Clinic manifestations in granulomatosis with polyangiitis.
Int J Immunopathol Pharmacol, 2016.
29(2): p.
151-9.
6.
Liu, S.
, et al.
, Pituitary Involvement in Granulomatosis with Polyangiitis:A Retrospective Analysis in a Single Chinese Hospital and a Literature Review.
Int J Endocrinol, 2019.
2019: p.
2176878.