Case report

Fever in a patient with

ANCA-associated vasculitis

*Hypertension: Enalapril, Furosemide

*Dyslipidemia: Pravastatin

*Ischemic heart disease: 2008 Angina

73 years-old white woman

PRIOR MEDICAL HISTORY

*ANCA-associated vasculitis (MPO):

#Jan/2011: (2 months) asthenia, anorexia, fever of unknown origin

(37º-38ºC), arthralgia and myalgia

CRP: 12 mg/dl ESR: 110 mm/h

-Renal involvement (Proteinuria: 510 mg/24h, 4-10 RBC/f)

Focal necrotizing glomerulonephritis with extracapillary

proliferation

-Neurological involvement: Mononeuritis multiplex

-Immunology: p-ANCA, MPO 222 IU/ml

-Microbiology (blood, urine, sputum): negative

-CT body: Normal

Treatment: MYCYC Trial

Prednisone (1 mg/kg/day) +

Mycophenolate mofetil (1g bid) +

Cotrimoxazol 800/160 mg/3 times per week

During admission:

*Acute coronary syndrome without ST elevation

#Coronary angiography: critical lesion of descending artery

and stent was placed.

Bisoprolol, Aspirin, Clopidogrel

*H1N1 Flu: treated with oseltamivir.

At 3 months, complete remission was achieved.

Clinically without symptoms (only paresthesia)

CRP: 1 mg/dl ESR: 28 mm/h

-Renal involvement (Proteinuria: 153 mg/24h, 1-3 RBC/f)

-Immunology: ANCA MPO 29 IU/ml

Treatment: Prednisone (12.5 mg/day + MMF [1 g bid])

*ANCA-associated vasculitis (MPO):

CURRENT DISEASE:

#June/2011: (2 weeks) fever (38ºC), arthralgia and malaise

-Physical examination: Alert, oriented.

No skin lesions. No signs of arthritis. No lymphadenopathies.

Normal breath sounds.

Rhythmic heart sounds without murmurs or signs of heart failure.

Abdomen: soft, painful deep palpation diffusely. No masses nor organomegaly.

Preserved bowel sounds.

Neurologic: Normal (paresthesia without changes)

Preserved distal pulses. No signs of deep vein thrombosis.

Thyroid size and consistency normal.

#Blood test: (abnormal results)

-PCR 3.6 mg/dl (<1mg/dl). ESR 50 mm/h.

-BCC: Leukocytes 8.61 109/l (80% neutrophils), Erythrocytes 3.15 1012/l,

hemoglobin 92 g/L, MVC 95 fl, Reticulocyte 4.5%. Iron 44 mcg/dl, folic acid and

vitamin B12 normal.

-Haptoglobin 2.92 g/l, Ferritin 341 ng/dl, Transferrin 2 g/l.

-Creatinine 1.1 mg/dl, Liver function test normal. LDH 420 IU/L.

Protein 50 g/l, Albumin 31 g/l.

-Proteinogram: Increase of a-globulins 1 and 2 fractions (no monoclonality)

-Urinalysis: Leucocytes 4-10/field, Erythrocytes 1-3/field.

-24-hour Urine Collection: Protein 81 mg/24h. Prot-creat ratio 124 mg/g.

-Beta 2 microglobulin 5 mg/l (0.1-2.3 mg/l)

-ANCA MPO 14.8 IU/l, ANCA PR3 Negative.

In your opinion, this patient had…..

1.Urinary infection, of course

2.Probably, she had a vasculitis flare

3.She had fever as adverse event of MMF

4.Fever secondary to neoplasm (solid or hematological)

5.It doesn't matter! systemic steroids should be immediately

increased

In addition to diagnostic work-up, what

would you do?

1. I’m sure that she had an urinary infection and antibiotics

should be initiated

2. Vasculitis flare is the most probable option and

corticosteroids should be increased

3. Be patient!! Paracetamol and wait for the results of

diagnostic work-up

#Microbiology:

-Blood Culture x 2: Negative.

-Urine Culture: Negative.

-Sputum Culture: Negative.

#Echocardiogram: Normal. No vegetation.

#Abdomino-pelvic CT: Normal.

#Colonoscopy: Normal.

Diagnostic work-up and……

After 20 days of admission, the patient persisted with fever……but clinically

without changes

CRP: 2.4 mg/dl ESR: 54 mm/h

#Microbiology:

-Blood Culture x 4: negative

-Urine Culture x 3: negative

-Sputum Culture: negative

-Serology (EBV, CMV, Coxiella): negative

#Gallium bone scan: Normal

#Sinuses CT: Partial occupation of ethmoid air cells bilaterally

#PET-CT: Normal

Evolution……

In your opinion, this patient had…..

1. An infection, I suppose

2. I was right!!, she had a vasculitis flare!!

3. A drug fever is a real option

4. Don’t forget neoplasm (solid or hematological)!!

5. This patient is the typical case of factitious fever

The patient had vasculitis activity

Treatment: PDN 17.5 mg/day + MMF 3 g/day (MYCYC)

Discharged at home….

In our opinion……

But…

• #Thoracic CT: Multiple pulmonary embolism and….• #Doppler: Deep venous thrombosis in both legs

– Right: Superficial femoral, popliteal, posterior tibial and peroneal veins thrombosis– Left: Superficial femoral vein thrombosis

Eureka!!!! PE is obviously the cause of the

unknown fever

1. Yes, I’m sure. ANCA-associated vasculitis are associated with

high risk of thrombosis.

2. PE is only an incidental finding.

3. PE does not explain the unknown fever.

Fever persisted without clinical and laboratory changes…..

Evolution……

LMWH was started and…….

Gastrointestinal bleeding in the form of rectal bleeding

(enterorrhage)

Gastrointestinal endoscopy: gastric and duodenal ulcers

Fever persisted without clinical and laboratory changes…..

Evolution……

A diagnostic test was performed……..

LMWH was started and…….

Gastrointestinal bleeding in the form of rectal bleeding

(enterorrhage)

Gastrointestinal endoscopy: gastric and duodenal ulcers

#Pathologic study of ulcers: CMV inclusions

#Microbiologic study: CMV PCR blood +

16,788 copies/ml

Treatment:

Ganciclovir with improvement of the patient

Enterocolitis by CMV

PE + DVT

ANCA-vasculits

Discussion

CMV infection

PE + DVT

ANCA-vasculitis

Discussion

CMV infection

PE + DVT

ANCA-vasculitis

Incidence rate of venous thrombosis

Ann Intern Med 2005;142:620-6

#83% of VTEs occurred within a period of 2 months prior to or following a diagnosis of active AAV

198 patients: 143 WG, 34 MPA, 21 RLV

Median follow-up period since diagnosis of AAV: 6.1 yrs

(range: 0.2–17.6 yrs).

Incidence of AAV-associated VTE during active and inactive disease

Rheumatology 2008;47:530-4

Healthy population (same age) 0.3

#52% of VTEs occurred within a period of 3 months prior to or following a diagnosis of active AAV

#Etiology

*Endothelial lesion

*Hypercoagulability

*Relationship between WG and genetic factors predisposing to thrombotic events??

*CYC and corticosteroids??

#Chronic inflammation does not seem to be an independent factor to thrombosis

Activity phase

Discussion

CMV infection

PE + DVT

ANCA-vasculitis

• CMV in patients with AASV is lower than that in transplantation

• 2.2% of patients

• Although valganciclovir and surveillance polymerase chain reaction (PCR) is available and used in transplant patients at a high risk of developing CMV, there are no recommendations for their use in patients with autoimmune disease on immunosuppression.

535 AAV patients (1995-2002)

Median duration of follow-up was 5.2 years

133 (25%) deaths were recorded

Causes of death within and after the first year of follow-up

Discussion

CMV infection

PE + DVT

ANCA-vasculitis

• Reported in the medical literature almost 100 times• Theories:

– CMV triggers thrombosis by enhancing platelets and leukocytes adhesion to infected endothelial

– CMV increases the circulatory levels of factor VIII. – CMV transiently induces production of anti-phospholipid antibodies

• Incidence of thrombosis among acute CMV infection hospitalized patients: 6.4%

• Incidence of acute CMV infection among thrombosis hospitalized patients: 1.9–9.1%. Most (n=64; 65.9%) reported patients were immunocompetent

• Mean age of reported patients was 39.7±14.9 years. Female– male ratio was 1:1

• DVT/PE, splanchnic vein thrombosis and splenic infarction were the most prevalent thromboses associated with acute CMV infection

Discussion

CMV infection

PE + DVT

ANCA-vasculitis

-Three patients with AAV (1 WG and 2 MPA) and PE-DVT associated with CMV infection.

-All three patients were under treatment with CYC and CS (high dose).

-CMV Reactivation: 2 cases (flu-like syndrome) 1 case (assymptomatic).

-Probable etiology:

Endothelium infection lead recruitment of inflammatory cells

*Endothelial cells are infected by CMV and endothelium is the main reservoir of CMV during acute infection

-Patients with AAV and active CMV infection should be treated with prophylactic anticoagulation.

Conclusions

*Increased incidence rate of VTE in AAV.

*Relationship with activity of AAV.

*Etiology unknown.

*CMV infection in AAV patients is rare.

*There are no recommendations for the use of CMV PCR and prophylactic valganciclovir in patients with autoimmune disease on immunosuppression.

*There are no recommendations of prophylactic anticoagulation in AAV patients with CMV infection.

Thank you for your attention