Intern Report 7.1

Case Presentation by Dr. Henry White

Chief Complaint: Headache and fever

History of Present Illness: 13 year old male presents complaining of a headache for the last 2 days and a fever 4 days. The headache gradually started it is global in distribution, constant ache, 6-8/10 over the last 24 hours, currently at a 7/10.  It improves with ibuprofen or acetaminophen, it is not aggravated by sight or sound, and he denies any vision or hearing changes. The fever has been ranged between 99-101 for the past 4 days.

The parents state he is currently being evaluated for a constellation of symptoms, but no diagnosis has been made.  These include microscopic hematuria and occasionally pink tinged urine for the last 3 weeks.  Sporadic bilateral conjunctivitis without uveitis per ophthalmology with no vision changes or pain.  He has had polymigratory arthralgias over the past month, mostly located in his elbows and knees, but also in the small joints of his hands, feet and ankles bilaterally, sparing hips and shoulders.  This pain improves with the ibuprofen.  He has also had a blotchy rash over legs, ankles and elbows, with lower extremities affected more than the upper.  Parents also deny any sick contacts, and say the patient was previously healthy before these symptoms started one month ago.

ROS:
General: Positive for fever and for 5 pound weight loss over last month with overall decreased activity level. Negative chills/sweats
HEENT: occasional epistaxis, no sore throat or congestion
Pulmonary: Intermittent cough, no dyspnea/wheezing
Cardiovascular: No chest pain
Gastrointestinal: Positive anorexia, no nausea/vomiting/diarrhea/constipation/blood in stool/melena, no abdominal pain
Musculoskeletal: no weakness or myalgias
Integumentary: no increased bruising or bleeding

Past Medical History: none – currently being worked up for above
Surgical History: none
Medications: ibuprofen, last dose 2 hours prior to arrival, acetaminophen, unknown eye drops
Allergies: none
Family History: hypertension
Social History: no alcohol/tobacco/other drugs, patient denies any sexual history

Physical Exam

Vitals: BP 125/76,HR 100,RR 14,T 100.1, 98% on RA, 5’2” weighing 122 lbs
General: Patient is lying on exam bed in obvious discomfort, holding his head with both hands

HEENT: normocephalic, scalp nontender to palpation, bilateral  conjunctivitis (represented below), EOMI without pain through visual range of motion, 20/20 vision b/l , MMM with no posterior oropharynx erythema or ulcerations

Neck: no lymphadenopathy noted, neck supple with no meningeal signs.

Pulmonary: Slight crackles over bilateral lower lung fields, no wheezes, good air exchange, no accessory muscle use or peripheral cyanosis

Cardiovascular: RRR with no r/g/m/c, 2+ D.P/Radial pulses b/l, brisk capillary refill

Abdomen: soft, nontender, nondistended

Genitourinary: normal, no inguinal adenopathy

Musculoskeletal: Musculoskeletal: Pain with active motion of elbows R>L, and ankles equal bilaterally, no pain with passive motion.  Able to ambulate normally but with significant amounts of pain.  5/5 strength in all extremities, good muscle tone in all limbs.  Joints nontender to palpation, no warmth, swelling or redness over any joint

Integumentary: Nonblanching, flat purpura over b/l lower extremities with concentrated over the anterior shin/ankles with some extension into soles of feet, as well as some over b/l elbows.  Not painful to palpation, some petechia noted over elbows/forearms.  No ecchymosis/abrasions/blisters noted, no involvement of torso or facial areas.

Neurological: AOx3, CN 2-7, 9-12 intact, speech fluid, heel to shin and finger to nose normal b/l, sensation intact to light touch over all extremities

case 7.1j

Question 1

This patient was admitted to Observation overnight, during which he developed some hemoptysis and epistaxis.  Bleeding stopped spontaneously, but patient was sent for chest CT that showed multiple cavitary lesions.  What is the most likely diagnosis in this patient?
a)  Kawasaki’s Disease
b)  Polymyalgia Rheumatica
c)  Wegner’s Granulomatosis
d)  Lyme Disease

Question 2

What is the gold standard for diagnosis of this disease?
a)  Biopsy
b)  ANCA
c)  Clinical diagnosis, no single lab test diagnostic
d)  Western Blot and ELISA serology

Question 3.

What is the mainstay of treatment for this disease?
a)  Doxycycline
b)  Long term corticosteroids
c)  Long term corticosteroids and cyclophosphamide
d)  IVIG and aspirin

Answers: 1. C, 2. A, 3. C

Answer Discussion

  1. The above vignette is a description of pediatric Wegner’s patient.  Definitely a challenging disease process with a lot of overlap with other conditions  It is a small vessel vasculitis classically taught to affect kidneys and lungs, but also can present with many other symptoms.   This patient presents with renal, pulmonary, cutaneous, and musculoskeletal symptoms.  Kawasaki’s disease is a large vessel vasculitis which classically presents as a high fever for more than 5 days with a predominance of conjunctivitis, mucous membrane involvement, and lymphadenopathy and potentially many other symptoms.  And while there are overlaps between kawasaki’s and Wegner’s, the low grade fever is more in line with Wegner’s.  Polymyalgia Rheumatica can also present with a large range of symptoms, with the arthralgias focused on the neck, shoulders and hips.  Lyme disease is a tick borne infection that can present during a spectrum of the disease process.  Early manifestations include a target rash and flu-like symptoms with later symptoms predominately affecting neurological and cardiac systems.
  2. While there are numerous tests to help rule in or out Wegner’s as the possible disease state, only a tissue sample can give the definitive diagnosis.  A sample taken from an active site of inflammation is diagnostic, and necessary due to the potential severe side effects of medical treatment.  ANCA testing is the laboratory test of choice, but only 82-94% sensitive.  Serology is the testing of choice for Lyme disease, and Kawasaki’s and Polymyalgia are clinically diagnosed and no single test is diagnostic.
  3. The mainstay of treatment for Wegner’s is steroids and immunosuppression with cyclophosphamide/methotrexate/rituximab.  This is important to know because Wegner’s patients undergoing treatment will be functionally immunosuppressed and at risk for overwhelming infections, even PCP.  Patients are also at risk for DVTs secondary to the disease progress, and untreated, the disease can be fatal by as little as 5 months.  Doxycycline is the first line treatment for Lyme disease.  Long term steroids are the treatment for Polymyalgia Rheumatica, but immunosuppressants are required for Wegner’s.  IVIG and aspirin are the treatment for Kawasaki’s.

Discussion:

This is a pediatric case of Granulomatosis with Polyangiitis (Wegner’s), a predominately small vessel vasculitis.  Though the two most common vasculitidies of childhood are Henoch-Schonlein purpura and Kawasaki disease, Wegner’s is a potentially lethal disease process if not treated appropriately.

The clinical presentation can be misleading as well, early symptoms are non-specific including fever, malaise, anorexia and weight loss as well as migratory arthralgias and can persist for months before other organ involvement.

Ocular symptoms can include conjunctivitis, scleritis, proptosis or uveitis

Wegner’s also can present with numerous ENT symptoms, including epistaxis, sinusitis, persistent rhinorrhea or even saddle nose deformity or laryngotracheobronchial stenosis.  Pulmonary manifestations can involve anything from intermittent coughing or wheezing to hemoptysis, dyspnea pulmonary fibrosis or pulmonary arterial hypertension with chest x-rays variably showing nodules, opacities and possibly infiltrates.  CT scan can show nodules, cavitary lesions or infiltrates

Cardiac and gastrointestinal symptoms are much less common, ex. pericarditis

Renal disease is one of the most common manifestations.  Glomerulonephritis develops in up to 80% of patients within the first 2 years, and is common at time of diagnosis.  ANCA positive patients are at greater risk for progression to end stage renal disease.  Other common signs are usually nephritic range proteinuria, hematuria, and AKI with cellular casts

Musculoskeletal disease usually presents as migratory arthralgias and myalgias

Cutaneous disease is present in up to half of cases and the most common lesion is leukocytoclastic angiitis – shown in example picture, but may also have focal necrosis/ulceration, hives, livida reticularis or tender nodules.

Nervous system involvement can present with cranial nerve abnormalities, CNS lesions or external ophthalmoplegia

There are multiple diagnostic criteria including the American College of Rheumatology (ACR) and Chapel Hill Consensus Conference Criteria (CHCC), both criteria are limited in distinguishing Wegner’s from Microscopic Polyangiitis, and recommend a definitive diagnosis with tissue biopsy from a site of active inflammation (lung/kidney).  Confirmation with biopsy is also indicated before starting a patient on immunosuppressant therapy with steroids and cyclophosphamide/methotrexate/rituximab etc.  ANCA is positive in 82-94% of cases.  Other lab values include an elevated ESR, elevated CRP, leukocytosis, normochromic normocytic anemia, thrombocytosis or thrombocytopenia and evidence of AKI.

CHCC guidelines might permit the diagnosis of Wegners in the absence of biopsy with:

  1. Radiographic evidence of pulmonary involvement for more than 1 month
  2. Upper airway symptoms for more than 1 month as listed above
  3. Glomerulonephritis
  4. ANCA positive

After remission induction, patients remain at risk for flare-ups, usually following an infection, and are also at increased risk for PCP or disseminated VZV.  Patients are also at increased risk for DVTs and long term side effects of the immunosuppressing medications.

Vasculitides Overview

Large Vessel Vasculitides

Temporal Arteritis: Commonly women in their 60’s/70’s.  Multiple systemic symptoms, as well as ischemic symptoms to branches of internal and external carotid.  30-40% also have Polymyalgia Rheumatica.  Lab assessment can include ESR, CRP, and anemia.  Treatment is corticosteroids, most effective within 24hrs of symptom onset.

Takayasu’s Arteritis (Pulseless disease): Chronic recurring disease affecting aorta and it’s branches. Primarily seen in young women.  Early diagnosis extremely difficult, symptoms are minor and nonspecific.  Later symptoms include uneven to absent pulses, claudication, retinopathy, strokes, and other ischemic type symptoms.  Treatment is prednisone, and further treatment may require immunosuppressants.

Medium Vessel Vasculitides

Polyarteritis Nodosa: Predominately in males in their 50’s/60’s, but can present at any age. Early symptoms include fevers, myalgias, arthralgias, and cutaneous manifestations (usually palpable purpura possibly with ulcerations), later manifestations include peripheral neuropathy and bowel ischemia.  Treatment is corticosteroids and add immunosuppressants if there is organ involvement.

Buerger’s Disease: Vaso-occlusive disease of young male smokers typically in lower extremities.  Symptoms can start as mild paresthesia’s/pain and progress to severe pain with claudication and possibly ulceration.  Treatment is abstinence from tobacco, and possibly calcium channel blockers.  Half of all patients who continue using tobacco need amputation.

Small Vessel Vasculitides

Behcet’s Disease: A chronic relapsing vasculitis that can affect large vessels, presents with oral/genital ulcers, skin lesions and possibly ophthalmologic/ neurologic/ gastrointestinal manifestations, and typically men between 25-35.  Oral ulcers are an early sign and required for diagnosis.  Kidney and cardiac involvement is rare, and diagnosis is by tissue biopsy. Treatment is focused on presenting symptoms.

Wegner’s Granulomatosis: discussed above

Churg-Strauss: It is a granulomatis vasculitis of multiple organs presenting as asthma and allergic rhinitis with eosinophilia.  Associated with allergy/atopic disorders.  Asthma usually presents during adulthood.  Pulmonary, ENT, and cutaneous symptoms predominate along with nonspecific symptoms of fever and weight loss.  Neurological and cardiac symptoms are also common.  Labs may show eosinophilia >1500/mm3, possibly p-ANCA, and chest x-ray may show Loffler’s syndrome/consolidation/cavitation.  Diagnosis is by tissue biopsy, and treatment is corticosteroids and possibly cyclophosphamide.

Microscopic Polyangiitis: Another ANCA positive vasculitis with a high degree of overlap with Wegner’s, with common symptoms of alveolar hemorrhage and glomerulonephritis, with the other most common symptoms including weight loss, mononeuritis multiplex, fever and cutaneous findings.  Diagnosis is by tissue biopsy, and treatment is corticosteroids and immunosuppressants.

Goodpasture’s Syndrome (Anti-GBM syndrome): Caused by the build-up of anti-glomerular basement membrane antibodies in the alveolar and glomerular basement membrane.   The disease has bimodal peak incidence during the 20’s and 50’s/60’s.

Like Wegner’s, initial symptoms include fever, malaise and arthralgia.  Hemoptysis occurs in 70% of cases, and glomerulonephritis is another frequent complication of the disease.  Notable tests include elevated ESR, UA with RBC casts, and Anti-GBM Ab positive.  Diagnosis is made with kidney biopsy, and treatment is corticosteroids and possibly immunosuppressants, and patients may end up requiring renal transplant if able to get anti-GBM antibodies to undetectable levels.

Henoch-Schonlein Purpura: Another small vessel vasculitis with a large degree of overlap with Wegner’s disease.  It typically involves the skin, gastrointestinal tract, and kidneys.  The disease predominately affects the pediatric population, and male to female ratio of 2:1.  Up to 2/3 of patients have a history of a respiratory infection 10 days before developing symptoms.  Classically, these symptoms include abdominal pain, fever, palpable purpura, hematuria and arthralgias. Gastrointestinal complaints in 70% with renal involvement in up to 50%.  Neurological involvement is rare.  Treatment is aimed at the underlying cause, if applicable, and multiple possible treatment regimens are currently being researched.  However, this disease is usually self limited, over the course of 6-8 weeks, and prolonged treatment may not be needed.

Key Points:

Wegner’s is a complex disease process potentially involving many different organ systems.  In medical school it was taught as the vasculitis that involves the kidneys and lungs, but it’s important to be aware that it can involve much more than those systems.

Missing the diagnosis can potentially have severe consequences in terms of morbidity and mortality.  Important lab/imaging work-up includes Urinalysis with microscopic analysis for urinary sediment and presence of blood, BMP (they know what these tests are for, CBC .  ANCA, ESR, CRP, LFTs, hepatits panel, HIV screen, and blood cultures as indicated to rule out other disease processes.  A baseline chest x-ray or possibly CT to assess pulmonary involvement.

Wegner’s Diagnosis is based on tissue biopsy.  Patients with suspected Wegner’s are an indication for admission and further work-up for diagnosis as well as medical treatment induction.

Patients being treated for Wegner’s are immunosuppressed and at risk for infections including disseminated VZV and PCP.  They are also at risk for DVT’s as well as numerous medication side effects.

References: 

  1. American Academy of Ophthamology – http://www.aao.org/theeyeshaveit/red-eye/immunologic-conjunctivitis.cfm
  2. John’s Hopkins Vasculitis Center – http://www.hopkinsvasculitis.org/types-vasculitis/microscopic-polyangiitis/
  3. Bosch et al, Treatment of Antineutorphil Cytoplasmic Antibody Associated Vasculitis – http://jama.jamanetwork.com/article.aspx?articleid=208292, JAMA 2007
  4. Lehrmann, Jill and Sercombe, Clare, Systemic Lupus Erythematosus and the Vasculitides, Rosen’s Emergency Medicine 7th edition
  5. Cabral et al, Classification and incidence of childhood vasculitis, uptodate.com updated June 5th 20013
  6. Falk et al, Clinical manifestations and diagnosis of granulomatosis with polyangiitis and microscopic polyangiitis, uptodate.com updated September 25th 2012
  7. Gnann Jr., John, Antiviral therapy of Varicella Zoster virus infections Chapter 65 of Human Herpesviruses: Biology, Therapy and Immunoprophylaxis 2007  http://www.ncbi.nlm.nih.gov/books/NBK47401/

3 Responses

  1. seems young for wegener’s but that is most likely, biopsy for dx and steroids and cycolphospamide for tx

  2. Bleeding, rash, joint pains, and conjunctivits, eh? That sounds like…

    1) c. Wegner’s Granulomatosis

    I think the gold standard for nearly anything, paritcularly a chronic inflammatory condition would be getting tissues, so:

    2) a. Biopsy

    Treatment for a chronic, likley autoimmune inflammatory condition? I’m guessing something to stop the inflammation and something to stop the autoimmuneness.

    3) c. Corticosteroids and cyclophosphamide

  3. Sounds like Wegener’s (1-C), which is treated with steroids and cyclophosphamide (3-C). Definitive diagnosis is made by biopsy (2-A). Wikipedia informs me that it is now called granulomatosis with polyangiitis since Friedrich Wegener (not Wegner) was a Nazi, and people tend not to like Nazis. Thanks, Henry.

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