Tag Archives: Rheumatology


Today we presented a very interesting case of anti-MPO vasculitis with renal biopsy confirming a pauci-immune necrotizing, crescenteric glomerulonephritis.

We first reviewed the common features of small-vessel ANCA associated vasculitides [AAV] -granulomatosis with polyangiitis; microscopic polyangiitis; eosinophilic granulomatosis with polyangiitis:

Common Systemic Signs and Symptoms– fevers, weight loss, arthralgias, malaise

  • Common Organ-Specific Manifestations
    • Kidney
      • Hematuria, proteinuria, AKI caused by GN
    • Skin
      • Purpura caused by leukocytoclasic angiitis in dermal venues and atertioles
    • Abdominal Pain and Fecal Occult Blood
      • From mucosal and bowel wall infarcts
    • Mononeuritis Multiplex from arteritis in peripheral nerves
    • Necrotizing sinusitis from upper respiratory tract mucosal angiitis
    • Pulmonary hemorrhage from alveolar capillaritis
  • Unique Organ-Specific Manifestations
    • GPA has necrotizing granulomatous inflammation seen most commonly in the respiratory tract
    • eGPA has blood eosinophilia and a history of asthma

Classification Systems

We reviewed that renal biopsy is not generally able to distinguish between the various AAVs, but rather will only be ‘pauci-immune’. The diagnosis, like all of rheumatology, truly is a beautiful integration of clinical, serological, and histological.

The 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides clarified nomenclature for us and several important aspects of care has emerged from it.

Serologies in AAV

We know that vascular inflammation is cased by activated neutrophils and monocytes because of ANCAs. These ANCAs bind to a variety of antigens, most notably proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA). PR3 is tightly linked to C-ANCA and MPO to P-ANCA. In relation to our traditional clinicopathological (CPC) diagnoses of MPA, GPA and eGPA, we note the following:


Key takeaways are that not all “MPA, GPA and EGPA” is ANCA+, and when it is, the pattern of antigen-antibody complex is not specific! In other words, in a patient with PR3-ANCA, 75% of the time their CPC diagnosis is GPA but 40% of the time it is MPA. Putting aside the CPC diagnosis for a moment, we see that there are consistent, specific associations between PR3-ANCA/MPO-ANCA and certain clinical manifestations. For example, there is worse renal survival in MPO-ANCA patients and PR3-ANCA has consistently been shown to have a higher relapse rate and mortality rate compared to MPO-ANCA. For now, both systems of identification are useful (a serotype and CPC diagnosis) and in the future, I wonder if treatment will differ between the two. For now, regardless of the serotype of CPC diagnosis of MPA or GPA, the treatment is the same!

Treatment of MPA/GPA (eGPA tx is slightly different)


  • High dose steroids and either cyclophosphamide OR Rituximab (decision is complex and based on side effect profile i.e Rituximab in patients with concerns fertility or alopecia or if previously been on cyclophosphamide)
  • Indications for plasmapheresis include
    • Evidence of pulmonary hemorrhage (some say all, some say those who did not respond quickly to steroids)
    • Rapidly deteriorating kidney function or severe kidney dysfunction
    • Patients who have a concomitantly positive anti-GBM


  • Approx 80% of patients enter remission with induction therapy, but relapses are common (especially with PR3-ANCA serotype and lung or URT disease
  • Either azathioprine, mycophenolate or rituximab
  • Optimal duration not well-established, some say 12 months after remission is attained, followed by a gradual reduction

Source: National Kidney Foundation’s Primer on Kidney Diseases 7th ed, Gilbert & Weiner, 2018

UpToDate- https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-initial-immunosuppressive-therapy?

Anti-HMGCR Immune-Mediated Inflammatory Myositis

Today we discussed a fascinating case of statin-related anti-HMGCR positive immune-mediated inflammatory myositis (also called necrotizing autoimmune myositis). The case highlighted the importance of a framework approach to diseases.

We first went over the framework for true muscle weakness, which can be anatomically divided as follows


Source: Frameworks for Internal Medicine (Dr. Andre Mansoor from OHSU). Available on Amazon (highly recommended!)

To help us localize the lesion to a myopathy, we used the following framework to determine that it was likely a myopathy.


The differential for myopathy is broad, and generally is the same for an elevated CK and non-traumatic, non-exertional rhabdomyolysis. The causes can be divided as follows. If you like mnemonics, think Drug-REGIIME for the various categories.


Once we narrowed the differential to an inflammatory myopathy, we utilized the following chart that guided us to the probable conclusion that it was an immune-mediated necrotizing myopathy (also known as necrotizing autoimmune myopathy). This was confirmed by a highly positive anti-HMGCR antibody


Adapted from a NEJM Article: https://www.nejm.org/doi/full/10.1056/NEJMra1402225

Clinical Pearls about INMN/NAM:

  • Can occur in association with viral infections, malignancy, in patients with CTD such as scleroderma or in patients taking statins
  • Can start acutely or sub-acutely with severe proximal muscle weakness and markedly elevated CK values of between 10-100k ULN (2K-20K)
  • A rare diagnosis, but some experts believe that polymyositis is overdiagnosed and that INMN may actually be more common!
  • Two antibodies are highly specific though not sensitive for the condition (anti-SRP and anti-HMGCR)
  • The majority of anti-HMGCR positive cases are related to known exposure to a prescribed statin (~70%)
  • Treatment is to discontinue the statin but most cases will require prompt immunosuppression
    • Statin-induced muscular events are on a spectrum, and include the following:
      • 1) Mildly elevated CK and myalgias
      • 2) Rhabdomyolysis
      • 3) Self-limited toxic myopathy
      • 4) IMNM
    • It is only IMNM that generally does not improve with merely cessation of the drug and it generally needs immunosuppression
  • Biopsy is required to make the diagnosis but the presence of the antibody will often result much more quickly and in our case, the patient started on immunosuppresion prior to the biopsy results because the clinical profile fit perfectly with this diagnosis

Scleroderma, maybe!

Thanks to Paige for presenting the case of a middle aged homeless man who presented with heart failure exacerbation, found to have digital ischemia and subsequently diagnosed with scleroderma and likely contribution from cocaine-induced Raynaud’s!

Clinical Pearls

  • Break digital ischemia down to its culprit vessels to help you formulate a DDx: large, medium, and small (see below)
  • Raynaud’s phenomenon can be primary (idiopathic) or secondary to autoimmune conditions, hematologic disorders, drugs/toxins, environmental factors, or hypothyroidism.
  • Treatment of Raynaud’s involves avoiding known triggers, calcium channel blockers, and phosphodieterase inhibitors.
  • Three antibodies are associated with scleroderma: anti-centromere (limited cutaneous systemic sclerosis), anti-Scl70 (diffuse cutaneous systemic sclerosis), and anti-RNA polymerase III (diffuse cutaneous systemic sclerosis).  Patients with the latter antibody are more likely to develop scleroderma renal crisis.
  • Avoid steroids in patients with scleroderma because they can precipitate renal crisis!

Digital Ischemia

Large vessel

  • Atherosclerosis
  • Arterial dissection
  • Takayasu
  • Thoracic outlet

Medium vessel

  • Thromboangiitis obliterans (Buerger’s disease)
  • PAN
  • Hypercoagulability (APLS, DIC)
  • Scleroderma
  • Endocarditis
  • Trauma
  • Post-surgical

Small Vessel

  • Lupus
  • Scleroderma
  • Cryoglobulinemia
  • Other connective tissue diseases
  • Hypercoagulability
  • Endocarditis
  • Paraproteinemia
  • Polycythemia
  • Disfibrinogenemia
  • Trauma
  • Frostbite
  • Post-surgical

Raynaud’s Phenomenon:

  • Exaggerated vascular response (vasospasm) to cold temperature or emotional stress, manifested by discomfort and sharply demarcated color changes of the skin of the digits.
  • Primary Raynaud’s: Those without a definable cause, idiopathic
    • Onset is 15-30 years
    • More common in women
    • Occurs in multiple family members
    • Higher prevalence in people with fibromyalgia and migraines though unclear linkage.
  • Secondary Raynaud’s: There is a cause
    • Autoimmune rheumatic diseases
      • Systemic sclerosis, SLE, MCTD, sjogren’s, DM/PM
    • Drugs/toxins: cocaine, amphetamines, chemo (cisplatin, bleomycin)
    • Hematologic abnormalities: cryoglobulinemia, cold agglutinin disease, paraproteinemia, POEMS, cryofibrinogenemia
    • Occupational/environmental: vascular trauma, use of vibrating tools, frostbite, CTS
    • Hypothyroidism


  • Localized
    • Morphea
    • Linear scleroderma
  • Systemic cutaneous
    • Limited:
      • Face, hands, feet
      • 10-15% of patients may develop pHTN, ILD, or CREST
      • >70% survival at 10 years
      • Anti-centromere antibody
    • Diffuse
      • Early and significant renal, ILD, GI, and myocardial disease
      • Survival 50-60% at 10 years
      • Anti-Scl70
      • Anti-RNA polymerase III

Screen for malignancy in patients with new diagnosis of scleroderma!

Extracutaneous disease:

  • Pulm:
    • ILD (75%)
    • Pulmonary HTN (10-40%)
    • Lung cancer
  • GI (90%):
    • Esophageal dysmotility (GERD-like symptoms)
  • Renal:
    • Scleroderma renal crisis (15%)
  • MSK:
    • Inflammatory arthritis (rare)
  • Vascular:
    • Digital ischemia,
    • Pulmonary HTN,
    • Scleroderma renal crisis
    • MI
    • GAVE


  • Avoid steroids (it can precipitate scleroderma renal crisis)
  • Biologics: modest benefit to slow progression/severity of complications if started early in disease course
  • Otherwise, treatment is organ based

BONUS Thromboangiitis obliterans (Buerger’s disease)

  • Nonatherosclerotic, segmental, inflammatory disease that affects the small to medium-sized arteries and veins of the extremities
  • Usually young smokers
  • Associated primarily with tobacco products but cannabis arteritis has also been reported and is clinically indistinguishable.
  • Can present with superficial thrombophlebitis, Raynaud’s, digital ischemia, other organ ischemia (cerebral, coronary, internal thoracic, renal, and mesenteric arteries), or joint complaints.
  • Work up
    • Labs to rule out other similar disorders:
      • Acute phase reactants
      • Immunologic panel – ANA, RF, complements, anticentromere antibody, anti-scl70
      • Complete hypergoabulability screen
      • Tox panel for cocaine, amphetamines, and cannabis
    • ABI: a normal ABI does not rule out this disease because vessel occlusion could be limited to distal vasculature. Could perform digit plethysmography or toe pressures to confirm.  Abnormal test is not specific to TAO.
    • Vascular imaging:
      • MRA or CTA may not provide sufficient spatial resolution for the distal digits so it’s best to image the entire aorta and upper and lower extremities for evidence of disease that has not yet clinically manifested itself.
      • Angiographic findings would be similar to patients with cocaine, amphetamine, or cannabis ingestion related digital ischemia.
    • DDx
      • PAD: usually only in lower extremities as opposed to both upper and lower.
      • Thromboembolic disease
      • Vasculitis
      • Repetitive trauma
    • Treatment:
      • Smoking cessation
      • Intermittent pneumatic compression for lower extremities.
      • Vasodilators
        • IV prostaglandins (iloprost) à best studied but not very practical because it’s a 6 hour daily infusion
        • Phosphodiesterase inhibitors (cilostazol, sildenafil, tadalafil)
        • CCB (nifedipine)
      • Outcomes:
        • Largest series of 224 patients who stopped smoking had a vascular event-free survival of 41% at 5 years and 23% at 10 years.
          • Amputation free survival was 85, 74, and 66% at 5, 10, and 15 years

Takayasu Arteritis!

Thanks to Eric for presenting the case of a young woman who presented with acute onset of night sweats, chest pain, and fatigue on subacute symptoms of cough and unintended weight loss, with CT chest showing mediastinal fatty infiltration which turned out to be thickening of the aortic arch and descending arteries consistent with Takayasu arteritis!

Clinical Pearls 

  • The two main large vessel vasculitides are Giant Cell arteritis (GCA) and Takayasu arteritis.
  • Takayasu primarily affects young women with the greatest prevalence of disease noted in Asia.  GCA primarily affects older patients (>50 years).
  • There is no diagnostic test to help with diagnosing Takayasu arteritis and for obvious reasons, biopsy is usually not possible.  Some diagnostic criteria have been established to help (see below) and imaging tends to be the most helpful.

Takayasu Arteritis

  • Epi
    • Takayasu is a rare, chronic vasculitis of unknown etiology and primarily affects the aorta and its primary branches.
    • Women are affected in 80 to 90 percent of cases, with an age of onset that is usually between 10 and 40 years.
    • Though it has a worldwide distribution, the greatest prevalence is in Asia.
  • Classification criteria have been developed for Takayasu as a means of categorizing patients for research studies.  Rule in the diagnosis if at least three of the following are present:
    • Age at disease onset ≤40 years
    • Claudication of the extremities (tends to happen later in the disease course and after systemic symptoms of fever and malaise have already started)
    • Decreased pulsation of one or both brachial arteries aka “pulseless disease”
    • Difference > 10 mmHg in SBP between arms
    • Bruit over one or both subclavian arteries (as in our patient!) or the abdominal aorta
    • Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities, not due to arteriosclerosis, fibromuscular dysplasia, or other causes
  • Imaging of the arterial tree by MRA or CTA is important to help with diagnosis, evaluate the arterial lumen, mintor disease course, and decide on need for surgical intervention.
  • Disease can be limited or extensive at diagnosis (see image below) and tends to recur over time (as opposed to GCA which doesn’t usually recur).  Poor prognostic indicators include significant arterial narrowing at presentation or fibrosis (inflammation is reversible but fibrosis is irreversible).  Arterial wall thickening alone (in the absence of luminal narrowing) has an unknown impact on prognosis.
  • The mainstay of treatment is immunosuppression with steroids (typically 40-60mg prednisone daily for average weight adult).  Some small studies show added benefit with the addition of disease modifying agents.

    Angiographic classification of Takayasu
    Arteriographic classification of Takayasu .  Red indicates area of disease activity.  Dotted line represents the diaphragm: https://doi.org/10.1371/journal.pone.0145855.g001
  • Differential Diagnosis of Takayasu
    • Atherosclerosis
    • Fibromuscular dysplasia (look for string of beads on imaging!)
    • Behcet’s disease
    • Giant cell (temporal) arteritis (GCA)
    • IgG4-related disease
    • Infectious aortitis
    • Other diseases that can present with large-vessel vasculitis/aortitis such as Cogan’s syndrome, relapsing polychondritis (can cause aortic and mitral regurg), and spondyloarthropathies

Adult Onset Still’s Disease

Thanks to Dr. Szumowski for sending us the case of a middle aged man who presented with acute L knee swelling and pain one week after a viral URI syndrome, initially concerning for septic joint.  His clinical course was complicated by recurrent high daily fevers, a diffuse maculopapular rash, and knee arthrocenteses and joint washes that were clean leading to a diagnosis of Still’s disease!

Clinical Pearls

  • Still’s disease is a diagnosis of exclusion! Yamaguchi criteria can help with ruling in the diagnosis.
  • Still’s remains a multi-systemic disorder of unknown etiology because it’s difficult to diagnose and rare (0.16 cases per 100,000).
  • RF and ANA are generally negative but can be positive in <10% of patients with Still’s in low titers.
  • ~66% of patients present with sore throat secondary to cricothyroid perichondritis or aseptic nonexudative pharyngitis.
  • The disease is often recurrent. Predictors of poor outcome include erosive polyarthritis on presentation and shoulder/hip involvement.

Still’s disease:

  • Described in 1897 by George Still, it is a systemic inflammatory disorder of unknown etiology
  • Some clarifications on nomenclature:
    • Systemic juvenile idiopathic arthritis (sJIA): first presentation <17 years old, previously referred to as Still’s disease
    • Adult onset Still’s disease (AOSD): first presentation  > 17 years old
  • Epidemiology of AOSD:
    • 0.16 cases per 100,000
    • No sex predominance (F=M)
    • Bimodal age distribution with peak between 15-25 and another 36-46 years of age.  New diagnosis in patients >60 have been reported.
  • Etiology:
    • Poorly understood but likely a combination of genetic predisposition, environmental triggers (viruses such as echo, coxsackievirus B4, mycoplasma, yernisnia, lyme, etc), activated innate immunity leading aberrant production of pro-inflammatory cytokines
  • Diagnostics:
    • High ESR and CRP
    • Very high ferritin levels
    • Ultimately a clinical diagnosis so it’s important to exclude potential mimickers
      • Yamaguchi criteria are the most sensitivity (93.5%)
      • Fautrel’s Criteria are the most specific (98.5%)Diagnostic criteria
  • Treatment
    • Largely empirical since clinical trial data is lacking
    • High dose steroids are first line when systemic symptoms predominate
    • MTX is second line
    • NSAIDs are not good
    • Biologic agents for refractory cases (IL1 antagonist anakinra or canakinumab), IL6 antagonist tocilizumab, or TNF inhibitors.
  • Course:
    • Monocyclic pattern (systemic single episode)
    • Polycyclic pattern (multiple episodes, usually <1 /year)
    • Chronic pattern (persistently active disease with poly arthritis)

      AOSD patterns
      Giacomelli, R. et al. Journal of Autoimmunology. 2018
  • Prognosis:
    • Poor prognostic indicators:
      • Hip and shoulder involvement
      • Erosive polyarthritis at initial diagnosis

Hydralazine-induced ANCA associated vasculitis!

Thanks to Jen for presenting the case of a middle-aged lady with h/o HTN on hydralazine and PE noted to have progressively worsening glomerulonephritis and a discoid skin rash, with anti-MPO and anti-histone antibody positive serologies concerning for drug-induced ANCA associated vasculitis!

Clinical Pearls

  • Many cases of drug-induced lupus are actually drug-induced ANCA vasculitis!
  • Medications associated with drug induced ANCA-vasculitis include hydralazine (most common and most severe presentation), followed by methimazole/PTU, and minocycline.
  • Drug-induced vasculitis tends to present with anti-histone antibody positivity (sensitive but less specific).  Drug-induced ANCA vasculitis can be anti-MPO positive especially in the case of hydralazine.
  • Treatment involves witholding the offending agent.  In the case of hydralazine induced ANCA-vasculitis, steroids and additional immunosuppressive therapy (cytoxan or rituxan) are also indicated to reduce progression to ESRD.


  • Severity:
    • >500 eos ⇒ eosinophilia
    • > 1500 eos ⇒ severe eosinophilia
    • > 5000 eos ⇒ severe eosinophilia at risk of end organ damage
  • Etiology (NAACP-P)
    • Neoplasms
      • Monoclonal leukemias (eosinophil proliferation)
      • Polyclonal: T cell lymphomas, Hodgkin lymphoma, some solid organ tumors (cervical, ovarian, gastric, colon, urotherlial, and squamous cell carcinomas)
    • Allergies
    • Adrenal insufficiency (super rare)
    • CTD
      • EGPA, RA
    • Parasites/bugs
      • Parasites: remember that only multicellular parasites can cause eosiniphilia
      • Other bugs: ABPA, cocci, HIV
    • Primary eosinophilic syndromes

Drug-induced lupus:

  • M:F is 1:1 but hydralazine induced lupus is more common in women
  • Mechanism is poorly understood and genetic predisposition may play a role. More likely to happen in patients who are slow acetylators
  • Autoantibodies:
    • Anti-histone antibodies: 95% sensitive
    • Other antibodies are uncommon
  • Drugs: long list!
    • Procainamide, hydralazine, chlorpromazine, quinidine, minocycline, PTU, statins, anti-TNF agents, IFN, methyldopa
    • Weaker associations: AEDs, antimicrobials, beta blockers, lithium, HCTZ, amiodarone, cipro etc.
  • Treatment:
    • Stop offending agent
    • Joint symptoms: NSAIDs
    • Skin symptoms: topical steroids
    • Hydral-induced vasculitis: need cytotoxic or other immunosuppressive therapy. Treatment similar to ANCA positive vasculitis
  • Prognosis:
    • Resolution of symptoms weeks to months

Drug induced ANCA positive vasculitis:

  • Patients typically present with constitutional symptoms, arthralgias/arthritis, and cutaneous vasculitis
  • Strongest association with hyperthyroidism meds, hydralazine, and minocycline (hydral is the most common)
  • Rare, but should be aware of this association because it impacts management and because it is often not diagnosed until too late in the disease course.  In fact, many cases of drug induced lupus are actually drug induced ANCA-associated vasculitis
  • In a small case series of hydral-induced ANCA-associated vasculitis of 10 patients, 90% had renal involvement of whom 7 recovered at 6 month follow up (though one required HD).
    • Hydralazine-induced ANCA vasculitis is generally p-ANCA pattern with anti-MPO positivity (might also have anti-lactoferrin or anti-elastase)
    • Treatment involves immunosuppression with steroids and cytoxan or rituxan.
  • Non-hydralazine drug-induced ANCA vasculitis is typically treated with stopping the offending agent and has a better prognosis than its hydralazine-induced counterpart. In fact, ANCA positivity without clinical vasculitis is common especially in cases involving PTU.

Culture Negative Endocarditis 5/7/2019

We recently had a case of a middle age man with SLE on chronic prednisone, ESRD on PD, presenting with acute on chronic shoulder pain x 10 days. Presentation was initially concerning for septic arthritis, and joint washout revealed gross purulence from the shoulder joint. Cultures were sent but no additional fluid studies were obtained.

A subsequent TTE, and later a TEE, confirmed a mitral valve vegetation concerning for concurrent infective endocarditis. However, multiple sets of blood cultures, fungal cultures, synovial fluid culture from the initial I&D/wash out, and even 16S PCR of the synovial fluid were all negative. This is a rare case of culture negative endocarditis which is later thought to be more likely Libman Sacs!

Septic Arthritis

  • Epidemiology
    • Risk factors: Advanced age, pre-existing joint dz, recent surgery or injection, SSTI, IVD, indwelling catheter, immunosuppression.
    • Most cases arise from hematogenous seeding, hence bacteremia is common.
    • Direct inoculation: usually due to trauma, surgery/injections, or wounds.
  • Microbiology
    • Usually mono-microbial, and Staph aureus is the most common cause of septic arthritis in adults.
    • GNR can be seen in older adults or in immunocompromised patients
  • Presentation
    • Monoarthritis is most common
      • Edematous, painful, warmth, limited ROM
      • Older patients may not be febrile
    • 20% of cases can present as oligoarticular or polyarticular infection. Polyarticular septic arthritis is more likely to occur in pts with RA
    • Most common affected joint is the knee
    • Could be a manifestation of infective endocarditis, esp amongst IVDU
  • Diagnosis
    • Synovial fluid analysis and culture, should be obtained prior to abx
    • Positive gram stain or culture is gold standard and diagnostic
      • PCR only required in rare cases since most non-gonococcal cultures obtained prior to antibiotics return positive. Negative cultures can result due to recent abx or atypical organism.
    • In pts with purulent synovial fluid (WBC 50k-150k) but culture negative, a presumptive dx can be made.
      • Likelihood of septic arthritis inc with inc leukocyte count
    • Blood cultures should be obtained
    • Should also evaluate for endocarditis given most common organism is staph aureus
    • Imaging:
      • Always get a radiograph to evaluate for concurrent bone/joint involvement
      • CT/MRI can be useful if looking for an effusion
  • DDx
    • Infectious
      • Gonococcal arthritis
      • Lyme disease
      • TB arthritis
      • Viral (usually polyarticular), i.e. Zika, Dengue, chikungunya, parvo, rubella, adenovirus
    • Non-infectious
      • Crystal dz
      • Reactive arthritis
  • Management
    • Joint drainage, severe infectious may require repeated aspiration or even wash out.
    • Abx
      • Most cases are staph, MRSA cases on the rise
      • Suspect pseudomonas if pt is immunocompromised or has h/o IVDU
      • Intra-articular abx: typically not used
      • Duration:
        • Staph aureus with bacteremia: At least 4 weeks
        • Staph aureus without bacteremia: at least 14 days IV, followed by 1-2 weeks PO
        • Bone involvement: 4-6 weeks
        • Any organisms, any bone involvement: 4-6 weeks
        • Other organisms: Typically at least 4 weeks

Culture Negative Endocarditis

  • Definition: Endocarditis without an identified organism in at least 3 independent blood cultures with negative growth after 5 days
  • Epidemiology
    • 2-7% of IE cases
    • 3 most common causes:
      • Previous abx
      • Inadequate samples
      • Atypical organisms (fastidious bacteria i.e. zoonotic microbes, fungal)
  • Microbiology
    • Farm animal exposure: Brucella, Coxiella (Q-fever)
    • Homeless: Bartonella Quintana
    • Cat: Bartonella hensale
    • Ingestion of unpasteurized milk: Brucella, Coxiella
    • Immunocompromised: Fungi, Coxiella
    • HACEK: Most common agents of culture negative endocarditis
      • Haemophilis aphrophulus
      • Actinobacillus
      • Cardiobacterum hominis
      • Eikenella corrdens
      • Kingella
  • Diagnosis
    • PCR, histology, special cultures are helpful.
    • PCR
      • 16S Ribosomal DNA: Bacteria
      • 18S Ribosomal DNA: Fungi
  • Non-infectious DDx
    • APLS, associated with Q fever
    • Acute rheumatic fever
    • Atrial myxoma
    • Libman Sachs endocarditis (non-bacterial thrombotic endocarditis or NBTE)
      • Seen in:
        • SLE
        • Advanced cancer
        • Hypercoagulable state
    • Vasculitis
    • Mural thrombus

NBTE (Non-bacterial thrombotic endocarditis)

  • Epidemiology
    • Rare affected all age group with no sex preference, most commonly 40s – 80s
    • Most commonly associated with pts with concurrent SLE or advanced malignancy (lung cancer, pancreatic cancer, gastric cancer)
    • Other associated conditions: APLS, rheumatic heart disease, RA.
  • Pathophysiology
    • A form of non-infectious endocarditis characterized by deposition of thrombi on halve valves, most commonly mitral or aortic
  • Presentation
    • Usually asx but high risk of thromboembolic events
    • May present with acute stroke or coronary ischemia
  • Diagnosis
    • Exclusion: Demonstration of vegetations on echo in absence of systemic infection in patients with risk factors.
  • Management
    • Systemic anticoagulation
      • Clinical experience and retrospective studies had shown this is beneficial due to high rate of emboli in pts with NBTE
    • Treat underlying condition
    • Surgery
      • Surgical excision for NBTE vegetation, can be considered in only selective cases and generally avoided.

Hypersensitivity Pneumonitis Secondary to… Oyster Mushrooms 4/29/2019

Today we went over a case from the HumanDx Project (Credit goes to Dr. Maki Cronin, SSM Health St. Louis University Hospital). A young woman presents with 5 months of cough, dyspnea, and unintentional weight loss over the past 5 months in setting of working at an in-door oyster mushroom farm for the past 8 months. She was tachycardic and febrile on presentation, with crackles and clubbing on exam. CT revealed e/o fibrosis and GGO, and BAL revealed significant lymphocytosis. This presentation is consistent with a diagnosis of hypersensitivity pneumonitis, and more specifically, mushroom worker’s lung!

Hypersensitivity Pneumonitis (HP)

This condition has many faces/names:

  • Bird fancier’s lung (feathers, bird droppings)
  • Cheese-washer’s lung (Cheese Fancier per Sarasa)
  • Coffee worker’s lung
  • Compost lung (aspergillus)
  • Farmer’s lung (moldy hay)
  • Hot tub lung (hot tubs)
  • Mushroom worker’s lungs (mushroom)
  • Sauna worker’s lungs (contaminated sauna water)
  • Wine-grower’s lung (moldy grapes)


  • 300 known antigens so far, most common (accounting for 75%) are:
    • Farming
    • Birds
    • Water contamination


  • Hypersensitivity to an environmental antigen leading to a type IV hypersensitivity reaction (they love asking these questions on tests for some reason) in genetically susceptible patients
    • Type 1: IgE mediated, immediate onset (min to hours)
      • Ex: Food allergies, PCN allergy, insect sting
    • Type 2: Cytotoxic hypersensitivity, Ab-mediated cell destruction
      • Drug induced cytopenias, Graves thyroiditis
    • Type 3: Immune complex formation
      • Ex: serum sickness, Arthus reactions, vasculitis, drug fever
    • Type 4: Cell-mediated delayed hypersensitivity
      • Activation of T-cells
      • Hours or days after antigen exposure
      • Ex: Tuberculin sensitivity, contact dermatitis, HP
  • Interstitial inflammation and infiltration with lymphocytes, later on granulomas and fibrosis develop over time


  • Acute:
    • Occurs in sensitized pts with high level antigen exposure
    • Fever, chills, cough, chest tightness, dyspnea, nausea 4-8 hours after exposure
    • Exam: Tachypnea, inspiratory crackles, no wheezing
  • Chronic:
    • Occurs in pts with long-term low-level exposure
    • Months to years onset of exertional dyspnea, cough, fatigue, weight loss
    • Clubbing, fevers are uncommon but can happen
    • Over time: Pulmonary fibrosis, resp failure
  • Subacute:
    • Falls between acute and chronic forms


  • A combination of clinical suspicions with exposure history, with assistance of imaging
  • CXR: Neither sensitive nor specific, may show reticular or nodular opacities
  • HRCT: typically shows profuse centrilobular nodules, predominantly GGO, more chronic exposure will lead to fibrosis, traction bronchiectasis
    • Mosaic pattern with areas of GGO is classic
    • More chronic picture leads to fibrosis, which can lead to traction bronchiectasis
    • Bronchiectasis is a chronic condition where the walls of the bronchi are thickened from inflammation and infection.
  • PFT: Can be obstructive, restrictive, or mixed. Obstruction more commonly seen in chronic.
  • BAL: Very sensitive but non-specific.
    • BAL lymphocytosis (often greater than 50%) is helpful but non-specific. Can also see lymphocytosis in COP and NIP but not this high.
  • Biopsy: Rarely done
  • Antigen-specific immunoassays: very high false positive rate, role unclear.


  • Corticosteroids, usually pred 60 1-2 weeks, then tapered over 2-4 weeks for acute/subacute cases
  • Chronic: Longer course of prednisone
  • Remove from environmental exposure ASAP


  • Reversible if detected early and antigen exposure is eliminated
  • Chronic: leads to fibrosis, which is NOT reversible.

Crowned Dens Syndrome!

Thanks to Eric and Naina for presenting the fascinating case of an elderly man who presented to the ER with acute, progressive shoulder and neck pain/stiffness that started after a visit to the dentist, found to have Crowned Dens Syndrome (???!!!) on CT imaging!

Clinical Pearls

  • The exam maneuvers we use to determine nuchal rigidity (neck stiffness, Kernig, Brudzinski signs) are not sensitive for meningitis.  Kernig and Brudzinski, when present, are highly specific.  Jolt accentuation is more useful as a screening tool because it is highly sensitive (>90%) but not very specific (~60%).
  • Make sure to check out Beers list when prescribing new meds for our geriatric patients.
  • For patients presenting with traumatic neck pain, consider using NEXUS or Canadian C spine rules to help you determine whether CT imaging is necessary.
  • Crowned Dens Syndrome is a rare finding in patients with CPPD and refers to deposition of calcium pyrophosphate crystals in and around the atlanto-axial articulation, which resembles a crown on CT imaging (image here).
  • The knee accounts for 50% of all acute CPPD flares.

Nexus criteria

  • No indication for CT if all of the following criteria are met
    • Absence of posterior cervical spine tenderness
    • Normal level of alertness
    • No evidence of intoxication
    • No abnormal neurologic findings
    • No painful distracting injuries

Canadian C-spine Rule

  • Step 1: CT indicated if any of the following are present:
    • Age > 65 years
    • Dangerous mechanism of injury
    • Paresthesias in the extremities
  • Step 2: Assess for low risk factors that allow for safe examination of the cervical spine range of motion
    • Simple rear-end mechanism
    • Sitting position in the ED
    • Ambulatory at any time
    • Delayed onset of neck pain
    • Absence of midline cervical spine tenderness
    • If ALL of these are present proceed to step 3
  • Step 3: Examine range of motion
    • Test active range of motion
    • Perform radiography in patients who are not able to rotate their neck actively 45 degrees both left and right. Patients able to rotate their neck, regardless of pain, do not require imaging


  • Umbrella term that covers
    • Pseudogout: acute synovitis/flare
    • Chondrocalcinosis: radiographic calcification in hyaline and/or fibrocartilage
    • Pyrophosphate arthropathy
  • Epi
    • 4-7% of adults
    • ~50% of those with radiographic findings are >84 years of age
  • Clinical manifestations
    • Asymptomatic (majority)
    • Acute CPP crystal arthritis: self limited acute or subacute attacks of arthritis involving one or several extremity joints. Knee is affected in over 50% of all acute attacks followed by wrists, shoulders, ankles, feet, and elbows.
      • Triggers: Trauma, surgery, severe medical illness. Abnormalities in serum calcium, magnesium, bisphosphonates, hemochromatosis.
    • Chronic CPP arthritis
      • Chronic inflammatory arthritis (5% of cases): resembles RA, multiple joints involved
      • Chronic osteoarthritis: Most prevalent form of symptomatic disease.
    • Severe joint degeneration
    • Spinal involvement
      • Crowned dens syndrome: rare, characterized by severe acute or recurrent axial neck pain, neck and shoulder girdle stiffness, and associated fever, elevated inflammatory markers, and CPP or calcium phosphate crystal deposition on CT in and around the atlanto-axial articulation
        • DDx would include PMR, Milwaukee shoulder (deposition of hydroxyapatite crystals, commonly seen in women >70 years of age) less frequently meningitis, cervical discitis, or inflammatory spondyloarthritis
        • Favorable response to NSAIDs and colchicine

IgG4 related disease!

Thanks to John for presenting the case of a middle aged man from Vietnam with history of smoking who presented to the hospital with painless jaundice with imaging concerning for malignancy, found to have IgG4 related autoimmune pancreatitis!

Clinical Pearls

  • For imaging of the biliary tree:
    • Ultrasound is best for stones
    • CT is better for parenchymal disease
    • ERCP/MRCP is best for intraductal masses or stones
  • IgG4 related disease is more common in men >50 years of age.  It can affect many organs, similar to sarcoid.
  • It is an inflammatory and fibrotic systemic conditions where organs form tumefactive lesions rich in IgG4 plasma cells.
  • Diagnosis requires biopsy.  Serum IgG levels may be normal even in active disease.  However, a significantly elevated level is highly sensitive/specific (>95%) for IgG4 related disease.
  • Treatment involves steroids + immunomodulating therapy.

Approach to high bilis!

conjugated hyperbili

unconjugate hyperbili

DDx for painless jaundice:

  • Cancer (pancreatic, cholangiocarcinoma)
  • Meds/toxins
  • Viral hepatitis
  • ESLD
  • CHF
  • Hemolysis

IgG4 related disease

  • First described in 2003
  • Majority men (62-83%) and > 50 years of age.
  • Inflammatory and Fibrotic systemic condition where organs have tumefactive (tumor forming) lesions with an infiltrate rich in IgG4 plasma cells and often elevated IgG4 serum levels (but not always!)
  • The pathophys is poorly understood but thought to be a combination of autoimmune and allergic mediated processes.

Clinical features:

  • Subacute onset, typically few systemic signs/symptoms
  • 30% of those with autoimmune pancreatitis also have tubulointerstitial nephritis at presentation.
  • Pancreatic involvement 
    • Manifestations include a uniformly enlarged pancreas (sausage pancreas on imaging), pancreatic mass which can mimic cancer, recurrent pancreatitis, or strictures.
  • Biliary involvement
    • Biliary strictures leading to obstructive jaundice as well as sclerosing cholangitis
  • ANY organ can be affected (eg: thyroiditis, interstitial nephritis, salivary involvement), much like sarcoid

Spectrum of IgG4-related disease

IgG4 spectrum
Source: UpToDate


  • Need tissue biopsy for diagnosis.  Serum serologies are only suggestive.


  • Steroids + immunomodulating therapy.  

Chronic pancreatitis

Etiologies of Chronic Pancreatitis (progressive inflammatory changes in the pancreas that result in permanent structural damage and histologic fibrosis)

  • Alcohol abuse(45%) as well as cigarette use
  • Recurrent acute pancreatitis
  • Genetic (eg: CFTR, SPINK mutations)
  • Chronic ductal obstruction
  • Systemic diseases (eg: SLE, hyperparathyroidism, hypertriglyceridemia)
  • Idiopathic
  • Autoimmune: Can be Type 1 (part of IgG4 related disease) or Type 2 (idiopathic) 

Clinical manifestations of chronic pancreatitis

  • Epigastric abdominal pain most common symptom however
  • Pancreatic insufficiency (only after 90 %of pancreatic function lost) and manifests as steatorrhea and glucose intolerance/diabetes
  • Remember that chronic pancreatitis puts you at increased risk for PANCREATIC CANCER


  • Amylase/Lipase usually NORMAL so not as helpful
  • 72 hour quantitative fecal fat (steatorrhea alone is non-specific!)
  • Fecal elastasehas high sensitivity and specificity for chronic pancreatitis
  • KUB can show calcificationshinting towards chronic pancreatitis and MRCP/ultrasound can show pancreatic duct obstructions, dilations, strictures or fluid collections


  • Alcohol and smoking cessation!
  • Creon supplementation, may also need fat-soluble (A,D,K,E) supplementation
  • Analgesics for abdominal pain which is extremely hard to control. Minimize opioids but may be necessary for refractory pain.
  • Specialized approaches include celiac nerve blocks, endoscopic surgery and surgical resection