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

Scleroderma 

  • 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

Management:

  • 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

Journal Club!

Quick rundown of the articles we talked about today in morning report:

  1. ANDROMEDA-SHOCK trial, JAMA 2019: RCT of 424 patients with septic shock randomized to capillary refill vs lactate to target resuscitation efforts.  Primary outcome of interest was 28 day mortality.  While the difference between the two groups was not statistically significant, the study may have been underpowered.  Interestingly, there were lower rates of organ dysfunction at 72 hours with the cap refill guided resuscitation than lactate.  So keep doing your cap refill bedside exam!
  2. E-cigarettes vs nicotine-replacement therapy (NRT): Multi-center RCT in the UK that randomized 886 people to e-cigarettes or NRT of their choice for 3 months.  Outcome of interest was abstinence from smoking at 6 months and 1 year.  They found a significantly higher rate of abstinence in the e-cigarette group than the NRT group.  However, while only 9% of the abstinent NRT users were still using NRTs at 1 year, over 80% of the abstinent e-cigarette users were still using e-cigarettes at the end of the study period!  Together with the alarmingly high incidence of e-cigarette use amongst adolescents, the results of this study would have to be interpreted cautiously.
  3. EAGLES trial. Lancet. 2016: Multi-center, double-blind, RCT looking at neuropsychiatric effects of varenicline (Chantix), bupropion, or nicotine patch or placebo involving ~4k people without psych history and 4k people with psychiatric history.  Study found that Chantix resulted in the highest rates of sustained abstinence across all study arms.  In the psychiatric cohort, there were no differences between the treatment groups in terms of rates of psychiatric events. Bottom line: use Chantix whenever you can to help your patients trying to quit smoking!
  4. EXTEND trial. NEJM. 2019: Multi-center, randomized, placebo-controlled trial of 225 patients who presented with ischemic stroke within 4.5-9 hours after onset of symptoms with radiologic evidence of salvageable brain tissue randomized to receive tPA vs conservative management.  The primary outcome of interest was functional status at 90 days and was significantly better for the intervention group vs control arm.  Caveats are that symptomatic intracranial hemorrhage was six times higher in the intervention group than the control arm.  65% of the patients in the study woke up with neurologic deficits and had an unknown time of onset.
  5. Thyroid hormone replacement for subclinical hypothyroidism (Feller et al. JAMA. 2018): Meta-analysis of 21 RCTs with 2192 patients randomized to hormone replacement or no replacement.  The study found no significant difference in qualify of life, thyroid replacement symptoms, fatigure/tiredness, depression, cognition, or SBP after 12 months of therapy.  Based on this study, the new guidelines state that in patients with no symptoms of hypothyroidism or non-specific symptoms of hypothyroidism who have fT4 within normal limits and TSH <20, thyroid hormone therapy is strongly recommended against.

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

Strongyloidiasis

Thanks to the Human Dx Project for providing us with this fascinating case of a middle aged woman with history of asthma who presented with acute onset of fever and epigastric abdominal pain as well as a chronic progressive cough, found to be febrile, tachycardic, and ill appearing, with E coli bacteremia of unknown source.  Further history taking revealed a similar hospitalization several months prior with idiopathic E coli bacteremia.  Strongyloides titers were sent and markedly elevated.  She was treated with ceftriaxone and ivermectin and made a full recovery.


Clinical Pearls: 

  • Absence of eosinophilia does not rule out strongyloides.  Keep in mind that those presenting with severe illness and hemodynamic instability are commonly in a high cortisol state which can lead to eosinophil apoptosis.  Also, in those with history of steroid use (even for short periods of time), eosinophil count can be negative.
  • Think of strongy in anyone with the right travel history, older age, malnutrition, HIV, or steroid use.
  • Signs and symptoms can be quite non-specific so a high index of suspicion is required to make the diagnosis.
  • Think of strongyloides in a patient with history of recurrent GNR bacteremia of unknown etiology!

Strongyloidiasis 

Epidemiology

  • Higher incidence noted going from yellow to orange to red on the map above
  • Epidemiology
    • Typically in travelers to endemic areas, immigrants from endemic regions, or anyone with barefoot contact with infested soil.
    • Risk factors include older age, malnutrition, HIV, and steroid use
  • Signs and symptoms
    • Infected people can be asymptomatic or minimally symptomatic for years:
      • Could also have mild waxing and waning GI, skin, or pulmonary symptoms for years
      • Eosinophilia without symptoms
    • Skin: urticarial, larvae currens (see picture below), angioedema, erythrodermalarvae currens
    • Pulmonary: chronic cough, hemoptysis, recurrent pneumonia, astham that gets worse with steroids
    • GI: upper abdominal pain, duodenitis, diarrhea, anorexia, recurrent enteric GNR bacteremia
    • Disseminated disease/hyperinfection syndrome:
      • Increased parasite burden due to autoinfection (see picture below)
      • Massive dissemination of larvae to lungs, liver, heart, CNS, and endocrine glands
      • Can present with septic shock or multiorgan failure

        Strongy life cycle
        Greaves, D. BMJ 2013; 347:f4610
  • Diagnosis:
    • Stool O&P: <50% sensitive and requires multiple samples due to intermittent shedding
    • Serologies: 89% sensitive
  • Treatment:
    • Ivermectin or albendazole
    • Hyperinfection/disseminated disease: above PLUS broad-spectrum antibiotics

Quick review of endemic dimorphic fungi:

  • Southwest US ⇒ Cocci
  • Ohio & Mississippi River Valley ⇒ Histo
  • Southeast/South-central US ⇒ Blasto
  • Southeast Asia ⇒ Penicillium
  • South America ⇒ Paracocci, histo, blasto, cocci

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.

Eosinophilia

  • 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.

Pneumocystis jiroveci pneumonia with a cavitary lesion 5/8/2019

Credit goes to Dr. Scott Burns from Roper Hospital in Charleston for his case on the Human Diagnosis Project.

Today we discussed a case of a young man with otherwise no medical history presenting with subacute dry cough, malaise, and weight loss. On exam he was septic on presentation with notable oral thrush. CXR revealed bilateral interstitial infiltrates and a RUL cavity with air fluid level which was confirmed on CT. LDH was elevated. He was confirmed HIV positive with a low CD4 count in the single digits, and BAL confirmed the diagnosis of PCP/PJP pneumonia!


Oral Thrush: NEVER assume normal, extremely rare in immunocompetent patients, so if you see this, consider whether the patient could be immunocompromised.


Cavitary Lung Lesion DDX

  • Mycobacteria
    • TB
    • M kansasii
  • Bacterial
    • Pseudomonas
    • Enterobacteriaceae
    • Klebsiella
    • Streptococci
    • Nocardia
    • Anaerobes
    • Staph aureus
  • Fungi
    • Crypto
    • Aspergillus
    • Histoplasma
  • Rare
    • Bacterial: Legionella, rhodococcus
    • Mycobacteria: MAC
    • Fungi: PCP/PJP, mucormycosis, blasto
    • Others: Vasculitis

PCP

Epidemiology

  • Immunocompromised patients
    • HIV with CD4 < 200
    • BMT, organ transplant patients
    • Leukemia/lymphomas
    • Rheumatology conditions
    • Primary immunodeficiencies
  • Rarely occurs in immunocompetent patients

Presentation

  • Typically subacute onset of pulmonary symptoms, non-productive cough, fever chills, malaise, SOB
  • Might have other clues of immunocompromised status

Diagnosis

  • CXR: Classic description is bilateral interstitial infiltrates
    • Rare instances: Lobar infiltration, nodules, cavitary lesions, pneumothorax
  • CT: Higher sensitivity but might not be necessary for the dx
  • LDH: Sensitive but not specific if elevated. An elevated LDH in an HIV patient without other medical co-morbidities that might inc LDH should raise suspicions for PCP
  • Beta D glucan: For HIV patients, good sensitivity, not that specific. If elevated, raises suspicions for PCP.
  • Gold standard: either visualize the organism via induced sputum (yield is variable, variable sensitivity but 100% specific), or via BAL.
  • Can also use 18S PCR

Management

  • First line: TMP-SMZ, 15-20 mg/kg. PO just as good as IV, duration 21 days
  • Sulfa allergy:
    • Mild to moderate: Desensitization
    • Severe: alternative agents
      • Clinda + primaquine
      • Trimethoprim + dapsone
      • Atorvaquone
      • Pentamidine
      • For severe disease, Clinda + primaquine or IV pentamidine is preferred.
    • Adjunctive steroids
      • ABG: If PaO2 < 70, or Aa gradient > 35, or hypoxemia on pulse ox, adjunctive steroid is indicated and has been shown to improve mortality
      • Pred 40mg BID x 5 days, then 40mg daily x 5 days, then 20mg daily x 11 days, total 21 days

Remember your Aa gradient equation!

Aa-gradient = PAO2 (calculated from the alveolar gas equation) – PaO2 (measured PaO2 on ABG)

PAO2 = FiO2 (baromeric pressure – water pressure) – PaCO2/(respiratory quotient)

Assuming sea level and a standard respiratory quotient of 0.8, this equation can be simplified to:

PAO2 = 150 – PaCO2/0.8