Background

• >500 eos/microL is considered abnormal
• Mild (500-1500); moderate (1500-5000); severe (>5000)
• Hypereosinophilic syndrome: >1500, with target organ damage (i.e. eosinophilic gastroenteritis, myocarditis, neuropathy) without an identifiable cause
• Primary hypereosinophilic syndrome: myeloproliferative neoplasm that produces mature eos
• Levels of blood eos are labile. Sustained elevated levels should prompt work-up and monitoring for organ-associated damage (i.e. heart, lung, kidney, skin, nerves, blood vessels).
• Target organ damage is unusual in mild eosinophilia.

Differential Diagnosis

• The degree of eosinophilia rarely helps in identifying the cause except at extremes (very mild associated w/ asthma & allergic rhinitis, >20k/microL associated w/ myeloid neoplasm)
• Infection, meds, allergy, and hypersensitivity disorders (i.e., asthma, urticaria, eczema) account for >95% of cases.
• Acquired
• Allergy/immunology: atopic dermatitis, asthma (<1500), rhinitis, DRESS
• CV: hypersensitivity myocarditis (incl. Loffler’s), atheroemboli
• Derm: atopic dermatitis, episodic angioedema with eosinophilia, Kimura disease, eosinophilic fasciitis/cellulitis/panniculitis/folliculitis, recurrent cutaneous necrotizing eosinophilic vasculitis
• Endocrine: adrenal insufficiency (cortisol stimulates eosinophil apoptosis)
• GI: eosinophilic esophagitis/gastroenteritis
• Infectious: helminthes (hookworm and schisto esp in returning traveler most common, and strongy, toxocariasis, trichellosis, filariasis), amoebiasis, aspergillosis (ABPA), cocci, HIV (typically 2/2 OI)
  • Acute bacterial or viral infection tend to decrease eos. Therefore it is unlikely that a patient with eosinophilia and fever has a bacterial or viral infection.
• Med/toxin: sulfa derivatives, anticonvulsants, antibiotics, ASA, NSAIDs, anti-rheumatics, allopurinol, food allergy (almost any drug or remedy can cause eosinophilia)
• Neoplastic: Primary hypereosinophilic syndrome, Acute eosinophilic leukemia (variant of AML, immature eos in peripheral smear), Chronic eosinophilic leukemia, CML, systemic mastocytosis, lymphomas, some solid tumors (typically adeno)
• Neuro: hypereosinophilic syndromes, EGPA (mononeuritis multiplex), eosinophilic meningitis
• Pulm: allergic rhinitis, asthma, eosinophilic pneumonia, chronic rhinosinusitis, EGPA
• Renal: AIN, dialysis
• Rheum: eosinophilic granulomatosis with polyangiitis (EGPA). Rare but seen in DM, RA, Sjögren’s, IBD, sarcoid, granulomatosis with polyangiitis, SLE, Bechets, IgG4.

Idiopathic

• Hypereosinophilic syndromes (<1% of cases) (heterogeneous group, Males>>Females, most are likely clonal)
• Chronic idiopathic eosinophilia: persistent elevation w/o organ damage and neg w/u and stable clinical course

Familial (rare, autosomal dominant)

Evaluation (Determine presence/degree of organ involvement and the etiology)

• Acutely ill or very elevated eos count (e.g. >100k): admit
• Outpatient with organ involvement: typically workup can be carried out as outpatient but will likely need referral to specialist of the organ involved or to hematologist
• Otherwise healthy, completely incidental: outpatient workup

All-Comers:

• History: pertinent ROS includes weakness, fevers, fatigue, rhinosinusitis, cough, SOB, CP, dysphagia, GERD sx, diarrhea, rash (pruritus, nodules, angioedema), myalgia, LAD. Must review prior eos counts, medication history (and OTCs), travel, occupational, dietary hx
• Physical exam: targeted to look for evidence of end-organ involvement: skin (most common organ involved; look forrash, urticaria, angioedema), HEENT (watery discharge, swollen conjunctiva, pale/bluish nasal mucosa), lung (adventitious sounds), GI, heart (cardiomyopathy), and nervous system (peripheral neuropathy, rarely meningitis or CNS vasculitis)

Diagnostics: (no evidence-based guidelines)

• Get further eval for:
  • Any patient with >1500eos/microL on 2 labs spaced apart by >1-2 weeks
  • >500/microL and sx/signs of organ involvement or travel to parasite endemic area
• Peripheral smear, CMP, UA, trop, B12, strongy serology, flow cytometry for lymphocyte subsets, CXR, tryptase (seen in mastocytosis and myeloid HES)
• Select patients when suspicion of specific diagnosis is high: bone marrow, IgG subtypes, ANCA, cortisol testing, stool O&P x3, HIV, HTLV-1, serologies for specific parasites, CT (lymphoma, solid tumors, vasculitis), tissue biopsy
• Consider cessation of offending medication if drug-induced is suspected

Note: Up to 50 percent of asymptomatic traveler w/ eosinophilia do not have a cause identified despite exhaustive work-up

When to refer:

• Eosinophilia (>1.5 x 10⁹/L) persisting for >3 months with no obvious cause or rising levels should be referred to hematology. Specific organ involvement (referral to that specialist)

Follow-up caveats

• For patients with severely elevated eos (e.g. >100k), urgent therapy with high dose steroids should be initiated after collecting lab workup and discussion with hematology.
  • Those with potential exposure to strongy should be treated empirically with ivermectin before starting high-dose steroids.
• There is no consistent time course to expect resolution of eosinophilia following cessation of offending medication.
• For patients with milder forms of primary eosinophilia (e.g. < 1500/microliter) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken.

Weller PF, Klion AD. Approach to the patient with unexplained eosinophilia. UpToDate. May 3, 2016.

Weller PF, Klion AD. Eosinophil biology and causes of eosinophilia. UpToDate. Dec 5, 2017.

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Background

• >10% total WBC, usually >500-800 absolute value
• Often occurs with neutrophilia

Differential Diagnosis (reactive vs. clonal)

Reactive:

• Infectious (most common cause): TB, syphilis, brucella, listeria, rickettsiae, typhoid, malaria, trypanosomiasis, VZV, subacute bacterial endocarditis
• Inflammatory: lupus, RA, sprue, PMR, GCA, PAD, sarcoidosis, ITP, IBD, ACS
• Other: pregnancy, post-splenectomy, neutropenia and bone marrow recovery, hemolytic anemia (and sickle cell), ITP, depression, corticosteroids, colony-stimulating factors, ziprasidone, radiation tx, cutaneous myeloid dendritic cell dyscrasia

Clonal:

• Neoplastic: Hodgkin’s and non-Hodgkin’s lymphoma, CMML, MDS/MPN, CML, AML, solid tumors (carcinoma)

Evaluation

• Exam: particular attn. to LAD, organomegaly, constitutional sx, infectious sx

Diagnositics

• Smear (maturity, dysplasia). Note: smear abnormal lymphocytes like hairy cells & sezary cells can be called monocytes on auto analyzer
• Look for associated cytopenias or elevated differential counts (Neutropenia or atypical lymphocytosis can be seen with viral infxn)
• If e/o dysplasia or blasts on smear -> flow cytometry, immunohistochemistry, heme c/s and bone marrow bx
• If sustained monocytosis on repeat testing after investigation for reactive causes is negative, then proceed with heme c/s and likely marrow bx

Lynch DT, Hall J, Foucar K. How I investigate monocytosis. Int J Lab Hematol. 2018;40(2):107-114.

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Background

• Serum AG = [measured cations] - [measured anions] ≈ [Na] - ([Cl] + [HCO3]) = [unmeasured anions] - [unmeasured cations]
• Normally 6±3, primarily determined by negatively charged proteins (80% of which is albumin)

Differential Diagnosis

• Lab error (most common)
• Hypoalbuminemia [∆AG= 2.5(4-[Albumin])]
• Severe Non-gap hyperchloremic metabolic acidosis
• Increases in unmeasured cations: K, Ca, Mg, Li
• Monoclonal or polyclonal gammopathy (in particular IgG)
• Iodine intoxication
• Bromide ingestion/intoxication (component of pyridostigmine, some herbal medications)
• Polymyxin B
• Negative AG: most often due to laboratory artifact in measurement of Na or Cl. Causes include: severe hypernatremia (>170) or overestimation of chloride level 2/2 marked hyperlipidemia, multiple myeloma, intoxication with salicylate, bromide or iodine

Background

• Gamma gap = Total protein – Albumin
• Abnormal if >4g/dL
• Elevated gamma gap is always abnormal and should be investigated
• Overproduction of any non-albumin serum protein (i.e. fibrinogen in chronic inflammation or transferrin in severe iron-deficiency anemia)
• Majority is from excess immunoglobulins (mono- or polyclonal)
• Elevated gamma gap has been associated with increased mortality.

Differential Diagnosis

1. Monoclonal gammopathy: (NB: present in up to 8 percent of healthy geriatric patients)

• Plasma/B-cell disorders: most commonly multiple myeloma or MGUS, but also caused by solitary plasmacytoma, Waldenström macroglobulinemia, AL amyloidosis, CLL, non-Hodgkin’s lymphoma, Castlemans, POEMS, post-transplant
• Inflammatory: SLE, RA, Sjögrens, scleroderma, psoriatic arthritic, PMR
• Infectious: HCV, HIV
• Other: pyoderma gangrenosum, acquired vWD, acquired C1-esterase inhibitor deficiency, cryoglobulinemia, myelodysplastic syndrome and others

2. Polyclonal gammopathy: polyclonal expansion in immunoglobulins – caused by anything that stimulates a sustained inflammatory response

• Liver: cirrhosis, chronic hepatitis (infectious or non-infectious) 
• Infectious: chronic infection, HIV, TB, mono, malaria, endocarditis, osteo
• Inflammatory: SLE, RA, sarcoidosis, Sjögrens
• Neoplastic/Heme: non-Hodgkin’s lymphoma, lymphoproliferative disorders, solid tumors, thalassemia
• Other: chronic pulmonary disease, Graves/Hashimotos, IBD, idiopathic
• In one study, etiology of polyclonal gammopathy was: liver disease 61%; connective tissue disease 22%; chronic infection 8%; hematologic disorders 5%; and, non-hematologic malignancy 3%. 

Evaluation

• SPEP: Screens for M-protein (monoclonal protein) and calculates its concentration if present. A polyclonal increase in immunoglobulins appears as a broad based peak.
• Serum immunofixation (IFE): more sensitive than SPEP and characterizes heavy and light chain type of the monoclonal protein but doesn’t give concentration (i.e.IgG kappa).
• Free light chains (FLC): 16 percent of multiple myeloma produces only Bence Jones proteins (free light chain that is not bound to a heavy chain). Can replace 24-hr UPEP as screening for MM. NB: elevated in renal insufficiency (GFR<60)
• UPEP/ urinary IFE: must be from a 24hr urine collection sample. All patients with a plasma cell dyscrasia should have baseline UPEP. Its use in screening has been largely obviated by FLC.
• If M-protein is >2.5g-3.0g, patient should have a Ca, Cr, IFE, UPEP/FLC, bone survey, possibly a bone marrow aspirate and abdominal CT (if suspecting Waldenström), and a referral to Hematology.. 
• NB: M-protein may cause other laboratory artifact, including low HDL, high bilirubin, and inaccurate PO4 level.

Juraschek SP, Moliterno AR, Checkley W, Miller ER. The Gamma Gap and All-Cause Mortality. PLoS ONE. 2015;10(12):e0143494.

Dispenzieri A, Gertz MA, Therneau TM, Kyle RA. Retrospective cohort study of 148 patients with polyclonal gammopathy. Mayo Clin Proc. 2001;76(5):476-87.

   Rajkumar SV. Laboratory methods for analyzing monoclonal proteins. Mar 19, 2018.

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Elevated bicarbonate

Differential Diagnosis

Primary metabolic alkalosis: 

• Loss of gastric secretions (loss of HCl from vomiting, NGT suction)
• Laxative abuse
• Diuretics (loop and thiazide)
• Mineralocorticoid excess
• Hypokalemia
• Compensatory response to chronic respiratory acidosis (i.e., COPD, OHS, chronic opioids)
• Bartter and Gitelman sydromes (also see concomitant hypokalemia)
• Contraction alkalosis
• Hypoalbuminemia
• Post-hypercapnea: seen when a patient with chronic respiratory acidosis is placed on ventilator. Should administer chloride to correct hypochloremia and allow bicarb wasting.
• Hypercalcemia and the milk-alkali syndrome
• Rapid infusion of alkali fluid: bicarbonate, acetate, lactate, citrate (>8 units blood), FFP
• Crack-cocaine use in dialysis patient

Emmett M, Szerlip H. Causes of metabolic alkalosis. UpToDate. Nov 6, 2017.