A Slice of PIE Neal Waechter, MD

Disclosure and Objectives No financial support Present case Discuss approach to case Discuss outcome of case

Case 30 year old woman with chronic cough HPI: 10 weeks ago: first “asthma exacerbation” (mild exercise-induced asthma for years), reports to urgent care (Visit #1) Symptoms: Cough Moderate to severe dyspnea Fever 101 Fatigue/malaise Treatment: nebulizer Advair inhaler

Case HPI 8 weeks ago: Return to urgent care still feeling ill (visit #2) Symptoms still febrile (101) still dyspneic despite using Advair as prescribed cough now productive of green, sometimes dark brown sputum Treatment Amoxacillin x 10 days

Case HPI 5 weeks ago: Return to urgent care with same complaints (Visit #3) Symptoms Improved very slightly after amoxacillin, but promptly returned to previous levels Persistent fever, productive cough, dyspnea Treatment Azithromycin x 5 days

Case HPI 1.5 weeks ago: Return to urgent care with persistent symptoms (Visit #4) and new chest pain Symptoms Unchanged fever, cough, dyspnea, no help from azithromycin New onset of sharp left-sided pleuritic chest pain, thought she broke a rib Diagnostic tests CXR – “patchy airspace disease in RUL, suspicious for pneumonia” Treatment Augmentin 875 BID x 10 days

Case HPI 1 week ago: Follow-up with PCP (Visit #5) Symptoms: unchanged Exam: Temp 100.2 Diffuse wheezing Treatment Continue antibiotics Resume Advair Follow-up CXR in one week

Current Visit: Follow-up abnormal CXR HPI Current Visit: Follow-up abnormal CXR Symptoms: Still intermittent fever up to 101 Chest pain has largely resolved Dyspnea, productive cough continue w/o hemoptysis

ROS Negative leg pain, h/o DVT/PE (VQ performed 2 years ago during pregnancy for chest pain was negative), arthralgia, rash, dysuria, GI symptoms Positive for mild myalgias, occasional headaches

Case PMH Mild intermittent/exercise-induced asthma, long history Allergic rhinitis Migraine Depression SH Non-smoker One child age one, currently breastfeeding Work – case manager and social worker in Geriatrics, currently not working Exposure History No known exposure to TB, last PPD April 2002, negative No birds, exotic pets No recent travel FH: Mother had DVT when bedridden with acute viral hepatitis GM had DVT, unknown risk factor Allergies: Cephalexin Meds: Albuterol, Pirbuterol, Advair

Case Exam 230 pounds, BP 110/80, HR 76, T 96.7 Appeared comfortable, no resp distress Decreased breath sounds upper right posterior lung field, egophony Normal percussion and tactile fremitus No wheezes or rales No clubbing or cyanosis Normal ENT, lymph node, cardiovascular, abdominal, musculoskeletal, skin

Case CXR (IMAGE)

What next? What are the likely possibilities? What can we not miss?

Initial Thoughts – “Can’t Miss” Atypical infectious pneumonias Fungal TB/mycobacterial Collagen Vascular Diseases Vasculitis (esp. Churg-Strauss) Cancer Venous Thromboembolism and other embolic disease

Initial Plan Diagnostics CBC: WBC 12.7, Hgb 13.3, Plt 315 ESR: 50 CRP: 2 Chem: Cr 0.7, ALT 26 UA: Sp gr >1.030, 2-5 wbc, 0-1 rbc, neg dip One sputum for AFB (difficulty producing adequate specimen) pending

Case Summary So Far History of mild intermittent asthma Chronic Cough Dyspnea Intermittent fever Leukocytosis Persistent pulmonary infiltrates on CXR Multiple areas of airspace disease on CT, upper lobe/peripheral predominance

Differential Diagnosis Airway Disorders Asthma CF Pulmonary infections TB Other mycobacteria Fungi Parasites Opportunistic organisms Cancer

Differential Diagnosis Pulmonary vascular disorders Pulmonary embolism/infarction Vasculitis and Pulmonary Renal Syndromes Wegener’s Goodpasture’s Churg-Strauss Environmental/Occupational Lung disease Hypersensitivity pneumonitis

Differential Diagnosis Interstitial Lung Diseases Idiopathic Fibrosing Interstitial Pneumonias UIP (IPF) RB-ILD (DIP) AIP NSIP BOOP Sarcoidosis Collagen Vascular Diseases Amyloidosis Pulmonary Alveolar proteinosis Pulmonary Infiltrates with Eosinophilia (PIE)

“Light bulb” Recall cases of eosinophilic pulmonary syndromes from residency with similar presentation No sig exposure to TB, no evidence of PE, cancer, on CT, no occupational exposures, no sig travel, doesn’t really fit other diagnoses on list Patient has a history of asthma Elevated WBC, but no diff – could this be eosinophilia? Plan: Add differential to yesterday’s blood

On to something… Diff: 2180 eosinophils 6950 neutrophils 3210 lymphs 40 basophils 302 monocytes 2180 eosinophils

PIE Pulmonary Infiltrates with Eosinophilia (PIE) Infections Helminths Loffler’s syndrome (Ascaris, hookworm, strongyloides) Non life cycle pulmonary invasion (paragonimiasis,others) Tropical pulmonary eosinophilia (Wucheria) Sometimes, Coccidiomycosis Rarely, TB Medications/crack cocaine NSAIDS/Salicylates Minocycline Trimethoprim/sulfamethoxazole ABPA Churg-Strauss Idiopathic Hypereosinophilic syndromes Idiopathic eosinophilic pneumonia Acute eosinophilic pneumonia Chronic eosinophilic pneumonia

Coming to a diagnosis ABPA Typically a sino-pulmonary syndrome with prominent sinus symptoms Must have skin prick test or serum IGE/IGG positive for Aspergillus Typical CT finding is widespread proximal bronchiectasis with upper lobe predominance, mucus plugging, and patchy infiltrates/atelectasis In this case… Not entirely ruled out – did not do skin test or serum antibody tests No sinus disease symptoms/signs CT findings not characteristic (does not exclude diagnosis) Possible…

Coming to a diagnosis Churg-Strauss Vasculitis (Allergic granulomatosis and angiitis) Eosinophilic, small arterial and venous vasculitis Asthma in >95% of cases, usually severe requiring chronic corticosteroids Multiple organ involvement (mononeuritis in >70%, skin rash in majority, eosinophilic gastroenteritis in majority) P-ANCA positive in >70% CT may show enlarged peripheral pulmonary arteries, fleeting patchy infiltrates, pulmonary nodules, pulmonary hemorrhage, pleural effusions Pleural effusions are eosinophilic, exudative Gold standard for diagnosis is open lung biopsy In this case… P-ANCA and C-ANCA are negative CT findings are not characteristic Asthma is not severe enough, and there does not appear to be involvement of other organs REJECTED

Coming to a diagnosis Idiopathic Hypereosinophilic syndromes Rare, multi-organ progressive syndromes with high morbidity Chronic peripheral eosinophilia, >1500 for >6 months No identifiable cause (helminths, etc) Significant organ involvement (not benign eosinophilia) In this case… Disease is limited to lungs Relatively benign course Only ~ 2 months of symptoms REJECTED

Coming to a diagnosis Acute eosionphilic pneumonia Less than 7 days of illness at presentation Hypoxemic respiratory failure is common (>50% of patients) Peripheral eosionphilia may be a late finding, but BAL fluid and lung tissue/pleural fluid are highly eosinophilic Radiographic findings are diffuse, patchy infiltrates without a pattern In this case… Symptoms have been present for too long Respiratory symptoms are fairly mild CT findings are not characteristic - in this patient they are peripheral, not random REJECTED

Coming to a diagnosis Idiopathic Chronic Eosinophilic Pneumonia (AKA Carrington’s Disease) Twice as common in women as in men Pre-existent asthma in majority, not necessarily severe No association with cigarettes Syndrome Characterized by Respiratory and systemic symptoms including fever Absence of extrathoracic organ involvement Alveolar and peripheral eosionophilia in nearly all Elevated inflammatory markers in most Elevated serum total IGE levels in majority Pulmonary infiltrates, usually peripheral on X-ray (“photographic negative” of pulmonary edema). While not specific enough to be pathognomonic, this pattern is rare in other diseases. In this case… A good match patient demographic symptoms lab findings x-ray findings

Idiopathic Chronic Eosinophilic Pneumonia Treatment Little research evidence Could not find randomized controlled trials Few prospective case series Several review articles offering expert opinion Expert consensus: uniformly responsive to corticosteroids Prednisone, 40-60mg/day standard initial therapy Gradual taper over 6-12 months Unknown role for inhaled corticosteroids

Idiopathic Chronic Eosinophilic Pneumonia Outcome Nearly complete remission of symptoms expected within a few days of treatment Relapses are the rule as steroids are tapered Perhaps half will require long-term corticosteroids for symptoms Benign course: <5% develop BOOP with pulmonary fibrosis, even fewer with clinically significant fibrosis

Back to the case Patient referred to Pulmonary Clinic once diagnosis became clear Prednisone was initiated at 60mg/day, tapered to 15mg/day over 3 weeks The Advair was continued She felt much better within a few days. Fever completely resolved. CXR improved by 7 days CXR cleared at two months As of 11/4, she has some residual cough and chest tightness, with albuterol rescue 2 - 4 times per week (vast improvement but worse than before the onset of this illness)

Bibliography Up to Date Current Medical Diagnosis and Treatment, 2004 Robbins Pathologic Basis of Disease Marchand, E et al. “Idiopathic Eosinophilic Pneumonia. A Clinical and Follow-up Study of 62 cases.” Medicine. 1998; 77: 299-312 Marchand, E et al. “ICEP and Asthma. How Do They Influence Each Other?” Eur Respir J. 2003; 22: 8-13 Marchand, E et al. “Idiopathic Chronic Eosinophilic Pneumonia.” Orphanet Encyclopedia, updated June 2004.