Wendy presented a case of a middle age woman presenting with 4-6 weeks history of cough, shortness of breath, subjective fever and chills, non-improving after three courses of antibiotics. She was treated multiple times for presumed atypical CAP (bilateral infiltrates on CXR), and she presented again with worsening respiratory failure. Her infectious work up so far has been negative. CT Cx revealed bilateral infiltrates mainly in the peripheral lower lung zones.

---

Let’s go over non-resolving pneumonia and “typical pneumonia” for a little bit first.

“Typical” Pneumonia

• Typically see sx improvement within 3-5 days of appropriate tx.
• Vitals and O2 requirement expect to improve in 2 days
• Fatigue and cough may take 2+ weeks to resolve.
• Radiographic improvement usually takes weeks to months to clear up

If your patient is not improving within an expected time frame, then it’s time to broaden that differential! (The following are just some suggested ddx to consider)

Non-infectious causes (20% of the time)

• Neoplasm:
  • Bronchogenic carcinoma, endobronchial obstruction secondary to mass effect, lymphoma
• Inflammatory:
  • Vasculitis: GPA, pulmonary alveolar hemorrhage
  • Eosinophilic pneumonia
  • Acute interstitial pneumonia
  • Bronchiolitis obliterans organizing pneumonia (BOOP) or cryptogenic organizing pneumonia (COP)
    • Subacute, 75% of pts have sx < 2 months prior to diagnosis, flu like presentation initially mimicking an atypical pneumonia, patchy infiltrates also mimics pneumonia on chest radiograph.
  • Sarcoidosis
  • Connective tissue disease
  • Rare: Pulmonary alveolar proteinosis, plastic bronchitis
• Drug-induced: Amiodarone, nitrofurantoin, chemo
• PE
• Pulmonary edema in abnormal lung architecture i.e. severe bullae seen in COPD patients.

Infectious causes

• Streptococcus pneumoniae PNA: responsible for most cases of non-resolving infectious causes due to complications, i.e. multi-lobar involvement, drug resistance, co-morbidities.
• Legionella
• Mycoplasma pneumoniae
• Chlamydia pneumoniae
  • Risk factors: SNF, military recruits
• Haemophilus:
  • Risk factors: Elderly, immunocompromised
• TB: Always on the DDx here.
• Fungi: Always on the DDx here.
  • Aspergillus
  • Histo
  • Blasto
  • Cocci
  • Crypto
• Nocardia
• Actinomyces
• PJP (HIV history)
• Löffler’s syndrome
• Complicated infection
  • Abscess (EtOH, poor dental hygiene at risk for anaerobes), might need prolonged course of abx.
  • Empyema: More likely in younger patients and those with illicit drug use

Diagnostic Approach in non-resolving cases of “pneumonia”

• Assess for risk factors for delayed resolution, i.e. age, medical co-morbidities, pneumonia severity, and the pathogen involved.
• If non-resolution, repeat history, assess for clues for atypical pathogen or non-infectious etiology. Ask if you’re treating the right bug if you’re sure that it’s an infectious cause (i.e. fungal?)
• At this point, consider Chest CT and additional tests as needed. If CT is non-diagnostic, consider:
  • Bronchoscopy with BAL +/- transbronchial biopsy
  • CT-guided FNA if e/o LAD or lesion
  • Last resort: Consider surgical lung biopsy

---

Cryptogenic Organizing Pneumonia

Pathophysiology

• Idiopathic diffuse interstitial process affecting distal bronchioles, alveolar ducts + walls leading to alveolar epithelial injury.

Epidemiology

• Unknown! But pts are typically 40-60s, equally reported in M and F.

Risk Factors

• Unclear, condition is not that well understood.

Presentation

• Subacute to chronic cough, dyspnea, fever, malaise, may have an acute flu-like phase followed by a prolonged persistent of milder symptoms.
• Typically diagnosed as CAP but fail to response to empiric abx.
• Most common features:
  • Persistent non-productive cough (72%)
  • Dyspnea (66%)
  • Fever (51%)
  • Malaise (48%)
  • Weight loss (57%)
• Lung exam: Ranging from normal to crackles

Diagnosis

• Labs: Non specific but 50% of pts p/w leukocytosis, and elevated ESR (>100) and CRP are seen in 70-80%
• CXR: Bilateral, patchy infiltrates
• HRCT:
  • Usually reveals patchy air-space consolidations, GGO, small nodular opacities, and bronchial wall thickening. Patchy opacities occur more frequently in the peripheral and lower lung zones.
  • Mediastinal LAD might be present in rare cases
  • Closely resembles chronic eosinophilic pneumonia
• PFT: Restrictive most commonly. DLCO is reduced in majority of cases, indicating gas exchange abnormalities.
• Bronchoscopy + BAL:
  • Findings typically non-specific in COP but mainly done to rule out other etiology.
  • BAL: Might see increased lymphocytes, neutrophils, and eosinophils with lymphocytes predominance.
• Trans-bronchial Lung biopsy: Usually done to ID other disease processes, non-specific findings in COP mimicking ILD.
• Surgical Lung Biopsy: Will need a large sample

Management

• No major RCTS so generally tx decisions are based on guidelines, experience, and case series.
• Mild dz: Observe
• Persistent symptomatic/worsening:
  • Oral glucocorticoids, usually up to 100mg/day but typically 60mg daily starting, x 4- 8 weeks, then taper over 3-6 months.
  • Serial radiographs
  • Failure to response to steroids:
    • Cyclophosphamide can be considered
    • Cyclosporine
    • Rituximab
  • Long term glucocorticoid dependence:
    • Can consider steroid sparing agents i.e. azathioprine (TPMT level!)
  • Severe, respiratory failure: High dose steroids initially then transition to orals.

Prognosis:

• 2/3 of pts respond well to glucocorticoids with complete resolution of sx.
• 1/3 have persistent symptoms and pulmonary abnormalities
• Overall, better prognosis compared to ILD!

---

Take Home Points:

• Typical illness script is a patient (men & women equally) in his/her 40-60s presenting with a chronic pneumonia like clinical picture not improving on antibiotics.
• Chest radiograph with bilateral patchy infiltrates involving small airways/alveoli wall predominantly seen in the lower peripheral lung zones.
• Responds well in most cases to corticosteroids, but most cases will need a prolonged course.
• Check out this article from Chest for more learning!