Loefflers syndrome differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Overview

Loeffler syndrome must be differentiated from other diseases that cause pulmonary eosinophilia, such as Churg-Strauss, drug and toxin-induced eosinophilic lung diseases, other helminthic and fungal infection related eosinophilic lung diseases, and nonhelminthic infections such as Coccidioidomycosis, and Mycobacterium tuberculosis.

Differentiating Loeffler syndrome from other pulmonary eosinophilia syndromes on the basis of etiology.

Diseases Clinical manifestations Para-clinical findings Additional findings
Symptoms Physical examination
Lab Findings Imaging Histopathology
Increased Eosinophil

count

Other lab findings CXR CT Scan
Helminthic

and fungal infection-related

eosinophilic lung diseases

Transpulmonary

passage of larvae (Loffler's syndrome)

  • Cough
  • Sputum production
  • Wheezing
  • Fever
  • Crackles
  • Mild to moderate
  • Usually 5-20%
  • Stool exam
  • Parasites and ova can be found in the stool 6-12 weeks after the initial parasitic infection.
  • Immunoglobulin E (IgE) level
  • Might be elevated.
  • Round or oval opacities (several millimeters to several centimeters)
  • In both lungs
  • Generally present when blood eosinophilia exceeds 10%
  • Migratory
  • May become confluent in perihilar areas
  • Generally clear spontaneously
  • Areas of ground-glass opacity (halo) around consolidation
  • Nodules
  • Dilated airways within the lesion
  • Bronchoscopy and bronchoalveolar lavage
  • May show increased eosinophilic count.
  • Sputum analysis or gastric lavage
  • May occasionally show Larvae of Ascaris or the other parasites with pulmonary cycle.
  • Ascaris lumbricoides
  • Hookworms such as:
  • Ancylostoma duodenale
  • Necator americanus)
  • Strongyloides stercoralis
Tropical

pulmonary

eosinophilia

  • Cough
  • Breathlessness
  • Fatigue
  • Fever.
  • Wheezing
  • Crackles
  • 40 to 70 percent (>3000/microL) plus elevated IgE levels ( >1000 units/mL)
  • Serum IgE levels
  • Antifilarial antibodies
  • Diffuse opacities
  • Around 20% of patients have a normal CXR
  • Reticular and small nodular opacities
  • Bronchiectasis
  • Air trapping
  • Calcification
  • Mediastinal adenopathy
  • Wuchereria bancrofti
  • Brugia malayi
  • The diagnostic criteria for tropical pulmonary eosinophilia include:
    • a history supportive of exposure to lymphatic filariasis;
    • a peripheral eosinophilia count greater than 3 × 109/L);
    • an elevated serum IgE levels (> 1000 kU/L);
    • increased titers of antifilarial antibodies;
    • peripheral blood negative for microfilariae; and
    • a clinical response to diethylcarbamazine.
Allergic bronchopulmonary aspergillosis
  • Repeated episodes of:
  • Bronchial obstruction, inflammation
  • Mucoid impaction
  • Can lead to:
  • Bronchiectasis
  • Fibrosis
  • Respiratory compromise
  • Clinical picture of ABPA is dominated by underlying asthma (or cystic fibrosis)
  • Bronchial obstruction
  • Fever
  • Malaise,
  • Expectoration of brownish mucous plugs
  • Peripheral blood eosinophilia
  • Hemoptysis
  • Wheezing
  • Fever
  • Crackles
  • Wheezing
Mild to moderate
  • Immunological tests for Aspergillus
  • Sputum staining and sputum cultures
  • Skin test for Aspergillus sp.
  • Early in the disease
  • Normal
  • Changes of asthma.
  • Transient patchy areas of consolidation may be evident representing eosinophilic pneumonia.
  • Late stage
  • Bronchiectasis may be evident.
  • Mucoid impaction in dilated bronchi can appear mass-like or sausage shaped or branching opacities (finger in glove sign).*
  • Pulmonary collapse may be seen as a consequence of endobronchial mucoid impaction.
  • Fleeting shadows over time can also be a characteristic feature of this disease.
  • These opacities usually appear and disappear in different areas of the lung over a period of time as transient pulmonary infiltrates.
  • HRCT:
  • Widespread proximal cylindrical bronchiectasis with upper lobe predominance and bronchial wall thickening.
  • Central bronchiectasis with normal tapering of distal bronchi (classic manifestation of ABPA, neither sensitive nor specific)
  • Asthmatic bronchiolitis, eosinophilic pneumonia, bronchocentric granulomatosis, and mucoid impaction of bronchi
  • +/- bronchocentric granulomatosis (pulmonary eosinophilia in the absence of endobronchial fungi)
  • Minimal criteria include:
  • The presence of asthma and/or cystic fibrosis,
  • A positive skin test to Aspergillus sp., an IgE > 417 IU/mL (or kU/L)
  • An increased specific IgE or IgG Aspergillus sp. antibodies
  • The presence of infiltrates on a chest X-ray
Heavy

hematogenous

seeding

with

helminths

  • Depends on the organism for example:
  • Periorbital edema, myositis, and eosinophilia (Trichinellosis)
  • Depends on the organism for example:
  • Periorbital edema
  • Tenderness in muscles
  • Fever
  • (Trichinellosis)
Mild to

moderate to

high

  • Trichinellosis: Ab will be positive 2-8 weeks after infection
  • Strongyloides: ELISA is generally positive while stool examination is often negative.
  • Strongyloides:
  • Diffuse ground glass opacities
  • Miliary nodules,
  • Reticular opacities
  • Airspace opacities ranging from multifocal to lobar distribution.
  • Adult respiratory distress syndrome :If widespread air space shadowing is seen on chest radiography
  • Rarely: granulomatous changes leading to pulmonary fibrosis.
  • Transient nodular or diffuse pulmonary infiltrates on the chest x-ray
  • Spontaneous pneumothoraces have been described infrequently.
  • Similar to Loeffler syndrome
  • Ascarids and hookworms
  • Trichinellosis
  • Disseminated strongyloidiasis
  • Cutaneous and visceral larva migrans
  • Schistosomiasis
  • Prior treatment with glucocorticoids may be a risk factor.
Pulmonary parenchymal invasion
  • Fever
  • Crackles
  • Wheezing
  • Eosinophilia is prominent in the early stages of disease but minimal with established disease
  • Ab testing Useful in later infection with Paragonimus
  • Nodular with surrounding areas of ground glass
  • Peripheral
  • Common in the mid- and lower lung zones
  • Nodular with surrounding areas of ground glass
  • Peripheral
  • Common in the mid- and lower lung zones
  • Finding eggs in the sputum or bronchoalveolar lavage fluid
  • Helminths such as paragonimiasis
Nonhelminthic infections Coccidioidomycosis
  • Manifests as a community-acquired pneumonia (CAP) approximately 7 to 21 days after exposure
  • Fever
  • Crackles
  • Wheezing
  • Nail clubbing
  • Mild
  • Antibody testing may be negative early in the course of disease
  • Polymerase chain reaction (PCR)
  • Rarely demonstrate nodules or cavities in the lungs, but these images commonly demonstrate lung opacification, pleural effusions, or enlargement of lymph nodes associated with the lungs.
  • Computed tomography scans of the chest are better able to detect these changes than chest x-rays
  • Papanicolaou or Grocott's methenamine silver staining. These stains can demonstrate spherules and surrounding inflammation.

Types:

  • Acute coccidioidomycosis, sometimes described in literature as primary pulmonary coccidioidomycosis
  • Chronic coccidioidomycosis
  • Disseminated coccidioidomycosis, which includes primary cutaneous coccidioidomycosis
Mycobacterium tuberculosis
  • Cough
  • Weight loss
  • Fatigue
  • Night sweating
  • Sputum production
  • Fever
  • Chills
  • Mild
  • Quantiferon gold
  • Positive PPD
  • Elevated ESR
  • In active pulmonary TB, infiltrates or consolidations and/or cavities are often seen in the upper lungs with or without mediastinal or hilar lymphadenopathy.
  • Old healed tuberculosis usually presents as pulmonary nodules in the hilar area or upper lobes, with or without fibrotic scars and volume loss.
  • Bronchiectasis and pleural scarring may be present.
  • Ziehl-Neelsen stain, or fluorescent stains such as auramine
  • Caseating granulomas containing Langhans giant cells, which have a "horseshoe" pattern of nuclei.
  • Culture in Lowenstein-Jensen, and solid agar-based such as Middlebrook 7H11 or 7H10
  • Tuberculosis can involve almost every organ in human body such as skin, renal, glands, eyes, neurons, etc.
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
  • Sinusitis
  • Asthma,
  • Skin, cardiovascular, gastrointestinal, renal, and neurologic systems may also be involved.
  • Fever
  • Crackles
  • Wheezing
  • 1500 cells/microL
  • > 10 percent of the total leukocyte count
  • Antineutrophil cytoplasmic antibodies (ANCA)
  • Myeloperoxidase (MPO) perinuclear staining pattern
  • Transient and patchy opacities without lobar or segmental distribution
  • lung biopsy:
  • Eosinophilic infiltrates
  • eosinophilic vasculitis (especially of the small arteries and veins)
  • Interstitial and perivascular necrotizing granulomas
  • Areas of necrosis
  • Skin, cardiovascular, gastrointestinal, renal, and neurologic systems may also be involved.
Drug- and toxin-induced eosinophilic lung diseases
  • Asymptomatic pulmonary infiltration with eosinophils
  • Chronic cough with or without dyspnea, fever, acute eosinophilic pneumonia, and
  • DRESS:
  • Skin eruption
  • Fever, Facial edema
  • Enlarged lymph nodes
  • History of initiation of a culprit medication two to six weeks prior to disease onset
  • Fever
  • Crackles
  • Wheezing
  • Mild to moderate
  • Eosinophil fraction >25% in the BAL fluid
  • Bilateral peripheral infiltrates with segmental consolidation
  • Diffuse reticular or interstitial findings
  • Diffuse ground-glass infiltrates
  • Wandering peripheral consolidations
  • Pleural effusion
  • Eosinophil fraction >25% in the BAL fluid
  • Medications such as:
  • Nonsteroidal antiinflammatory drugs
  • Phenytoin
  • L-tryptophan
  • Antibiotics (nitrofurantoin, minocycline, sulfonamides, ampicillin, daptomycin)
  • Toxins such as:
  • Aluminum silicate and particulate metals •Sulfite •Scorpion stings •Inhalation of o heroin, crack cocaine, or marijuana •Inhalation of organic chemicals, dust or smoke, during rubber manufacture, fireworks, firefighting, tobacco smoking •Abuse of 1,1,1-trichloroethane (Scotchgard)
Chronic eosinophilic pneumonia
  • Predominantly in women and nonsmokers
  • Following radiation therapy for breast cancer
  • Cough, fever, progressive breathlessness, weight loss, wheezing, and night sweats; asthma accompanies or precedes the illness in 50 percent of cases
  • Fever
  • Crackles
  • Wheezing
  • ≥40 percent
  • Eosinophilia may be absent in 10-20% of patients
-
  • Bilateral peripheral or pleural-based infiltrates described as the "photographic negative" of pulmonary edema is virtually pathognomonic for the disease (in 33% of cases)
  • Pleural effusion
  • Cavitation
  • BAL eosinophilia ≥25 percent is suggestive of CEP.
  • Nodular bronchial mucosal lesions
  • Necrotizing eosinophilic inflammation
  • Lung biopsy:
  • Interstitial and alveolar eosinophils and histiocytes, including multinucleated giant cells
  • Fibrosis (minimal)
  • Organizing pneumonia (common)
-
Idiopathic acute eosinophilic pneumonia
  • Acute respiratory failure in a previously healthy patient
  • Acute febrile illness of less than seven days' duration, characterized by:
  • Nonproductive cough
  • Dyspnea,
  • Fever
  • Crackles
  • Wheezing
  • ≥25 percent
-
  • Non specific but might reveal
  • Diffuse pulmonary opacities on imaging
  • Bronchoalveolar lavage that reveals ≥25 percent eosinophils
  • When the diagnosis is uncertain lung biopsy is recommended:
  • Histopathologic findings include:
  • Diffuse alveolar damage
  • Hyaline membranes
  • Marked numbers of interstitial and lesser numbers of alveolar eosinophils
  • Often associated with recent initiation or resumption of cigarette smoking
  • Less commonly with heavy inhalational exposure to smoke, fine sand, or dust
Diseases Symptom Physical exam Increased Eosinophil count

(High)

Other lab findings CXR CT Scan Histopathology Additional findings
Sarcoidosis
  • Mild to moderate
  • Angiotensin-converting enzyme
  • Chitotriosidase
  • Soluble interleukin-2 receptor
  • Hypercalcemia
  • Kveim test
  • Honeycombing
Like tuberculosis, sarcoidosis can involve almost every organ in human body such as skin, renal, glands, eyes, neurons, etc.
Pulmonary Langerhans cell histiocytosis (Histiocytosis X)
  • Crackles
  • Wheezing
  • Mild to moderate
  • CD1a +ve
  • S100 +ve
  • CD207 (langerin) +ve
  • Low urine specific gravity (1.008)
  • Low specific gravity persisted during a water deprivation test
  • Urine osmolality and urine specific gravity normalize following desmopressin administration
  • Mild hyperinflation
  • Coarse reticular interstitial markings
  • Peripheral ring shadows suggesting cysts formation
  • Head CT scan may be helpful in the diagnosis of Langerhans cell histiocytosis.
  • Findings on head CT scan suggestive of Langerhans cell histiocytosis include:
  • Multiple osteolytic lesions
  • Full thickness bone destruction
  • “Button sequestrum” sign
  • Electron microscopy Langerhans cell histiocytosis is characterized by Birbeck granules, which are electron dense, cytoplasmic, tennis racket-like bodies.
  • Immunohistochemistry
  • CD1a +ve
  • S100 +ve
  • CD207 (langerin) +ve
  • On Tc 99m MDP whole body bone scintigraphy, Langerhans cell histiocytosis is characterized by an increased uptake of Tc 99m at hitiocytic lesion located around the ribs, spine, and pelvis.
Idiopathic pulmonary fibrosis
  • Crackles
  • <10 percent

Abnormal arterial blood gas (ABG)

Pulmonary function test

  • Peripheral reticular opacities, more common on the base of lungs
  • Honeycomb appearance of the lower lobes
  • Measurement of static lung volumes using body plethysmography or other techniques typically reveals reduced lung volumes (restriction). This reflects the difficulty encountered in inflating the fibrotic lungs.
  • The diffusing capacity of carbon monoxide (DLCO) is invariably reduced in IPF and may be the only abnormality in mild or early disease. Its impairment underlies the propensity of patients with IPF to exhibit oxygen desaturation with exercise.

References

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