Loefflers syndrome differential diagnosis

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		Nothing Cough Dyspnea Chest pain, Ffatigue, malaise, Ffever Weight loss Arthritis	+/- Mild fever Crackles Skin rash, Uveitis Eerythema nodosum	Mild to moderate	Angiotensin-converting enzyme Chitotriosidase Soluble interleukin-2 receptor Hypercalcemia Kveim test	Hilar lymphadenopathy Lung infiltrates Evidences ofpulmonary fibrosis in sever cases	Parenchymal perilymphatic nodules. Honeycombing	Non-caseating granulomas	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)		Bone pain Chest pain Cough Fever Malaise Polyurea Rash Shortness of breath Polydipsia Weight loss	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 Elevated bilirubin concentration Abnormal liver enzymes Elevated alkaline phosphatase Anemia ThrombocytopeniaElevated erythrocyte sedimentation rate Elevated CRP	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	Light microscopy: Clusters of dendritic cells Kidney-shaped nucleus Abundant foamy cytoplasm Fine, granular chromatin pattern Prominent eosinophils Fibrosis Other inflammatory cells may be present (neutrophils, plasma cells, and multinucleated giant cells) 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		Dyspnea Nonproductive cough Clubbing Crackles Pulmonary Hypertension Discomfort in the Chest Fast, Shallow Breathing Unintended Anorexia Fatigue Aching joints and muscles	Crackles	<10 percent	Abnormal arterial blood gas (ABG) May indicate hypoxia, hypercapnia, and respiratory acidosis Pulmonary function test May indicate a restrictive pulmonary disease A FEV1/FVC ratio > 80% indicates restrictive disease	Peripheral reticular opacities, more common on the base of lungs Honeycomb appearance of the lower lobes	Honeycomb appearance of the lungs which are cystic air spaces of different sizes. The cysts are mostly located in the sub-pleural area. Traction bronchiectasis Lung architectural distortion Ground glass opacities Interlobular septal thickening	Proliferation of mesenchymal cells Areas of different fibrosis degree Dense deposition of collagen fibers Overproduction of extracellular matrix Poor differentiated pulmonary architecture Honeycomb cysts (sub-pleural cysts)	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.