Eosinophilic pulmonary syndromes

• Eosinophilic pulmonary syndromes are the family of lung diseases in which eosinophils accumulate in the airspaces or interstitium, producing cough, breathlessness, fleeting shadows and, often, blood eosinophilia.
• The same blood eosinophil can produce very different illnesses depending on what drives it: an allergic fungal reaction in asthma (allergic bronchopulmonary aspergillosis, ABPA), a small-vessel vasculitis (eosinophilic granulomatosis with polyangiitis, EGPA), idiopathic acute or chronic eosinophilic pneumonia, drug hypersensitivity, parasitic infection or a clonal haematological disorder.
• First sort the patient into a category, because management follows from the cause: ABPA needs corticosteroids plus an azole; EGPA needs immunosuppression guided by severity and endotype; acute eosinophilic pneumonia responds to short-course corticosteroids; chronic eosinophilic pneumonia needs longer steroid therapy or biologics; Löffler syndrome and tropical pulmonary eosinophilia need treatment of the parasite.
• Diagnosis usually rests on the combination of peripheral blood eosinophilia, bronchoalveolar lavage (BAL) eosinophilia (at least 5% of cells in general pulmonary eosinophilia; 25% or more in acute, 40% or more in chronic eosinophilic pneumonia) and characteristic CT, with exclusion of infection, drugs and neoplasm.
• Because these conditions mimic one another, a new diagnosis of eosinophilic lung disease should always be followed by a careful drug history, parasite exposure history, ANCA testing and, where appropriate, testing for clonal eosinophilia.

By the end of this page you should be able to:

1. Classify the eosinophilic pulmonary syndromes by mechanism and natural history, including Löffler syndrome, tropical pulmonary eosinophilia, ABPA, EGPA and acute and chronic eosinophilic pneumonia.
2. Explain why peripheral blood eosinophilia, BAL eosinophilia and chest CT are used, and interpret their thresholds.
3. Recognise the clinical and radiological patterns that separate ABPA, EGPA and acute from chronic eosinophilic pneumonia, including the "photographic negative" chest radiograph of chronic eosinophilic pneumonia.
4. Plan the immediate and long-term management of each condition, including drug doses, and the red flags that change treatment.
5. Adapt the approach to low-resource settings and to the parasite-associated disease that is common there.

A useful first sorting separates the syndromes by behaviour and by whether disease is confined to the lung:

• Simple pulmonary eosinophilia (Löffler syndrome). A transient, often self-limited eosinophilic infiltration of the lungs, most frequently associated with parasitic infection; it is milder than the true eosinophilic pneumonias and usually resolves. ^[1]
• Tropical pulmonary eosinophilia (TPE). A hypersensitivity reaction to microfilariae of Wuchereria bancrofti and Brugia malayi, with marked peripheral eosinophilia and pulmonary infiltrates. ^[4]
• Allergic bronchopulmonary aspergillosis (ABPA). A hypersensitivity reaction to Aspergillus fumigatus in patients with asthma or cystic fibrosis, producing eosinophilic mucus, central bronchiectasis and, often, raised IgE.
• Eosinophilic granulomatosis with polyangiitis (EGPA). A systemic, ANCA-associated small-vessel vasculitis whose canonical triad is asthma, eosinophilia and systemic vasculitis, with neuropathy, sinus disease and sometimes cardiac involvement. ^[2]
• Acute eosinophilic pneumonia (AEP). An acute illness (onset within 1 month) resembling severe community-acquired pneumonia or ARDS, usually in young male smokers, with dramatic response to corticosteroids and rare relapse. ^[1]
• Chronic eosinophilic pneumonia (CEP). A subacute illness (symptoms 2 to 4 weeks or more) of older, mostly female, non-smokers with asthma, peripheral consolidations on imaging, peripheral eosinophilia and a relapsing course needing longer treatment. ^[1][6]
• Hypereosinophilic syndrome and clonal disease. Eosinophilia accompanied by organ damage, sometimes from a kinase fusion (for example FIP1L1::PDGFRA), which redirects therapy to imatinib. ^[2]
• Drug-induced eosinophilic pneumonia. Triggered by a wide range of drugs; management is withdrawal of the drug plus corticosteroids. ^[5]

ABPA and TPE are not primarily diseases of the lung interstitium but of allergic reaction to an external antigen (fungus or filarial microfilaria). EGPA is the only member of this list that is a necrotising vasculitis, which is why excluding the others is essential before immunosuppression is started. ^[2]

Pulmonary eosinophilia as a whole is rare, but its components differ markedly in frequency. AEP is uncommon: about 400 cases have been reported and, in military cohorts, the incidence is 9.1 to 11.0 cases per 100,000 person-years. ^[1][5] CEP accounts for 1 to 3% of interstitial lung diseases. ^[1] EGPA is rare, with only several cases per million per year, presenting in the fourth to sixth decades and slightly more often in women. ^[2] TPE is uncommon even where filariasis is common: fewer than 0.5% of the roughly 130 million people infected with filariasis develop it, mainly in the Indian subcontinent and Southeast Asia. ^[4] ABPA affects 1% to 15% of people with cystic fibrosis and about 2.5% of adults with asthma, an estimated 4.8 million people worldwide. ^[3]

Each syndrome has its own trigger profile, which is the single most useful piece of history:

• Löffler syndrome follows parasitic infection most often, but can follow drugs or inhaled allergens. ^[1]
• TPE follows infection with Wuchereria bancrofti or Brugia malayi, transmitted by mosquitoes. ^[4]
• ABPA requires asthma or cystic fibrosis plus sensitisation to Aspergillus fumigatus. ^[3]
• EGPA emerges from severe, late-onset, adult asthma with nasal polyposis and eosinophilia, often with a type 2 inflammatory background; environmental triggers include allergens, infection and, possibly, drugs that modulate the type 2 axis. ^[2]
• AEP is linked to a recent change in smoking (starting, restarting or passive smoking), vaping, inhalational exposures and several drugs. About 31% of cases are smoking-related, 17% drug-induced and the rest idiopathic. ^[1][5]
• CEP occurs in non-smokers, usually with adult-onset asthma and atopy, and may follow drugs or infection. ^[1][6]
• Drug-induced disease has been reported with antibiotics (daptomycin in particular), NSAIDs, SSRIs, immune checkpoint inhibitors, targeted cancer drugs and amiodarone among many others. ^[5]

All of these diseases are driven by eosinophil recruitment and degranulation, but the route differs. In Löffler syndrome and TPE the lung sees a hypersensitivity response to a parasite antigen, with immune-complex and cell-mediated inflammation. ^[4] In ABPA, repeated inhalation of Aspergillus spores in thick asthmatic mucus drives an IgE-mediated type I reaction, with type III and IV components, producing allergic mucin and damage to the bronchial wall. ^[3]

In AEP, airway and epithelial damage may induce interleukin-33, which recruits and activates eosinophils; the result is an ARDS-like picture with eosinophilic infiltrates and, in severe cases, diffuse alveolar damage. ^[1] In CEP, chronic type 2 inflammation with IL-5 and eotaxins maintains eosinophil accumulation; up to 50% of patients have asthma and the disease relapses during steroid taper, suggesting persistent immune drive. ^[1][6]

EGPA combines two inflammatory arms. In ANCA-negative, eosinophil-dominant disease, IL-5 drives eosinophil maturation and degranulation (major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin), producing tissue injury and, characteristically, cardiac, pulmonary and gastrointestinal disease. In ANCA-positive disease (about 30 to 40% of patients, usually MPO-ANCA), neutrophil activation produces necrotising vasculitis of small to medium vessels and pauci-immune glomerulonephritis. ^[2] Eosinophils are the central effectors in both arms, which is why draining the IL-5 axis with mepolizumab or benralizumab is effective. ^[2]

Löffler syndrome is usually mild: transient cough, breathlessness and patchy opacities that clear. TPE presents with paroxysmal cough, wheeze, dyspnoea and nocturnal symptoms that closely mimic asthma; systemic features include fever, weight loss and fatigue. ^[4] IgE is very high, above 1000 IU/mL, and blood eosinophilia is marked (absolute counts in the tens of thousands in published cases). ^[4] About 7% of cases have extrapulmonary manifestations, and thrombosis has been reported as a consequence of eosinophil-mediated hypercoagulability. ^[4]

ABPA presents in a person with asthma or cystic fibrosis who develops worsening asthma, productive cough with thick sputum or plugs, fleeting pulmonary opacities, wheeze and, in advanced disease, central bronchiectasis, finger clubbing and loss of lung function. ^[3] Stages run from acute disease through remission, exacerbation, corticosteroid-dependent asthma and, finally, fibrotic lung disease. ^[3]

EGPA usually evolves in stages over years: severe adult-onset asthma; chronic rhinosinusitis with nasal polyps; then eosinophilia and infiltrates; and finally systemic vasculitis. ^[2] The features that mark the systemic phase are mononeuritis multiplex, palpable purpura, gastrointestinal pain or bleeding, renal disease (especially in ANCA-positive patients) and, importantly, cardiac involvement (myocarditis, pericarditis, mural thrombus), which is a major determinant of survival. ^[2]

AEP mimics severe pneumonia or ARDS: fever, non-productive cough, marked hypoxaemia and bilateral infiltrates developing within days; severe hypoxaemic respiratory failure requiring ventilation is common. ^[1] Blood eosinophilia is often absent at onset and appears later. ^[1]

CEP evolves over weeks to months with cough, dyspnoea, low-grade fever, night sweats, malaise and unintentional weight loss. ^[1][6] Asthma is present in about 50 to 90% of patients, usually adult-onset and often worsening after CEP begins. ^[1][6] Frank respiratory failure is rare. ^[1]

The eosinophilic syndromes mimic one another and many common diseases. A table of separation:

CEP must be separated carefully from EGPA. CEP is lung-limited, ANCA-negative, and has characteristic peripheral consolidations; systemic vasculitis (neuropathy, purpura, glomerulonephritis, cardiac disease) points to EGPA. ^[2][6] ABPA is separated by raised Aspergillus-specific IgE/IgG, very high total IgE and central bronchiectasis. ^[3] HRCT and, when needed, BAL or biopsy clarify the diagnosis. ^[1][2]

Peripheral blood eosinophilia is defined as more than 500 cells/uL in most references (some use above 0.5 x 10^9/L). ^[1][6] In general pulmonary eosinophilia, BAL eosinophils above 5% of the differential is abnormal; in AEP the diagnostic threshold is 25% or more, and in CEP 40% or more. ^[1] BAL eosinophilia can be lower if corticosteroids have already been given, so sampling before treatment is important. ^[1]

HRCT is the imaging standard. In AEP it shows ground-glass opacities, interlobular septal thickening, pleural effusion (in 60 to 100% of cases), bronchovascular bundle thickening, consolidation and centrilobular nodules, mimicking ARDS or cardiogenic pulmonary oedema. ^[1] In CEP it shows dense, patchy peripheral consolidation and ground-glass change in the outer two-thirds of the mid to upper lung fields; pleural effusions and mediastinal nodes are uncommon. ^[1] The classic plain chest radiograph in CEP shows dense peripheral infiltrates that have been described as a "photographic negative" of pulmonary oedema, but this appears in fewer than 50% of cases. ^[1]

In TPE, chest films show miliary or nodular infiltrates, sometimes with air trapping and mediastinal nodes; the film can be normal in up to 20% of cases. ^[4] In ABPA, CT shows central bronchiectasis with normal tapering of distal bronchi (signet ring and "string of pearls" appearances) and high-attenuation mucus plugs in about 28% of patients. ^[3]

• ANCA. MPO-ANCA is positive in roughly 30 to 40% of EGPA and supports that diagnosis. ^[2][6] CEP and the other syndromes are usually ANCA-negative. ^[2][6]
• IgE and Aspergillus-specific antibodies. Total IgE is more than 1000 IU/mL in classic (Rosenberg-Patterson) ABPA, and Aspergillus-specific IgE/IgG are raised. Newer criteria may use lower thresholds (some reviews cite total IgE of at least 500 IU/mL). ^[2][3]
• Filarial serology/antigen. DEC response, microfilarial antibody or circulating filarial antigen (sensitivity 100%, specificity 94% in one series) confirm TPE. ^[4]
• Blood counts, film and, where indicated, bone marrow and FIP1L1::PDGFRA testing. These exclude clonal eosinophilia. ^[2]
• Strongyloides screening or empiric ivermectin before immunosuppression in patients with epidemiological risk, because of the risk of hyperinfection. ^[2]
• Drug history is mandatory before calling any case idiopathic. ^[5]

• AEP: acute onset with fever within 1 month, bilateral diffuse infiltrates, PaO2 60 mmHg or below or oxygen saturation 90% or below on room air, BAL eosinophilia of 25% or more or eosinophilic pneumonia on lung biopsy, and absence of other known causes. ^[1]
• CEP: respiratory symptoms for 2 to 4 weeks, diffuse alveolar consolidation with air bronchogram and/or ground-glass opacities, BAL eosinophilia of 40% or more or peripheral blood eosinophilia of at least 1000/mm3, and absence of other known causes. ^[1]
• ABPA: no single test establishes it; central bronchiectasis with normal tapering of distal bronchi remains the pathognomonic finding; total IgE is more than 1000 IU/mL in classic criteria and may be accepted at lower levels (at least 500 IU/mL in some recent criteria) when other criteria are met; Aspergillus-specific IgE/IgG are raised; eosinophils are at least 500/uL in steroid-naïve patients. ^[2][3]
• EGPA: the 2022 ACR/EULAR classification criteria require a weighted score of 6 or more (eosinophils at least 1.0 x 10^9/L, +5; obstructive airway disease, +3; nasal polyps, +3; extravascular eosinophilic inflammation, +2; mononeuritis multiplex, +1; ANCA or anti-proteinase-3 ANCA, minus 3; haematuria, minus 1). These are classification criteria, not a clinical diagnosis. ^[2]

Löffler syndrome is usually mild and self-limiting; treatment is directed at the underlying parasitic, drug or allergic trigger, and most patients do not need corticosteroids. ^[1]

TPE is treated with anti-filarial therapy. DEC is the drug of choice; a standard regimen is 6 mg/kg/day in three divided doses for 21 days (equivalent in practice to about 300 mg daily in three divided doses for 3 weeks). ^[4] Single-dose ivermectin reduces microfilaraemia by 90% in Wuchereria bancrofti infection but has no effect on adult worms; DEC kills about 50% of adult worms. ^[4] Corticosteroids are added in severe or prolonged disease. About 20% of treated patients relapse over 5 years, and delayed treatment risks progressive interstitial fibrosis. ^[4]

Treatment is corticosteroids (for the hypersensitivity and exacerbations) together with an azole antifungal such as itraconazole to reduce the Aspergillus burden and steroid dependence. ^[2] Stage III exacerbations are marked by new infiltrates with peripheral eosinophilia and doubling of remission-level IgE. ^[3] In selected patients with severe asthma or disease refractory to standard therapy, biologics used in type-2-high asthma may be considered. ^[2]

The response to corticosteroids is usually dramatic, with improvement within 48 hours and resolution of infiltrates within 1 month. For severe respiratory failure, high intravenous doses up to 500 mg/day of methylprednisolone are used, switching to oral prednisone 40 to 60 mg/day when improvement occurs; oral prednisone is continued for 2 to 4 weeks followed by tapering. Relapse after treatment is uncommon. ^[1]

Corticosteroids are the treatment of choice: prednisone at about 0.5 mg/kg/day for 4 to 6 weeks, then 0.25 mg/kg/day for 8 weeks, then tapering by about 5 mg each month. ^[1] Relapse is common and up to 50% of patients require long-term low-dose oral corticosteroids or high-dose inhaled corticosteroids to maintain control. ^[1][6] Recurrent or corticosteroid-dependent disease, which occurs in roughly 20% of patients, often requires prolonged therapy. ^[6]

Biologics targeting IL-5 are increasingly used as steroid-sparing therapy in relapsing or corticosteroid-dependent CEP, though evidence comes mainly from case series rather than randomised trials. Mepolizumab (100 mg or 300 mg subcutaneously every 4 weeks) and benralizumab (30 mg subcutaneously every 8 weeks, with 4-weekly loading doses for the first three) deplete eosinophils and reduce relapse, sometimes allowing steroid withdrawal; reslizumab (3 mg/kg intravenously every 4 weeks) is an alternative. ^[6] In EGPA, mepolizumab at 300 mg subcutaneously every 4 weeks and benralizumab at 30 mg subcutaneously every 4 weeks are approved for remission induction and sustained steroid sparing. ^[2]

Management follows disease severity and immunological endotype. ^[2]

• Non-organ-threatening disease: high-dose corticosteroids (oral prednisolone) with a steroid-sparing approach; maintenance with low-dose corticosteroids plus a conventional immunosuppressant.
• Organ- or life-threatening disease (rapidly progressive glomerulonephritis, severe cardiomyopathy, alveolar haemorrhage): high-dose corticosteroids combined with cyclophosphamide or rituximab for induction. ^[2]
• Relapsing or refractory disease: anti-IL-5 agents (mepolizumab 300 mg subcutaneously every 4 weeks, or benralizumab 30 mg subcutaneously every 4 weeks) induce remission and spare steroids. ^[2]
• Endotype-guided choice: rituximab is preferred in ANCA-positive, vasculitic-dominant disease, while anti-IL-5/IL-5R therapy is the mainstay of ANCA-negative, eosinophil-dominant disease. ^[2]
• Adjuncts: standard asthma and sinus care, infection prophylaxis when using cyclophosphamide, and cardiac monitoring when cardiac involvement is present.

In settings where HRCT and advanced microbiology are scarce, treat the syndrome that the clinical picture most supports; a chest radiograph, peripheral eosinophil count, basic parasitology, ANCA (where available) and a careful drug and travel history are the high-yield tools. Corticosteroids and DEC are inexpensive; anti-IL-5 biologics are usually not available and referral is needed. In asthma-associated disease, keep ICS use appropriate to the asthma label and avoid unnecessary oral steroids for ABPA/CEP beyond what the eosinophilic disease itself requires. ^[3][4]

• TPE: progressive interstitial fibrosis and irreversible damage with delayed treatment; relapse. ^[4]
• ABPA: bronchiectasis, chronic sputum production, fibrotic lung disease, loss of lung function. ^[3]
• AEP: hypoxaemic respiratory failure and ventilation; very rare relapse. ^[1]
• CEP: relapse in up to 50%, corticosteroid toxicity, and, in long-standing disease, progressive pulmonary fibrosis. ^[1][6]
• EGPA: cardiac disease (the major determinant of mortality), neuropathy, renal failure, gastrointestinal ischaemia. ^[2]
• Drug-induced disease: can be life-threatening (ARDS); discontinuation and corticosteroids are essential. ^[5]

With prompt corticosteroids, AEP rarely relapses and recovery is excellent. ^[1] CEP responds rapidly but relapses are common, so prolonged low-dose therapy is often needed. ^[1][6] EGPA has heterogeneous outcomes: cardiac and renal involvement drive mortality, and the Five-Factor Score stratifies risk. ^[2] TPE does well if treated early, but 20% relapse within 5 years; treated TPE is unlikely to progress to fibrosis. ^[4] ABPA ranges from remission to fibrotic lung disease depending on stage and control of asthma. ^[3]

There is no population screening for eosinophilic lung disease. Prevention consists of treating asthma well (reducing the substrate for ABPA), prompt treatment of filariasis and geohelminth infection, infection control and careful prescribing and monitoring of drugs known to induce pulmonary eosinophilia, and educating patients to report new cough or breathlessness promptly. ^[3][4][5]

Children. ABPA can occur in children with cystic fibrosis or asthma; AEP is reported in adolescents; TPE occurs in children in endemic areas. Management uses age-appropriate steroid and drug doses and specialist involvement. ^[3][4]

Pregnancy. Treat the underlying syndrome with specialist input; corticosteroids are generally preferred, with anti-filarial and immunosuppressive choices individualised.

Immunocompromised patients. Excluding opportunistic infection and neoplasm is even more important; high eosinophil counts in such patients should not be dismissed as benign.

• Eosinophilic pulmonary syndromes share eosinophil accumulation in the lung but have different mechanisms: parasite hypersensitivity (Löffler, TPE), allergic fungal disease (ABPA), idiopathic acute or chronic pneumonia, drug injury and vasculitis (EGPA).
• Löffler syndrome is mild and usually self-limiting; TPE is a mosquito-borne microfilarial hypersensitivity with very high IgE and dramatic DEC response, but 20% relapse.
• ABPA occurs in asthma or cystic fibrosis, is diagnosed by central bronchiectasis (pathognomonic), raised Aspergillus-specific IgE/IgG and high total IgE; management combines corticosteroids with itraconazole.
• AEP mimics ARDS, is diagnosed by BAL eosinophils of at least 25% and responds rapidly to 2 to 4 weeks of corticosteroids, rarely relapsing; blood eosinophilia is often absent at onset.
• CEP is a subacute, relapsing disease of older asthmatic (mostly female) patients with peripheral consolidations whose classic "photographic negative" chest radiograph appears in fewer than 50% of cases; treatment is prednisone 0.5 mg/kg/day then slow taper, with anti-IL-5 biologics for relapsing, steroid-dependent disease.
• BAL eosinophil thresholds are 5% (general eosinophilic pneumonia), 25% (AEP) and 40% (CEP); blood eosinophils above 500/uL (or at least 1000/mm3 for CEP) are supportive.
• EGPA is the systemic vasculitic member: asthma, eosinophilia and neuropathy/sinus/cardiac/renal disease; ANCA (usually MPO) in 30 to 40%; treatment is by severity and endotype, with corticosteroids plus cyclophosphamide or rituximab for organ-threatening disease and anti-IL-5 agents for relapsing/refractory disease.
• Always exclude drug causes, parasitic infection and clonal eosinophilia before labelling a case idiopathic or starting immunosuppression.

• Asthma.
• Bronchiectasis.
• Parasitic infections and filariasis.
• Drug-induced lung disease.
• Vasculitis and ANCA-associated disease.
• Hypereosinophilic syndrome.