CONTENTS
- Eosinophilic lung disease
- Specific diseases
- DRESS syndrome
- AEP (acute eosinophilic pneumonia)
- CEP (chronic eosinophilic pneumonia)
- ABPA (allergic bronchopulmonary aspergillosis)
- EGPA (eosinophilic granulomatosis with polyangiitis)
- HES (hypereosinophilic syndromes)
- Simple pulmonary eosinophilia (Loeffler syndrome)
- Strongyloides
- NAEB (nonasthmatic eosinophilic bronchitis)
- Questions & discussion
abbreviations used in the pulmonary section: 2
- ABPA: Allergic bronchopulmonary aspergillosis 📖
- AE-ILD: Acute exacerbation of ILD 📖
- AEP: Acute eosinophilic pneumonia 📖
- AFB: Acid Fast Bacilli
- AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
- ANA: Antinuclear antibody 📖
- ANCA: Antineutrophil cytoplasmic antibodies 📖
- ARDS: Acute respiratory distress syndrome 📖
- ASS: Antisynthetase Syndrome 📖
- BAL: Bronchoalveolar lavage 📖
- BiPAP: Bilevel positive airway pressure 📖
- CEP: Chronic eosinophilic pneumonia 📖
- COP: Cryptogenic organizing pneumonia 📖
- CPAP: Continuous positive airway pressure 📖
- CPFE: Combined pulmonary fibrosis and emphysema 📖
- CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
- CTEPH: Chronic thromboembolic pulmonary hypertension 📖
- DAD: Diffuse alveolar damage 📖
- DAH: Diffuse alveolar hemorrhage 📖
- DIP: Desquamative interstitial pneumonia 📖
- DLCO: Diffusing capacity for carbon monoxide 📖
- DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
- EGPA: Eosinophilic granulomatosis with polyangiitis 📖
- FEV1: Forced expiratory volume in 1 second 📖
- FVC: Forced vital capacity 📖
- GGO: Ground glass opacity 📖
- GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
- HFNC: High flow nasal cannula 📖
- HP: Hypersensitivity pneumonitis 📖
- IPAF: Interstitial pneumonia with autoimmune features 📖
- IPF: Idiopathic pulmonary fibrosis 📖
- IVIG: Intravenous immunoglobulin 📖
- LAM: Lymphangioleiomyomatosis 📖
- LIP: Lymphocytic interstitial pneumonia 📖
- MAC: Mycobacterium Avium complex 📖
- MCTD: Mixed connective tissue disease 📖
- NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
- NSIP: Nonspecific interstitial pneumonia 📖
- NTM: Non-tuberculous mycobacteria 📖
- OP: Organizing pneumonia 📖
- PAP: Pulmonary alveolar proteinosis 📖
- PE: Pulmonary embolism 📖
- PFT: Pulmonary function test 📖
- PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
- PPFE: Pleuroparenchymal fibroelastosis 📖
- PPF: Progressive pulmonary fibrosis 📖
- PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
- RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
- RP-ILD: Rapidly progressive interstitial lung disease 📖
- TNF: tumor necrosis factor
- UIP: Usual Interstitial Pneumonia 📖
diagnostic approach
history
- ? Wheezing.
- ? Skin rash.
- ? Nasal/sinus symptoms.
- ? Gastrointestinal symptoms.
exposure review
- Travel, especially:
- Medications (including over the counter medications).
- Inhalational exposures (e.g., tobacco, vaping, dust, or smoke exposure).
laboratory studies to consider
- Blood count:
- CBC with differential cell count and blood smear (evaluate for dysplastic cells).
- Review prior eosinophil levels if available (chronic vs. acute eosinophilia).
- Nonspecific markers:
- IgE level. 📖
- CRP (C-reactive protein) may be elevated in DRESS, AEP, CEP, or EGPA.
- Procalcitonin (if patient is being treated for pneumonia).
- Involvement of other organ systems?
- Infectious disease evaluation:
- HIV test.
- Sputum for culture, including fungal culture (for aspergillus).
- Stool for ova & parasites.
- Evaluation for fungal pneumonia (coccidiomycosis especially).
- Strongyloides serology, if potential prior exposure. 📖
- Inflammatory disease evaluation:
- If concern for ABPA (allergic bronchopulmonary aspergillosis): Check IgG and IgE anti-aspergillus antibodies.
- If concern for EGPA (eosinophilic granulomatosis with polyangiitis): Check ANCA +/- anti-MPO and anti-PR3. 📖
- If concern for HES (hypereosinophilic syndrome): Check B12 level, serum tryptase level, +/- PCR for gene translocations. 📖
- If IgG4-related disease is considered: IgG4 level.
imaging studies to consider
- Imaging:
- Chest CT scan.
- CT chest/abdomen/pelvis should be strongly considered in any patient with eosinophilia >1,500 of unclear etiology, to evaluate for splenomegaly, lymphadenopathy, pulmonary involvement, and/or occult neoplasm. (36485140)
- Transthoracic echocardiogram to evaluate for cardiac involvement.
some cognitive schema for considering possible diagnoses
is there multisystem involvement?
- Diseases that solely involve the lungs:
- AEP (acute eosinophilic pneumonia).
- CEP (chronic eosinophilic pneumonia).
- ABPA (allergic bronchopulmonary aspergillosis).
- Diseases that cause multi-system involvement:
- EGPA (eosinophilic granulomatosis with polyangiitis).
- HES (hypereosinophilic syndrome).
- DRESS (drug reaction with eosinophilia and systemic symptoms).
- Systemic infection (e.g., coccidiomycosis, HIV).
- (Further discussion of differentiating EGPA vs. HES here: 📖)
is the onset acute or chronic?
- Acute onset suggests:
- AEP (acute eosinophilic pneumonia).
- Loeffler syndrome.
- DRESS (drug reaction with eosinophilia and systemic symptoms).
- Chronic onset suggests:
- CEP (chronic eosinophilic pneumonia).
- ABPA (allergic bronchopulmonary aspergillosis).
- HES (hypereosinophilic syndromes). (37055090)
is there an asthma history and/or IgE elevation?
- ABPA (allergic bronchopulmonary aspergillosis). 📖
- CEP* (chronic eosinophilic pneumonia). 📖
- EGPA* (eosinophilic granulomatosis with polyangiitis). 📖
- * indicates diseases associated with nasal polyposis.
- (More on IgE elevation: 📖)
is the disease steroid-refractory?
- Diseases that should respond to steroid:
- AEP (acute eosinophilic pneumonia).
- CEP (chronic eosinophilic pneumonia).
- Diseases that can be refractory to steroid:
- EGPA (eosinophilic granulomatosis with polyangiitis).
- HES (hypereosinophilic syndrome).
- DRESS (drug reaction with eosinophilia and systemic symptoms).
- Systemic infection (e.g., coccidiomycosis, HIV).
initial therapeutic approach
Whenever possible, a specific diagnosis should be established. However, for a critically ill patient it may not always be possible to immediately establish a diagnosis. If the patient is deteriorating and the diagnosis remains unclear, the following considerations may be useful:
(1) discontinue any potentially causative medications
(2) consider empiric treatment for strongyloidiasis 📖
- Empiric steroid may exacerbate strongyloidiasis.
- For patients who have lived in endemic regions, it may be reasonable to test and/or treat empirically for Strongyloides (with ivermectin).
(3) empiric steroid therapy
- Empiric steroid may be reasonable for some patients with acute respiratory failure due to eosinophilic lung disease.
- The primary drawback of steroid is that it may prevent definitive tissue diagnosis (which is important for patients with chronic/systemic disorders, such as eosinophilic granulomatosis with polyangiitis).
basic definition of eosinophilia
- Eosinophilia = absolute eosinophil count >500/uL (or >0.5 billion/L).
- Mild eosinophilia = absolute eosinophil count 500 – 1,500/uL (0.5 – 1.5 billion/L).
- 1-2% of the population may have this level of eosinophilia, often due to allergies.
- This level of eosinophilia by itself doesn't necessarily mandate an evaluation. (36485140)
- In the context of severe illness (e.g., ICU admission with “pneumonia”), this level of eosinophilia is abnormal and may be an important sign of eosinophilic lung disease.
- Hypereosinophilia = absolute eosinophil count >1,500/uL (or >1.5 billion/L).
- 💡 The absolute eosinophil count is most important (not the relative percentage of eosinophils). (31690387)
interpreting eosinophil count in acute critical illness (e.g., pneumonia)
- Generally, bacterial pneumonia causes a low eosinophil count (due largely to an endogenous cortisol response).
- Even mild-moderate eosinophilia in a patient with acute/subacute pulmonary disease suggests some form of eosinophilic lung disease.
- For a patient admitted to the ICU with acute pneumonia, >300-400 eosinophils/uL may raise the possibility of eosinophilic lung disease (e.g., acute eosinophilic pneumonia).
- Another consideration is that patients with adrenal insufficiency may have abnormally elevated levels of eosinophils, which is disproportionate to their degree of illness.
interpreting eosinophil count in patient on chronic steroid
- Among patients who are chronically on >5 mg/day prednisone, the eosinophil count will generally be very close to zero.
- In the context of chronic steroid use, even a “normal” eosinophil count might actually be pathologically elevated. (Fishman 2023)
interpreting eosinophil count in asthma or COPD
eosinophil count in asthma
- Eosinophils are predominantly located in tissues, so blood levels may not correlate perfectly with tissue levels.
- Elevated blood eosinophil levels may be a reflection of T2-high types of asthma (e.g., atopic asthma). This is clinically relevant, as it may guide personalized therapeutic interventions.
- <100 eosinophils/uL suggests a lack of airway eosinophilia.
- >300 eosinophils/uL suggests the presence of airway eosinophilia (e.g., eosinophils in sputum). (figure below).
- >400 eosinophils/uL may predict a 42% elevation in the risk of a severe exacerbation in the coming year. (Piggott 2022)
eosinophil count in COPD
- Eosinophil count predicts the likelihood of benefit from inhaled steroid, especially among patients with frequent COPD exacerbations:(29331313, 31553837)
- Eosinophil count <100/uL suggests minimal benefit from inhaled steroid.
- Eosinophil count 100-300/uL suggests moderate response to inhaled steroid.
- Eosinophil count >300/uL suggests good response to inhaled steroid.
atopic
- Asthma, allergic rhinitis, and/or atopic dermatitis.
- These usually cause eosinophilia <1,500/uL.
- In a patient with asthma, >1,500/uL eosinophils suggests one of the following eosinophilic lung diseases that is associated with asthma:
- ABPA (allergic bronchopulmonary aspergillosis). 📖
- Typically ~8-40% eosinophils.
- >>40% eosinophils may suggest an alternative diagnosis.
- EGPA (eosinophilic granulomatosis with polyangiitis). 📖
- Virtually all patients have eosinophilia (>1,000/uL eosinophils in 80%).
- Food allergy.
medications
clues suggesting a drug reaction
- 🔎 Extrapulmonary symptoms, especially a skin rash (suggests DRESS syndrome 📖).
- 🔎 The clinical picture is consistent with AEP (acute eosinophilic pneumonia), but the peripheral eosinophilia is more dramatic than would generally be expected (>1,000/uL). (Fishman 2023)
- 🔎 Temporal relationship between initiation of a medication and development of pneumonia. (33965157)
medications that may cause eosinophilic pneumonia
- The same group of medications are usually implicated in both acute and chronic eosinophilic pneumonia (AEP or CEP), as listed below. Medications that may cause DRESS syndrome are listed separately here: 📖.
- Antimicrobial:
- Amphotericin B.
- Ampicillin.
- Azithromycin.
- Cephalosporins, including ceftaroline.
- Ciprofloxacin.
- Chloroquine.
- Clarithromycin.
- Colistin, inhaled.
- Dapsone.
- Daptomycin.
- Ethambutol.
- Imipenem/cilastatin.
- Isoniazid.
- Levofloxacin.
- Minocycline.
- Nitrofurantoin.
- Penicillins.
- Pyrimethamine.
- Sulfonamides.
- Cardiovascular:
- ACE-inhibitors (captopril, perindopril).
- Beta-blockers.
- Amiodarone.
- Hydrochlorothiazide.
- Mexiletine.
- Simvastatin.
- Cancer therapies:
- Chemotherapeutics:
- Bleomycin.
- Cisplatin.
- Fludarabine.
- Gemcitabine.
- Methotrexate.
- Targeted therapies:
- Osimertinib.
- Immune checkpoint inhibitors.
- Chemotherapeutics:
- Neuro/psych:
- Antidepressant (e.g., amitriptyline, duloxetine, fluoxetine, imipramine, sertraline, trazodone, venlafaxine).
- Antiepileptic: carbamazepine, levetiracetam, phenytoin, valproic acid.
- Antipsychotic: risperidone.
- Other:
- Acetaminophen.
- Erythromycin.
- Leukotriene receptor antagonists (montelukast, zafirlukast).
- Mesalamine.
- NSAIDs (aspirin, ibuprofen, indomethacin, especially naproxen).
- Penicillamine.
- Pirfenidone.
- Propylthiouracil.
- Sulfasalazine.
- Tacrolimus.
- TNF-inhibitors (e.g., Infliximab).
medications associated with DRESS syndrome: 📖
infection
- HIV infection (~10% rate among treatment-naive). (31757229)
- Fungal infection:
- Coccidiomycosis (eosinophilia is not uncommon, eosinophilia may range up to 25% of the differential). (17619571)
- Rarely: Cryptococcosis, histoplasmosis.
- Helminths:
- Protozoa (Dientamoeba fragilis, Cystoisospora belli formerly Isospora belli).
neoplastic & paraneoplastic
neoplastic eosinophilia
- HES (hypereosinophilic syndrome; 30-70% eosinophils). 📖
- Eosinophilic leukemia.
- Systemic mastocytosis.
paraneoplastic eosinophilia
- Epidemiology:
- 10% of patients with lymphoma (Hodgkin disease, T-cell lymphomas, acute lymphoblastic leukemia).
- 3% of patients with lung cancer.
- Occasionally seen with other malignancies:
- Squamous cell carcinoma of the skin or nasopharynx.
- Adenocarcinoma of the breast, kidney, stomach, colon, uterus, or cervix.
- Transitional cell bladder carcinoma.
- Clinical presentation:
- Eosinophilia is often marked (>5,000/uL).
- Usually asymptomatic.
- Eosinophilic pneumonia can occur in patients with markedly elevated peripheral eosinophil counts (with pulmonary infiltrates, dyspnea, and wheezing).
other
diseases involving eosinophilic tissue infiltration
- AEP (acute eosinophilic pneumonia). 📖 Peripheral eosinophilia often isn't seen, or may be subtle.
- CEP (chronic eosinophilic pneumonia). 📖 Eosinophilia seen in ~85% of patients. Usually eosinophils constitute 10-40% of leukocytes, but this may range up to 80%.
- HES (hypereosinophilic syndrome).
- EGPA (eosinophilic granulomatosis with polyangiitis).
- Eosinophilic esophagitis, other eosinophilic gastrointestinal diseases.
- Eosinophilic fasciitis.
miscellaneous
- Adrenal insufficiency.
- Sarcoidosis. 📖
- Inflammatory bowel disease.
- IgG4-related disease.
- Hyper-IgE syndrome.
- Transplant rejection, GVHD (graft-versus-host disease).
- Radiation therapy.
- Atheroembolism.
- Bullous pemphigoid.
Normally, eosinophils constitute <1-3% of cells in bronchoalveolar lavage fluid.
~3-25% eosinophils is nonspecific. Causes include:
- Hypersensitivity pneumonitis.
- Asthma.
- IPF (idiopathic pulmonary fibrosis), connective tissue-associated ILD.
- Sarcoidosis.
- Pneumocystis.
- Radiation pneumonitis.
- Pneumoconiosis.
- Infection. (Murray 2022)
>25% eosinophils = alveolar eosinophilia. Causes include:
- Only involves lung:
- AEP (acute eosinophilic pneumonia): >20-25% eosinophils.
- CEP (chronic eosinophilic pneumonia): Generally >40% eosinophils.
- RBILD and/or DIP can cause marked eosinophilia. (Murray 2022)
- Extrapulmonary involvement:
- EGPA (eosinophilic granulomatosis with polyangiitis)
- Hypereosinophilic syndrome (may see >70% eosinophils).
- DRESS syndrome.
- Paraneoplastic eosinophilia.
- Coccidioidomycosis may rarely cause eosinophilic pneumonia. (29206477)
- Simple pulmonary eosinophilia (including parasitic infection such as Ascaris, Strongyloides, or Toxocara).
Normal IgE levels are <360 ng/mL (<150 IU/ml or kU/L).
causes of IgE >1,000 ng/mL (>417 IU/ml or kU/L) include
- Allergic dermatitis.
- Asthma:
- IgE may vary from zero to >2,000 ng/ml (>834 IU/ml).
- Higher levels of IgE suggest atopic asthma (aka T2-high endotypes).
- Very high IgE levels don't necessarily indicate an alternative diagnosis. However, markedly elevated IgE levels may be consistent with a diagnosis of ABPA (allergic bronchopulmonary aspergillosis).
- ABPA (allergic bronchopulmonary aspergillosis).
- IgE is usually >1,000 ng/ml (>417 IU/ml).
- Normal IgE virtually excludes ABPA.
- IgE correlates with disease activity.
- EGPA (eosinophilic granulomatosis with polyangiitis).
- CEP (chronic eosinophilic pneumonia):
- IgE is usually normal or mildly elevated in CEP.
- IgE is >1,000 kU/L in ~15% of patients with CEP.
- Hyper-IgE (a rare immunodeficiency syndrome).
- Cryptococcosis (this occurs as an allergic reaction to invasive infection). (17619571)
basics
- DRESS nomenclature is somewhat confusing:
- Some patients may lack eosinophilia.
- Some patients may lack cutaneous manifestations.
- DIHS (drug-induced hypersensitivity syndrome) is an alternative name, for these reasons.
- The pathophysiology of DRESS syndrome frequently involves reactivation of various herpesviruses (usually human herpesvirus 6, EBV, or CMV). (33341203) DRESS exists along the same axis of immune dysfunction as HLH (hemophagocytic lymphohistiocytosis). Patients with severe DRESS syndrome can experience a DRESS/HLH overlap syndrome. (32964443)
- DRESS may encompass several syndromes involving specific organs:
- DILI (drug-induced liver injury).
- Drug-induced acute interstitial nephritis.
- Allopurinol hypersensitivity syndrome, abacavir hypersensitivity syndrome, etc.
- DRESS syndrome may involve the lungs, but it will generally manifest with predominantly non-pulmonary manifestations.
medications most frequently implicated in DRESS syndrome
It's often impossible to know with certainty whether a medication causes DRESS syndrome. Consequently, it's impossible to create a list that is comprehensive and definitive. Below are the drugs most commonly implicated in DRESS syndrome. A more comprehensive list may be found at PneumoTox.com: 🌊
- Antibiotics:
- Amoxicillin, ampicillin.
- Anti-mycobacterial agents (ethambutol, isoniazid, pyrazinamide, rifampin).
- Antiretroviral agents (abacavir, boceprevir, efavirenz, nevirapine, raltegravir, telaprevir).
- Azithromycin.
- Dapsone.
- Levofloxacin.
- Minocycline.
- Piperacillin-tazobactam.
- Streptomycin.
- Trimethoprim-sulfamethoxazole.
- Vancomycin. (30566546)
- Antiepileptics:
- Carbamazepine.
- Lamotrigine.
- Oxcarbazepine.
- Phenobarbital.
- Phenytoin.
- Valproic acid.
- Cancer medications:
- Daclizumab.
- Imatinib.
- Sorafenib.
- Vemurafenib.
- NSAIDs (e.g., celecoxib, diclofenac, ibuprofen).
- Other:
clinical manifestations of DRESS syndrome
latency after starting the medication
- DRESS typically occurs ~2-6 weeks after starting the medication, but it can lag up to three months or longer after medication initiation. (37082745, 33341203)
- Latency period may be shorter in:
- Younger patients.
- Patients with impaired drug metabolism.
- Rapid-onset DRESS may occur with antibiotics (<15 days after initiation). (34777921)
- Prior drug exposure may cause DRESS to develop within hours to days. (35625735)
- ⚠️ DRESS diagnosis shouldn't be dismissed based on a short latency period between drug exposure and disease onset. (34777921)
prodromal symptoms
- These usually precede skin findings by several days.
- May include:
skin manifestations (~99%)
- Maculopapular rash is most common (85%): (33341203)
- Usually starts as an itchy or burning maculopapular rash that rapidly progresses to become diffuse and coalescent. The rash may have a deeper, more violaceous color than most drug rashes. (34777921)
- Initially this tends to involve the face, upper torso, and arms. Eventual spread often involves most of the skin surface.
- Facial edema (~75%) may cause symmetric swelling involving the midface, periorbital region, and even the ears (mimicking angioedema). (37082745, 33341203) This may be a very helpful diagnostic finding. Unfortunately, laryngeal edema may occur (which can cause airway compromise). (30566546)
- Mucus membrane involvement occurs in up to half of patients, but usually only at a single site. (37082745)
- Atypical manifestations:
- Urticarial and atypical targetoid eruptions have also been described. (30566546)
- Pustules may rarely occur. This must be differentiated from AGEP (acute generalized exanthematous pustulosis).
liver injury (~75%)
- The liver is the most commonly involved visceral organ and the primary source of mortality. (30566546)
- Liver function tests assume variable patterns (they may be hepatocellular, cholestatic, or mixed). (30566546) Fulminant hepatic failure can occur.
kidney injury (~33%)
- Usually renal involvement is mild, but severe interstitial nephritis with acute kidney injury can occur (especially with allopurinol, carbamazepine, and dapsone). (37082745)
- Clinical features of acute interstitial nephritis may include:
- New-onset proteinuria.
- Hematuria.
- Sterile pyuria (and eosinophiluria, if this is checked).
pulmonary manifestations (~25%)
- Pulmonary features may precede or follow other manifestations. (33002503)
- Dyspnea, dry cough, and hypoxemia may be seen. Clinical manifestations may resemble AEP (acute eosinophilic pneumonia), with escalation to cause ARDS. (33002503, 37055090)
- Radiology may show interstitial pneumonitis and/or pleural effusion. (37082745)
cardiac involvement (~10%)
- Eosinophilic myocarditis or pericarditis may occur. (37082745)
- Cardiac involvement is often delayed, occurring an average of 70 days after initial symptoms. (35625735)
- Myocarditis is most often reported in association with minocycline, allopurinol, ampicillin, dapsone, and trimethoprim-sulfamethoxazole. (33341203)
other manifestations
- Meningitis, encephalitis (e.g., headache, seizure, cranial nerve palsy). (37082745)
- Gastrointestinal hemorrhage.
- Pancreatic involvement.
diagnostic evaluation of DRESS syndrome
⚠️ Laboratory abnormalities may be absent initially (lagging behind skin involvement). (34777921)
blood abnormalities
- Eosinophilia:
- Atypical lymphocytosis (~70%). (34777921)
- Thrombocytopenia, anemia, or pancytopenia can occur (suggesting an element of hemophagocytic lymphohistiocytosis).
- Leukocytosis or leukopenia may occur.
inflammatory markers
- CRP (C-reactive protein) may be highly elevated.
- Ferritin may be elevated.
end-organ damage
- Acute kidney injury with abnormal urinalysis (discussed further above).
- Liver function test abnormalities (discussed further above).
evaluation for alternative diagnoses may include:
- Blood cultures.
- Testing for hepatitis A, B, and C.
- ANA testing (antinuclear antibody).
- Testing for chlamydia and mycoplasma. (34777921)
skin biopsy
- ⚠️ DRESS is generally not a histopathological diagnosis. Histology is not specific for DRESS, as a variety of histologic changes may be found, for example: (33341203)
- More severe DRESS may associate with confluent keratinocyte necrosis.
- Milder disease may associate with spongiotic epidermal change.
- Interface vacuolization is often seen. (34777921)
- Skin biopsy may help eliminate alternative diagnostic possibilities, but it's not required for the diagnosis of DRESS. (33341203)
diagnosis of DRESS syndrome
primary differential diagnoses
- AGEP (acute generalized exanthematous pustulosis):
- SJS/TEN (Steven Johnson Syndrome/Toxic Epidermal Necrolysis)
- Suggested by widespread epidermal sloughing and more pronounced mucosal involvement.
- SJS/TEN causes less frequent or milder visceral involvement. (35338896)
- Skin biopsy should be used to exclude SJS/TEN if this is a concern.
- Hypereosinophilic syndromes. 📖 Hypereosinophilic syndromes much less frequently involve the liver as compared to DRESS. (35625735)
- Serum sickness may be suggested by polyarthritis and less pronounced fever. (35338896)
- Toxic shock syndrome may cause a diffuse erythematous rash. Multiorgan failure with shock is more prominent than in DRESS.
- Hemophagocytic lymphohistiocytosis (HLH) may cause skin manifestations (e.g., generalized maculopapular rash). (19818067) Please note that DRESS and HLH often coexist.
- Adult-onset Still's disease: rash is usually nonpruritic, macular, and salmon colored, affecting predominantly the trunk and extremities. (35338896)
diagnosis of DRESS: it's not skin deep
- The RegiSCAR score may be used as a diagnostic criterion. 🧮 However, early in the disease course patients may not yet meet criteria for DRESS syndrome.
- Ultimately, the diagnosis of DRESS is based on careful assessment of supporting evidence as well as exclusion of alternative diagnostic possibilities. This often hinges on a careful assessment of visceral organ involvement (e.g., hepatic and/or renal dysfunction), rather than solely on skin manifestations.
treatment of DRESS syndrome
staging evaluation for any patient with DRESS syndrome
- Liver function tests and INR.
- Urinalysis and renal function.
- Echocardiogram and troponin level.
- Ferritin, C-reactive protein level, and fibrinogen to survey for HLH (hemophagocytic lymphohistiocytosis). 📖
- Evaluation for virus reactivation (blood PCR for CMV, EBV, HHV-6, and HHV-7). If detected, this is a poor prognostic sign and suggestive of possible benefit from antiviral therapy (although this remains unknown). For patients with refractory disease, these tests may be repeated over time. (32964443, 34777921)
steroid
- Steroid has traditionally been considered the front-line therapy for DRESS syndrome, although newer data is suggesting that cyclosporine is superior.
- Therapy is indicated for visceral organ involvement (e.g., aminotransferases >5 times normal, renal failure, pulmonary involvement, cardiac abnormalities, or hemophagocytosis).
- Dose & type of steroid:
- The usual dose is ~1 mg/kg/day PO prednisone, with a gradual taper over ~6 weeks. (33341203)
- Some authors advocate for 1-1.5 mg/kg/day IV methylprednisolone to ensure adequate absorption and activity in patients who may have gastrointestinal or hepatic dysfunction. (34777921)
- Higher doses could be considered in life-threatening cases (e.g., a three-day pulse of 500-1,000 mg IV methylprednisolone daily). (21527371) For patients with features of hemophagocytic lymphohistiocytosis, dexamethasone could alternatively be considered. 📖
- Problems with steroid use for DRESS include the following: (36844223)
- (1) A long taper is required (which increases steroid-induced side effects).
- (2) Response to steroid is often slow.
- (3) Relapse of DRESS often occurs, even with minimal tapering of steroid dose.
calcineurin inhibitors (predominantly cyclosporine)
- An emerging body of literature suggests that cyclosporine might be an appropriate front-line therapy for DRESS syndrome.
- Calcineurin inhibitors inhibit activation and proliferation of T-cells, which more precisely addresses the immunological abnormalities in DRESS syndrome. Compared to steroid, cyclosporine could represent a targeted therapy that may be more effective. (36844223)
- Cyclosporine seems to be required only for a relatively short period of time, at relatively low doses (e.g., 5 mg/kg daily is one third of the starting dose used in organ transplantation). This supports the concept that cyclosporine is effectively targeting the immunopathology of DRESS syndrome (rather than acting as a nonspecific agent).
- Several case series have emerged suggesting that cyclosporine is effective and safe. (32159726, 37632913)
- A 1-2 week course of calcineurin inhibitors is likely far safer than a several-month regimen of steroid.
- In severe cases, steroid may be used in combination with cyclosporine, followed by a steroid taper over weeks rather than months. (36844223) Rare patients may fail to respond to either steroid or cyclosporine monotherapy, but may respond better to a combination of these treatments. (37632913)
- The dosing regimen, contraindications, and pharmacology of cyclosporine is discussed here: 📖
other therapies
- Patients with coexisting HLH (hemophagocytic lymphohistiocytosis) may require additional therapy directed at HLH, as described here: 📖
- Intravenous immunoglobulin (IVIG) may be considered among patients with life-threatening features (hemophagocytosis, spinal cord involvement, encephalitis, hepatic failure, or respiratory failure). (37082745) The mechanism of action could include neutralization of HHV-6. (37082745)
- JAK-inhibitors have demonstrated efficacy in two cases of steroid-refractory disease. (34777921)
- For patients with detectable viremia, suppression of viral replication is theoretically attractive. However, to date this has not been well investigated.
prognosis of DRESS syndrome
- Mortality is substantial (~5%), driven largely by fulminant hepatitis. (37082745)
- Indicators of poor prognosis may include: (37082745)
- Eosinophil count >6,000/uL.
- Thrombocytopenia or pancytopenia.
- Coagulopathy.
- Potential late sequelae:
- Delayed myocarditis may occur several months after the initial diagnosis.
- Autoimmune disorders may emerge over time (e.g., lupus, type-1 diabetes, autoimmune hemolytic anemia, and autoimmune thyroiditis). (30566546)
Acute Eosinophilic Pneumonia (AEP) is a rare inflammatory lung disease, which can cause younger adults to develop respiratory failure requiring intubation. This is an important disorder to be aware of because, if treated aggressively with steroid, patients will rapidly recover. Although the disease is rare, it will be encountered with some regularity in the ICU.
epidemiology of AEP
primary AEP
- Generally seen in younger adults (e.g., ~20-40 years old).
- Often triggered by inhalation exposures:
- Most often, tobacco/marijuana use (including vaping or hookah). AEP is particularly related to the initiation of smoking, or a recent increase in tobacco exposure.
- Inhalational substance use (e.g., cocaine, heroin, methamphetamine). (27231866)
- Other environmental stimuli:(Fishman 2023)
- Tear gas.
- Firewood dust.
- Indoor renovation.
- Cave exploration.
- Fireworks.
secondary AEP
- Numerous medications may cause this (see the list above 📖).
- Thoracic radiotherapy.
- HIV.
- Influenza type H1N1.
clinical presentation of AEP
general presentation
- Acute hypoxemic respiratory failure, usually evolving within a week (but occasionally developing within a few weeks).
- This will frequently be misdiagnosed as severe pneumonia.
- AEP often precipitates the need for intubation.
clinical findings
- Hallmark symptoms that each occur in >80% of patients: (31253537)
- Dyspnea (~100%).
- Nonproductive cough (~90%; lack of sputum production may help distinguish from typical bacterial pneumonias).
- Fever (~100%). (37055090)
- Pleuritic chest pain is often seen.
- Other features of systemic inflammation:
- Myalgias in about half of patients.
- Night sweats and chills may occur.
- Abdominal complaints may occur.
laboratory tests for AEP
peripheral eosinophilia
- Peripheral eosinophilia (>500/uL) is present in only about a third of patients.
- >1000/uL may suggest the possibility of drug-induced acute eosinophilic pneumonia. (Fishman 2023)
- However, the definition of eosinophilia using a cutoff of >500 eosinophils/mm3 may be suboptimal in this context. Patients admitted to the ICU due to pneumonia will usually have reduced eosinophil counts. (19519944) Therefore, the presence of eosinophil counts of ~300-500 eosinophils/mm3 may not technically constitute “eosinophilia,” but it may be abnormal within the context of a patient admitted to ICU with presumed severe pneumonia.
- Eosinophilia may emerge over time, if the patient receives no steroid therapy.
- 💡 Repeat the differential cell count for patients who have been admitted to the hospital for several days and have not received steroid.
- Leukocytosis with neutrophilia is often seen.
inflammatory markers
- C-reactive protein can be markedly elevated, with values often lying in the range of ~90-200 mg/L.
- Procalcitonin can be mildly-moderately elevated. (31776322)
- IgE levels may be elevated.
radiology of AEP
three findings are most often seen:
- (1) Airspace opacities are invariably present:
- Description:
- Typically these are patchy GGO (ground glass opacities).
- With increasing disease severity, these may evolve into bilateral areas of consolidation.
- Distribution:
- Description:
- (2) Smooth thickening of the interlobular septa:
- On chest X-ray, interstitial abnormalities may manifest as Kerley B lines (visible in about a third of cases).
- On CT scan, this septal thickening can be observed directly (~90%). (37055090) The combination of septal thickening and ground-glass opacities may produce a crazy-paving pattern.
- (3) Pleural effusions (~70% of patients):
- These are often bilateral and small to moderate. (Fishman 2023)
- ⚠️ In many cases, not all three features will be present. This may cause AEP to be radiologically indistinguishable from numerous other processes (e.g., pneumonia).
other findings
radiological differential diagnosis may include:
- Cardiogenic pulmonary edema:
- Hantavirus.
- Diffuse alveolar hemorrhage.
invasive diagnostic tests for AEP
thoracentesis
- Effusions are exudative.
- Typically they will reveal eosinophilia, with 10-50% eosinophils. (The differential diagnosis of eosinophilic pleural effusion is discussed further here: 📖)
bronchoalveolar lavage (BAL)
- Eosinophilia will be seen (>25%), unless steroid has already been administered.
- Lymphocytosis and neutrophilia may also occur. (29206477)
overall approach to the diagnosis of AEP
clues to consider AEP as a diagnosis:
- Acute illness following initiation of smoking, vaping, or other overt inhalational injury.
- Respiratory failure following initiation of high-risk medications (especially daptomycin).
- Severe “pneumonia” in a young and generally healthy person, who wouldn't be expected to develop severe pneumonia.
- Peripheral eosinophilia can be a useful clue (although this is usually absent).
common differential diagnostic considerations:
- In a young and immunocompetent patient, the differential may be relatively narrow (e.g., AEP versus bacterial pneumonia).
- In an immunosuppressed patient, or a patient with significant infectious exposures, the differential diagnosis will be broader.
bronchoscopy versus empiric therapy
- Empiric therapy with steroid (and sometimes also antibiotics) may be considered in some situations, especially if:
- Clinical context is highly suggestive of AEP (e.g., respiratory failure following smoking initiation).
- The differential diagnosis is narrow enough to empirically treat all likely etiologies with a reasonably narrow treatment regimen (e.g., corticosteroid plus azithromycin and ceftriaxone).
- The patient is too unstable for bronchoscopy, or at significant risk from bronchoscopy (e.g., bronchoscopy would probably precipitate or require intubation).
- Bronchoscopy will often be required. Reasons to perform bronchoscopy may include the following:
- Bronchoscopy is required for a definitive diagnosis of AEP.
- A broad differential diagnosis exists, which cannot be treated empirically without a ridiculously broad array of antibiotics (e.g., the differential diagnosis includes pneumocystis, bacterial pneumonia, AEP, and fungal pneumonia).
- If the patient has already been intubated, then bronchoscopy may be performed with minimal additional risk to the patient.
- Thoracentesis revealing eosinophilia might abrogate the need for bronchoscopy in some situations.
treatment of AEP
- Identification and removal of any inciting cause (e.g., medication).
- Patients should be educated about the risks of smoking. Help with quitting should be offered as appropriate.
- Steroid:
- The initial regimen for a critically ill patient might be ~60-125 mg methylprednisolone IV q6hr, until substantial improvement is seen (usually <2 days). Less ill patients may be started on lower doses of steroid (e.g., 30-60 mg prednisone PO daily). Steroid may be tapered off over two weeks (a recent series found equivalent efficacy between a 2-week and a 4-week steroid course). (29206477)
- Patients should respond rapidly to steroid, usually within 1-2 days. Failure to respond to steroid suggests an alternative diagnosis.
- AEP generally doesn't spontaneously relapse. However, multiple episodes are possible if patients are re-exposed to triggering antigens (especially smoking). This is unlike many other interstitial lung diseases, which may flare as steroid is being tapered.
- Empiric antibiotics:
- Patients will often receive empiric antibiotics initially, before the diagnosis of AEP has been secured.
- Once a diagnosis of AEP has been reached, antibiotics should be discontinued.
epidemiology of CEP
- The age range is broad, with a peak incidence around ~30-45 years old. (Fishman 2023)
- 2:1 female predominance. (Murray 2022)
- <10% of patients with CEP are actively smoking.
- Overall, CEP is the most common cause of eosinophilic pneumonia in nontropical areas with a low prevalence of parasitic infection. (37055090)
- Asthma & atopia:
- About half of patients have asthma prior to the development of CEP. Patients may also develop asthma simultaneously, or after the diagnosis of CEP. (28035877)
- CEP is also associated with other atopic disorders (e.g., allergic rhinitis, nasal polyps, eczema, urticaria).
- Radiotherapy may trigger CEP, usually occurring ~3-10 months after completion of therapy. (Murray 2022)
- Medications may cause CEP (see the list above 📖).
clinical presentation of CEP
- Chronic, insidious onset over weeks to months.
- Most common symptoms:
- Cough (90%) is usually dry, or productive of scanty mucoid sputum. (Fishman 2023)
- Constitutional symptoms:
- Night sweats, fever (as high as 40C).
- Anorexia, weight loss (50%).
- Dyspnea (50%) is variable in severity, but rarely requires intubation.
- Wheezing (40%).
- Less commonly:
- May cause chest pain or hemoptysis.
- Rhinitis or sinusitis (20%). (Murray 2022)
laboratory studies in CEP
- Peripheral blood eosinophilia:
- Present in ~85% of patients. ~15% of patients may have eosinophil levels <500/uL. (26527441)
- Usually eosinophilia is 10-40%, but it may be as high as 80%.
- Usually >1,000/uL eosinophils.
- CRP (C-reactive protein) elevation is common.
- IgE elevation: IgE may be >1,000 IU/ml in 15% of patients. (Murray 2022)
radiology of CEP
alveolar infiltrates
- Quality:
- Non-segmental.
- Range from GGO (ground glass opacities) to dense consolidation.
- Margins are often ill-defined. (Walker 2019)
- Distribution:
- Peripheral (or, occasionally, both peripheral and central).
- Bilateral.
- Typically upper lobe predominant, with lower lung zone involvement being infrequent. (Murray 2022)
- Migration may occur over weeks-months (unlike simple pulmonary eosinophilia, where migration occurs faster).
- Disease recurrence may cause infiltrates to reappear in the same configuration as seen previously. (Walker 2019)
- Prevalence:
- Chest X-ray appears as the “photonegative of pulmonary edema” in ~25% of patients (i.e., a reverse batwing appearance).
- CT demonstrates a peripheral distribution of infiltrates in nearly all patients.
other features
- Septal thickening is common. (Murray 2022)
- Mediastinal lymphadenopathy may occur in ~25-50% of patients, but doesn't tend to be bulky.
- Small pleural effusions are uncommon, seen in only ~10% of patients. (Murray 2022)
- In longstanding disease (>2 months), band-like opacities and lobar atelectasis may be seen. (Walker 2019)
bronchoscopy in CEP
- Bronchoalveolar lavage invariably shows eosinophilia (which may range from 12-95% of leukocytes). (27231866) >40% eosinophils helps exclude helminth or fungal disease, supporting a more confident diagnosis of CEP. This cutoff is frequently listed in the literature, but it's a bit conservative.
- Endobronchial lesions may rarely be visible, with biopsy revealing eosinophilic infiltration. This is nonspecific, since similar lesions may occur with EGPA (eosinophilic granulomatosis with polyangiitis), hypereosinophilic syndrome, or even asthma. (26527441)
approach to diagnosis of CEP
main components of the diagnosis:
- Clinical presentation.
- Radiology.
- Blood eosinophilia.
- Bronchoscopy.
- Exclusion of alternative diagnostic possibilities.
- HES (hypereosinophilic syndrome) should be carefully considered (distinction is explored here: 📖).
diagnostic criteria
- (1) Diffuse alveolar consolidation with air bronchograms and/or ground-glass opacities, especially with peripheral predominance.
- (2) Eosinophilia at BAL >25-40% -OR- peripheral eosinophilia >1,000/uL.
- (3) Respiratory symptoms for at least 2-4 weeks.
- (4) No other known cause of eosinophilic lung disease (especially medications). (Murray 2022, 37055090)
management of CEP
steroid is the initial therapy
- The initial dose is usually ~0.5 mg/kg of prednisone. Patients should start improving within ~2-3 days, otherwise the diagnosis should be reconsidered. Fever and oxygenation improve first, whereas radiographic improvement may take 1-2 weeks. (Fishman 2023)
- Steroid may be slowly weaned off over a period of three months. A small study demonstrated equivalent outcomes when steroid was weaned over 3 months versus over 6 months. (25614171) Cottin 2023 recommends beginning with 0.5 mg/kg prednisone for two weeks, then 0.25 mg/kg prednisone for two weeks, followed by a gradual taper. (37055090)
response to therapy
- Complete resolution of symptoms and chest x-ray abnormalities usually occurs within 2-4 months.
- Response to therapy may be assessed based on the following parameters:
- Resolution of symptoms.
- Complete suppression of eosinophilia.
- Radiographic improvement in chest X-ray (in most cases).
- Improvement in pulmonary function tests (FVC, TLC, and DLCO).
relapse management
- Relapse is common and should respond to steroid (usually 20 mg/day prednisone is sufficient). (Murray 2022)
- If relapse is difficult to control with steroid, an alternative diagnosis should be considered (e.g., hypereosinophilic syndrome, or eosinophilic granulomatosis with polyangiitis).
- Biologic agents show promise as steroid-sparing therapy (e.g., mepolizumab, benralizumab).
patients with comorbid asthma
- In patients with comorbid asthma, asthma control often deteriorates following a diagnosis of CEP. More aggressive therapies for asthma may be required. It's conceivable that maintenance steroid inhalers may also reduce the likelihood of CEP recurrence.
basics
- Allergic bronchopulmonary aspergillosis (ABPA) involves the following sequence of events:
- (#1) Aspergillus fumigatus colonizes the airway. This isn't normal, but rather it tends to occur in people with airway abnormalities that prevent clearance of the fungus (e.g., mucus production due to cystic fibrosis or asthma).
- (#2) An IgE-mediated allergy to the colonizing Aspergillus develops. This causes the patient to be continually exposed to an antigen that incites allergic inflammation.
- (#3) Persistent inflammation leads to tenacious mucus production that causes airway obstruction, eventually leading to bronchiectasis.
- Clinically, ABPA often manifests as patients with asthma or cystic fibrosis whose disease becomes increasingly difficult to control (e.g., steroid-dependent asthma).
epidemiology of ABPA
- The most common age of onset is ~20-40 years old.
- Asthma:
- ~2% of all asthmatic patients are affected.
- ~10% of patients with steroid-dependent asthma are affected.
- ABPA usually occurs among patients with extensive history of atopia.
- May be more common among older patients.
- Cystic fibrosis: ~10% of patients are affected. (Fishman 2023)
- ABPA may rarely occur in other contexts that interfere with normal clearance of fungi from the airways (e.g., bronchiectasis, COPD).
clinical manifestations of ABPA
- The disease spectrum is broad, for example:
- Expectoration of mucus plugs (brown or tan flecks) is suggestive of ABPA.
- Constitutional symptoms: Fever, flu-like symptoms, weight loss.
- Bronchiectasis may eventually develop, leading to:
- Increased sputum production.
- Hemoptysis, which may occur in ~1/3 of patients (due to bronchiectasis).
- Digital clubbing.
diagnostic studies in ABPA
- Peripheral blood eosinophilia:
- Total IgE level:
- IgE is generally >1,000 ng/ml (>417 IU/ml).
- Normal IgE virtually excludes ABPA (in the absence of systemic steroid therapy).
- IgE correlates with disease activity (reduction by 25-50% may indicate remission, whereas increase by ~50% suggests relapse).
- IgE against Aspergillus fumigatus:
- Aspergillus fumigatus-specific IgE >0.35 kUa/L has 99% sensitivity for ABPA, so it's an ideal screening test. (37055090, 35236565) This is more sensitive than skin prick tests to identify sensitization.
- Specificity is ~70%, so this is not specific for ABPA. (35236565)
- Levels may increase following treatment of ABPA, so this cannot be used to monitor treatment efficacy. (35236565)
- IgG against Aspergillus fumigatus:
- This is a component of the clinical definition of ABPA (see below).
- High-level IgG may be more suggestive of CCPA (chronic cavitary pulmonary aspergillosis) than ABPA. (Murray 2022)
- Sputum fungal smear & culture:
- Hyphal elements may be seen on fungal smear.
- Culture is positive for Aspergillus in ~50% of patients. Repeat cultures may increase sensitivity. (Murray 2022)
- Specificity is limited, because Aspergillus is widely present. (35236565)
radiology of ABPA
[#1/3] migratory infiltrates
- Potential causes:
- (a) Atelectasis (2/2 bronchial obstruction).
- (b) Postobstructive pneumonia (2/2 bronchial obstruction).
- (c) Eosinophilic pneumonia.
- Mainly involve the upper lobe.
- Initially can mimic pneumonia.
- Infiltrates are often transient (lasting 1-6 weeks), but can persist for several months. (Fishman 2023)
[#2/3] mucus inspissation
- Mucus inspissation of bronchi (MIB), with or without high-attenuation mucus may occur. This is discussed further here: 📖
- A tree-in-bud pattern or centrilobular nodules due to bronchiolar impaction may also occur.
[#3/3] central bronchiectasis
- Bronchiectasis is present in ~80% of patients.
- Among patients with asthma, >3 lobes with bronchiectasis is very specific for ABPA.
- Bronchiectasis is typically central. However, in some patients it may eventually extend out to the lung periphery. (30713049)
- Bronchial wall thickening may be seen.
differential diagnosis of ABPA
The differential diagnosis will vary depending on the patient's specifics, but some common considerations may include:
- ABPA-adjacent conditions (discussed further in the section below):
- SAFS (severe asthma with fungal sensitivity).
- OATB (obstructive Aspergillus tracheobronchitis).
- Bronchocentric granulomatosis due to aspergillosis (patients usually have asthma and fulfill diagnostic criteria for ABPA).
- ABPM (allergic bronchopulmonary mycosis).
- CCPA (chronic cavitary pulmonary aspergillosis).
- Other causes of bronchiectasis: 📖
- Other causes of MIB (mucus inspissated bronchi): 📖
- Other causes of eosinophilic lung, especially those associated with asthma:
- CEP (chronic eosinophilic pneumonia).
- EGPA (eosinophilic granulomatosis with polyangiitis).
more detail about some ABPA-adjacent conditions
severe asthma with fungal sensitivity (SAFS)
- Basics: SAFS may be roughly conceptualized as a mild form of ABPA.
- Diagnostic criteria for SAFS:
- (1) Poorly controlled asthma despite >500 ug/d of fluticasone or equivalent, near continuous oral steroid (>50% of the time), or >1 oral steroid taper per year.
- (2) IgE is elevated but <1,000 ng/ml (<417 IU/ml).
- (3) Positive immediate skin test reactivity to Aspergillus fumigatus, or elevated specific serum IgE to A. fumigatus.
- (4) Absence of serum precipitins (by gel diffusion) or elevated specific serum IgG to A. fumigatus.
- (5) No radiographic evidence of bronchiectasis or infiltrates.
- Treatment:
obstructive Aspergillus tracheobronchitis (OATB)
- This involves some elements in common with ABPA:
- Mucus plugs due to Aspergillus fumigatus.
- Peripheral eosinophilia may occur.
- Elevated IgE against Aspergillus may occur.
- Further discussion: 📖
bronchocentric granulomatosis due to aspergillosis
- Basics:
- Bronchocentric granulomatosis is defined pathologically, by the replacement of bronchial mucosa with necrotizing granulomatous tissue. Eosinophilic infiltration of the bronchioles is prominent. Scattered fungal hyphae may be seen in half of cases.
- In many patients, bronchocentric granulomatosis may be considered to represent a severe and localized manifestation of ABPA (allergic bronchopulmonary aspergillosis). (Fishman 2023)
- Epidemiology:
- Aspergillus seems to be the cause in about half of all patients with bronchocentric granulomatosis.
- Patients usually have asthma and fulfill the clinical criteria of ABPA (allergic bronchopulmonary aspergillosis). (Murray 2022)
- Symptoms are usually chronic. They may include cough, hemoptysis, dull chest pain, and constitutional symptoms (low-grade fever, malaise). (Fishman 2023)
- Imaging:
- May be similar to ABPA, but lung involvement is more commonly focal and peripheral, often in an upper lobe.
- Occasionally, multiple nodular or mass-like lesions may simulate malignancy. (Fishman 2023)
- Differential diagnosis: Bronchocentric granulomatosis may also occur in response to other infections (e.g., tuberculosis, histoplasmosis, blastomycosis, mucormycosis, or invasive aspergillosis).
- Diagnosis requires biopsy.
- Management may include steroid and possibly additional therapies for ABPA.
allergic bronchopulmonary mycosis (ABPM)
- Allergic bronchopulmonary mycosis (ABPM) refers to a wider spectrum of pathogens which can produce ABPA-like illness.
- Aspergillus fumigatus is the most common cause of ABPM. However, other causes include: other Aspergillus species, Alternaria spp., Bipolaris spp, Candida albicans, Curvularia spp., Penicillium spp., Pseudallescheria boydii, Schizophyllum commune. These fungi share a common property of being able to grow at body temperature (thermotolerant).
- Non-aspergillus bronchopulmonary mycosis is similar to ABPA, but patients less frequently have a history of preceding asthma. (26621297) Diagnosis is based on the same general principles. Laboratory testing for sensitivity to rare fungi may be more difficult to obtain and interpret. Consequently, isolation of fungal species from sputum may have a greater role in identifying the involved fungus. In particular, the presence of fungal hyphae within eosinophilic mucus plugs is extremely suggestive of ABPM. (Ueki 2022)
diagnostic criteria for ABPA
Numerous diagnostic criteria for ABPA exist, but none is perfect. Diagnostic criteria may help draw attention to key elements of the diagnosis, but shouldn't be followed rigidly.
general diagnostic criteria for ABPA
- All of the following criteria are required (although some patients with early disease may not satisfy this). (2013 ISHAM criteria 23889240)
- (1) Either asthma or cystic fibrosis.
- (2) Elevated IgE levels:
- Typically should be >1,000 ng/ml (>417 IU/ml).
- However, if the patient meets all other criteria, then less markedly elevated IgE levels may be accepted.
- (3) Allergic hypersensitivity to Aspergillus, based on either:
- Aspergillus skin test positivity (immediate wheal and flare reaction).
- Elevated IgE against Aspergillus fumigatus.
- (4) Two of the following criteria:
- Presence of precipitins or IgG antibodies against Aspergillus fumigatus.
- Total eosinophil count >500 cells/uL in a steroid-naive patients (may be historical).
- Radiographic features consistent with ABPA. These may be transient (e.g., consolidation, nodules, finger-in-glove opacities, fleeting infiltrates) or permanent (e.g., bronchiectasis and pleuropulmonary fibrosis).
one schema for conceptualizing ABPA and adjacent conditions
treatment of ABPA
monitoring & when to treat
- ABPA can be controlled, but it cannot be cured. Consequently, monitoring of disease activity is important to properly titrate treatments. (33304395)
- Disease activity may be monitored every 2-3 months initially (including IgE levels, pulmonary function tests, and chest radiography).
- Infiltrates on chest X-ray:
- Overall, infiltrates may be the strongest indicator for treatment (as this may imply parenchymal lung tissue injury).
- Infiltrates should resolve after 1-2 months of therapy. (Fishman 2023)
- Recurrent disease may be heralded by recurrent pulmonary infiltrates in the absence of any symptoms. (Fishman 2023)
- IgE levels:
- IgE should decrease by >25-33% within six weeks of starting steroid therapy. (30713049)
- IgE levels usually don't normalize, but a new baseline level will be established after achieving disease control (often about half of the original IgE level).
- If IgE levels subsequently double compared to their baseline value, this suggests considering more aggressive therapy (even if the patient is asymptomatic). (Fishman 2023)
steroid
- Steroid is a front-line therapy for ABPA.
- An RCT demonstrated that a medium-dose regimen is as effective as higher doses of prednisone: (26585431)
- 0.5 mg/kg prednisone for 1-2 weeks.
- 0.5 mg/kg prednisone on alternate days for 6-8 weeks.
- Dose reduction by 5-10 mg every two weeks, until discontinuation.
- ⚠️ Chronic cavitary pulmonary aspergillosis may occur as a complication of ABPA in ~5-10% of patients. If this occurs, then the use of steroid could be harmful. (35236565)
itraconazole 💉
- Itraconazole is generally utilized as a steroid-sparing agent. It reduces airway inflammation, disease recurrence, and disease progression. The duration of therapy isn't standardized, but itraconazole is often continued for at least 4-6 months (200 mg BID). (Murray 2022)
- One randomized controlled trial compared itraconazole monotherapy versus prednisolone among 131 patients with ABPA and asthma. Both therapies had equivalent effects on IgE levels, time to exacerbation, and lung function. Prednisolone was slightly more effective overall (response of 100% vs 88%), but this came at the cost of increased side effects in the prednisolone group. This trial provides robust evidence that itraconazole is an effective therapy for ABPA with the potential to help minimize steroid exposure. (29331473)
- Itraconazole interacts with numerous medications, including budesonide and fluticasone. Thus, inhaled beclomethasone or ciclesonide may be the preferred inhaled steroid in this context. (Murray 2022)
- Voriconazole might be even more effective than itraconazole, with one RCT suggesting equal efficacy compared to prednisolone. (30049743) Increased efficacy of voriconazole as compared to itraconazole could relate to superior bioavailability and/or increased efficacy against Aspergillus (noting that voriconazole is generally considered a front-line agent for serious Aspergillus infection). Currently, voriconazole may be used as an alternative therapy in patients with a contraindication to itraconazole, or in patients who fail to respond to itraconazole.
adjunctive therapies
- Asthma therapies for patients with asthma:
- Patients should receive guideline-directed asthma therapies.
- Inhaled steroid may be helpful for treatment of intercurrent asthma. However, it's unclear whether this can treat ABPA. (21498933)
- Bronchiectasis should be managed with usual therapies, if present (e.g., airway clearance). 📖
- AFRS (allergic fungal rhinosinusitis) should be treated if present. Treatment of this may include debridement of the sinuses, along with medical management (e.g., steroid and itraconazole). (35236565)
biologic therapies 📖
- Mepolizumab (anti-IL5) decreased steroid use, decreased exacerbations, and improved quality of life in a series of 20 patients with ABPA and asthma. (32052155) RCTs are lacking, but given the ability of IL5 inhibition to suppress eosinophil activity, this would seem to be a rational therapy.
- Omalizumab (a monoclonal IgG1 antibody that functions as an IgE-receptor blocker) may be useful in refractory disease. (30713049)
ABPA in the context of cystic fibrosis (CF)
basics of ABPA in cystic fibrosis
- ABPA occurs in 10% of patients with cystic fibrosis.
- Diagnosis of ABPA in cystic fibrosis is more challenging than in asthma, because patients with CF may have bronchiectasis and mucus plugging at baseline.
features that may support a diagnosis of ABPA include:
- Clinical features of atopy:
- Asthmatic features (i.e., PFTs show reversible airway obstruction).
- Other clinical features of atopy.
- Peripheral eosinophilia.
- IgE >1,000 ng/ml (>417 IU/ml).
- Immunologic sensitivity to Aspergillus:
- IgE anti-Aspergillus antibody.
- IgG anti-Aspergillus antibody.
- Clinicoradiological divergence from usual findings in cystic fibrosis, e.g.:
- Abnormalities on chest imaging unresponsive to antibiotics and standard therapy for cystic fibrosis.
- High-attenuation mucus is suggestive of ABPA.
- Clinical deterioration not attributable to another cause. (32920094)
management
- Treatment is generally extrapolated from patients with asthma (as discussed above).
- One study reported successful use of an abbreviated steroid regimen when combined with prolonged itraconazole therapy. (32147521)
- Prednisone was tapered off over 18 days (2 mg/kg/day for three days, then 1 mg/kg/day for five days, then 0.5 mg/kg/day for five days, then 0.25 mg/kg/day for five days, then off). Meanwhile, itraconazole was continued as maintenance therapy for a year.
- More aggressive use of itraconazole with minimization of steroid dosing may be especially beneficial in patients with cystic fibrosis, to optimize bone health.
epidemiology of EGPA
- EGPA is extremely rare (~1 per 3 million).
- Disease onset usually occurs between the ages of ~40-50 and only rarely above >65 years old. (Fishman 2023)
- EGPA occurs almost exclusively among patients with atopic asthma (99%).
- Asthma is usually longstanding and difficult to control.
- Most patients also have allergic rhinitis.
clinical evolution of EGPA
These phrases describe the typical disease evolution. However, these don't invariably occur in order. An individual patient may present with more of an eosinophilic infiltrative or vasculitic phenotype. (37055090)
[1] prodromal atopic phase
- Asthma is the central feature (present in ~95% of patients). (20118383)
- Rhinosinusitis and/or nasal polyposis are common (~70% of patients). (Fishman 2023; 37055090)
- Septal nasal perforation does not occur (unlike granulomatosis with polyangiitis).
- Serous otitis media may occur. (32194765)
- This phase usually lasts for years.
[2] eosinophilic infiltrative phase/phenotype (~60%)
- Marked blood eosinophilia and eosinophilic tissue infiltration may cause:
- Eosinophilic pneumonia (usually resembles chronic eosinophilic pneumonia).
- Gastrointestinal involvement (eosinophilic enteritis).
- Eosinophilic myocarditis.
- Eosinophilic cellulitis.
- This phase may last for years (with remission and recurrence).
- Patients are often ANCA-negative.
[3] vasculitic phase/phenotype (~40%)
- Vasculitis may cause:
- Mononeuritis multiplex.
- Palpable purpura.
- Necrotizing glomerulonephritis.
- Manifestations related to the ear, nose, and throat. (28767340)
- Alveolar hemorrhage due to capillaritis (rare).
- Constitutional symptoms may include fever, weight loss, myalgias, and arthralgias. (Fishman 2023)
- Patients are more likely to be ANCA-positive.
organ system involvement in EGPA
pulmonary & sinuses (>90%)
- Asthma and rhinosinusitis (discussed further in the section above).
- Eosinophilic pneumonia: Often similar in presentation to CEP (chronic eosinophilic pneumonia), but this may also be acute. (37055090)
- PE (pulmonary emboli) risk also increases in EGPA.
skin (~60%)
- Palpable purpura.
- Subcutaneous nodules (especially involving scalp and extensor surfaces of extremities). (Murray 2022, 36198182)
- Erythematous rashes.
- Urticaria.
neurologic & neuromuscular
- Peripheral involvement:
- Mononeuritis multiplex (~75%).
- Weakness or neuropathic pain can occur.
- Diaphragmatic paralysis due to phrenic nerve involvement can occur. (32194765)
- The central nervous system is less often affected (e.g., cranial nerve impairment, seizure, subarachnoid hemorrhage, cerebral infarction). (Fishman 2023)
cardiac
- Epidemiology of cardiac involvement:
- Cardiac involvement occurs in <20% at diagnosis but eventually in ~40%.
- Although less common, cardiac involvement is a primary cause of death.
- Cardiovascular involvement correlates with eosinophilic tissue infiltration (rather than vasculitis). Patients with cardiac involvement are usually ANCA-negative. (30526985)
- Pericarditis or pericardial effusion.
- Eosinophilic myocarditis:
- Predominant type of cardiac involvement.
- Late gadolinium enhancement in a subendocardial location on MRI may suggest EGPA, unlike other nonischemic cardiomyopathies. (35396053)
- Other findings may include
- Conduction system disease.
- Myocardial infarction due to vasculitis.
- (Endomyocarditis and mural thrombus are uncommon – and would potentially suggest hypereosinophilic syndrome.)
gastrointestinal
- Eosinophilic esophagitis, gastroenteritis, or colitis may occur. (27231866)
- Mesenteric vasculitis may cause pain, diarrhea, gastrointestinal bleeding, or perforation.
kidney
- Glomerulonephritis may occur in ~50% of patients.
- Renal failure occurs in only ~10%.
laboratory tests in EGPA
- Peripheral eosinophilia:
- It occurs in virtually all patients, although eosinophilia may be masked by steroids.
- 80% of patients have >1,000 eosinophils/uL.
- Eosinophils are usually between 5,000-20,000/uL or 20-90% of the leukocytes. (Murray 2022; Fishman 2023)
- IgE:
- Elevated in 75% of patients.
- IgE levels are typically 500-1,000 ng/mL.
- ANCA is found in only 40%:
- Usually, the type is pANCA, anti-MPO antibodies.
- ANCA-negative patients are more likely to have prominent eosinophilic tissue infiltration. (25091763) Alternatively, ANCA-positive patients are more likely to have prominent vasculitic manifestations. (27231866) These clinical phenotypes are discussed above in the section on the clinical evolution of EGPA.
- If anti-PR3 is found, this suggests the possibility of GPA (granulomatosis with polyangiitis) – which may be associated with eosinophilia.
- CRP is commonly elevated. (27231866)
radiology in EGPA
parenchymal involvement is similar to other eosinophilic pneumonias (primary finding)
- Fleeting alveolar infiltrates are most common. They are usually non-lobar and nonsegmental. The density of opacities ranges from ground glass opacities to consolidation. The overall pattern may be indistinguishable from CEP (chronic eosinophilic pneumonia) or simple pulmonary eosinophilia.
- Distribution:
- There is often a peripheral predominance.
- There is no predominance of upper or lower lung fields. (Walker 2019)
- Nodular lesions are occasionally seen within areas of ground glass opacification.
- Interlobular septal thickening is relatively common (~50% of patients). This may reflect heart failure, eosinophilic infiltration of the septa, or mild fibrosis. (Shepard 2019)
airway abnormalities include
- These findings may also be seen in asthma:
- Tree-in-bud pattern of centrilobular nodules (<10 mm).
- Bronchial wall thickening.
- Occasionally, bronchiectasis may occur. (Murray 2022)
pleural effusion (~25% of patients)
- Effusions are usually mild. They may result from various pathophysiological processes:
- (1) Effusion(s) may be due to cardiomyopathy.
- (2) Effusion(s) may be due to eosinophilic pleuritis.
- Clinically, this can be suggested by pleuritic chest pain.
- Pleural fluid analysis reveals exudative effusions, with elevated levels of eosinophils and low glucose. (Fishman 2023)
other findings
- DAH (diffuse alveolar hemorrhage) due to alveolar capillaritis is rare. (27231866)
- Irregular stellate configuration of pulmonary vessels may be seen. (Fishman 2023)
- Mediastinal lymphadenopathy can occur in ~25% of patients. (27719981)
invasive diagnostic studies in EGPA
bronchoscopy
- Bronchoscopy may be useful for evaluating eosinophilia and excluding infection. Diagnostic criteria include an eosinophilia of >25% (see below).
- Transbronchial biopsy is generally inadvisable, given its inability to reliably assess for vasculitis.
tissue diagnosis
- Tissue diagnosis is desirable but not always needed.
- Potential sites for biopsy include:
- Skin (safest site; among patients with palpable purpura, skin biopsy invariably shows necrotizing vasculitis that can be accompanied by extravascular granulomas). (37161084)
- Kidney (if active glomerulonephritis).
- Nerve, muscle.
- Gastrointestinal tract (seldom used in clinical practice). (37161084)
- Lung biopsy is seldom pursued. If a biopsy is undertaken, a surgical biopsy is desirable to obtain adequate tissue to evaluate the blood vessels. Histologic findings include eosinophilic infiltrates and necrotizing granulomatous vasculitis.
- Biopsies of sinonasal mucosa or polyps are often nondiagnostic. (37161084)
diagnosis in EGPA
- Numerous diagnostic criteria exist for EGPA, but none have been properly validated for prospective diagnosis (especially for patients without a tissue biopsy demonstrating vasculitis). Guidelines caution against the use of any diagnostic criteria. (37055090)
- The differential diagnosis for eosinophilic lung disease with multisystem organ manifestations is explored above: ⚡️
- Some similar diagnoses that should be differentiated from EGPA include:
- HES (hypereosinophilic syndrome) should be carefully considered (the distinction is explored here: 📖)
- Granulomatosis with polyangiitis (GPA) can sometimes present with peripheral or tissue eosinophilia. (37161084)
- HIV. (37161084)
- IgG4-related disease. (37161084)
- Idiopathic systemic eosinophilic vasculitis (occurs in patients without asthma). (37055090)
management of EGPA
remission induction
- (1) Steroid is the primary remission induction agent for all patients. However, the optimal dose remains unclear. (Fishman 2023)
- Prednisone is often started at 1 mg/kg/day for 3-4 weeks, followed by a taper to 5-10 mg/day by 12 months. (Murray 2022, )
- An initial pulse of methylprednisolone 500-1,000 mg/day IV for 3 days may be indicated in the most severe cases, especially with myocardial involvement. (Murray 2022, 36198182, 37161084)
- (2) The Five-Factor Score may be used to determine if an additional agent is needed for induction therapy.
- Original five-factor score: (37161084)
- Renal insufficiency (creatinine >1.7 mg/dL).
- Proteinuria >1 gram/day.
- Cardiac involvement.
- GI involvement.
- CNS involvement.
- Revised five-factor score: (37161084)
- Age >65.
- Renal insufficiency (creatinine >1.7 mg/dL).
- Cardiac involvement.
- GI involvement.
- Absence of ear, nose, and throat involvement.
- Patients with a five-factor score of zero may receive induction therapy with steroids alone, at prednisone 0.5-1 mg/kg/day. (27231866)
- Patients with a five-factor score of one or higher require more aggressive induction therapy. However, aside from the five-factor score, there are additional disease manifestations that may indicate the need for more aggressive induction (e.g., fulminant mononeuritis multiplex, ocular involvement, severe alveolar hemorrhage). (Murray 2022) The optimal second agent for patients with more severe disease is unclear:
- Guidelines recommend either rituximab or cyclophosphamide. (37161084) Rituximab might have a relatively greater benefit for patients with anti-MPO antibodies. (de Moraes 2024)
- Other options could potentially include azathioprine, methotrexate, or mepolizumab (the latter was demonstrated to be effective in an RCT). (28514601)
- Original five-factor score: (37161084)
maintenance therapy
- Maintenance immunosuppression is generally also required. If cyclophosphamide is used to induce remission, cyclophosphamide will usually be transitioned to a less toxic agent after 4-6 months. (Fishman 2023)
- Options for maintenance therapy include the following treatments, which function as steroid-sparing agents:
- Rituximab (severe disease only).
- Mepolizumab.
- Traditional immunosuppressives (e.g., azathioprine or methotrexate).
- Steroids should be tapered to the minimal effective dose. (37161084)
disease monitoring & relapse
- Biomarkers often don't correlate well with disease activity. (37161084) Nonetheless, the following factors may sometimes be trended over time:
- IgE level.
- Peripheral eosinophil counts (ideally maintaining the absolute eosinophil count <1,000/uL). (33002503)
- (Note that p-ANCA is not generally helpful in monitoring disease activity). (Fishman 2023)
- Respiratory relapses:
- Defined as an isolated exacerbation of asthma and/or ear/nose/throat manifestations. A relapse of asthma alone will usually be associated with a peripheral eosinophil count <1,000/uL. (Murray 2022)
- Treatment usually involves steroids and mepolizumab, as well as optimization of asthma treatment.
- Systemic relapse:
- Defined as the involvement of additional organ systems.
- Severe systemic relapse is treated similarly to initial induction therapy.
- Nonsevere systemic relapse may be treated with steroids and mepolizumab. (37161084)
biological therapies
- Agents specifically targeting eosinophil activity may control EGPA and comorbid asthma (with a superior side-effect profile compared to steroids).
- A multicenter RCT involving patients with relapsed or refractory disease found that mepolizumab 300 mg monthly (an anti-IL5 monoclonal antibody) improved remission rates, reduced steroid dosing, and decreased the relapse rate. (28514601) Consequently, mepolizumab was FDA-approved for this application.
- Small uncontrolled series have similarly suggested benefits from reslizumab and benralizumab. (33065367)
Hypereosinophilic syndromes (HES) refer to a group of syndromes involving peripheral eosinophilia (>1500/uL) that causes end-organ damage. More common syndromes include the following:
myeloid HES:
- Basics:
- Primary problem is a clonal proliferative of eosinophils with myeloproliferative features (e.g., hepatosplenomegaly, anemia, thrombocytopenia).
- Usually this is caused by a FIP1L1-PDGFRalpha fusion gene that promotes proliferation (that may be detected via PCR).
- Epidemiology: male predominance, most often seen in patients 20-40 years old. (27178895)
- Common clinical features: splenomegaly, skin, pulmonary, cardiac involvement. (Taton 2022)
lymphocytic HES:
- Basics:
- Primary problem is an abnormal clone of T-cells that secrete excessive amounts of IL-5. Underlying T-cell lymphoma needs to be excluded (and unfortunately, about 10% of patients will eventually progress to overt T-cell lymphoma over several years). (Taton 2022)
- IL-5 stimulates the nonclonal proliferation of eosinophils.
- Epidemiology: equally common in men and women.
- Clinical manifestations: skin, lymphadenopathy, rheumatological manifestations. (36485140, Taton 2022)
idiopathic HES:
- Hypereosinophilic syndrome without identified cause that isn't due to myeloid HES or lymphocytic HES.
clinical presentation of HES
Almost any organ can be affected (either with eosinophilic infiltration or thromboembolism). Additionally, nonspecific constitutional symptoms may be present (fever, night sweats, anorexia, weight loss). More common organ-system manifestations are listed below. Different types of HES tend to affect different organs, as shown in the following figure:
cardiac involvement is often prominent (60%), and may include:
- Endocardium involvement causing thrombus formation.
- Endomyocardial fibrosis causing restrictive cardiomyopathy.
- Dysfunction of chordae tendineae causing mitral and tricuspid regurgitation.
- Arrhythmia.
- Heart block.
- Pericarditis is less frequent. (27231866)
pulmonary (40%)
- Overall, respiratory manifestations are usually mild. (Murray 2022) Pulmonary involvement is much more common with myeloid HES than with lymphocytic HES. (Taton 2022)
- Eosinophilic airway infiltration:
- Chronic dry cough may be a prominent feature, along with wheezing and dyspnea.
- Pulmonary function tests may show an obstructive pattern. (ERS handbook 3rd ed.) However, asthma is uncommon (if encountered, asthma would be more suggestive of another eosinophilic lung disease, such as eosinophilic granulomatosis with polyangiitis). (20118383)
- Eosinophilic pneumonia.
- Pulmonary vascular disease:
- (i) Thrombotic pulmonary embolism.
- (ii) Eosinophilic inflammation of the pulmonary arteries may cause pulmonary arterial hypertension that is reversible with anti-eosinophil therapy. (Taton 2022)
- Cardiogenic pulmonary edema.
- Other potential manifestations:
- Angioedema.
- Pleural effusion.
- Chronic rhinosinusitis, polyposis.
gastrointestinal
- Eosinophilic esophagitis, gastroenteritis, colitis.
- Ascites.
- Hepatitis, cholangitis.
- Cholecystitis. (Taton 2022)
skin
- Urticaria, angioedema, erythroderma, or dermatographia (especially in lymphocytic HES).
neurologic
- Peripheral neuropathy.
- Ischemic cardioembolic stroke(s).
- Encephalitis.
other
- Renal thrombotic microangiopathy. (29395353)
- Lymphadenopathy, splenomegaly.
- Arterial/venous thrombosis, Raynaud phenomenon, digital necrosis.
- Fasciitis, myositis, synovitis, arthritis. (Taton 2022)
laboratory studies in HES
myeloid HES
- Blood count may show:
- Anemia.
- Thrombocytopenia.
- Increased circulating myeloid precursors.
- Dysplastic eosinophils.
- Markers of myeloproliferative disorders may be seen:
- Elevated B12 levels (>1000 pg/mL). (27231866, Taton 2022)
- Elevated leukocyte alkaline phosphatase (not widely available).
- Elevated tryptase level (>12 ng/mL) is a marker of myeloid HES, correlating with increased end-organ fibrosis. (27231866, Taton 2022)
- PCR to evaluate for various fusion genes (including FIP1L1-PDGFRalpha) is the definitive diagnostic test. This is a send-out test panel (e.g., Mayo Clinic test ID EOSDF).
lymphocytic HES
- IgM and IgG levels are usually elevated. (27231866, 36485140)
- Diagnosis involves identification of a clonal and/or aberrant T-cell population in peripheral blood. (36485140)
chest radiology may reveal a variety of abnormalities in HES
- Small nodules with or without a halo of ground-glass attenuation. (Murray 2022)
- Focal areas of ground glass attenuation or consolidation, mostly in the periphery. (Murray 2022) There is no predominance of upper- or lower-lobe infiltrates. (Walker 2019)
- Pleural effusion(s).
- Interlobular septal thickening, bronchial wall thickening. (27719981)
- Lymphadenopathy.
- Cardiogenic pulmonary edema may result from heart failure.
diagnosis of HES
differentiation of HES from CEP (chronic eosinophilic pneumonia) or EGPA (eosinophilic granulomatosis with polyangiitis)
- These diseases can involve several similar features:
- Airway involvement (CEP and EGPA are associated with asthma; HES may cause cough and airflow obstruction).
- Peripheral eosinophilia.
- Eosinophilic pneumonia.
- Sinus involvement.
- Some clinical features that may be helpful:
- Extrapulmonary manifestations indicate either EGPA or HES (whereas CEP should involve only the lungs).
- Asthma diagnosis (based on pulmonary function tests) would argue against HES.
- CRP (C-reactive protein) is generally elevated in EGPA, but not in HES. One study comparing these two disorders found that a CRP level <36 mg/L was 95% sensitive and 94% specific for a diagnosis of HES as opposed to EGPA. (30317003)
- ANCA positivity supports EGPA. Unfortunately, ANCA is only ~40% sensitive for EGPA, so ANCA will generally be negative (which is nonspecific).
- IgE levels 📖 may be elevated in CEP or EGPA. Most patients with pulmonary manifestations due to HES will have myeloid HES, which does not generally increase IgE levels (although IgE levels may be elevated in lymphocytic HES). (30504328)
- Clinical differentiation can be impossible, especially early in the disease course. If doubt exists, blood PCR to evaluate for myeloid HES may help exclude HES prior to diagnosing the patient with CEP or EGPA. (Taton 2022)
role of invasive diagnostic tests
- Bone marrow biopsy may be needed to exclude underlying malignancy (consult hematology if doubt exists).
- Bronchoalveolar lavage:
- May be used to confirm the presence of eosinophilic pneumonia.
- May be helpful to exclude alternative diagnoses (e.g., infection).
- Lung biopsy:
- Histopathology usually doesn't have a substantial role in diagnosis.
- Lung pathology may not allow for differentiation between HES and other forms of eosinophilic pneumonia, such as CEP (chronic eosinophilic pneumonia). (Taton 2022)
- The main rationale for a biopsy would be to differentiate between HES versus EGPA (eosinophilic granulomatosis with polyangiitis). Finding eosinophilic granulomas or necrotizing vasculitis would support a diagnosis of EGPA.
management of HES
initial approach to HES with severe manifestations
- Steroid:
- Steroid is the mainstay of therapy for most types of hypereosinophilic syndrome, especially acute management among patients with severe manifestations. (27231866) A common dose is prednisone 1 mg/kg daily, but this may need to be adjusted based on disease severity.
- ⚠️ Myeloid HES patients are often refractory to steroid monotherapy. (36485140) This may be especially problematic among patients with predominantly pulmonary involvement (which is frequently caused by myeloid HES).
- Imatinib may be initiated if there is suspicion of myeloid HES.
- Ivermectin: Patients with possible exposure to endemic areas of Strongyloides should be empirically treated with ivermectin (200 ug/kg PO once). (27231866)
myeloid HES
- Front-line therapy generally involves a combination of:
- (1) Prednisone 1 mg/kg/day initially.
- (2) Imatinib mesylate 100 mg/day. (Taton 2022)
- If successful, imatinib will cause eosinophils to die. This may cause massive release of eosinophil granule contents, causing a transient disease exacerbation (e.g., cardiac decompensation). (27231866)
- Co-administration of steroid during initial therapy may prevent clinical deterioration.
- Second-line therapies might include: (Taton 2022)
- JAK (Janus kinase) inhibitors.
- Imatinib mesylate dosed up to 400-800 mg/day may be effective in a subset of patients who fail to respond to lower doses. Alternatively, other tyrosine kinase inhibitors may be used for patients with imatinib resistance (e.g., dasatinib, nilotinib, sorafenib). Selection may depend on an individual patient's specific genetic rearrangement. (Murray 2022)
- Hydroxyurea.
- Pegylated interferon-alpha.
lymphocytic HES
- Front-line initial therapy for patients with active disease usually involves steroid.
- Biologic therapies targeted against eosinophils may be very helpful:
- Mepolizumab (monoclonal antibody against IL5) may be especially beneficial, and is now FDA-approved.
- Benralizumab may also be utilized (a biologic agent that blocks the IL5 receptor). (27231866)
epidemiology
- Simple pulmonary eosinophilia can be idiopathic, but it's generally caused by either helminths or medications:
- Parasitic infection, e.g.:
- Ascaris lumbricoides.
- Strongyloides.
- Toxocara canis.
- Medications & exposures:
- In modern practice, medications may be the most common etiology.
- See the list above 📖.
clinical presentation
- Acute onset, usually with resolution over a month.
- (1) Nonspecific pulmonary symptoms (which may be minimal or absent).
- Nonproductive cough.
- Dyspnea, wheezing.
- Blood-tinged sputum.
- (2) Constitutional symptoms (fevers, myalgias).
- (3) Rash.
laboratory studies
- Peripheral eosinophilia (often >60%).
- If caused by helminth infection: Stool for ova/parasites will be negative initially, but may become positive after 2-3 months.
imaging
- Radiographic features are usually more dramatic than pulmonary symptoms (which may be minimal or absent).
- The overall picture is often similar to CEP (chronic eosinophilic pneumonia). The distinguishing feature is that in simple pulmonary eosinophilia infiltrates migrate over a period of days, whereas in CEP infiltrates migrate over a period of weeks-months.
- Migratory, ill-defined, patchy, non-segmental consolidations.
- Distribution:
- Peripheral distribution is the most notable aspect of the distribution.
- Upper and middle lung predominance. (Shepard 2019)
- Abnormalities are migratory (resolving in some areas and reappearing in others over a course of days).
- Nodules may be seen on CT scan in ~40% of cases. A halo sign of surrounding ground glass opacification is frequently seen.
- Bronchial wall thickening is commonly seen. (27719981)
- Features that should not be seen: (Shepard 2019)
- Cavitation.
- Pleural effusion.
- Lymphadenopathy.
management
- (1) Treat the underlying cause:
- Discontinue any offending medication.
- Treat a parasitic infection, if found. Follow-up stool examination for ova/parasites may be indicated over a 2-3 month period, to identify and treat an infection.
- (2) The disease is otherwise generally self-limited.
- Steroids usually aren't needed.
basics
- Strongyloides is unique due to its ability to persist and replicate within a human host. This may allow for persistent infection over decades, as well as disseminated hyperinfection due to immunosuppression.
- Strongyloides is an important consideration when initiating immunosuppressive therapy (especially steroids), as this may precipitate a life-threatening Strongyloides hyperinfection.
- As Strongyloides migrate around the body, they ferry enteric bacteria with them. In some cases this may be a source of bacteremia or even bacterial CNS infection (which can be polymicrobial).
epidemiology: acquisition of strongyloidiasis
- Strongyloides is primarily located in tropical and subtropical areas (especially within Africa, Southeast Asia, Central America, South America, and the Caribbean). Within the United States, it is endemic within the southern United States and Appalachia.
- Infection may be acquired due to contact with soil, or ingestion of contaminated food.
- Following acquisition, infection may persist for up to ~50 years.
chronic strongyloidiasis
clinical presentation of chronic strongyloidiasis
- Patients are usually asymptomatic, but intermittent symptoms can occur.
- Gastrointestinal:
- Heavy worm burden may cause epigastric discomfort, nausea/vomiting, small bowel obstruction or ileus, or gastrointestinal bleeding.
- A mild chronic colitis may occur, with protein-losing enteropathy. This may lead to weight loss and malabsorption.
- Dermatologic:
- Larval invasion of the perianal region may cause transient, raised, red serpiginous lesions over the buttocks and lower back.
- Migrating larvae may cause a pathognomonic eruption due to “larva currens” – a pruritic, raised lesion advancing as fast as 1 cm/hr.
- If Strongyloides isn't treated, this may recur intermittently over a period of decades.
- Pulmonary symptoms:
- Migration of worms through the lungs may cause coughing, wheezing, and hemoptysis (Loeffler syndrome). Repeated episodes may be misdiagnosed as bacterial pneumonias or as asthma exacerbations. (Fishman 2023)
- Radiologically this will resemble simple pulmonary eosinophilia. 📖
diagnosis of chronic strongyloidiasis
- Eosinophilia may be seen in ~10-70% of patients.
- A clue may be that patients have chronic, low-level eosinophilia for months to years.
- Serology for Strongyloides (e.g., IgG measurement using ELISA).
- This is the best screening test for chronic infection.
- It has a sensitivity of ~90%. False-negative results can occur in the context of immunocompromise (especially hyperinfection syndrome). (Fishman 2023)
- Specificity is >95%, due to some cross-reactivity with other helminths.
- Stool for ova and parasites:
- Patients often have a low worm burden, so stool examination is negative in ~50-75% of patients.
- ⚠️ Negative stool ova/para does not exclude chronic strongyloidiasis.
treatment of chronic strogyloidiasis
- Even if patients are asymptomatic, treatment is indicated to prevent subsequent risk of hyperinfection.
- Standard therapy is a single dose of oral ivermectin (200 mcg/kg PO). Previously two doses were utilized, but an RCT demonstrated that a single dose is equally efficacious. (31558376) This is 85% effective. Serologies may be obtained 3-6 months later to confirm eradication (post-treatment serology should be <60% of pretreatment levels, otherwise repeat therapy may be considered). (29395353)
- Empiric therapy: If there is a substantial concern for strongyloidiasis and the patient needs to be started on steroid immediately, it may be reasonable to treat empirically (to avoid precipitating hyperinfection). (35396957) This depends on several factors:
- (1) The likelihood of Strongyloides (empiric therapy is most reasonable for patients with a history of living in hyperendemic regions and who also have eosinophilia)
- (2) The turnaround time for Strongyloides serologies.
- (3) The intensity of immunosuppression (more intense immunosuppression carries a higher risk of triggering Strongyloides hyperinfection).
strongyloides hyperinfection
most common causes of Strongyloides hyperinfection
- Immunosuppressive medications:
- Steroid may be the most common precipitant. Prolonged steroid carries the highest risk (e.g., prednisone ≧20 mg/day for >1 month), but cases have been reported following as few as six days of treatment. (32561442, 35396957)
- Transplantation (stem cell or solid organ).
- Tumor necrosis factor inhibition.
- Rituximab.
- Chemotherapy.
- Hematologic malignancies.
- HIV, HTLV-1 (human T-cell lymphotropic virus).
- Additional factors that may promote hyperinfection include chronic renal failure, malnutrition, diabetes, and alcoholism.
clinical presentation of Strongyloides hyperinfection
- Gastrointestinal:
- Gastrointestinal symptoms are prominent.
- Severe enterocolitis may cause pain, nausea/vomiting, diarrhea, ileus, obstruction, and bleeding.
- Dermatologic:
- Serpiginous urticarial rashes may occur (“larva currens”).
- Purpuric and petechial rashes may occur, sometimes in a periumbilical pattern.
- Pruritus ani.
- Pulmonary:
- Cough, wheezing, and hemoptysis may occur.
- Radiology may initially show a micronodular pattern (which can mimic miliary tuberculosis). However, eventually this may worsen with the development of diffuse pulmonary infiltrates. Worms traffic bacteria into the lungs, which may eventually lead to a superimposed polymicrobial bacterial pneumonia.
- Bacterial infection:
- Meningitis or brain abscess may occur.
- Gram-negative bacteremia may occur, which may cause septic shock.
diagnosis of Strongyloides hyperinfection
- Eosinophil counts are usually normal. (Fishman 2023)
- Strongyloides may be found in most body fluids (e.g., sputum, bronchoalveolar lavage, urine, ascitic fluid, and even cerebrospinal fluid). Stool examination for ova and parasites has high sensitivity.
- Skin biopsy may be helpful (larvae are seen in and around blood vessels with extravasated erythrocytes).
- Bacteremia and/or fungemia with enteric flora may occur (worms carry these pathogens from the gut into the bloodstream). (35396957)
- Strongyloides serology. (35396957)
treatment of Strongyloides hyperinfection
- Mortality may be high, so aggressive therapy is needed.
- Anthelmintic therapy:
- Single or combination therapy may be used (e.g., ivermectin +/- albendazole).
- Ivermectin may not be absorbed well due to gastrointestinal involvement, so rectal or IV/SC administration may be considered if available. Prolonged therapy with ivermectin may also be needed (e.g., 200 ug/kg/day for a minimum of 14 days and until the stool is negative). (35396957)
- Broad-spectrum antibacterial therapy may be indicated for management of polymicrobial bacterial infections caused by migrating larvae (e.g., pneumonia, bacterial CNS infection).
- Immunosuppressive therapy should be weaned, as able.
basics
- Eosinophilic bronchitis involves cough without airflow obstruction or abnormal chest imaging.
epidemiology
- Accounts for ~20% of chronic cough referred to pulmonology clinics. (ERS handbook 3rd ed.)
- Associations:
- Some medications.
- Occupational exposure to acrylates, welding fumes, formaldehyde, isocyanate, or flour. (Murray 2022)
clinical presentation
- Patients generally present with chronic cough.
- Sometimes a triggering occupational exposure or inhaled allergen can be identified. (ERS guideline 3rd ed.)
diagnostic studies/criteria
- (1) Spirometry and methacholine challenge are normal.
- (2) Chest imaging is normal.
- (3) Evidence of eosinophils:
- >3% sputum eosinophils (although most laboratories cannot analyze this).
- Blood eosinophil levels may be somewhat higher than normal (e.g., mean of 350/mm3). (33002503) This may be similar to eosinophilic asthma (figure below).
- (Bronchoalveolar lavage eosinophil counts are generally low.). (34311509)
treatment
- Inhaled steroid is generally effective.
- Avoidance of any potentially causative antigens or medications.
- Some patients may progress to develop chronic airflow obstruction. (Piggott 2022)
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References
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