HYPERSENSITIVITY PNEUMONITIS AND

PULMONARY EOSINOPHILIA SYNDROMES

Presented by : Dr. AneeshModerators : Dr. Gayathri Devi and Dr. Pavan Kumar

HYPERSENSITIVITY PNEUMONITIS

INTRODUCTION• First described in 1874• Also called extrinsic allergic alveolitis• Definition: It is an inflammatory disorder of the lung involving

alveolar walls and terminal airways that is induced by repeated inhalation of a variety of organic agents in a susceptible host.

• Despite the words ‘hypersensitivity’ and ‘allergic’ it is not an atopic illness*

• 80-95% cases are non smokers – anti inflammatory effects of nicotine

• Active smoking history – reduces likelihood of diagnosing HP• Frequency of hypersensitivity pneumonitis depends on…

Environmental exposureSpecific antigenSeason of the yearGeographic locationOccupational exposure

CAUSATIVE AGENTS

CAUSATIVE AGENTS

Antigen exposure

Immune complex

mediated injury

Perpetuation of injury by T-cell

activity

• Most evidence suggests T-cell mediated events• Humoral immunity especially in acute HP – not been excluded• HP – example of an immune mediated lung injury

• At clinical presentation – T cell driven inflammation• Predominantly CD8+ based response• IFNγ is expressed along with CXCL9 and CXCL10*• IL12 , IL18 , TGF-β & TNF-α are implicated (macrophages and T cells in

the lung)• Humoral response secondary to CD4 stimulation produces IgG

antibodies

PATHOGENESIS

• Only 1% of people exposed to agent develop the illness• Most individuals have normal innocuous IgG response• Recent respiratory infection can precipitate the pathological

process

PATHOGENESIS

Acute – lymphocytic infiltration

Chronic - fibrosis

Subacute – granuloma formation

The immunopathogenesis is an overlap of 3 phases

Acute phase

PATHOGENESIS

After inhalation – antigens bind to IgG antibody

Initiate complement cascade – C5 activates macrophages

Macrophages secrete chemokines and cytokines (MIP1α and IL8)

Attract neutrophils

2-9 hours later develop a T cell and monocyte response

PATHOGENESIS

Subacute phase• After recruitment of the macrophages – the fairly young ones

develop into epitheloid cells• Lead to the formation of multinucleated giant cells – thus non

caseating granulomas• The exact mechanism is undefined

PATHOGENESIS

Chronic phase• Early collagen formation by myofibroblasts occur – around the

granuloma• Activated alveolar macrophages produce TGFβ*• Mast cells play an active role in the fibrotic changes• Pro-collagen III is linked to recruitment and proliferation of

monocytes and lymphocytes• Mast cells – source, but response is not like in atopy

CLINICAL MANIFESTATIONS

• The clinical picture is similar to an interstitial pneumonitis• Varies from patient to patient• Presentation can be acute, sub acute or chronic

Acute form• Symptoms occur 2-9 hours after antigenic exposure • Cough, fever, chills, malaise, dyspnea• Resembles an influenza like illness• Symptoms clear if antigen exposure is removed

CLINICAL MANIFESTATIONS

Subacute form• Symptoms occur insidiously over weeks• Cough and dyspnea common• Dyspnea may progress to a severe illness requiring hospitalization• Symptoms can clear out if exposure is removed• Subacute illness is often interspersed with acute exacerbations of

acute illness (eg. Workplace related)

CLINICAL MANIFESTATIONS

Chronic form• Continuous low level exposure, repeated acute illness or

prolonged subacute forms can lead to chronic disease• Symptoms tend to be subtle (difficult to diagnose)• Cough, weight loss, malaise, progressive dyspnea• Examination might reveal inspiratory crackles and digital clubbing*• Evidences of interstitial fibrosis or emphysema • Progressive illness – oxygen dependence, pulmonary hypertension

and respiratory failure

DIAGNOSIS

• Low incidence – hence often goes undiagnosed or misdiagnosed• History of exposure is vital – although despite history, patient can

have a predominantly systemic illness with little respiratory findings

• All forms of HP may have elevated ESR, CRP, RA factor, LDH and serum immunoglobulin levels

• Neutrophilia and lymphopenia occurs initially • EOSINOPHILIA is not a feature

DIAGNOSIS

Chest radiographs• No specific or distinct changes• May be normal even in symptomatic patients• Acute/subacute forms – poorly defined, patchy, diffuse infiltrates,

nodular infiltrates or consolidation• Chronic form

• Diffuse reticulonodular infiltrates • Honeycombing pattern later• Apical sparing is common

HRCT

Acute phase• Ground glass opacity• Reticulonodular pattern• Confluent alveolar opacification

Subacute phase• Ground glass opacity• Centrilobular nodules

Chronic• Patchy emphysema• Interstitial fibrosis• Honeycombing pattern• Sub pleural linear opacification

DIAGNOSIS

Patchy ground-glass opacitiesWith areas of air trapping

DIAGNOSIS

Serum precipitins• Specific precipitin test for reactivity can be done• Especially in doubtful cases• However, a positive test only suggests exposure – but not the

association

Pulmonary function tests• Restrictive/obstructive pattern with loss of lung volume• Impaired diffusion capacity and reduced compliance• Bronchospasm & bronchial hyper-reactivity (Acute phase)• PFT can return to normal in acute/subacute phases

Bronchoscopy and broncho alveolar lavage• BAL reveals intense lymphocytosis (predominantly CD8+ cells)• Neutrophils predominate in the acute phase• Lymphocytosis predominates in subacute and chronic • Mastocytosis correlates with disease activity

Lung biopsy• Can be diagnostic• However, indicated only if no diagnosis is attained• When done, is the gold-standard for diagnosis of HP

DIAGNOSIS

DIAGNOSTIC CRITERIA(At least 4)

(At least 2)

DIFFERENTIAL DIAGNOSIS

TREATMENTA. Avoidance of the antigen

• Identification of the causative agent• Remove the patient from the environment (eg. geographic) or the

agent form the environment (eg. Pigeons)• Pollen masks, personal dust respirators, air stream helmets,

ventilated helmets

B. Glucocorticoid therapy• Acute phase – steroids may not be necessary• Subacute phase – Prednisolone 1mg/kg/day for 7-14 days, then

tapered over 2-6 weeks• Chronic phase – steroids are of little or no value, lowest dose for

maintenance, Supportive treatment with oxygen

Summary of hypersensitivity pneumonitis

PULMONARY EOSINOPHILIA SYNDROMES

INTRODUCTION• Definition: A heterogeneous group of disorders characterized by

varying degrees of pulmonary parenchymal or blood eosinophilia.• Loeffler first identified the condition in 1932• Also called pulmonary infiltrates with eosinophilia or eosinophilic

pneumonia• The precise role of eosinophils in the pathogenesis of the

eosinophilic pneumonias is not clear• However

• Initiation• Perpetuation• Amplification of tissue inflammation • Injury have been attributed to eosinophils

CLASSIFICATION

LOEFFLER’S SYNDROME

• A clinical syndrome characterized by• Mild respiratory symptoms• Peripheral blood eosinophilia• Transient, migratory pulmonary infiltrates

• Immune hypersensitivity to Ascaris lumbricoides and other parasites• Affects people of all ages• Clinical features

• The pulmonary manifestations begin approximately 9 to 12 days following ingestion

• Low-grade fever• Nonproductive cough• Dyspnea (mild to severe)• Occasional hemoptysis

• Respiratory manifestations are self limited, resolving in 1 to 2 wks• Peripheral blood from patients reveals eosinophilia.• Expectorated sputum frequently contains eosinophils• Chest X ray shows

• Transient, migratory, nonsegmental interstitial & alveolar infiltrates

• Ascaris larvae may be identified in sputum or gastric aspirates• Stool examination for ova and parasites is typically negative until 8

weeks after the onset of the respiratory syndrome.• Lung histology striking eosinophilic infiltration of interstitium and

alveolar-capillary units

LOEFFLER’S SYNDROME

LOEFFLER’S SYNDROME

DRUG AND TOXIN INDUCED EOSINOPHILIC PNEUMONIA

• Several drugs have been implicated, many are commonly used

Acetylsalicylic acid L-Tryptophan

Amiodarone Methotrexate

Bleomycin Minocycline

Captopril Nitrofurantoin

Carbamazepine Penicillamin

Propylthiouracil Phenytoin

Sulfasalazine Gold salts

• Radiation therapy for breast cancer• Iodinated contrast agents• Heroin (inhaled)• Respiratory symptoms vary widely in severity, from a mild

Loeffler’s-like to severe fulminant respiratory failure.• A concomitant skin rash and pleural effusion can support the

diagnosis of drug-induced eosinophilic pneumonia.• Elimination of exposure to the drug or other toxin - resolution of

symptoms, eosinophilia, pulmonary infiltrates, and normalization of lung function within a month.

DRUG AND TOXIN INDUCED EOSINOPHILIC PNEUMONIA

TROPICAL PULMONARY EOSINOPHILIA

• Tropical pulmonary eosinophilia (TPE) was first described in the early 1940s by Weingarten, in India

• Characteristic symptoms are• Malaise, anorexia, weight loss, • Paroxysmal dry cough with dyspnea or wheezing, • Marked peripheral blood eosinophilia,• Spontaneous resolution over several weeks

• The illness is seen mainly in South and South-east Asia, as well as in Africa

TROPICAL PULMONARY EOSINOPHILIA

• It is a hypersensitivity reaction to microfilariae from Wuchereria bancrofti and Brugia malayi• Microfilariae have been demonstrated in the lung, liver and lymph

nodes of typical cases• High antifilarial antibody titres are found in patients and the titre

diminishes after cure• Histamine release from basophils challenged with filarial antigen is

much higher in patients with pulmonary eosinophilia than in patients with other manifestations of filarial infection

• The condition responds dramatically to antifilarial treatment.

TROPICAL PULMONARY EOSINOPHILIA

• It is a syndrome of immunological hyper-responsiveness to microfilariae in the lungs.

• Males > Females

Clinical features – apart from symptoms mentioned• Cough and wheeze that is worse at night• Presentation can be similar to status asthmaticus • Chest pain,• Muscle tenderness,• Pericardial and CNS involvement• Rarely, patients remain asymptomatic.• Coarse crackles, rhonchi• Generalized lymphadenopathy & hepatosplenomegaly may be present

TROPICAL PULMONARY EOSINOPHILIA

Laboratory findings• Extreme peripheral blood

eosinophilia (>3000 cells/mm3 )• Serum IgE >1000 U/ml• BAL may reveal intense

eosinophilic alveolitis

Radiological findings• Bilateral indefinite mottling

uniformly distributed in both lung fields - middle and lower zones

• Increased broncho-vascular markings

• Cavitation and pleural effusion

TROPICAL PULMONARY EOSINOPHILIA

Treatment• Diethylcarbamazine in a dose of 2mg/kg orally three times a day for

14–21 days or for as long as 4 weeks• It is directly filaricidal to both adult worms and microfilariae.• It can also enhance the binding of granulocytes, macrophages,

antibodies, and complement to the surface of microfilariae.• Clinical improvement is dramatic within 7 days of administration• Acute relapses - in up to 20 % of patients and they require 2-4mg/kg

for 21 days• Although seldom fatal, untreated TPE often leads to the

development of chronic interstitial lung disease.

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (MYCOSIS)

• It is a disorder caused by a complex hypersensitivity (I and III) response to inhaled fungal antigens.

• Most commonly by Aspergillus species (Aspergillus fumigatus)• When induced by non-Aspergillus species, the syndrome is called

allergic broncho pulmonary mycosis.• Other cases may be due to

• Candida• Pseudomonas aeruginosa• Aspergillus terreus• Helminthosporium • Curvularia lunata

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (MYCOSIS)

Clinical features• Typically nonspecific• Dyspnea, wheezing, poor asthma control,• Cough (commonly productive of thick, brown mucus plugs),• Malaise, low-grade fever, hemoptysis (occasionally)• Antecedent history of recurrent asthma, other atopic conditions• ABPA can complicate asthma and cystic fibrosis• 5 clinical stages have been identified

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (MYCOSIS)

Clinical Stages

Radiological findings

• Typical findings are parenchymal infiltrates and bronchiectasis

• They have a predilection for upper lobes

• “finger-in-glove opacities”

• “tramline shadows”

• “toothpaste shadows”

• “ring shadows”

• lobar consolidation

Extensive infiltrates with tubular configuration and ‘‘gloved finger” appearance

Highresolution CT scan image of impacted bronchus (arrow) and chronic inflammatory changes

High-resolution chest CT image, showing moderate bronchiectasis, with areas of mucoid impaction and atelectasis of the right middle lobe.

Treatment goals

Controlling symptoms

Preventing exacerbations

Preserving normal lung

function

• Systemic corticosteroids are the mainstay of therapy• Therapy for stage I or III disease

• Prednisone 0.5-1 mg/kg a day for 2weeks, followed by 0.5 mg/kg every other day for 6 to 8 weeks.

• A subsequent taper (by 5 to 10 mg every 2 weeks) over 3 months can then be tried.

• A low maintenance dose (~7.5 mg/day) may be required long term to prevent recurrences

• IgE levels monitored 1 - 2 months of an acute exacerbation and followed every 2 months thereafter since levels may rise.

• Escalation of steroids if IgE >100%• CXR should be monitored every 3 months• Inhaled corticosteroids - bronchospasm• Steroid-sparing agent for symptomatic exacerbations and

pulmonary infiltrates

• Itraconazole 200 mg bid for 16 weeks – shown benefit despite ABPA not being a fungal ‘infection’

• Especially useful in steroid resistant ABPA• Also demonstrated utility in ABPA associated with Cystic Fibrosis• The efficacy of itraconazole in ABPA is lower in patients on proton

pump inhibitors

• Nystatin, Amphotericin B, Miconazole, Clotrimazole, Natamycin, are generally ineffective in controlling ABPA.

Complications• Chronic or recurrent lobar

atelectasis• Allergic Aspergillus sinusitis• Aspergillus tissue invasion• Aspergilloma (rarely)

IDIOPATHIC ACUTE EOSINOPHILIC PNEUMONIA

• Acute eosinophilic pneumonia (AEP) has been recognized as a distinct clinical entity.

• History of atopy is not essential• Occurs in recently commenced smokers and who have been

involved in activities with unusual exposures*• It presents as an acute illness with fever, myalgias, cough,

dyspnea, pleuritic chest pain with diffuse crackles & hypoxemia• Lasts between 3-30 days• Blood eosinophil count may be normal• IgE elevated and BAL fluid will contain eosinophils (25-50%)

Radiological findings

Diffuse bilateral alveolar andinterstitial infiltrates on chest X ray

Diffuse parenchymal ground-glass opacity and consolidation on CT

• Idiopathic AEP is a diagnosis of exclusion considered in patients with ALI or ARDS without a typical antecedent illness.

• Methylprednisolone 60 to 125 mg 6th hourly in respiratory failure• Thereafter, oral prednisone 40 -60 mg per day for 2 -4weeks and

tapered over weeks.• Prognosis is generally good

IDIOPATHIC ACUTE EOSINOPHILIC PNEUMONIA

CHRONIC EOSINOPHILLIC PNEUMONIA

• First described as a clinical entity in 1969• Women > Men, usually Caucasians.• 30 to 40 years of age• 33-50% patients have history of atopy• Subacute presentation, with symptoms over several months

• low-grade fevers• wheeze• drenching night sweats• Moderate weight loss• Cough (dry mucoid)• May develop dyspnea and lead to ARDS

CHRONIC EOSINOPHILLIC PNEUMONIA

Radiological findings • Infiltrates are bilateral, mid- to upper lung zones, and may mimic

loculated pleural fluid. • The areas of consolidation are patchy and dense and can have ill-

defined margins.• Common CT scan findings include ground-glass opacities without

clear consolidation

Treatment• Corticosteroids are the mainstay of therapy for CEP.• Dramatic clinical, radiographic, and physiological improvement• Prednisolone 40-60mg/day, tapered and stopped

The prognosis of CEP is generally favorable.

CHURG-STRAUSS SYNDROME

• Necrotizing vasculitis in several organs• Associated with eosinophilic tissue inflammation and

extravascular granulomas• Occurring in asthmatics• With associated fever and peripheral hypereosinophilia

• Also called allergic angiitis or allergic granulomatosis

CHURG-STRAUSS SYNDROME

• Asthma: History of wheezing or diffuse high-pitched expiratory rhonchi.• Eosinophilia: Eosinophilia >10% on differential white blood cell count.• Mono- or polyneuropathy: Development of mononeuropathy,

multiple mononeuropathies, or polyneuropathy attributable to systemic vasculitis.

• Pulmonary infiltrates, non-fixed: Migratory or transitory pulmonary infiltrates attributable to vasculitis.

• Paranasal sinus abnormality: History of acute or chronic paranasal sinus pain or tenderness or radiographic opacification of the paranasal sinuses.

• Extravascular eosinophils: Biopsy including artery, arteriole or venule showing accumulations of eosinophils in extravascular areas.

ACR diagnostic criteria

ProdromalPhase

• Late onset allergic rhinitis and atopy*

• Lasting for >10 years

Eosinophilic phase

• Marked blood eosinophilia

• Eosinophillic infiltration of lung, GI tract or skin

Vasculitic phase

• Vasculitis of the small and medium vessels

• Vascular and extravascular granulomas

• Constitutional symptoms

• Worsening asthma symptoms

CHURG-STRAUSS SYNDROME3 Clinical phases

CHURG-STRAUSS SYNDROME

• Chest findings are of asthma, with pulmonary infiltrates on chest radiographs

• Mononeuritis multiplex is common (upto 72%)• Skin lesions (purpurae, subcutaneous nodules)• Renal disease (Interstitial nephritis, FSGS, hematuria, albuminuria)

is less severe• Myocardial involvement* occurs in 39% - likely cause for mortality

• Investigations reveal eosinophilia, pANCA positivity, RA factor may be positive, pleural fluid shows eosinophilic exudate.

CHURG-STRAUSS SYNDROME

• Prednisone 60 mg/day for 6 to 12 weeks, aiming to eliminate constitutional symptoms and cardiac, renal, neurological, or other vasculitic manifestations.

• Once the vasculitic phase is controlled, steroids may be tapered

• Low dose steroids for a year• azathioprine, cyclophosphamide,

high-dose methylprednisolone, or chlorambucil if initial treatment fails

Intense perivascular inflammation witheosinophilia

HYPER-EOSINOPHILIC SYNDROME

• This rare syndrome is characterized by marked peripheral blood eosinophilia and by eosinophilic infiltration of many organs in the absence of a known cause

• The three principal clinical features defining it• (1) persistent blood eosinophilia greater than 1500/μl for > 6 months• (2) symptoms and signs of end-organ dysfunction• (3) no other identifiable underlying cause of eosinophilia.

• Symptoms are similar to AEP - fever, night sweats, anorexia, malaise, weight loss, pruritus and cough.

• Blood eosinophilia and high IgE levels

HYPER-EOSINOPHILIC SYNDROME

• Respiratory involvement (40%)• Nocturnal, minimally productive cough and wheeze• Pulmonary hypertension, ARDS, and pleural effusions can occur• Chest radiograph may reveal transient focal or diffuse pulmonary

infiltrates

• Cardiac disease – major cause for morbidity and mortality• Relentlessly progressive CHF due to eosinophilic myocarditis and

endocarditis, intracardiac thrombi, and endocardial fibrosis.• Bacterial endocarditis has also been noted• Echocardiographic follow-up at 6-month intervals – recommended

• Neuropsychiatric dysfunction (60%)

HYPER-EOSINOPHILIC SYNDROME

Treatment• Prednisolone 1mg/kg/day tapered• Hydroxyurea 0.5 to 1.5 g per day• Vincristine, etoposide and chlorambucil have been used

Approaching eosinophilic pneumonias

TAKE HOME MESSAGES

• A complete occupational and exposure history is vital• Elimination of the provocative agent is extremely important• Early evaluation of patients with mild to moderate respiratory

symptoms with absolute eosinophil count and seum IgE levels can point at eosinophila syndromes

REFERENCES

• Fishman's Pulmonary Diseases and Disorders – 4th edition• Harrison's Principles of Internal Medicine - 18th edition• Crofton and Douglas's Respiratory Diseases – 5th edition

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