PULMONARY EOSINOPHILIAS

ppt presentation on pulmonary eosinophilias

1. pulmonary eosinophilias Presenter : Dr. Ashutosh Date : 15/06/2017

2. INTRODUCTION In 1932, Loeffler first identified the association between pulmonary infiltrates and eosinophilia . Subsequently, Crofton separated the eosinophilic pneumonias into five groups on the basis of clinical criteria: Loeffler’s syndrome, Prolonged pulmonary eosinophilia , pulmonary eosinophilia associated with asthma, tropical eosinophilia , and Periarteritis nodosa .

3. In 1952, Reeder and Goodrich coined the term pulmonary infiltrates with eosinophilia (PIE syndrome) to refer to these disorders. However, it was subsequently appreciated that pulmonary infiltration With eosinophils can occur in the absence of peripheral blood eosinophilia . As a result, in 1969, Liebow and Carrington broadened the description of the term eosinophilic pneumonia to include all disorders characterized by infiltration of the lungs with eosinophils , with or without an excess of eosinophils in the peripheral blood.

4. Definition : Eosinophilic pneumonias are defined as a heterogeneous group of disorders characterized by varying degrees of pulmonary parenchymal or blood eosinophilia . 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

5. classification

6. 1. Loeffler’s syndrome Also called as Simple Pulmonary Eosinophila In 1932 Loffler first described it as 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 Low-grade fever Nonproductive cough Dyspnea (mild to severe) Occasional hemoptysis

7. The pulmonary manifestations begin approximately 9 to 12 days following ingestion and occur during the migration of larvae through the lung. Respiratory manifestations are self limited, resolving in 1 to 2 wks P eripheral blood from patients reveals moderate to extreme eosinophilia . Expectorated sputum, if present, frequently contains eosinophils Chest X ray shows Transient, migratory, nonsegmental interstitial & alveolar infiltrates(often peripheral or pleural based) Pulmonary function evaluation typically reveals a mild to moderate restrictive ventilatory defect with a reduced diffusing capacity for carbon monoxide ( DlCO ).

8. 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 shows striking eosinophilic infiltration of interstitium and alveolar-capillary units

9. Loeffler’s syndrome

10. TREATMENT Since Loeffler’s syndrome may be induced by a variety of exposures, a search for an etiologic agent should be undertaken. Bronchodilators and rarely corticosteroids may be used for alleviation of Pulmonary symptoms, although these are usually self-limited. In cases due to Ascaris , treatment with oral mebendazole (100 mg twice a day for 3 days) should be given to prevent late GI manifestations of Ascaris infestation, which may include malnutrition, diarrhea, abdominal pain, and/or intestinal obstruction typically 8 weeks or more after onset of respiratory symptoms. Since stool specimens are negative for ova and parasites early in the illness, clinical follow-up over a 2- to 3-month period is indicated.

11. 2. Drug and toxin induced eosinophilic pneumonia

12. 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

13. Other causes are Radiation therapy for breast cancer Iodinated contrast agents Heroin (inhaled ) Drug and toxin induced eosinophilic pneumonia

14. Have an acute or subacute onset and are not always related to either the cumulative dose of drug used or the duration of treatment. Respiratory symptoms vary widely in severity, from a mild Loeffler’s -like symptoms( dyspnea , cough & fever) to severe fulminant respiratory failure. Wheezing may be present, but obstructive physiology is not common on pulmonary function testing.

15. A diagnosis of drug- or toxin-induced eosinophilic pneumonia is based upon a careful review of drug and other exposures (including nonprescription drugs, herbal preparations, street drugs, and environmental exposures). Other causes of eosinophilic lung disease should be excluded. A concomitant skin rash and pleural effusion can support the diagnosis of drug-induced eosinophilic pneumonia. Although radiographic findings are not specific, interstitial or alveolar infiltrates are typically evident on chest radiograph and common high-resolution chest computed tomographic (HRCT) findings include bilateral consolidation and ground-glass opacities, both of which are frequently peripherally located.

16. The prognosis is favorable in most cases. Elimination of exposure to the drug or other toxin - resolution of symptoms, eosinophilia , pulmonary infiltrates, and normalization of lung function within a month. Supplemental therapy with corticosteroids is not universally required, but it may hasten recovery in patients who are severely ill.

17. 3. 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 India and South-east Asia, as well as in Africa

18. It is a rare manifestation of parasitic infection, TPE occurs in less than 1 percent of patients infected with lymphatic filariae . It is a hypersensitivity reaction to microfilariae from Wuchereria bancrofti and Brugia malayi Approximately 4 times more common in men, most patients with TPE manifest the disease between the age of 25 and 40 years, although children and older adults may also be affected.

19. 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 . On Physical examination Coarse crackles, rhonchi Generalized lymphadenopathy & hepatosplenomegaly may be present

20. Laboratory findings Extreme peripheral blood eosinophilia (>3000 cells/mm 3 ) Serum IgE >1000 U/ml high titers of filarial-specific IgE and IgG , measured by complement fixation or hemagglutination techniques, BAL may reveal intense eosinophilic alveolitis Microfilariae are not found in blood or sputum, and examination of stool or urine for Ova and parasites is negative (although patients from endemic countries may be simultaneously infected with other parasites). In contrast, microfilariae have been identified in lung and lymph node tissue, especially when lymphadenopathy is present.

21. Pulmonary function tests reveal an obstructive ventilatory defect in up to 30 percent of patients, particularly when symptoms have been present less than 1 month. A restrictive ventilatory defect and reduced DlCO , with or without a concomitant obstructive defect, are typical of long-standing disease. Lymph node biopsies may reveal degenerating microfilariae or adult worms, surrounded by aggregates of eosinophils , their granule products,and giant cells.

22. Radiological findings Bilateral indefinite mottling uniformly distributed in both lung fields - middle and lower zones Increased broncho -vascular markings Cavitation and pleural effusion

23. 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 21-30 days

24. Alternative antifilarial drugs (e.g., ivermectin ) or a trial of corticosteroids may be useful therapies for the chronic variant of the disease, although controlled studies of these agents are lacking. Although seldom fatal, untreated TPE often leads to the development of chronic interstitial lung disease.

25. 4. 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

26. Greenberger and Patterson have proposed five minimal essential criteria needed to establish the diagnosis, including

27. 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

28. Allergic bronchopulmonary aspergillosis (Mycosis) Clinical Stages

29. 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

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

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

32. Treatment goals

33. Systemic corticosteroids are the mainstay of therapy Therapy 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

34. 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.

35. Complications Chronic or recurrent lobar atelectasis Allergic Aspergillus sinusitis Aspergillus tissue invasion Aspergilloma (rarely)

36. 5. Idiopathic Acute Eosinophilic Pneumonia Acute eosinophilic pneumonia (AEP) has been recognized as a distinct clinical entity . More common in younger men, with a mean age of approximately 30 years. History of atopy is not essential. Occurs in recently commenced smokers and who have been involved in activities with unusual exposures(such as cave exploration, plant repotting, woodpile moving, and indoor renovations). No definite seasonal variation has been identified, (more in summer). It presents as an acute illness with fever, myalgias , cough, dyspnea, pleuritic chest pain with diffuse crackles & hypoxemia Symptoms may lasts upto 30 days with avg. of 3 days

37. Moderate Leucocytosis is typical but blood eosinophil count may be normal Serum IgE elevated and BAL fluid will contain eosinophils (25-50%). Pulmonary function tests reveal a restrictive ventilatory defect with a reduced DLCO.

38. Radiological findings Diffuse bilateral alveolar and interstitial infiltrates on chest X ray Diffuse parenchymal ground-glass opacity and consolidation on CT

39. Small to moderate bilateral pleural effusions are common. Fluid analysis typically reveals a high pH and marked eosinophilia . Light microscopic examination of lung tissue reveals prominent eosinophil infiltration in alveolar spaces, bronchial walls, and, to a lesser degree, the interstitium . The pathological pattern of diffuse alveolar damage with eosinophilic infiltrates should suggest the possibility of AEP.

40. Idiopathic AEP is a diagnosis of exclusion & considered in patients with ALI or ARDS without a typical antecedent illness . Methylprednisolone 60 to 125 mg 6 th hourly in respiratory failure Thereafter, oral prednisone 40 -60 mg per day for 2 -4weeks and tapered over weeks. Prognosis is generally good

41. 6.Chronic eosinophillic pneumonia First described as a clinical entity by Carrington and coworkers in 1969 Women > Men, usually Caucasians. 30 to 40 years of age 33-50% patients have history of atopy , allergic rhinitis , or nasal polyps. 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

42. Rarely ,patient may develop, arthralgias , skin rash, pericarditis or unexplained heart failure Patients with CEP frequently manifest a moderate leukocytosis . The majority (66 to 95 percent) have peripheral blood eosinophilia , with eosinophils constituting more than 6 percent of their leukocyte differential. ( till 90% eosinophils have been documented) A moderate normochromic , normocytic anemia and thrombocytosis may be present . The ESR is typically elevated (greater than 20mm/hour ), and IgE levels are elevated in up to one-half of cases. Analysis of BAL fluid reveals increased eosinophils , typically accounting for 40 percent or more of the white blood cell (WBC ) differential . Blood and sputum cultures routinely fail to identify an infectious etiology in these patients.

43. Carrington and colleagues described three radiographic features that are characteristic for CEP : peripherally based, progressive dense infiltrates; rapid resolution of infiltrates following corticosteroid treatment, with recurrences in identical locations; and ( 3) The appearance of infiltrates as the “photographic negative of pulmonary edema.

44. Radiographic appearance of chronic eosinophilic pneumonia (CEP). Variable computed tomography appearance of infiltrates in two patients with chronic eosinophilic pneumonia. Peripheral upper-lobe predominant infiltrates may have a ground-glass appearance ( A) or may appear as regions of dense consolidation or nodular opacity ( B).

45. 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 . The characteristic “photographic negative of pulmonary edema” appearance (which occurs in less than 50 percent of cases) results if extensive infiltrates surround major portions of or the entire lung. Common CT scan findings include ground-glass opacities without clear consolidation. Mediastinal lymphadenopathy may be present .

46. Treatment Corticosteroids are the mainstay of therapy for CEP . Even patients presenting with severe respiratory failure may respond well to steroid treatment. Dramatic clinical, radiographic, and physiological improvement occurs with steroid treatment. In most cases , treatment with steroids leads to defervescence within 6 hours, reduced dyspnea , cough, and blood eosinophilia within 24 to 48 hours, resolution of hypoxia in 2 to 3 days, radiographic improvementwithin 1 to 2weeks, complete resolution of symptoms within 2 to 3 weeks, and Normalization of the chest radiograph within 2 months .

47. Prednisolone 40-60mg/day, continued until 2 weeks after resolution of symptoms and radiographic abnormalities. then tapered and stopped. Treatment is usually maintained for at least 3 months and optimally for 6 to 9 months. The prognosis of CEP is generally favorable. Clinical, hematological, or radiographic evidence of relapse occurs in approximately one-third to one-half of patients when steroids are tapered or discontinued . The reinstitution of steroids generally leads to improvement, and relapses do not appear to indicate a worse prognosis, increased likelihood of treatment failure, or increased morbidity.

48. 7. CHURG-STRAUSS SYNDROME The histopathology and clinical features associated with this disease entity were first described in 1951 by Churg and Strauss, as a Form of 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 . Develops most commonly in patients between the ages of 38 to 50 . CSS tends to follow a subacute course, with symptoms ranging over months to years.

49. 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

50. 3 Clinical phases

51. Most of the respiratory manifestations of CSS occur in the prodromal and eosinophilic phases of the disease. Nearly all patients have asthma at some point in the illness. Upper airway allergic disease, including sinusitis, rhinitis, and polyposis , is seen in 75 to 85 percent of patients and may be the presenting symptom. Spirometry may reveal an obstructive ventilatory defect.

52. Cardiac manifestations : not present on initial presentation of CSS . However , they typically occur during the vasculitic phase of the disease and are a major source of morbidity and the principal cause of death (in up to 50 percent of cases) from the disorder. Progressive congestive heart failure (CHF) occurs in 47 percent of cases because of myocardial infiltration by eosinophils or ischemic cardiomyopathy resulting from necrotizing vasculitis of the coronary arteries. Others causes being. Acute pericarditis cardiac tamponade Constrictive pericarditis

53. CNS Manifestations : Mono- or polyneuropathy (most notably mononeuritis multiplex) is present in 69 to 75 percent of cases . other include cranial nerve impairment ( especially optic neuritis), seizure , subarachnoid hemorrhage, and cerebral infarction . Cerebral hemorrhage and infarction are common causes of patient death . Skin findings : localized crops. nonthrombocytopenic purpura , tender cutaneous or subcutaneous nodules (which may ulcerate ), urticaria , a maculopapular rash, petechiae , ecchymoses , or livedo reticularis . GI manifestations : Eosinophilic gastroenteritis or vasculitis that can lead to diarrhea, abdominal pain , intestinal obstruction, cholecystitis , pancreatitis, bleeding, liver function test abnormalities, and bowel perforation .

54. Renal manifestations: Interstitial nephritis, focal segmental glomerulonephritis ( oftenwith necrotizing features), hematuria , and albuminuria are common.

55. CSS have a striking but fluctuating degree of peripheral blood eosinophilia (20 to 90 percent of the WBC differential), generally greater than that seen with asthma alone. Serum total IgE levels are typically elevated (range, 500 to 1000 U/ml) Most patients have a normochromic , normocytic anemia and moderate elevation of their ESR. 70 to 75 percent of patients have positive antinuclear cytoplasmic antibody with a perinuclear staining pattern ( pANCA ). RA factor may be positive. Laboratory examination of pleural fluid, if present, reveals an acidotic eosinophilic exudate with low glucose levels. Pleural biopsy shows chronic pleuritis with eosinophilic infiltration. BAL reveals an increased percentage of eosinophils .

56. Chest findings are of asthma, with transient , migratory nonlobar , nonsegmental , often peripheral pulmonary infiltrates, with no regional predilection. High-resolution CT scanning has demonstrated patchy peribronchial thickening, pulmonary artery enlargement (in comparison to the corresponding bronchi), irregular stellate configuration of some vessels, areas of septal thickening, and scattered patchy parenchymal opacities with ground-glass or consolidated appearance.

57. Pathological appearance of small arteriole in Churg -Strauss vasculitis . Intense perivascular inflammation with Eosinophilia .

58. 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 Untreated patients have a poor prognosis; up to 50 percent die within 3 months after the onset of vasculitis .

59. 8. IdiOPATHIC 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

60. 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 Manifest as 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 %) include encephalopathy with neuropsychiatric dysfunction, memory loss, gait disturbances with or without signs of upper motor neuron injury, visual changes, hemiparesis . Peripheral neuropathy with sensory and/or motor axonal loss (no vasculitic or eosinophilic infiltration) is extremely common in IHS

61. Laboratory findings associated with IHS include an elevated total serum IgE (25 to 38 percent), hypergammaglobulinemia , circulating immune complexes (32 to 50 percent ), and an ESR above 15 mm/h (68 percent ). Elevated serum B12 and leukocyte alkaline phosphatase levels are also noted.

62. Treatment Prednisolone 1mg/kg/day fo r several weeks followed by tapered Hydroxyurea 0.5 to 1.5 g per day may be added to the regimen if there is evidence of further disease progression, with the aim of reducing the peripheral leukocyte count to the range of 5000 to 10,000. Vincristine, etoposide , cyclosporine and chlorambucil have been used

63. Approaching eosinophilic pneumonias

64. references Fishman's Pulmonary Diseases and Disorders – 4 th edition Harrison's Principles of Internal Medicine - 19 th edition Crofton and Douglas's Respiratory Diseases – 5 th edition

65. THANK YOU

66. 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