Asthma

1. Adult Asthma (Medicine) Mohd Hanafi Ramlee

2. History Asthma : derived from the Greek aazein , meaning "sharp breath." The word first appears in Homer's Iliad . In 450 BC . Hippocrates: more likely to occur in tailors, anglers, and metalworkers . Six centuries later, Galen: caused by partial or complete bronchial obstruction . 1190 AD, Moses Maimonides: wrote a treatise on asthma, describing its prevention, diagnosis, and treatment 17th century , Bernardino Ramazzini : connection between asthma and organic dust . 1901: The use of bronchodilators started. 1960s: inflammatory component of asthma was recognized and anti-inflammatory medications were added to the regimens.

3. What is known about asthma?

4. ASTHMA Chronic inflammatory condition of the airways characterized by; - airflow limitation (reversible with treatment ) - airway hyper-responsiveness to a wide range stimuli - inflammation of the bronchi In chronic asthma, inflammation maybe accompanied by irreversible airflow limitation Symptoms are cough, wheeze, chest tightness , and shortness of breath which often worse at night

5. Simple Definition A reversible chronic inflammatory airway disease which is characterized by bronchial hyper-responsiveness of the airways to various stimuli, leading to widespread bronchoconstriction , airflow limitation and inflammation of the bronchi causing symptoms of cough, wheeze, chest tightness and dyspnoea .

6. Epidemiology Common disease with unacceptably high morbidity and mortality Commonly underdiagnosed and undertreated Only 36.1% of adult asthmatics ever had their peak flow measured Higher prevalence in rural ( 4.5%) than in urban areas ( 4%) ,lower educational status(5.6%) and lower income Majority of patients(87.3%) had mild asthma; 9.9% had moderate asthma and 2.7% had severe asthma Among severe asthmatics, only 19.4% were on inhaled corticosteroids

7. Epidemiology

8. EPIDEMIOLOGY The prevalence of asthma has increased 61% over the last two decades. Asthma is the leading chronic illness among children. Asthma results in 10 million lost school days and 3 million lost work days. Deaths from asthma have increased by 31% since 1980.

9. Classification Extrinsic – implying a definite external cause more frequently in atopic inviduals (atopic – individual which tends to develop hypersensitivity by contact with allergens) often starts in childhood - accompanied by eczema Intrinsic/cryptogenic – no causative agent can be identified starts in middle age

10. Types of Asthma According to the severity: helpful for treatment and management .

11. Types of Asthma According to pathophysiology Allergic asthma Intrinsic (Non-Allergic) Exercise-induced Occupational (allergic) Steroid-resistant ABPA (allergic)

12. Pathogenesis Complex, not fully understood numbers of cells, mediators, nerves, and vascular leakage -activated by expose to allergens or several mechanism Inflammation Eosinophils , T-lymphocytes, macrophages and mast cell Remodeling Deposition of repair collagens and matrix proteins-damage Loss of ciliated columnar cells- metaplasia – increase no of secreting goblet cells

13. Pathologic features of asthma Inflammatory cell infiltration of the airways Increased thickness of the bronchial smooth muscle Partial or full loss of the respiratory epithelium Subepithelial fibrosis Hypertrophy and hyperplasia of the submucosal glands and goblet cells Partial or full occlusion of the airway lumen by mucous plugs Enlarged mucous glands and blood vessels

14. Pathophysiology Smooth muscle contraction Thickening of airway –cellular infiltration and inflammation Excessive secrection of mucus Genetic factor Cytokine gene complex (chromosome 5)-IL-4 gene cluster control IL-3, IL-4 , IL-5 and IL-13 Environment factor Childhood expose irritants or childhood infection

15. Pathophysiology Extrinsic asthma: Atopic/allergic, occupational, allergic bronchopulmoary aspergillosis . Atopic or allergic Dust, pollens, animal dander, food etc. Family history of atopy . ↑ s erum IgE . Skin test with Ag  wheal, flare ( Classical IgE mediated response) Exposure of pre- sensitised mast cells to the Ag stimulates chemical mediators from these cells. Type 1 hypersensitivity.

16. 1.Early phase Inhaled Antigen Sensitised mast cells on the mucosal surface  mediator release. Histamine  bronchoconstriction, increased vascular permeability. prostaglandin D 2  bronchoconstriction, vasodilatation. Leucotriene C4,D4, E4  Increased vascular permeability, mucus secretion and bronchoconstriction. Direct subepithelial parasympathetic stimulation  bronchoconstriction.

17. 2.Late phase starts 4 to 8 hours later Mast cell release additional cytokine Influx of leukocytes ( neutrophil,eosinophil ) Eosinophils are particularly important- exert a variety of effect

18. Pathophysiology Atopic Asthma Trigger Eg.dust,pollen , animal dander TH2 cell IL5 IL4 Eosinophil IgE B cell Mast cell IgE antibody Mediators Eg.Histamine , leukotrines Bronchospasm Increase vascular permeability Mucus production Immediate phase(minutes)

19. Bronchial inflammation Environment factor Genetic prediposition Bronchial hyperreactivity + trigger factors Cough, Wheeze, Breathlessness, Chest tightness Oedema BronchoC Mucus production Airways narrowing

20. Aetiology and triggers Complex and multiple environmental and genetic determinant Genetic factors Allergen exposure  house dust mite, household pets, grass pollen Atmospheric polution  sulphur dioxide, ozone, ciggerate smoke, perfume Dietary deficiency of antioxidants  vit E and selenium may protect asthma in children( freshfruits and vegetables )

21. Aetiology and triggers Occupational sensitizers isocyanates (from industrial coating, spray painting ) colophony perfumes(electronic industries ) Drugs NSAIDS B-blocker(B1 adrenergic blocker drug such as atenolol is avoided to treat HPT and angina in asthmatic pt Cold air Exercise  exercise-induced wheeze is driven by histamin and leukotrienes which are release from mast cells when epithelial lining fluid of the bronchi become hyperosmolar owing to drying and cooling during exercise Emotion

22. History Presenting symptoms: Cough ± sputum - time: become worse at night - duration: chronic / acute - associated with wheezing - fever? URTI Wheeze - max during expiration and accompanied by prolonged expiration

23. Cough History 1.Ask specifically about the symptoms: -Cough? how is the cough? more severe at night or on day? associated symptoms like dyspnea & wheezing? how long is the cough?  Recurrent?Any previous similar episode? Aggravated factor?like cough become severe after exercise?or the cough is initiated after exercise?

24. Cough History 2.If the cough is associated with dyspnea and wheezingis it relieved by bronchodilator? 3.Ask for any precipatating factors -whether the symptoms( cough,dyspnea,wheezing ) started after exposure to weather changes, dust, exercise, infection or drugs? 4.Is there any pets,carpet or feather pillow in home ?(easily trapped dust and the dust or animal fur will cause exacerbation of asthma)

25. Dyspnoea History Dyspnoea - onset: after exercise? cold? dust? animal fur? emotion? - severity and pattern: varies from day to day or from hour to hour - no chest pain

26. History Clinical features Recurrent episodes of wheezing,chest tightness,breathlessness and cough Precipitants- cold,allergen,pollutant,viral urti Exercise tolerance Disturbed sleep Other atopic disease Home-Pet?Carpet ? Occupation

27. History Clinical features Display diurnal pattern,symptoms and PEF worse in the morning Mild intermittent asthma-asymptomatic between exacerbation Persistent asthma-chronic wheeze and breathlessness

28. History 5.Any history of atopy ( eczema,hay fever) or allergic rhinitis? 6.Any family history of asthma?Any childhood asthmatics? 7.Whether he is a smoker or any family members is a smoker? 8.What is his occupation? Exposure to chemicals?

29. History Past medical history: Experienced asthma attack before Taking any medications: NSAIDs / β -blocker / aspirin (non atopic asthma) Family history: Has family history of asthma

30. History Social history: Occupation: expose to fumes/organic/chemical dust House: near to factory? Pets? Dust? Carpet? Feather pillow? Smoking in any family members

31. known asthmatic When he was diagnosed with asthma? How the asthma was diagnosed? Who diagnosed it? Whether he is on prophylaxis? What type of prophylaxis? How he get the drugs and how many dosage of the drugs? Whether he know how to deliver the drugs properly? How is his compliance to drugs?

32. Physical examination General inspection: - tachypnoeic , sign of respiratory distress, effort of breathing, cyanosis (life-threatening) Inspection: - fingers: tar staining - pulse rate: tachycardia and pulsus paradoxus , bradycardia (life-threatening) - used of accessory muscles or recession - wheezing

33. Chest Inspection : - shape: hyperinflated in severe asthma - movement of chest/silent chest (life-threatening) - chest deformity: - recession: Palpation: - chest expension may be reduce ( hyperinflated )/ normal - apex beat: may be displaced -vocal fremitus: decrease Percussion: - may be hyperresonance / normal Auscultation: - breath sound: vesicular - ronchi in expiratory phase, may be both in severe asthma - prolonged expiratory phase -vocal resonance decrease / normal

34. Clinical features Sign Tachypnoea,audible wheeze,hyperinflated chest,hyperresonant percussion note,diminished air entry,widespread polyphonic wheze Severe attack – inability to complete sentences, pulse >110bpm, RP>25/min, PEF 33-50% Life-threatening attack- silent chest,cyanosis,bradycardia,exhaustion , PEF < 33%,confusion Pulsus paradoxus ( exaggeration of the normal variation in the pulse volume with respiration, becoming weaker with inspiration and stronger with expiration )

35. Correlation The symptoms of asthma consist of a triad of dyspnea , cough , and wheezing . At the onset of an attack, patients experience a sense of constriction in the chest, often with a nonproductive cough . Respiration becomes audibly harsh; wheezing in both phases of respiration becomes prominent; expiration becomes prolonged; and patients frequently have tachypnea , tachycardia, and mild systolic hypertension. The lungs rapidly become overinflated . If the attack is severe or prolonged, there may be a loss of adventitial breath sounds, and wheezing becomes very high pitched . The accessory muscles become visibly active, and a paradoxical pulse often develops.

36. Diagnosing asthma

37. Diagnosing asthma Reversible and variable airflow limitation-as measured by a peak expiratory flow (PEF) meter in any of the following ways: PEF increases more than 15% and 200mls 15 to 20 mins after inhaling a short acting beta2 agonist , or PEF varies more than 20% from morning measurement upon arising to measurement 12 hours later in patients who are taking a bronchodilator , or PEF decreases more than 15% after 6 mins of running or exercise

38. Differential diagnosis Upper airway obstruction     Tumor     Epiglottitis     Vocal cord dysfunction     Obstructive sleep apnea Bronchomalacia Endobronchial lesion Foreign body Congestive heart failure Gastroesophageal reflux Sinusitis Adverse drug reaction     Aspirin     Beta-adrenergic antagonist     ACE inhibitors     Inhaled pentamidine Allergic bronchopulmonary aspergillosis Hyperventilation with panic attacks

39. Non-specific investigation Non-specific: - full blood count and differential count: increase number of eosinophils number - arterial blood gases - sputum test: number of eosinophils - chest X-ray : hyperinflated

40. Specific investigation Specific: - respiratory function test: 1. peak expiratory flow 2. spirometry - exercise tests -histamine/ methacholine bronchial provocation test - trial of corticosteroids

41. Reversibility Test This test is done to see whether the obstruction can be relieved by the use of a short-acting bronchodilator eg salbutamol An improvement of 15% or more (as measured on the peak flow meter) is diagnostic of asthma. However, in severe chronic disease or patient who has treated with long-acting bronchodilators , little reversibility will be demonstrated.

42. Reversibility test Forced expiratory manoeuvres before 20 minutes after inhalation of a beta-2-adrenoceptor agonist. Note the increase in FEV1 from 1.0 to 2.5 litres.

43. Peak expiratory flow rate Simple and cheap Subject take full inspiration then blow out forcefully into peak flow meter. Best used to monitor progression of the asthma and its treatment. To access possible occupational asthma PEFR value varies with sex, age and height.

44. Peak Expiratory Flow Rate (PEFR) The maximum rate of air breathed out as hard as possible through a measuring device called a peak flow meter, (after a full breath taken in). Reading is measured in litres /minute (l/min). Take 3 readings and choose the best Reading < 80% - presense of obstruction, but not diagnostic of asthma

45. Require to take a series of reading - on waking up - prior taking bronchodilator - after taking bronchodilator (before sleep)

46. PEF measurements During periods of well-being: provides measurement of the patients best PEF value which will provide the target for the doctor and the patient to aim for.Twice daily measurements before any inhaled bronchodilator tx will determine the diurnal variability of airway calibre.Good control of asthma means PEF variability is maintained at less than 10%. During symptomatic episodes: During an attack of asthma PEF fairly accurately measures the degree of bronchospasm.A PEF of less than 50% of normal or best suggests a very severe attack and a PEF of less than 30% suggests a life-threatening attack

47. Response to treatment

48. Occupational asthma

49. Spirometry Test It is the single best diagnostic test for patients with airflow limitation. A Spirometry Test - measures the volume of air blown out against time - gives more specific information about lung function. A value is calculated for the amount of air blown out in one second - “ Forced Expiratory Volume” or FEV1 ). This is divided by the total amount of air blown out until all air is expired - Forced Vital Capacity or FVC ). FEV1/FVC expressed as a percentage value

50. Reading is affected by age, gender and height Male Spirometry reading range Mild reduction: 2.5 litres or more Moderate reduction :1.5 to 2.49 litres Severe reduction :Less than 1.5 litre   Female Spirometry reading range Mild reduction :2.0 litres or more Moderate reduction: 1.0 to 1.99 litres Severe reduction: Less than 1.0 litre In asthma, the readings will be reduced, returning to normal between episodes

51. TLC VC RV IC FRC IRV ERV RV TV TLC : total lung capacity VC : vital capacity RV : reserve volume IC : inspirational capacity FRC : functional residual capacity IRV : inspirational reserve volume TV : tidal volume ERV : expiratory reserve volume Normal:75-80% Obstructive airway disease: reduced ratio Restrictive lung disease: ratio normal or increase (enhanced elastic recoil).

52. Exercise Test Done especially in children Peak flow reading measured before hand Ask patient to run for 6 min , to increase HR > 160 beats/min Cannot run – use cold air challenge , isocapnoiec (CO2) hyperventilation, aerosol challenge with hypertonic solution After exercise – take readings at intervals of 5, 10 and 15 minutes. Diagnosed asthma - fall in peak flow of 15% or more, after exercise.

53. Exercise test

54. histamine/ methacholine bronchial provocation test

55. Chest X-ray Showed lung hyperinflation . Not diagnostic of asthma Useful to rule out other causes eg . Pneumothorax ----------------------------------------------- Hyperinflation and increased bronchovascular markings

56. Allergies & Atophy Allergen Provocation Test In suspected occupational asthma and food-allergy related asthma Skin-Prick Test To identify allergens A drop of allergen is placed on skin , site is marked and pricked with needle, measured any weals

57. Approach to management

58. Management

59. Severity assessment for acute setting of AEBA Mild Moderate Severe Breathless Walking Talking At rest Can lie down Prefer sitting Hunched forward Talk in Sentences Phrases Words Alertness May be Usually agitated Agitated Central cyanosis Absent Absent Present Use of accessory muscle Absent Moderate Marked Sternal retraction Absent Moderate Marked Wheeze on auscultation Moderate , often end expiratory Loud Loud  Silent Chest Pulsus paradoxus Not palpable May be palpable Often palpable Initial PEF More than 80% 60 – 80% Less than 60% Oximetry on presentation More than 95% 91 – 95% Less than 90%

60. Severity of AEBA 1

61. Severity of AEBA 2

62. Severity of AEBA 3

63. Management of Chronic Asthma Aims of management to recognize asthma to abolish symptoms to restore normal or best possible long term airway function to reduce morbidity and prevent mortality

64. Approach of chronic asthma Education of patient and family Avoidance of precipitating factors Use of the lowest effective dose of convenient medications minimizing short and long term side effects. Assessment of severity and response to treatment.

65. 1) Education of patient and family Nature of asthma Preventive measures/avoidance of triggers       Drugs used and their side-effects        Proper use of inhaled drugs        Proper use of peak flow meter        Knowledge of the difference between relieving and preventive medications   Recognition of features of worsening asthma increase in bronchodilator requirement development of nocturnal symptoms reducing peak flow rates). Self management plan for selected, motivated patients or parents. The danger of non prescribed self medication including certain traditional medicines.

66. 2) Avoidance of precipitating factors The following factors may precipitate asthmatic attacks : Beta blockers  contraindicated in all asthmatics Aspirin and nonsteroidal anti-inflammatory drugs  if known to precipitate asthma, these drugs should be avoided. Allergens  e.g. house dust mites, domestic pets, pollen should be avoided whenever possible. Occupation  should be considered as a possible precipitating factor.     Smoking  active or passive. Day to day triggers  such as exercise and cold air. It is preferable to adjust treatment if avoidance imposes inappropriate restrictions on lifestyle. Atmospheric pollution . Food  if known to trigger asthma, should be avoided.

67. 3) Medication 2 major groups of drugs:

68. Drug Delivery The inhaled route is preferred for beta2-agonists and steroids as it produces the same benefit with fewer side effects Inhaled medications exert their effects at lower doses pMDI is suitable for most patients as long as the inhalation technique is correct Alternative methods include spacer devices,dry powder inhalers and breath-actuated pMDI Nebulised route is preferred in the management of acute attacks

69. 3 main groups of bronchodilators [ β 2 agonists]

70. 2.  Anti-Inflammatory Drug Corticosteroids Examples: Beclomethasone dipropionate ( Becotide , Becloforte , Beclomet , Aldecin , Respocort ) Budesonide ( Pulmicort ) Sodium cromoglycate ( Intal ) Other treatments Anti-histamines including ketotifen Anticholinergics Examples: Ipratropium bromide ( Atrovent ) Methylxanthines Examples: Nuelin SR, Theodur , Euphylline

71. Approach To Drug Therapy - "Stepwise Approach" [step 1] Start at the step most appropriate to severity, moving up if needed or down if control is good for > 3 months. Rescued courses of prednisolone may be needed STEP 1 MILD EPISODIC ASTHMA Infrequent symptoms No nocturnal symptoms PEF 80-100% predicted Treatment:  inhaled beta2 agonist "as needed" for symptom relief. If needed more than once a day, advance to Step 2

72. Approach To Drug Therapy - "Stepwise Approach" [step 2] STEP 2 MODERATE ASTHMA Frequent symptoms Nocturnal symptoms present PEF 60-80% predicted Treatment  inhaled steroids, e.g. beclomethasone or budesonide 200-800 mcg/day inhaled sodium cromoglycate plus  inhaled beta2 agonist "as needed"

73. Approach To Drug Therapy - "Stepwise Approach" [step 3 ] STEP 3 SEVERE CHRONIC ASTHMA Persistent symptoms Frequent nocturnal symptoms PEF 60% predicted or less Treatment:  inhaled beclomethasone or budesonide 800-2000 mcg/day plus inhaled beta2 agonist as needed plus, if necessary oral beta2 agonist preferably long acting, or inhaled long acting beta2 agonist, or inhaled ipratropium bromide 40 mcg 3-4 times a day, or oral theophylline (sustained release), or nebulised beta2 agonist, 2-4 times a day

74. Approach To Drug Therapy - "Stepwise Approach" [step 4] STEP 4 VERY SEVERE ASTHMA Persistent symptoms not controlled by step 3 medications Treatment:  as in step 3, plus oral steroids (the lowest dose possible) STEP DOWN Patients should be reviewed regularly. When the patient’s condition has been stable for 3-6 months, drug therapy may be stepped down gradually. The monitoring of symptoms and peak flow rate should be continued during drug reduction.  

75. Management of acute severe asthma RR >50/min PEFR <50% Pulse >140 beats/min breathlessness 10 puffs Bronchodilator and Metered Dose Inhaler High flow 02, bronchoD MDI, nebulizer(1-2h) Oral prednisolone (3-5d) Monitore PEFR/O2 B2 agonist / 02 if required PEFR <33% Tiredness Cyanosis Decrease respiratory effort Silent chest iv aminophylline Iv hydrocortisone Salbutamol Ipratropium bromide Adequate hydration antibiotic ICU Artificial ventilation Wean iv Β 2 Agonist Oxygen if required Oral prednisolone Monitor PEFR Patient’s education Review maintenance medication Review inhaler technique Follow up PEFR monitor DISCHARGE PLAN response Non- response Give treatment improve Not improve

76. Management Of Acute Asthma Aims Of Management To prevent death To relieve respiratory distress         To restore the patient’s lung function to the best possible level as soon as possible. To prevent early relapse

77. 1. Assess severe attack Severe attack: a) Unable to complete sentences b) RR>25/min c) PR>110 bpm d) PEF< 50% of predicted or best Life-threatening attack: a) PEF<33% of predicted or best b) Silent chest, cyanosis, feeble respiratory effort c) Bradycardia / hypotension d) Exhaustion, confusion, or coma e) ABG : normal/high P a CO 2 >5kPa (36mmHg) P a O 2 < 8kPa (60mmHg) low pH, e.g. <7.35

78. 2. Start treatment immediately Sit patient up & give high dose O 2 in 100% via non-rebreathing bag Salbutamol 5mg (or terbutaline 10mg) + ipratropium bromide 0.5 mg nebulized with O 2 Hydrocortisone 100mg IV/prednisolone 30 mg PO (both if very ill) CXR to exclude pneumothorax If life threatening features (above) present: Inform ITU, and seniors Add MgSO 4 1.2-2g IV over 20 min Give Salbutamol nebulizers every 15 min, or 10mg continuously per hour

79. Further management If improving 40-60% O 2 Prednisolone 30-60mg/24h PO Nebulized salbutamol every 4 h Monitor peak flow and O 2 saturations If not improving after 15-30min Continue 100% O 2 and steroids Hydrocortisone 100mg IV or prednisolone 30mg PO if not already given Give Salbutamol nebulizers every 15 min, or 10 mg continuously per hour Continue ipratropium 0.5 mg every 4-6h

80. Post-attempt…. If patient still not improving Discuss with seniors and ITU. Repeat salbutamol nebulizers every 15 mins MgSO 4 1.2-2g IV over 20 min, unless already given. Consider aminophylline, if not already on a theophylline. Alternatively, give salbutamol IVI. Monitoring the effects of treatment Repeat PEF 15-30min after initiating treatment Pulse oximeter monitoring: maintain SaO 2 >92 %. Check blood gases within 2h if:initial PaO 2 was normal/ raised or initial PaO2 <8 kPa (60mmHg) or patient deteriorating Record PEF pre- and post- β -agonist in hospital at least 4 times.

81. Once patient improving… Once patient is improving Wean down and stop aminophylline over 12-24 h. Reduced nebulized salbutamol and switch to inhaled β -agonist. Initiate inhaled steroids and stop oral steroids if possible Continue to monitor PEF. Look for deterioration on reduced treatment and beware early morning dips in PEF Look for the cause of the acute exacerbation and admission

82. Component 1: Patient-Doctor relationship

83. Component 2: Identify and Reduce Exposure to Risk Factors

84. Follow-Up and Monitoring Include review of symptoms and measurement of lung function PEF monitoring at every visit along with review of symptoms helps in evaluating the patient’s response to therapy and adjusting tx.PEF consistently >80% of the patient’s personal best suggests good control. Regular visits (at 1 to 6 month interval as appropriate) is essential even after control of asthma is established

85. Asthma Management Plan When PEF >80%: continue current dose of inhaled corticosteroids When PEF 60-80%:double the dose of inhaled corticosteroids When PEF 40- 60%:start rescue course prednisolone When PEF persists below 60% despite rescue course prednisolone with worsening symptoms,advised to come to EMERGENCY DEPT immediately

86. Management of asthma in pregnancy In general during pregnancy,asthma becomes worse in a third of women,is stable in another third and improves in the remaining third. Women should be reassured that their asthma medication carries less risk to the foetus than a severe asthma attack Inadequately treated asthma can cause maternal and foetal hypoxaemia,which leads to complications during pregnancy and poorer birth outcomes

87. Management: Pregnancy in asthmatics Treatment should be aggressive,with the aim of eliminating symptoms and restoring and maintaining normal lung function Beta2 agonists : No evidence of a teratogenic risk with the commonly used inhaled beta2 agonists Ipratropium bromide: appears to be safe for use during pregnancy Salmeterol / formoterol : not been tested extensively in pregnant women

88. Management: Pregnancy in asthmatics Theophyllines : may aggravate the nausea and GERD and can caause transient neonatal tachycardia and irritabilityTeratogenicity has been shown in animals. Sodium cromoglycate : no adverse foetal effects Inhaled corticosteroids: mainstay of tx in persistent asthma,good safety profile in pregnancy Oral corticosteroids: necessary for severe asthma in pregnancy but usually only for short periods.Increased risk of cleft palate in animals given huge doses of oral steroids Anti- leukotrienes : no data available

89. Labour and Breastfeeding Women with very severe asthma may be advised to have an elective caesarean section at a time when their asthma control is good Breastfeeding should be continued in women with asthma In general,asthma medications are safe during pregnancy and lactation and the benefits outweigh any potential risks to the foetus and baby

90. Allergic Rhinitis and Asthma 80% of patients with asthma have allergic rhinitis When allergic rhinitis is undetected or untreated,patients have frequent exacerbations not responding to conventional treatment Nasal inhalation of corticosteroids are mainstay of treatment with or without oral antihistamine

91. Status Asthmaticus Acute exacerbation of asthma that does not respond to standard treatment of bronchodilators and corticosteroids . Symptoms include chest tightness , rapidly progressive dyspnoea , dry cough and wheezing The lung failure means that oxygen can no longer be provided, carbon dioxide can no longer eliminated. Hence, leading to acidosis .

92. It is not just asthma Case Presentation / UMMC

93. MIBMH 10.5 years old boy, known case of mild intermittent asthma presented to HSB with: Fever, cough and runny nose ----- 1 wk. Hemoptysis and loss of appetite ---- 5d No night sweating . Seen by GP and managed with oral antibiotic and symptomatic treatment but the patient did not improve.

94. Review of symptoms The patient is unable to lie flat for the past 2 weeks due to feeling of breathlessness.

95. In HSB respiratory distress upon admission CXR: mediastinal mass on right perihilar region multiple cannon ball lesions in both lung fields, so CT thorax, abdomen and pelvis done Huge anterior mediastinal mass encasing great vessels with lung metastasis and lymphadenopathy . Referred to UMMC for possibility of malignancy.

96. Past history Asthma since age of 7 years not on regular follow-up or treatment/prophylaxis mild infrequent diurnal symptoms no interference with general activity or school attendance. acute exacerbation: twice a year and precipitated mainly by coldness. No hospital admission

97. Perinatal history : uneventful. Developmental history: attends school, average level, very shy. Immunization: full schedule. Allergy: allergic to dust. Family and social history: No ill family member. No H/O contact with T.B

98. O/E Looks lethargic, dyspneic RR 32/min with recessions, HR 120/min, SpO 2 96% on face mask O 2 5l/min, temp 36.4C No lymphadenopathy . Lungs: -reduced breath sounds on right medial and lower zones with crepitations on the right side CVS: S1 + S2 , no murmur. Abdomen: soft, liver 2cm firm.

99. Genitalia : pubic hair stage 3, penile length 7.5cm, testes 2 ml each. Breast tissue : gynaecomastia .

100. Growth parameters

101. Height: 166 cm Upper/lower segment ratio = 1

102. investigations FBC: Hb 11.9gm/dl wbc 12,600/ ul plt 397,000/ ul ANC 9,500/ ul . BUSE: Na 131mmol/l K 3.9mmol/l Cl 95mmol/l urea 2.4mmol/l creat 77umol/l LFT: alb 29gm/l t- bili 4umol/l ALP 146u/l ALT 41u/l AST 58u/l Ca 2.37mmol/l PO4 1.23mmol/l Mg 0.83mmol/l PBF: normal findings.

103. ESR: 110mm/hr CRP: 14.8mg/dl LDH: 511U/L

104. Radiological investigations

105. BhCG : <2 mu/ml (L) (0-10) AFP: 397040.9 (H) (0-6.7)

106. LH 11 mu/ml (H) (<0.1-6) FSH 33 mu/ml (H) ( 1.2-2.5) Estradiol <37 pmol /l (0-198) Testosterone 2.3 nmol /l (L) (8.4-28.7) DHEAS 0.5 umol /l (L) (2.2-15.2) Karyotyping : 47 XXY, how many cells? Any evidence of mosaic Klinefelter ? (waiting formal report).

107. diagnosis Mediastinal germ cell tumor with bilateral lung metastasis and pseudoprecocious puberty. Klinefelter syndrome.

108. Management and progress Respiratory support, required BiPAP . Required neb Salbutamol 4 hourly. Had spikes of fever, covered with Erythromycin and Ceftriaxone . After 4 days in PICU transferred to P6. Started chemotherapy(UKCCSG). Had NNF covered with piptazocin then imipenem and later on Ampho -B.

109. Became neutropenic . All blood and respiratory cultures have no growth.

110. Discussion

111. Klinefelter syndrome In 1942 Klinefelter et al published a paper on 9 men with large breasts, minimal sexual and body hair, small testes and inability to produce sperms. It is the most common syndrome assoc with male hypogonadism and infertility. Classically 47XXY, but many variants like 48 XXXY, 48XXYY,49XXXXY,49XXXYY,50XXXXYY. It is due to meiotic non-disjunction. mosaic patients may be fertile .

112. Features Hypogonadism (small testes and azoospermia-hyalinzation and fibrosis of seminiferous tubules). Gynaecomestia in late puberty (30-50%) due to increase estradiol /testosterone ratio. Psychosocia l problems. Elevated urinary gonadotrophins . Mental retardation is affected by number of X chromosomes (decreased IQ 15 points for each X chromosome) [most males with 47XXY have normal intellegence , 70% have minor developmental and learning disability]

113. Other features: Pes cavus , genu valgus , fifth finger clinodactily . Taurodontism (prominent molar teeth): 40% in Klinefelter , 1% in general population. Radio- ulnar synostosis - --- 49XXXXY.

114. Increased risk of: DM. CVS: varicose veins, venous ulcer, DVT , pulm embolism, mitral valve prolapse . Cancer: breast, leukemia, mediastinal germ cell tumors. Osteoporosis. Autoimmune disease (SLE, RA, Sjogren with increased mortality).

115. Mortality 40% of conceptions with Klinefelter survive fetal period. Mortality is not significantly higher in healthy individuals.

116. Prevalence: in USA 1:500-1000 Race: no race difference. Age: it goes undetected in most affected males until adulthood. the common indication for karyotyping is hypogonadism and infertility.

117. investigations Mid-puberty: increase FSH and LH, decrease testosterone. Increase estradiol /testosterone ratio----- gynaecomastia 80%. Cortisol should be checked (47% have low cortisol ). Decrease osteocalcin ---- bone resorption . Coagulation profile because of increased risk of DVT and pulm embolism. Karyotyping:47 XXY 80-90 % - 10% mosaic.

118. Germ cell tumors Classification: -suppressed differentiation: seminoma , dys - germinoma . -differentiation: Initial embryonal carcinoma Embryonic mature and immature teratoma Extra-embryonic( choriocarcinoma -yolk sac tumor{ endodrermal sinus tumor}) -mixed histology: mixed GCT.

119. Primary mediastinal germ cell tumors Comprise only 1-3% of germ cell tumors. Overall teratoma is the most common variant, seminoma is the most common malignant variant. Malignant variants are uncommon and more in males. Benign variants are equally disributed among males and females. Testicular examination, U/S and CT are mandatory to rule out testicular primary cancer.

120. Serum markers Alpha-fetoprotein: indicates malignant non- seminomatous type. BhCG : suggests trophoblastic component. Malignant non- seminomatous and mixed GCTs carry worse prognosis than other GCTs.

121. Association of M- GCTs with Klinefelter syndrome Klinefelter syndrome is present in 20% of patients with M-GCT. The incidence of M-GCT is 50 fold increased in patients with Klinefelter syndrome. M-GCT mask the usual clinical signs of Klinefelter syndrome by inducing puberty by BhCG .

122. Comparison of GCT between KS and general population Klinefelter syndrome: All contain non- seminominatous elements Present at younger age (mean 17 years) Precocious puberty is seen more often. Almost exclusively extragonadal . General population: Pure seminoma is the most common malignant variant. Older age at presentation (mean 29 years) Precocious puberty is less often. Only 2-5% extragonadal .

123. references http://emedicine.medscape.com/ Ann Thorac Surg 1998;66:547-548

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