1. Case Conference #3 Amaro-Aribon A2

2. Diagnostic approach to pleural effusion

3. The history and physical examination are critical in guiding the evaluation of pleural effusion. Chest examination of a patient with pleural effusion – dullness to percussion, decreased or absent tactile fremitus, decreased breath sounds, and decreased voice transmission, mediastinal shift to the opposite side Chest x-ray Approach to a Patient with Pleural Effusion Diagnostic Approach to Pleural Effusion in Adults, www.aafp.org/afp/20060401/1211.html

4. The first step in the evaluation of patients with pleural effusion is to determine whether the effusion is a transudate or an exudate. Diagnostic approach to pleural effusion Harrison’s Internal Medicine 17 th edition p.1658 Transudative pleural effusionExudative pleural effusion Occurs when systemic factors that influence the formation and absorption of pleural fluid are altered Occurs when local factors that influence the formation and absorption of pleural fluid are altered The leading causes are : left ventricular failure cirrhosis The leading causes are : bacterial pneumonia malignancy viral infection pulmonary embolism

5. Transudative and exudative pleural effusions are distinguished by measuring the lactate dehydrogenase (LDH) and protein levels in the pleural fluid. Thoracentesis – invasive procedure to remove fluid or air from the pleural space for diagnostic or therapeutic purposes Harrison’s Internal Medicine 17 th edition p.1658 Diagnostic approach to pleural effusion

6. Perform diagnostic thoracentesis: – if the etiology of the effusion is unclear – if the presumed cause of the effusion does not respond to therapy as expected. Pleural effusions do not require thoracentesis: – if they are too small to safely aspirate (<1 cm thickness on a lateral decubitus film) – if their presence can be explained by underlying congestive heart failure, etc. Diagnostic approach to pleural effusion http://emedicine.medscape.com/article/299959-diagnosis

7. Light’s criteria Exudative pleural effusions meet at least one of the following criteria, whereas transudative pleural effusions meet none: 1. pleural fluid protein/serum protein >0.5 2. pleural fluid LDH/serum LDH >0.6 3. pleural fluid LDH more than two-thirds normal upper limit for serum Diagnostic approach to pleural effusion Harrison’s Internal Medicine 17 th edition p.1658

8. The criteria misidentify ~25% of transudates as exudates. If one or more of the exudative criteria are met and the patient is clinically thought to have a condition producing a transudative effusion, the difference between the protein levels in the serum and the pleural fluid should be measured. If this gradient is greater than 31 g/L (3.1 g/dL), the exudative categorization by the criteria can be ignored because almost all such patients have a transudative pleural effusion. Diagnostic approach to pleural effusion Harrison’s Internal Medicine 17 th edition p. 1658

9. The primary reason to make this differentiation is that additional diagnostic procedures are indicated with exudative effusions to define the cause of the local disease. If a patient has an exudative pleural effusion, the following tests on the pleural fluid should be obtained: description of the fluid glucose level differential cell count microbiologic studies cytology Harrison’s Internal Medicine 17 th edition p. 1658 Diagnostic approach to pleural effusion

10. Harrison’s Internal Medicine 17 th edition p. 1658

11. Interpretation of the Arterial Blood Gas

12. Arterial Blood Gas ParameterPatient’s ABGNormal Values pH7.517.35-7.45 pCO245.6 mmHg35-45 mmHg HCO336.4 mEq/L22-26 mEq/L pO258.1 mmHg80-100 mmHg P/F ratio181 400 (60 y/o and below)

13. Interpretation pH- 7.51Alkalosis pCO 2 - 45.66 mmHg HCO 3 - 36.4 mEq/L pO 2 - 58.1 mmHgHypoxia P/F ratio- 181Hypoxia  Partially Compensated Metabolic Alkalosis with Hypoxia

14. ACR criteria for SLE

15. 1982 American College of Rheumatology Criteria for SLE The presence of 4 of the 11 criteria yields a sensitivity of 85% and a specificity of 95% for SLE. http://www.ncbi.nlm.nih.gov/pubmed/15580984

16. 1982 American College of Rheumatology Criteria for SLE Malar rashFixed erythema over malar areas, sparing nasolabial folds Discoid rashErythematous raised patches with keratotic scaling and follicular plugging PhotosensitivitySkin rash after exposure to sunlight, history or physical exam Oral ulcersOral or nasopharyngeal, painless, by physical exam Nonerosive arthritisTenderness, swelling, effusion in 2 or more peripheral joints Pleuritis or pericarditisConvincing history or physical exam or ECG or other evidence Renal disorder>0.5g protein/d or 3+ or cellular casts Seizures, psychosisNot due to drugs, metabolic derangement, etc Hematologic disorderHemolytic anemia or leukopenia (<4000 twice) or lymphopenia (<1500 twice) or thromobocytopenia (<100,000) without other causes Immunologic disorderAnti-dsDNA or anti-Sm or antiphospholipid antibodies (anticardiolipin, lupus anticoagulant, or false positive test for syphilis) Positive ANAHigher titers generally more specific (>1:160); must be in the absence of medications associated with drug-induced lupus Braunwald, et.al Harrison’s Priniciples of Internal Medicine 17 th ed. 2006. pg 2077 http://www.ncbi.nlm.nih.gov/pubmed/15580984

17. Reasons for immunocompromised state of the Patient

18. Immunocompromised state in our Patient: Patient has Systemic Lupus Erythematosus Patient is on the following medications: – Steroids (Methlyprednisolone) – Immunosuppressants (cyclophosphamide) – Biologics (Rituximab)

19. Systemic Lupus Erythematosus Autoimmune disease – An illness that occurs when the body tissues are attacked by its own immune system  inflammation and tissue damage An individual with lupus is more susceptible to infection than most people for two reasons: – Lupus directly affects a person's immune system and reduces his or her ability to prevent and fight infection. – Many of the drugs used to treat lupus suppress the function of the immune system and leave the body more prone to infection.

20. Effects Of Medications Used In The Treatment Of Lupus Steroids (methlyprednisolone) Cytotoxic drugs (cyclophosphamide) Rituximab - a monoclonal antibody that lowers B cell counts increase a person's susceptibility to infections because they suppress both abnormal and normal immune system function Reactivation of dormant infectious organisms

21. Chronic Steroid Use Methlyprednisolone – Useful in treatment of inflammatory and autoimmune reactions – Reverses increased capillary permeability and suppressing PMN activity  may decrease inflammation Methylprednisolone and other corticosteroids can mask signs of infection and impair the body's natural immune response to infection.

22. Mode of Action, Antimicrobial coverage and side effects of piperacillin-tazobactam and fluconazole

23. Piperacillin-Tazobactam It exerts its bactericidal activity by inhibition cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid sulphone, is a potent inhibitor of many beta- lactamases, in particular the plasmid mediated enzymes which commonly cause resistance to penicillins and cephalosporins including third-generation cephalosporins.

24. Commonly susceptible species Gram positive aerobes Gram negative aerobes Gram positive anaerobes Gram negative anaerobes Brevibacterium spp Enterococcus faecalis Listeria monocytogenes Staphylococcus spp. methicillin-sensitive Streptococcus pneumoniae Streptococcus pyogenes Group B streptococci Streptococcus spp* Branhamella catarrhalis Citrobacter koseri Haemophilus influenzae* Haemophilus spp. Proteus mirabilis Salmonella spp. Shigella spp. Clostridium spp. Eubacterium spp. Peptococcus spp. Peptostreptococcus spp. Bacteroides fragilis* Bacteroides fragilis group Fusobacterium spp. Porphyromonas spp. Prevotella spp* * Clinical effectiveness against this has been demonstrated in the registered indications. ($) Species showing natural intermediate susceptibility (+) Species for which high resistance rates (more than 50%) have been observed in one or more areas/ countries/regions within the EU.

25. Species for which resistance may be a problem Gram positive aerobesGram negative aerobesGram negative anaerobes Staphylococcus aureus, methicillin-sensitive Staphylococcus epidermis, methicillin-sensitive Enterococcus avium ($) Enterococcus faecium (+ $) Propionibacterium acnes ($) Viridans streptococci Actinobacter spp (+ $) Burkholderia cepacia Citrobacter freundii Enterobacter spp. Escherichia coli * Klebsiella spp. Proteus, indole positive Pseudomonas aeruginosa* Pseudomonas spp. * Pseudomonas stutzeri $ Serratia spp. Bacteroides spp. * * Clinical effectiveness against this has been demonstrated in the registered indications. ($) Species showing natural intermediate susceptibility (+) Species for which high resistance rates (more than 50%) have been observed in one or more areas/ countries/regions within the EU.

26. Inherently resistant organisms Gram positive aerobesGram negative aerobes Corynebacterium jeikeium Staphylococcus spp. methicillin resistant Legionella spp Stenotrophomonas maltophilia +$ * Clinical effectiveness against this has been demonstrated in the registered indications. ($) Species showing natural intermediate susceptibility (+) Species for which high resistance rates (more than 50%) have been observed in one or more areas/ countries/regions within the EU.

27. Adverse Reaction

29. Fluconazole

30. Antimicrobial coverage Blastomyces dermatitidis Candida spp. (except C. krusei and C. glabrata) Coccidioides immitis Cryptococcus neoformans Epidermophyton spp. Histoplasma capsulatum Microsporum spp. Trichophyton spp. https://online.epocrates.com/u/10a635/fluconazole

31. Adverse Reactions Serious ReactionsCommon Reactions hepatotoxicity seizures leukopenia agranulocytosis thrombocytopenia angioedema anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis QT prolongation torsades de pointes nausea headache rash vomiting abdominal pain diarrhea dyspepsia taste changes dizziness elevated liver transaminases https://online.epocrates.com/u/10a635/fluconazole

32. ANTIPHOSPHOLIPID SYNDROME CLINICAL MANIFESTATIONS

33. Cerebrovascular Manifestations cerebral ischemia (arterial thrombosis involves the brain in up to 35% of cases, causing transient ischemic attacks or strokes) venous sinus thrombosis chorea migraine transverse myelopathy seizures

34. Cerebrovascular Manifestations Sneddon syndrome multi-infarct dementia retinal venous thrombosis multiple-sclerosis-like symptoms psychosis

35. Cardiac Manifestations valvular disease (most commonly mitral regurgitation) affects 10-35% of the patients Libman-Sachs endocarditis coronary artery disease cardiomyopathy intracardiac thrombosis

36. Vascular Disease peripheral deep vein or recurrent superficial thromboses Venous thrombosis, particularly of the lower limb, occurs in up to 50% of patients with the syndrome.

37. Pulmonary Manifestations pulmonary embolism pulmonary hypertension intraalveolar pulmonary hemorrhage adult respiratory distress syndrome (ARDS) fibrosing alveolitis

38. Renal Manifestations renal vein and/or artery thrombosis (main branches) glomerular and small artery thrombosis cortical atrophy

39. Endocrine System Disease Addison's disease hypopituitarism

40. Hematological Manifestations thrombocytopenia autoimmune hemolytic anemia bleeding (extremely rare)

41. Gastrointestinal Manifestations Budd-Chiari syndrome esophageal necrosis intestinal ischemia hepatic necrosis

42. Skin Manifestations livedo reticularis skin ulceration cutaneous necrosis and infarction gangrene of digits

43. Obstetric Manifestations The risk of pregnancy loss in women with antiphospholipid antibodies is greatest from the 10th week of gestation onward (fetal period) The complications in pregnancy can also include preterm labor, low birth weight, preeclampsia, and stillbirth.

44. Diagnosis Criteria/Definition

45. Diagnosis criteria/definition thrombosis (arterial and/or venous) recurrent abortions (>2) thrombocytopenia and positive aCL or LA, occurring twice with an interval of at least 3 months

46. Clinical Criteria

47. one or more episodes of venous, arterial or small vessel thrombosis and/or pregnancy morbidity. Pregnancy morbidity was defined as follows – one or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, or – one or more premature deaths at or before the 34th week of gestation because of severe preeclampsia or eclampsia, or – three or more unexplained consecutive abortions before the 10th week of gestation

48. Laboratory Criteria IgG and/or IgM aCL in medium or high titers measured by a standard enzyme-linked immunoassay and/or LA detected according to the guidelines of the International Society of Thrombosis and Hemostasis, twice ore more, with an interval of at least 6 weeks between tests. Thus, in clinical practice a diagnostic workup for antiphospholipid antibodies should be considered in all patients with venous or arterial thrombosis and fetal loss for which there is no alternative explanation, particularly in the presence of recurrent manifestations

49. Complication of SLE and chronic steroids in this patient.

50. Complications of SLE Patient’s azotemia, would lead to kidney failure – Symptoms like bloody stools, changes in mental status, edema, etc. Hemolytic anemia – Symptoms like dark urine, splenomegaly, inc. heart rate,etc. Myocarditis – Symptoms like irregular heart beat, edema, etc. Seizures Serositis (pleural effusion or pericardial effusion) Thrombocytopenia – Symptoms like bruising, epistaxis, rash, etc Infections Reccurence of previous illnesses – As the same degree or worse case Harrison’s Principle of Internal Medicine, 17 th ed.

51. Complications of SLE CNS Lupus (“Neurological disorders in systemic lupus erythematosus patients” by Hawro, T.; et.al. in the journal of Pol Merkur Lekarski. 2009 Jan;26(151):43-8.) Results: Headache (38.64%) most prevalent symtoms Cerebrovascular disease(31.82%), prevalent among SLE patients with more active lupus course Seizures (13,64%) Mononeurpathy (13,64%) Cognitive impairment (6,82%) Polineuropathy (4,55%) Cranial neuropathy (2,77%) Acute confusional state (2,27%) Conclusion: High prevalence of nervous system manifestation in SLE indicates the need for neurological care in SLE patients. Headache is frequent but low specific sign of neuropsychiatric lupus. Neurological disease should incline toward more intense immunosuppressive therapy which may delay the nervous system destruction

52. Complications of Chronic steroids Neurologic Complications Myopathy Ocular Complications Hyperglycemia Gastrointestinal Complications – Peptic Ulcer Disease Pancreatitis Infection Bone Avascular Necrosis Osteoporosis Management of Chronic Steroid use by Keenan. Clinics in Chest Medicine Volume 18, Issue 3, 1 September 1997, Pages 507-520