An Unusual Presentation of a Known HIV Related Condition Presenting as a Septic Mimic

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Michael J. Kavanaugh, M.D., of U.S. Navy Medicine, presents "An Unusual Presentation of a Known HIV Related Condition Presenting as a Septic Mimic" at AIDS Clinical Rounds

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An Unusual Presentation of a Known HIV Related Condition Presenting as a Septic Mimic

  1. 1. M I C H A E L K A V A N A U G H A P R I L 4 , 2 0 1 4 AIDS CLINICAL ROUNDS
  2. 2. Disclosures  I have no relevant financial relationships with any commercial supporters.  Unlabeled/Investigational products and/or services will be mentioned in this CME offering.
  3. 3. 67 y/o Caucasian man with HIV/AIDS, OCT CD4+ 437/14%/VL undetectable who presents to NMCSD ER with complaint of progressive dyspnea and a mild dry cough for the last 7 days
  4. 4. History Continued  Initially, his dyspnea was with stairs  Progressed to flat surfaces  Baseline can walk a few miles, dyspnea with 1 city block and then at time of admission at rest for past 1-2 days  Dry cough for 7 days-no sputum or hemoptysis  10 lb weight loss over last 6 weeks  Denies any fevers  Reports that his home blood pressures have been low (systolic in 80s) so he stopped taking Lisinopril
  5. 5. Review of Systems  Constitution-no fevers or chills, +fatigue  HEENT-no sinus tenderness or rhinorrhea  Chest-one episode of substernal chest pain 4 days prior to admission-none at present, no palpitations  Resp-DOE – now at rest shortness of breath, slight dry cough, no sputum  GI-no abdominal pain, baseline chronic diarrhea-slight improvement recently  GU-increased nocturia (baseline 1x/night, now 4x/night over last 4 week)  MSK-Significant improvement in shoulder function after steroid injection in December  Neuro-noncontributory
  6. 6. PMH  HIV+; dx oct2006-presented with AIDS with PCP and was admitted with respiratory distress, requiring corticosteroid therapy which resulted in a flare of KS  Currently undetectable on Truvada/Atazanavir/ritonavir/Raltegr avir  Switched from Kaletra/Truvada to RAL/3tc/Ataz/Rit on 16sep 2012, previously on Atripla for short period  Genotype 10/12/06: PI mutations: I13V, M36L, L63P; no clinical resistance  Kaposi Sarcoma s/p systemic chemotherapy (doxorubicin)- Jan07-Nov07  Cryptosporidium-treated with nitazoxanide Sept10  BPH  HLD  Left Shoulder tendonitis-steroid injection Dec 2013  HTN  C diff-oct06  PCP-oct06; based on BAL giemsa  CKD (GFR 50)  ED  Stage I diastolic dysfunction  3rd degree AV block s/p pacemaker--2007, pacemaker recently checked OS PVD-jul07  B12 def.  gynecomastia  SCC L ear s/p MOHS-2008  L ear AK cryotherapy-Dec10  ?ABC hypersensitivity-Jul08  Diarrhea predominant IBS-since age 45; prior significant diarrhea while on Kaletra
  7. 7. Medical History continued  MEDS  Truvada  Raltegravir 400mg bid  Atazanavir 300mg daily  Ritonavir 100mg daily  Uroxatral 10mg qd  Lipitor 20mg qhs  Synthroid 75  Lisinopril 5mg-held for 1 day  Fish oil 2 pills (1200mg) qam  ASA 81mg qd  MVI (Ocuvite)  Allergies-Sulfa  Past Surgical History  Cholecystectomy 2009  Septoplasty  Skin excision for SCC  Shoulder injection (Dec 2013)  Social History  Married-lives with wife  Nonsmoker, No alcohol  Retired Navy MCPO
  8. 8. Exposure History  Travel: No travel outside US since 2006  Animals: 2 dogs  Food Exposure: noncontributory  Soil Exposure: occasional gardening in home, does not wear a mask  Other: Denies sick contacts
  9. 9. Physical Exam  T98.3 P94 R16 BP 132/72 99% RA wt 56 kg  GEN: NAD, A&Ox4, WDWN  HEENT: PERRL, EOMI, nl sclera, no photophobia, no throat inflammation.  NECK: nl thyroid, no neck masses, no JVD  HEART: RRR S1/S2, no M/G/R  LUNGS: CTA Bilaterally  ABD: Soft NT/ND, +BS, no HSM  LYMPHATICS: No LE edema, no axillary, groin, neck adenopathy.  EXT: No LE edema  MUSCULOSKELETAL: no joint effusions or pain, no muscle tenderness  DERM: Actinic keratoses on right cheek & on his forehead, also with 2 mm of purple hyperpigmentation on right cheek. No lesions or sores visible elsewhere. (+) for hyperpigmentation on right forearm from prior Kaposi's sarcoma  NEURO: CN 2-12 grossly intact, no focal deficits  PSYCH: no perceived mood disorder, nl demeanor with appropriate behavior.  LINES/DEVICES: Clean without signs of infection
  10. 10. Labs/Radiology  CBC 4.9/11.3/33.2/181 N77.4 L16.5  Lytes 131/3.6/93/26/31/1.3/200 Ca 8.9 Mg 2 P 2.1  AST 16 ALT 20 Alk P 68  T bili 2.6  Alb 3.6 total protein 6.5
  11. 11. Normal Chest Xray
  12. 12. Differential
  13. 13. Patient Evaluation  Urine Legionella pneumo Ag neg  Urine Streptococcus pneumoniae Ag negative  Urine Cultures negative  Blood Cultures negative  Respiratory Viral Panel-negative  Sputum Culture-negative  Sputum for silver stain-negative  Sputum PCP PCR negative
  14. 14. Hospital Course  CT Chest performed-negative  ECG and cardiac enzymes unremarkable  No antibiotics provided  No bronchoscopy performed  Diagnosed with a URI?  Also diagnosed with new onset DM-HbA1C 6.6  Diabetic teaching provided  No medications initiated  Held Lisinopril as possible source of cough  Fatigue improved without significant intervention
  15. 15. Clinic Follow up  Patient reports feeling very well  Walking 1-2 miles per day  Nocturia has returned to 1x per night (baseline)  Diarrhea has remained – actually improved over last 2 months  Shoulder feels very well  Afebrile  No cough or SOB  Blood Pressures off Lisinopril 120s-130s  Blood Sugars in 130-166
  16. 16. What Happened?
  17. 17. Another Comparable Case 50 year old male with HIV+ CD4 503/13% VL undetectable, on Truvada, atazanavir/ritonavir (RV168 protocol patient), prior KS (Jan 2012) treated with radiation presents for clinic follow-up with 20 lb weight loss over last 6 months
  18. 18. Pertinent History  Patient had intra-articular steroid injection (Aug 2013)-kenalog in left shoulder (2 years shoulder pain)  Developed fatigue, shakiness and drenching night sweats without fevers  Wasting of arms and legs  Dyspnea on exertion  Abdominal bloating  Increased urinary frequency (3x nocturia)  A1C increased from 6.3->7 in one month-post-prandial glucose 180  Lost 15 lbs in 4-6 weeks  New skin lesions requiring surgical removal
  19. 19. Pertinent History Continued  At time-period annotated on previous, he had a recent decrease in CD4 from 504/19% to 214/11%  Started on TMP/SMX  Weight loss, change in CD4, history of KS & new skin lesions  Concern of recurrence  Bloating sensation with weight loss  Received cholecystectomy  Adrenal insufficiency was “ruled out” by primary care provider
  20. 20. Past Medical History  HIV diagnosed 1996 – genotype 2001 M184V, K103R, L63, M36  Headache syndrome  Depression  Allergic rhinitis  Kaposi’s sarcoma Jan 2012  Radiation x 10  BPH s/p TURP  Herpes  Resolved hepatitis B  FHx  Family medical history:  Diabetes-maternal side  Breast CA maternal aunt  PSH  PRK  R inguinal hernia repair  TURP-1999  Cholecystectomy – Sep 13  Septoplasty  NKDA  Social History  Denies tobacco  + EtOH 4X/week  Denies ilicits  Currently in monogamous relationship, partner is seronegative  Works in health systems management
  21. 21. Medications  Atazanavir 300mg po daily  Ritonavir 100mg po daily  Truvada (tenofovir 300mg +Emtricitabine 200mg) po daily  Fexofenadine 60mg po bid  Atorvastatin 20mg po daily  Escitalopram 10mg po daily  Sumitriptan prn  Hydrocortisone  TMP/SMX
  22. 22. Physical Exam  T99.2 BP 134/86 P98 R14  Gen well appearing  Head-cushingoid with moon like facies  Neck-increased fat on posterior neck and upper back  Oral cavity normal  Lymph nodes-no abnormalities noted  Lungs cta (b)  CV RRR no murmur  Abd +bs, soft, NT, ND, well healed surgical scars  Musculoskeletal-arm thinning (b)  Neuro CN II-XII intact  Skin scattered purple plaques on arms, legs and bilateral feet
  23. 23. Evaluation  CBC 8.1/14.2/42.4/222 N 45.9 L 46.3 E 0.7  Lytes 144/3.6/105/23/10/0.9/104 Ca 8.4 Mg 2.3  Bili 2.1 Prot 6.5  Alk P 52 ALT 43 AST 26  UA SG 1.017 protein neg, gluc neg, pH 6  Skin lesions evaluated by dermatology including bx  Negative for KS
  24. 24. AM Cortisol  Cortisol AM Site/Specimen 03 Oct 2013 0910  Cortisol AM SERUM 9.760 <o> mcg/dL (6.2-19.4)  Cortisol AM Site/Specimen 03 Oct 2013 0840  Cortisol AM SERUM 7.210 <o> mcg/dL (6.2-19.4)  Cortisol AM Site/Specimen 03 Oct 2013 0800  Cortisol AM SERUM 0.778 (L) <o>mcg/dL (6.2-19.4)
  25. 25. Additional Labs  Thyroxine free 1.2 nl  HBA1C 7 (previous 6.3)  Liver enzymes (September) Alk P 213 ALT 162 AST 33 T bili 2.73 with dbili 0.35
  26. 26. Course continued  As steroid level waned-fatigue worsened  Endocrine consult-Diagnosed with Cushing’s Syndrome with secondary adrenal insufficiency  Started on hydrocortisone with taper  Recognized that ritonavir may be issue  Checked ACTH-low nml 8 (6-50 pg/mL)  MRI brain- nondiagnostic  Performed cosyntropin stimulation test normal (7.94->19) in one hour, stopped hydrocortisone
  27. 27. Which of the following is an appropriate screening test for Cushing’s Syndrome?  Urine Cortisol  Urine Metanephrines  Salivary Metanephrines  Cosyntropin (ACTH) stimulation test  Serum Metanephrines
  28. 28. Which of the following is an appropriate screening test for Cushing’s Syndrome?  Urine Cortisol  Confirmatory with Dexamethasone suppression test  Urine Metanephrines  Salivary Metanephrines  Cosyntropin (ACTH) stimulation test  Serum Metanephrines
  29. 29. Cushing’s Syndrome  Iatrogenic hypercortisolism (most common)  Ingested/injected/topical/inhaled steroids & megestrol acetate  Ectopic ACTH syndrome- 20 to small cell lung cancer or adrenal tumors  Cushing’s Disease-pituitary ACTH source  Factitious Cushing’s- surreptitious intake of steroids  Hypercortisolism can occur  Extreme stress (including sepsis)  Obesity and polycystic ovary syndrome  Severe prolonged major depressive disorder  Chronic alcoholism
  30. 30. Clinical Manifestations  Progressive Central obesity  Children with generalized obesity and growth retardation  Facial Fat accumulation “Moon facies”  Buffalo hump  Skin atrophy  Easy bruisability  Striae  Fungal infections  Hyperpigmentation-induced by increased ACTH (not cortisol)-binds melanocyte-stimulating hormone  Menstrual irregularities  Proximal muscle wasting –catabolism  Bone loss-can result in pathological fractures
  31. 31. Manifestations
  32. 32. Manifestations continued  Glucose intolerance  Stimulation of gluconeogenesis by cortisol & peripheral insulin resistance  Hyperglycemia in 10-15% of patients  Cardiovascular disease  Increased risk of MI and Stroke  Hypertension  Thromboembolic disease  Neuropsychiatric (labile, depressed, anxiety, panic attacks)  Increased frequency of Infections-inhibited immune system  Ophthalmologic findings-increased IOP & cataracts
  33. 33. Test for Cushing’s Syndrome  Daily urinary cortisol (24 hours best)  10 pm-8 am is acceptable alternative  Late evening salivary cortisol-only beneficial if extremely elevated  Low dose dexamethasone suppression test  Should suppress ACTH and subsequently reduce urine cortisol
  34. 34. Test of Adrenal Insufficiency  Morning cortisol level  > 11 ug/dL not adrenal suppression  <3 ug/dL adrenal suppression  Follow up study is cosyntropin (ACTH) stimulation test
  35. 35. Although idiopathic adrenal insufficiency in HIV is rare, what percentage of post-mortem evaluations of the adrenal gland are abnormal?  <5%  10%  25%  33%  66%
  36. 36. Although idiopathic adrenal insufficiency in HIV is rare, what percentage of post-mortem evaluations of the adrenal gland are abnormal?  <5%  10%  25%  33%  66%-common sources include CMV, Mycobacteria tuberculosis, Histoplasmosis, PCP, Toxoplasmosis and Kaposi’s Sarcoma
  37. 37. Adrenal Function in HIV  Higher basal cortisol & lower dehydroepiandrosterone  Overt adrenal insufficiency is uncommon  Hypercortisolism in the absence of Cushings  No treatment required  Hypocortisolism always requires treatment
  38. 38. Comparison with Lypodystrophy with PIs “pseudo Cushings”  Altered body adipose tissue  Truncal obesity  Peripheral wasting  Breast hypertrophy  “Buffalo hump”  Insulin hypersensitivity  Normal cortisol and normal dexamethasone suppression tests  Lack striae and easy bruisability
  39. 39. When combined with corticosteroids, which medication has been reported to be a contributing factor in iatrogenic Cushing’s Syndrome?  Etravirine  Ritonavir  Zidovudine  Tenofovir  Emtricitabine
  40. 40. When combined with corticosteroids, which medication has been reported to be a contributing factor in iatrogenic Cushing’s Syndrome?  Etravirine  Ritonavir  Zidovudine  Tenofovir  Emtricitabine
  41. 41. Ritonavir and Clearance of Steroids  Iatrogenic Cushing’s Syndrome with Osteoporosis and Secondary Adrenal Failure in Human Immunodeficiency Virus-Infected Patients Receiving Inhaled Corticosteroids and Ritonavir-Boosted Protease Inhibitors: Six Cases  Samaras, K, Pett S, Gowers, A et al. J Clin Endo and Metabolism 2005.  Review in 2008 reported 25 cases at that date of ritonavir and fluticasone combination
  42. 42. Clearance of steroids can be delayed by PI including ritonavir  6 patients reported to develop iatrogenic Cushings following inhaled fluticasone for asthma  Adrenal suppression noted in all 6 patients  When fluticasone removed-4/6 developed hypocortisolism  3/6 developed osteoporosis with pathological fx (1/6)  Exacerbation of DM (1/6)  These patients had prior lipodystrophy delaying diagnosis  Fluticasone is lipophilic-prior lipodystrophy may contribute  Wide range of variability of 24-hour urine free cortisol levels  Suppressed is suppressed  Remained suppressed for > 5 months
  43. 43. Samaras et al 2005 cont.
  44. 44. Cushing’s syndrome with adrenal suppression induced by inhaled budesonide due to a ritonavir drug interaction with a woman with HIV infection. Yoganthan K et al. 2011 Int J STD and AIDS  48 year old HIV+ woman with CD4 812 VL undetectable on darunavir/ritonavir emtricatabine and efavirenz (stable regimen for 3 years) presented with cushingoid features after taking inhaled budesonide for 18 months  Iatrogenic Cushings w/ secondary adrenal suppression  After cortisols resolved, Cushingoid habitus remained  2010-Prior reported case of budesonide & PIs resulting in Cushings in 37 year old African woman  Budesonide, beclomethasone & triamcinolone recommended as safer options  Fluticasone longest half life and most lipophilic
  45. 45. Iatrogenic Cushing’s syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted darunavir Hall JJ et al. 2013 Int J STD & AIDS  Triamcinololone is metabolized by CYP3A4  Ritonavir has greatest effect on CYP3A4 of the PIs  Case: 53 year old woman on darunavir/r who developed cushinoid symptoms 2 weeks after receiving single triamcinolone dose in left shoulder  Triamcinolone injection (both intra-articular and epidural) related Cushing’s Syndrome has been reported previously (usual dose 40-80 mg)  Follow on HPA axis suppression usually 2-6 months  No reports with cobicistat-but significant CYP3A4
  46. 46. Diabetes and Corticosteroids
  47. 47. Which of the following is the most sensitive test for diagnosis of glucocorticoid induced diabetes?  Random plasma glucose >200 mg/dl  75 g oral glucose tolerance test (2 hour value)> 150  Fasting plasma glucose>126  Hemoglobin A1C>6.5%
  48. 48. Which of the following is the most sensitive test for diagnosis of glucocorticoid induced diabetes?  Random plasma glucose >200 mg/dl  75 g oral glucose tolerance test (2 hour value)> 150  Fasting plasma glucose>126  Hemoglobin A1C>6.5%
  49. 49. Glucocorticoid Induced Diabetes and Adrenal Suppression  Lansang MC, Hustak L. Glucocorticoid-induced diabetes and adrenal suppresion: How to detect and manage them. Cleveland Clinic Journal of Medicine. 2011: 78: 748-756.  9% of patients with RA develop DM within 2 years of steroids  All types of glucocorticoid formulations including eye drops  Mechanism is insulin resistance in liver  Peak effect 4-6 hours after dose  Symptoms (either iatrogenic diabetes or Cushing’s) less likely if regimen mimics physiology (diurnal variation)  Insufficiency (Addison’s)-failure of adrenals or pituitary
  50. 50. Lansang et al. 2011 cont.
  51. 51. Early diagnosis and treatment of steroid-induced diabetes mellitus in patients with rheumatoid arthritis and other connective tissue diseases. Ito S et al. Modern Rheumatology 2014.  Mechanism-augmentation of hepatic gluconeogenesis & inhibition of glucose uptake in adipose tissue  Since steroids are administered in am, most hyperglycemia is afternoon post-prandial  Author recommended dividing steroid dosing
  52. 52. References  http://www.uptodate.com/contents/establishing-the-diagnosis-of-cushings- syndrome?source=search_result&search=cushings&selectedTitle=1%7E150 Accessioned 31 March 2014  http://www.uptodate.com/contents/epidemiology-and-clinical-manifestations-of-cushings- syndrome?source=search_result&search=cushings&selectedTitle=2%7E150 Accessioned 31 March 2014  Samaras, K, Pett S, Gowers, A et al. Iatrogenic Cushing’s Syndrome with Osteoporosis and Secondary Adrenal Failure in Human Immunodeficiency Virus-Infected Patients Receiving Inhaled Corticosteroids and Ritonavir-Boosted Protease Inhibitors: Six Cases. J Clin Endo and Metabolism 2005: 90:2005-36.  Lansang MC, Hustak L. Glucocorticoid-induced diabetes and adrenal suppresion: Howe to detect and manage them. Cleveland Clinic Journal of Medicine. 2011: 78: 748-756.  Yoganthan K et al. Cushing’s syndrome with adrenal suppression induced by inhaled budesonide due to a ritonavir drug interaction with a woman with HIV infection. Int J STD and AIDS. 2011:23:520-521.  Hall JJ et al. Iatrogenic Cushing’s syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted darunavir. Int J STD & AIDS. 2013: 24:748-756.  Ito S et al. Early diagnosis and treatment of steroid-induced diabetes mellitus in patients with rheumatoid arthritis and other connective tissue diseases. Modern Rheumatology 2014. 24:52- 59.  Gerardo J et al. Prevalence of abnormal adrenocortical function in human immunodefiency virus by low dose cosyntropin test. Int J of STD and AIDS. 2001: 12: 804-810.  Mayo, J et al. Adrenal Function in the Human Immunodeficiency Virus-Infected Patient. Arch Intern Med. 2002: 162: 1095-1098.  Foisy MM. et al. Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature.
  53. 53. Questions
  54. 54. Which of the following is the most sensitive test for diagnosis of glucocorticoid induced diabetes?  Random plasma glucose >200 mg/dl  75 g oral glucose tolerance test (2 hour value)> 150  Fasting plasma glucose>126  Hemoglobin A1C>6.5%
  55. 55. Which of the following is the most sensitive test for diagnosis of glucocorticoid induced diabetes?  Random plasma glucose >200 mg/dl  75 g oral glucose tolerance test (2 hour value)> 150  Fasting plasma glucose>126  Hemoglobin A1C>6.5%
  56. 56. When combined with corticosteroids, which medications has been reported to be a contributing factor in iatrogenic Cushing’s Syndrome?  Etravirine  Ritonavir  Zidovudine  Tenofovir  Emtricitabine
  57. 57. When combined with corticosteroids, which medications has been reported to be a contributing factor in iatrogenic Cushing’s Syndrome?  Etravirine  Ritonavir  Zidovudine  Tenofovir  Emtricitabine
  58. 58. Which of the following is an appropriate screening test for Cushing’s Syndrome?  Urine Cortisol  Urine Metanephrines  Salivary Metanephrines  Cosyntropin (ACTH) stimulation test  Serum Metanephrines
  59. 59. Which of the following is an appropriate screening test for Cushing’s Syndrome?  Urine Cortisol  Confirmatory with Dexamethasone suppression test  Urine Metanephrines  Salivary Metanephrines  Cosyntropin (ACTH) stimulation test  Serum Metanephrines
  60. 60. Although idiopathic adrenal insufficiency in HIV is rare, what percentage of post-mortem evaluations of the adrenal gland are abnormal?  <5%  10%  25%  33%  66%
  61. 61. Although idiopathic adrenal insufficiency in HIV is rare, what percentage of post-mortem evaluations of the adrenal gland are abnormal?  <5%  10%  25%  33%  66%-common sources include CMV, Mycobacteria tuberculosis, Histoplasmosis, PCP, Toxoplasmosis and Kaposi’s Sarcoma

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