1. Prof. Dr. Fawzy Megahed Khalil
Commentary case By
Prof. Dr. Fawzy Megahed Khalil
Ass. Lec. Raafat Saied

2. A 53-year-old man presented with fevers, left eye redness, and abdominal pain.

3. The condition started one month previously when the patient developed fever while undergoing workup for aortic valve replacement .

4. He has a history of remotely treated Hodgkin’s lymphoma, severe aortic stenosis and moderate mitral stenosis attributed to chemoradiation .

5. Medical history also included hypertension and hypothyroidism for which he was prescribed aspirin, furosemide, levothyroxine, and metoprolol succinate.

6. He also had a 6-year history of polyarthritis, 100-pound unintentional weight loss, and declining short-term memory

7. Long-term treatment with prednisone and methotrexate for presumed seronegative rheumatoid arthritis was stopped 2 months prior.

8. He was a nonsmoker with minimal alcohol consumption denied recent travel or insect bites

9. As a retired wood worker, he described frequent exposure to untreated wood imported from South America and Sub-Saharan Africa.

10. What is your differential diagnosis?

11. Infective endocarditis.
Systemic lupus erythematosis
Sero-negative arthropathy.
Recurrence of Hodgkin’s lymphoma.
Behcet’s disease.
AIDS.
Polyarteritis nodosa.
Other diagnosis.

12. What are the next steps to reach a diagnosis ?

13. Blood cultures obtained before antibiotics were negative.

14. Serologies for Coxiella, Brucella, and Bartonella species were negative.

15. Tests for human immunodeficiency virus antibody, Treponemal immunoglobulin-G, and Whipple’s DNA whole blood polymerase chain reaction were all negative.

16. Transthoracic echocardiogram showed aortic valve vegetation 1. 2 ˣ 0
Transthoracic echocardiogram showed aortic valve vegetation 1.2 ˣ 0.8 cm .

17. A diagnosis of culture- negative endocarditis was made .

18. That hospitalization was complicated by recurrent fevers and bilateral uveitis despite broad-spectrum antibiotics.

19. He was discharged with ceftriaxone and vancomycin for culture-negative endocarditis and had completed 4 weeks of a planned 6-week course.

20. Now he is presenting with fever, left eye redness and abdominal pain.

21. Band-like abdominal pain began 5 days previously, wrapped around his back, and radiated into the groin with associated dysuria.

22. He denied vision changes or headache, but he acknowledged photophobia.

23. On physical examination, he was febrile to 100
On physical examination, he was febrile to F with a heart rate of 109 beats/min and a blood pressure of 106/ 54 mm Hg. Left-sided conjunctival injection and decreased visual acuity were noted.

24. Auscultation revealed a harsh III/VI systolic murmur radiating to the carotid arteries, a II/VI diastolic murmur, and fine bibasilar crackles.

25. Physical examination was notable for lower abdominal tenderness without peritoneal signs, scrotal erythema with associated warmth and tenderness, and bilateral inguinal lymphadenopathy

26. Laboratory results were significant for an elevated erythrocyte sedimentation rate of 111 mm/h, C-reactive protein of mg/L, and leukocyte count of K/mL.

27. Blood cultures again showed negative results.

28. What is your differential diagnosis?

29. Infective endocarditis.
Marantic endocarditis.
Crhon’s disease.
Recurrence of Hodgkin’s lymphoma.
Behcet’s disease.
AIDS.
Polyarteritis nodosa.
Whipple’s disease.
Other diagnosis.

30. Lumbar spine magnetic resonance imaging was negative for osteomyelitis or epidural abscess, but showed paraspinal and psoas muscle inflammation.

31. Computed tomography scan of the abdomen and pelvis was negative apart from longstanding mesenteric lymphadenopathy

32. Scrotal ultrasound demonstrated bilateral epididymitis and mild orchitis
Transthoracic echocardiogram showed progression of the aortic valve vegetation from 1.2 ˣ 0.8 cm to 1.8 ˣ 0.8 cm.

33. What is your differential diagnosis?

34. Infective endocarditis.
Systemic lupus erythematosis
Crhon’s disease.
Behcet’s disease.
AIDS with Mycobacterium avium- intracellulare infection.
Polyarteritis nodosa.
Whipple’s disease.
Other diagnosis.

35. Fundoscopic examination revealed vitritis (Figure 1) and bilateral chorioretinal infiltrates, suspicious for Endophthalmitis. Vitreous fluid cultures were negative.

36. Figure 1 : Color photomicrograph with hazy view of the left retina due to significant vitritis.

37. Despite intravitreal injection of ceftazidime, vancomycin, and amphotericin B, the patient’s vision deteriorated, prompting bilateral vitrectomy.

38. He then underwent aortic and mitral valve replacement with tricuspid valve and aortic root repair for progressive valvular disease with culture-negative endocarditis thought not to be responding to empiric vancomycin and ceftriaxone.

39. Histology of the aortic valve was consistent with healing endocarditis (Figure 2).

41. What is your differential diagnosis?

42. Infective endocarditis.
Systemic lupus erythematosis
Crhon’s disease.
Amyloidosis.
Behcet’s disease.
AIDS.
Polyarteritis nodosa.
Whipple’s disease.
Other diagnosis.

43. Vitreal and aortic valve samples sent to the University of Washington for 16S ribosomal RNA sequencing returned positive for Tropheryma whipplei.

44. This provided a diagnosis of Whipple’s disease with cardiac, ocular, genitourinary, musculoskeletal, and neurologic manifestations.

45. How could you explain the deterioration of the patient condition despite 4 weeks therapy with ceftriaxone, a first-line treatment for Whipple’s disease,??????? .

46. The multisystem inflammatory symptoms were attributed to immune reconstitution inflammatory syndrome.

47. The migratory polyarthritis, myositis, epididymitis, and orchitis improve with a 14-day course of ceftriaxone postoperatively followed by trimethoprim- sulfamethoxazole maintenance therapy.

48. Eight months into trimethoprim- sulfamethoxazole therapy, he developed progressive fatigue, malaise, and limited exercise capacity. Workup was notable for profound iron deficiency anemia and hemolysis attributed to mechanical valve shear forces

49. Positron emission tomography computed tomography was negative for evidence of Whipple’s recurrence, but increased inflammatory markers raised concern for relapsed infection.

50. So ceftriaxone was reinitiated for 3 additional months with plans to resume oral maintenance therapy thereafter.

51. Whipple’s disease
In 1907, George Whipple described a patient with weight loss, fatty stools, and arthritis, calling the illness an “intestinal lipodystrophy,” later coined Whipple’s disease.

52. Approximately 100 years later, successful culture of the causative bacterium, Tropheryma whipplei, facilitated genomic sequencing, precipitating a new era of detection of Whipple’s disease.

53. T. whipplei was previously thought to be a rare pathogen, primarily affecting middle-age Caucasian men, with estimated prevalence of less than 1 per million.

54. However, the general prevalence in asymptomatic carriers by stool polymerase chain reaction ranges from 1.5% to 7%, and is much higher in sewage treatment workers (12%-25%).

55. Cardinal features of Whipple’s disease include migratory polyarthritis, weight loss, and diarrhea, but it is also responsible for a wide spectrum of other cardiac, musculoskeletal, genitourinary, and neurologic findings.

56. Molecular techniques demonstrate that T
Molecular techniques demonstrate that T. whipplei is one of the most common causes of culture-negative endocarditis.

57. Cardiac involvement has been reported in 17% to 55% of Whipple’s disease cases, ranging from endocarditis, myocarditis, and pericarditis, to congestive heart failure.

58. Ocular Whipple’s disease is rare and may cause decreased vision, floaters, eye redness, pain, and photophobia. Intraocular findings are typically bilateral and commonly present as chronic uveitis with vitritis.

59. Because the yield of culture is low, 16S ribosomal RNA sequencing of vitreal fluid may help confirm ocular involvement. Foamy macrophages are the histologic hallmark of Whipple’s disease.

60. These foamy macrophages are visible in any affected organ and may be present in valvular vegetations, although are not specific for T. whipplei infection.

61. Tissue-based broad-range 16S ribosomal RNA sequencing is a promising tool in the diagnosis of culturenegative bacterial endocarditis with an estimated sensitivity of 67%.

62. MANAGEMENT
Current treatment recommendations are to begin with intravenous ceftriaxone or penicillin for central nervous system penetration and then transition to oral maintenance therapy for 1 year with trimethoprim-sulfamethoxazole.

63. Doxycycline plus hydroxychloroquine is an alternative maintenance option for patients without neurologic involvement.

64. Paradoxical worsening of symptoms soon after treatment initiation is suggestive of immune reconstitution inflammatory syndrome, which occurs in approximately 10% of patients on appropriate therapy.

65. Treatment failure is common, highlighting the importance of close monitoring during and after therapy. Positron emission tomography computed tomography can help evaluate relapsed disease, but it is not yet recommended for routine surveillance.

66. Increased recognition of Whipple’s disease in the era of molecular diagnostics may lead to better insights about the best approach to treatment and monitoring of this protean disease.

67. Thanks