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					Infectious Diseases Case Conference #21
Daniel Caplivski, M.D.

Clinical Presentation
27 year-old man from Ecuador was admitted to an outside hospital with fevers and low back pain for 6 weeks prior to admission. The pain was midline with radiation down both legs. At times the pain was so severe that patient found it difficult to walk, but he did not note overt weakness.

Clinical Presentation
The patient denied bowel or bladder incontinence or sensory changes. He did note some episodic testicular pain, but no dysuria. The fevers he had had over the past 6 weeks to 103 would leave him with drenching night sweats. He had lost 20#’s over the period of a month.

Clinical Presentation
He denied cough, headache, photophobia, neck stiffness or visual changes. He noted mild diffuse abdominal pain, with some constipation, but no nausea or vomiting. The patient admitted to being depressed about his fevers and frustrated that despite numerous diagnostic tests he had undergone at an outside hospital, his condition had not been diagnosed.

Clinical History
PMH/PSH: the patient had a +ppd in 1999, for which he was treated with 6months of INH. Medications: acetaminophen, lansoprazole SH: Denied tobacco or intravenous drug use. Occasionally drank alcohol. Worked in a restaurant clearing tables. Sexual History: multiple female sex partners. Not always with condoms.

Clinical History
The patient lived in Queens. He had moved from Equador 9 years prior. He had not traveled outside of New York since then. He was originally from the countryside, near Cuenca. He had no pets and no sick contacts

Physical Exam
T 103 bp 120/70 hr 90 r 18 Gen--not cachectic, uncomfortable HEENT—PERRL, eomi, anicteric. No oropharyngeal lesions. Neck—supple no lymphadenopathy Cor—rrs1s2 no murmurs. Lungs—Clear to auscultation Abd—soft, mild diffuse tenderness, nl bs, no palpable organomegaly Ex—no edema, no stigmata of ie GU—no lesions, normal genitalia, no testicular or epididymal tenderness. Neuro—symmetric strength and deep tendon reflexes, no sensory changes. Ophthalmalogic Exam: no roth spots, no retinal lesions, bilateral anterior uveitis

Laboratory Values
Wbc 12.4 Hb 8.9 Hct 25.9 Plt 593 Mcv 90 Neut 87.4% Lymph 8.6% Alb/tp 2.2/5.8 Na 134 K 4.4 Cl 98 Co2 26 Bun/Cr 13/0.7 Ast/alt 151/147 Aph/ggt 103/108 Tb/ldh 0.6/132

Radiologic Studies
Chest X Ray: The heart, hila, mediastinal structures are normal. There are scattered minute infiltrates in the lower lobes bilaterallly. There is no pleural effusion. Bones are unremarkable.

Radiologic Studies
Abdominal Ultrasound. The liver is low normal size with contour microlobulation, slightly coarse echotexture, which together with splenomegaly suggests hepatocelllar disease. No focal lesion, no dilatation of the ducts, no stones in the gallbladder. The spleen measures 15 cm.

Radiologic Studies
CT scan abdomen/pelvis: Posterior bibasilar atelectasis is seen. Suggested sigmoid diverticula. No inflammatory processes. MRI of the spine revealed no epidural abscess.

Clinical Course
The patient had daily fevers to 102, 103. All blood and urine cultures were sterile. His liver function tests normalized. With each fever the patient complained of severe back and leg pains.

Differential Diagnosis

Further Laboratory Results
CRP: 4.9 (0-0.8) Smooth Muscle Titer: 1:40 ANA: negative Antimitochondrial Ab: negative Anti-DSDNA Ab: negative C3/C4 192/24 (WNL) CD4: 661, CD4% 44 CD4/CD8 ratio 2.39 Syphilis screen: negative HIV test: negative

Further Dietary History
The patient denied recent travel to Equador or ingestion of unpasteurized milk in this country. However, some relatives had brought back quesillo from a small farm in Equador.

Quesillo production
TRADITIONAL TECHNOLOGY: Whole raw milk is not subjected to any heat treatment. Usually, no starters are used and coagulation is solely obtained by renneting. As consumers prefer a mild cheese, its microbial population must be kept low.

Serology (Brucella Ab EIA)
Brucella IgG: 1 Brucella IgM: 11 Reference ranges: <9 negative 9-11 equivocal >11 positive

Brucellosis Microbiology
Species include melitensis, abortis, suis, canis, Small, Gram negative aerobic coccobacilli. Some species require CO2 enrichment of media for growth. Initial isolation may require prolonged incubation (>28 days)

Brucellosis History
In 1859 Marston provides first accurate description of Malta fever during the Crimean War. Bruce isolated the organism from the spleen of a patient who died of Malta Fever. Zammit identified goats as the reservoir in Malta Bang identified an organism that caused contagious abortions in cattle.

Brucellosis epidemiology
Zoonosis: a disease of domestic and wild animals that is transmittable to humans. Exists worldwide, including throughout Central and South America. Brucella abortis principally associated with cattle Brucella melitensis associated with goats and sheep.

Brucellosis Transmission
Large numbers of organisms are shed in milk, urine, and products of pregnancy in animals At risk: abbatoir workers, meat inspection, veterinary workers, laboratory workers, microbiologists. In general population the highest risk is unpasteurized milk or cheese consumption.

Brucellosis Clinical Presentation
Protean manifestations that can affect virtually every organ system. Fever, sweats, malaise, anorexia, fatigue, weight loss and depression. Incubation can be days to weeks. Undiagnosed syndrome can last for months. Physical findings are usually minimal.

Brucella Clinical Presentation
Skeletal: osteoarticular manifestations, especially sacroiliitis (20-30% of patients) Genitourinary—epididymoorchitis (2-40% of males) GI tract: anorexia, nausea, vomiting, abdominal pain, constipation. Liver: slight elevation of lft’s. Hepatosplenomegaly Endocarditis, neurobrucellosis, hepatic abscess less common

Anterior Uveitis and Brucellosis
Anterior structures of the uvea include the iris and the ciliary body. Ocular manifestations recorded in 147 patients in an endemic area (Turkey) Anterior uveitis was seen in 4.1% Posterior uveitis in 0.7% Conjunctivitis in 17.7%

Diagnostic Testing--Cultures
Recovery of organism from blood, bone marrow, liver allows diagnostic certainty. Rate of isolation from blood culture ranges from 15 to 80 percent. Increased sensitivity of blood cultures is seen with prolonged incubation, use of lysis-concentration methods, and biphasic media (Ruiz-Castaneda)

Diagnostic Testing--Serology
5 types of serologic tests: serum agglutination, complement fixation, Rose Benal agglutination, antibrucella Coombs, ELISA Classic testing used a cutoff of a single titer >1:160 Elisa IgG/IgM has an estimated sensitivity/specificity of 85% and 81%

Diagnostic Testing—Biopsy
Granulomatous hepatitis, hepatic microabscesses are suggestive in the right clinical setting. Bone Marrow granulomas, hemophagocytosis can be seen.

Diagnostic Testing: Osteoarticular Imaging Plain film findings in sacroiliitis are late findings. Straightening of the spine, and disk space narrowing are seen. CT can show early joint destruction and paraspinal abscess formation. Bone scans may detect inflammation earlier in disease

Treatment
Tetracycline and Streptomycin were the original treatment combination for many years. 6 weeks of therapy recommended for uncomplicated cases, 12 weeks for localized disease (neurologic involvement and osteoarticular disease).

Doxy/Rifampin vs. Doxy/Streptomycin A randomized, Double-blind Study

95 patients (81 with positive blood cultures) 44 in doxy/rifampin group x 45 days (+plus placebo saline injection x 15 days) 51 in doxy/streptomycin group x 45 days doxy, 15 days of streptomycin, (+placebo pill with vitamin B2 to darken the urine) Doses: Doxy 100mg q12, Rifampin 15mg/kg Streptomycin 1gm/day

Doxy/Rifampin vs. Doxy/Streptomycin A randomized, Double-blind Study

Mean follow-up 15.7 months 3 patients with Mean time to defervescence 4.2 days In patients with spondylitis 3/3 relapsed in DR group, 1/4 in DS group relapsed. Relapse rate at 12 months 4.9% (DR) and 4.3% (DS) groups (p>0.2)

Resolution
The liver biopsy culture grew Staphylococcus epidermidis Histology: Portal tracts with rare neutrophils, no bile ducts injury. Rare aggregation of neutrophils in lobules with occasional necrotic hepatocytes. No fibrosis, no evidence of chronic hepatitis. No granulomata seen. The findings are non-specific and can be seen in a variety of conditions including drug reaction, sepsis, and extrahepatic biliary obstruction.

Resolution
All cultures were held for 10 days but were discarded when no growth was seen All specimens were cultured in BACTEC media. The patient missed his appointment for follow-up serology. He said he did not feel the need to return since all of his symptoms had resolved after 6 weeks of rifampin and doxycycline.

References
Ariza, Javier, et al. Treatment of Human Brucellosis with Doxycycline plus Rifampin or Doxycycline plus Streptomycin A randomized, Double-Blind Study. Annals of Internal Medicine. 1992; 117: 25-30. Serra, Jordi, Vinas, Miquel. Laboratory diagnosis of brucellosis in a rural endemic area in northeastern Spain. International Microbiology (2004) 7:53-58 Gungur, K, Beki, NA, Namiduru, M. Ocular complications associated with brucellosis in an endemic area. Eur. J Ophthalmol. 2002 May-Jun; 12 (3): 232-7 Azira, Javier, Corredoira, Juan, et al. Characteristics of and Risk Factors for Relapse of Brucellosis in Humans. Clinical Infectious Diseases 1995;20: 1241-9 Young, Edward. Brucella Species. Mandell’s Princples and Practice of Infectious Diseases. 4th edition. Pp2053-2057 Wright, Steven. Brucellosis. Hunter’s Tropical Medicine and Emerging Infectious Diseases. 8th edition. P 416-420 Everett, E. Dale. Brucellosis, Uptodate. Version 12.3 Everett, E. Dale. Microbiology and epidemiology of Brucella. Uptodate. Version 12.3

Bonus Slide: Gottlieb, Geoffrey, et al. Kaposi’s Sarcoma: A Text and Atlas. Philadelphia 1988.

Kaposi’s Sarcoma: “The man we commemorate as the eponym of these conditions was born Moritz Kohn in 1837 in Kaposvar, Hungary…” “In 1871 he applied for and was granted a legal change of surname calling himself Kaposi after his birthplace, or rather its river, for Kaposvar means the fortress on the River Kapos.” “Kaposi should be pronounced KOP-osh-ee”


				
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