Infectious and reactive arthritis:

Question 1

What interleukins are important in defense against hepatitis C?

Answer 1

IL-28 A and B and IL-29 are ~200aa, type III interferons that stimulate antiviral state by turning on Mx proteins (interferon induced GTP binding protein), 2’, 5’-oligo adenylate synthetase (results in latent RNase L activation), and interferon stimulated gene factor three (ISGF3G). Polymorphisms vary in ability to counteract hepatitis C.

Question 2

What is the difference between NIs and NNIs in their actions inhibiting RNA polymerase?

Answer 2

RNA polymerase activity is inhibited by nucleotide analog inhibitors (NIs) which act at the active enzyme site and non-nucleotide analog inhibitors (NNIs) which act at allosteric sites.

Question 3

What assessment is needed prior to hepatitis C treatment?

Answer 3

Prior to treatment, patients with hepatitis C need to be assessed for cirrhosis, hepatocellular carcinoma, esophageal and gastric varices. Progression to cirrhosis is higher if immunosuppressed, alcohol ingestion, schistosomiasis, hepatitis B, HIV, and male sex,

Question 4

What are some extra hepatic complications of hepatitis C?

Answer 4

Extrahepatic complications of hepatitis C include mixed cryoglobulinemia, Sjogren’s syndrome, thrombocytopenia, liken planus, porphyria cutaneous tarda, insulin resistance, diabetes mellitus, diabetic neuropathy, autoimmune thyroiditis, B-cell lymphoproliferative disorder. Membranoproliferative glomerulonephritis, cardiomyopathy, central nervous system involvement can occur.

Question 5

How is hepatitis C spread?

Answer 5

Hepatitis C exposure is high in intravenous drug abuse, intrauterine device users, and those with tattoos. The risk of a needlestick from a known carrier is 1.8%. Improper sterilization of medical and dental equipment in Egypt has led to the highest prevalence worldwide.

Question 6

How does Trophorema whipplei cause disease?

Answer 6

Trophorema whipplei infection is a common cause of diarrhea in children and a very rare cause of systemic illness in adults.Trophorema whipplei causes Whipple’s disease by producing an overwhelming intracellular disseminated bacterial infection within macrophages. Gram staining reveals the organisms and PAS staining reveals carbohydrate deposits characteristic of the disease.The process is more akin to leprosy in terms of bacterial load and tempo.

Question 7

What are the musculoskeletal and neurologic manifestations of Whipple’s disease?

Answer 7

Neurologic involvement in Whipple’s disease usually presents as dysarthria, myoclonus, or oculomasticatory myorhythmia.Musculoskeletal involvement usually starts as arthralgia progressing to intermittent tenderness and effusions then persistent arthritis over eight years.

Question 8

When should the diagnosis of Whipple’s disease be a serious consideration?

Answer 8

Whipple’s disease should be considered in cases of joint pain with weight loss, diarrhea, and abdominal pain. Rare additional presentations include culture negative endocarditis, multiple sclerosis, maladsorption, and hypopituitarism.

Question 9

How does syphilitic chronic meningitis present?

Answer 9

Syphilitic meningitis is usually asymptomatic, but may present with acutely with headache, confusion, nausea and vomiting, and stiff neck. Inflammatory vasculitis resulting in posterior uveitis and diminished visual acuity. Additional manifestations include optic neuropathy, interstitial keratitis, uveitis, chorioretinitis and retinal vasculitis. Facial and auditory nerves may also be involved.

Question 10

What are the symptoms and initial laboratory findings indicative of Human Granulocytic Ehrlichiosis (HGE), Human Monocytic Ehrlichiosis (HME), or Human Granulocytic Anaplasmosis (HGA, anaplasmosis) due to Anaplasma phagocytophilum?

Answer 10

Ehrlichiosis is due to an obligate intracellular gram negative bacteria of the family Anaplasmataceae, genera Ehrlichia and Anaplasma. Symptoms usually include high fever, joint and muscle aches, and occur up to 14 days following a tick bite. Occasional rash occurs in HME. Leukopenia, thrombocytopenia, and elevated liver enzymes are common. Immunosuppression commonly follows. Death is usually due to respiratory distress syndrome, hepatitis, or opportunistic nosocomial infections. Doxycycline is recommended for all suggestive systemic illnesses if tick exposure is suspected. Tick bites should be watched and treated should fever develop.

Question 11

What are the diagnostic methods used for Human Monocytic Ehrilichiosis (HME), and Human Granulocytic Anaplasmosis (HGA)?

Answer 11

Diagnosis can be made by a serology using indirect fluorescent antibody test, peripheral blood or Buffy coat examination for intraleukocytic morulae, PCR for HME and HGA, immunochemical staining of ehrlichial or anaplasmal antigens in tissue. Due to cross reactivity among species and non standard procedures definite cut off levels for positivity are impossible but increasing titer x4 is convincing. HGA is carried by Ixodes scapularis in the eastern United States and I. pacificus in the western United States. HME is carried by the Lone Star tick (Amblyomma americanum.

Question 12

How are Human Granulocytic Ehrlichiosis (HGE), Human Monocytic Ehrlichiosis (HME), Human Granulocytic Anaplasmosis (HGA, anaplasmosis) due to Anaplasma phagocytophilum classified?

Answer 12

Current taxonomy has reclassified ehrlichea by ribosomal DNA into 3 genera-ehrlichia - E. chaffeensis Etc., anaplasma-phagocytophilum, previously known as E. phagocytophilia, E. muris, and neorickettsia previously known as E.sennetsu. Most such organisms have complex genomes with multiple tandem repeats and frequent mutations. They affect animals-horses, deer; only three affect humans. Major target of HGA is the neutrophil, and HME use the mononuclear phagocytic cell and macrophages.

Question 13

How does Anaplasmosis cause disease?

Answer 13

A. Phagocytophilum binds neutrophils that express CD15s (sialyated glycoprotein) by a specific platelet selection ligand. A phagocytophilum can evade oxidative killing by neutrophils but not monocytes. It also can prevent fusion of neutrophil cytochrome b558 granules, and delay apoptosis. At least 100 different surface proteins are available for switching expression, thus evading host defenses, causing chronic disease. Although antibody development does not correlate with resolution of infection, they can passively protect SCID mice, and complement receptor deficiency increases mortality.

Question 14

How do Ehrlichia cause disease

Answer 14

Ehrlichia does not produce vasculitis, thrombosis, or acute or chronic endothelial cell injury as richettsial diseases do. Non-follicular lymphadenopathy with disappearance of follicles and lymphocytes is common. A phagocytophilum infection in humans may cause parenchymal and perivascular lymphohistiocytic infiltrates and hematologic abnormalities are due to macrophage destruction rather than bone marrow suppression.

Question 15

How is hepatitis B excluded when considering immunosuppressive treatment?

Answer 15

Hepatitis B may flare when immunosuppression is started in tolerant patients, or when stopped if immunosuppression is controlling the hepatitis. Reactivated cytotoxic CD8+ T cell may induce more hepatic inflammation. During immunosuppression hepatitis is suppressed but viral production is not. Hepatitis B treatment may include pegylated interferon alpha, Lamivudine, Adefovir, Entecavir, Telbivudine, and Tenofovir and requires at least 1 year duration. GI consult help is necessary.

Question 16

What is the best screening test for hepatitis B?

Answer 16

Test for surface antigen (small medium large in lipid envelope HBsAg) and antibody (anti-HBs), and anti-core antibody (anti-HBc), e antigen (between nucleocapsid and envelope HBeAg) and antibody (anti-HBe) may be positive during ongoing hepatitis B infection. Hepatitis B DNA testing is done to help with treatment more than for screening. Hepatitis B core antigen (nucleocapsid protein HBcAg) stays in the nucleus and may be demonstrated via liver biopsy.

Question 17

What is the usual course of antigen/antibody changes during infection with hepatitis B?

Answer 17

During the initial course of hepatitis B Infection in adults, HBV DNA appears followed by hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). Hepatitis core antigen develops in hepatocytes but is not secreted but the e antigen (a secretory protein processed from the precore protein) does. All 3 appear prior to symptoms. IgM anti-HBc appears at the onset of symptoms. At the time of recovery HBV DNA disappears first, then anti-HBe replaces HBeAg and anti-HBs replaces HBsAg, and HBV decreases.

Question 18

What countries have a high incidence of hepatitis B (>8%) ?

Answer 18

All of Asia, South Pacific islands, and Africa, Middle East except Cyprus and Israel, Eastern Mediterranean-Malta and Spain, indigenous populations of Alaska, Canada, Greenland, South America-Ecuador, Venezuela and Amazon regions Bolivia, Brazil, Colombia, and Peru. All of Eastern Europe save Hungary, most of the Caribbean and in Central America Guatemala and Honduras.

Question 19

Who is at risk for infection by hepatitis B?

Answer 19

Other people at risk for hepatitis B include infants of parents with hepatitis B, household contacts of HsAg positive parents, sexual partners of HBsAG positive patient, people with multiple sexual partners, men who have sex with men, inmates, those with chronically elevated ALT or AST, infected with HCV or HIV, renal dialysis, all pregnant women, prior to immunosuppressive therapy.

Question 20

What determines prognosis during acute hepatitis B infection?

Answer 20

Prognosis is worse initially in severe cases with prolonged PT and encephalopathy. Those with chronic or intermittent ALT elevation are at risk for cirrhosis or HCC (hepatocellular carcinoma).

Question 21

What antiviral medication is available to treat hepatitis B?

Answer 21

Antiviral treatment Telbivudine (synthetic thymidine nucleoside analog, lamivudine (cytosine analog), adefovir (acyclic nucleotide reverse transcriptase inhibitor), Entecavir (hepatitis B viral nucleotide reverse polymerase inhibitor), or tenofovir (a nucleotide reverse transcriptase inhibitor).

Question 22

How is the hepatitis B virus genome organized?

Answer 22

The hepatitis B virus consists of a partially double-stranded DNA chains (~3000 nucleotides) that partially overlap forming a discontinuous circle. 4 proteins are produced, S producing HBsAg, with three sites of origin; the viral DNA polymerase, C producing HBcAg, alternate start site produces HBeAg, and X gene which is important in inducing hepatocellular carcinoma. The DNA produced is circular as part of each RNA chain is trimmed or elongated.

Question 23

What can cause a flare during the course of hepatitis B infection?

Answer 23

Hepatitis B disease flare occurs in those treated with rituximab, hematologic malignancies, and preparative therapy for bone marrow transplant. Reactivation in HBsAg positive or those with high levels of HBV DNA and anti-HBc positive, flares occur more often if male sex, or use of glucocorticoids.

Question 24

Why do steroids increased risk of flare of hepatitis B?

Answer 24

HBV DNA replication is increased during glucocorticoid treatment due to a steroid promoter in the viral genome.

Question 25

When should hepatitis B treatment be considered during the course of immunosuppressive treatment?

Answer 25

Antiviral treatment of hepatitis B should be considered: HBV carriers at the onset of cancer chemotherapy or immunosuppressive therapy, those with baseline HBV DNA <2000 units and should continue treatment until they reach treatment and point similar to immunocompetent patients. Antiviral treatment should not include interferon alpha due to its bone marrow suppressive effect.

Question 26

What is the initial evaluation or someone found to be infected with hepatitis B?

Answer 26

Initial evaluation if there is evidence of HBV infection should include CBC, hepatic panel, and prothrombin time, total bill, alk phos, albumin, test for HBV replication (HBeAg/anti-HBe, HBV DNA), test to rule out coinfection (anti-HDV, anti-HCV ), immunity HAV, screen for HCC (AFP, ultrasound if high risk), consider liver biopsy if meet criteria for chronic hepatitis.

Question 27

How should a patient tolerant to hepatitis B be followed?

Answer 27

Suggested follow-up for HBV tolerant patient-ALT every 3-6 months, liver biopsy if ALT> 2 times normal, liver biopsy if high HBV DNA and HBeAg positive. Evaluation for an active HBsAg carrier state includes ALT measurement every 3 months for one year, then every 6 to 12 months. Consider another biopsy if ALT> 2 times normal.

Question 28

Who should be immunized against hepatitis B?

Answer 28

Hepatitis B vaccine given at time zero, one month, and six months is indicated in persons needing immunosuppressive therapy, men who have sex with men, persons with multiple sexual partners or history of sexually transmitted disease, inmates of correctional facilities, persons would’ve ever injected drugs. Patients on dialysis, HIV are HCV-infected patients and family members, also members, and sexual contacts of HBV-infected persons.

Question 29

Who should be immunized against hepatitis A?

Answer 29

Immunization for hepatitis A should also be given to patients with hepatitis B as coinfection can precipitate a hepatitis B relapse.

Question 30

What immune changes characterize chronic hepatitis B infection?

Answer 30

Chronic hepatitis B infection is characterized by the continued presence of HBsAg, HBeAg, IgG anti-HBc, and HBV DNA. Infants are tolerant to HBV and are positive for HBeAg, have elevated HBV DNA, and normal ALT. Chronic hepatitis develops along with immune clearance (HBeAg changes to anti-HBe), ALT goes up as HBV DNA goes down. The inactive carrier state is characterized by anti-HBe with low HBV DNA and normal ALT. Reactivation is characterized by recurrent elevations of HBV DNA followed by ALT elevation, with a continually positive anti-HBe.

Question 31

What are the usual clinical outcomes following hepatitis B infection?

Answer 31

After an incubation period 1 to 4 months, hepatitis B infection is anicteric in 70% whereas fulminant hepatitis develops in 0.1 to 0.5%. Fulminant disease is due to massive hepatic necrosis from CD8 lymphocyte attack which dampens viral and antibody responses.

Question 32

Does the titer of ELISA antibody testing decrease following treatment of Lyme disease?

Answer 32

50% of 13 patients with early Lyme disease and 83% of five patients with late manifestations had positive VisE titers 8 to 15 years after successful antibiotic treatment. Persistent titers cannot be equated with spirochetal persistence. 8/24 patients with early Lyme disease and 18/21 patients with late manifestations had less than a fourfold decline in IgG anti-VisE titers.

Question 33

What is the incidence of asymptomatic Lyme disease?

Answer 33

A Swiss study shows clinical Lyme disease occurring in 3% of orienteers with positive titers occurring in 26%. 1/45 develop clinical disease following seroconversion. On Block Island in 2005 B burgdorerfi positivity (Eliza plus blot) was 9.5% (86/910) of voluntary participants of which over 80% with positive results had a history of Lyme disease. 10,936 vaccine participants, 269 developed Lyme disease (clinical +sero conversion), 30 did not report for immediate study, five had typical disease. 15 were asymptomatic. 15/25-60% of patients who sero converted during vaccine trial (New Haven) were asymptomatic prior to the tetracycline treatment after six months. Asymptomatic Lyme disease accounts for<7% 15/269 of those infected. 0-50% have asymptomatic infections with B burgdorferi. European studies generally have a higher incidence of asymptomatic disease. All agree that once positive, the antibody titer does not change much.

Question 34

Are patients who recover from treatment of Lyme disease protected against further attacks?

Answer 34

No. Perhaps in the first year following infection, there is a decreased incidence of recurrence, but most North American studies show no protection. The same is true for horses and dogs. Recurrences are diagnosed on the basis of clinical presentation and PCR testing. Treatment is indicated.

Question 35

How sensitive and specific is antibody testing (Eliza and blotting) for Lyme disease depending on the presentation?

Answer 35

Erythema migrans due to Lyme disease has a positive result <50%. Those who present with arthritis, neurological involvement, are almost always positive, and myocarditis is intermediate.

Question 36

How common are various manifestations of Lyme disease?

Answer 36

Signs of early disease include erythema migrans >90%, fatigue 70, fever 50, headache 50, arthralgia 45, myalgia 40, acute neurologic 15, arthritis 10, carditis <10, .

Question 37

Is treatment indicated after pulling off an engorged tick in an endemic area for Lyme disease?

Answer 37

Treatment is indicated if the tick was adult or nymph, had been attached for 36 hours or more, treatment can begin within 72 hours of tick removal, if the chance of tick infection >20%, and doxycycline can be used. if both parts are left in, leave it rather than risk contaminating the site from tick saliva. Doxycycline 200 mg single dose after tick removal reduces erythema migrans to 1/235 from 8/247. Starting treatment at the onset of erythema migrans is another acceptable option. Amoxicillin for prophylaxis is not indicated.