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EBV - Epstein Barr Virus diagnosis

Why is accurate diagnosis important? 1. Helps prevent severe complications, such as a rupture of the spleen 2. Helps prevent misdiagnosis with other viral or even more dangerous bacterial infections 3. Differentiation from lymphoma and leukemia so more severe conditions are not overlooked

Diagnostic scenarios 1.Differential diagnosis of EBV caused infections in patients presenting with typical signs of Infectious Mononucleosis 2.Searching for the causative agents in patients presenting with undefined clinical symptoms 3.To identify the EBV serostatus in solid organ donors and their recipients to prevent primary EBV infections in patients under immunesuppression (Post-Transfusion Lymphoproliferative Disorder (PTLD).

Different algorithms exist depending on guidelines and reimbursement schemes. Testing of EBNA-1 IgG as a first line marker is often used.

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EBV - Epstein Barr Virus Infection

EBV is a member of the herpesviridae family (which also includes HSV, VZV, CMV) Also called Human Herpesvirus 4 (HHV-4).

Belongs to the subfamily of the gamma herpes viruses and is lymphotropic EBV is causative agent of Infectious Mononucleosis (IM)

EBV is ubiquitous and one of the most common viruses in humans

  > 50% of the 5 year old children (non-industrialized countries) are infected

  < 50% of the 10 year old children (industrialized countries) are infected

   Per CDC 90-95% of adults between 30-40 years in the US are infected and  hence seropositive for EBV.

The virus is mainly transmitted by saliva, infrequently by sexual transmission, transplantation or blood   products.

During incubation, the pathogen replicates in epithelial cells of the salivary  glands and oral mucosa and is secreted via saliva. Reactivations occur frequently in life, but are not clinically relevant in immunocompetent hosts. After primary infection, the virus is secreted lifelong intermittently via saliva.

In childhood EBV infections are often asymptomatic. In adolescents EBV infection in 35-50% of infected individuals leads to infectious mononucleosis (IM), also called "kissing disease " or Pfeiffer’s glandular fever (“Pfeiffersches Drüsenfieber“). The incubation period ranges from 4-6 weeks. Common Symptoms of IM are fever, fatigue, swollen lymph nodes and sore throat. Less common symptoms are rash, spleno-/hepatomegaly and hepatitis. In rare cases complications seen during acute EBV infection are rupture of the spleen, upper airway obstruction, bacterial super infection and central nervous system complications. Symptomatic for 1-2 month.

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What is NGAL?

Neutrophil gelatinase-asscociated lipocalin (NGAL) First described as a 25 kDa protein bound to gelatinase from neutrophils Also known as lipocalin-2 and siderocalin. Known to play a role in fighting bacteria infections

Animal studies have shown NGAL is one of the earliest proteins induced in the kidney after ischemic or nephrotoxic insult.

Expanded studies have shown urinary NGAL to be an early marker of AKI in a variety of settings.   NGAL is one of the earliest proteins induced in the kidney after ischemic or nephrotoxic insult, and NGAL is easily detected in the urine soon after AKI. Many studies have shown that urine NGAL is an early marker of kidney injury in a wide variety of settings.

Larger prospective (validation) studies are underway to further define the role of urine NGAL in the early diagnosis, risk stratification, and prognosis of acute kidney injury.

Application of urine NGAL testing has the potential to improve patient outcomes and reduce the financial burden of AKI

Potential benefits of urine NGAL testing:

- Early diagnosis and initiation of therapeutic measures

- Risk stratification

- Predict clinical outcomes (e.g., length of hospital stay, mortality)

- Monitor response to therapy

- Facilitate clinical trials

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What is Acute Kidney Injury (AKI)?

Acute kidney injury (AKI) is a common and devastating problem in clinical medicine. Previously known as acute renal failure (ARF).

Characterized by an abrupt (hours to days) decline in kidney function.  Diagnosis usually based on either an elevation of serum creatinine and/or detection of decreased urine production (oliguria).

Occurs in a variety of clinical settings. Incidence varies from ~ 5% of hospitalized patients to > 30% of ICU patients, and is increasing dramatically.

Associated with significantly increased cost of care and substantial morbidity and mortality (e.g., 4 million attributable deaths worldwide per year)

“As a conservative estimate, roughly 17 million hospital admissions annually in the United States are complicated by AKI, resulting in over $10 billion in costs to the healthcare system”.

AKI is typically diagnosed as a rise in serum creatinine.   However, creatinine is not a good marker during acute changes in kidney function Serum creatinine is not specific for kidney injury, and levels can vary widely depending on a large number of non-renal factors (e.g., age, gender, muscle mass, hydration status, etc.) Because of large renal reserve, up to 50% of kidney function may be lost before serum creatinine rises Serum creatinine does not accurately depict kidney function until steady state has been achieved (up to 2 – 3 days after injury)

It is likely that the use of serum creatinine as a therapeutic trigger in clinical trials has resulted in the failure of promising therapeutic interventions

New test are developed...

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Current diagnosis of AKI ( Acute Renal Injury)

Creatinine is mostly used test for AKI, but creatinine is not AKI specific. The problems with Creatinine:

Creatinine is NO real-time marker for changes in kidney function There is Individual  differences in production rate, volume distribution and tubulus secretion. It is dependent of muscle mass, gender, diet, etc During loss of filtration (AKI) relatively slow increase in concentration with increasing kidney dysfunction disproportionally high (>50%) tubular secretion. Thus creatinine identifies AKI only after 48-72 hours (NephrolDialTransplant 2003;18:543) relative small changes have relatively high impact.

Potential markers for postoperative AKI

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Hyperhomocysteinemia: a new risk factor for degenerative diseases

Hyperhomocysteinemia (HHCY) is a consequence of disturbed methionine metabolism. It results from enzyme and/or vitamin deficiency. Epidemiological and clinical studies have proven HHCY to be an independent risk factor for atherosclerotic cardiovascular diseases, stroke, peripheral arterial occlusive disease and venous thrombosis. Trials in progress may clarify the “causality” of high homocysteine (HCY) concentrations and will assess the value of HCY lowering therapy. HHCY is also seen as a risk factor for neurodegenerative diseases such as cognitive impairment, dementia, Alzheimer’s disease, and also for depression. There is a high prevalence of HHCY as a syndrome of vitamin shortage in elderly subjects, which strongly increases with advancing age. Elderly people have a high frequency of vitamin B12 deficiency which is more reliably diagnosed by measurement of serum methylmalonic acid and holotranscobalamin II, the metabolically active B12 fraction, than by total serum vitamin B12. Subjects who follow a strict vegetarian diet also have a high prevalence of HHCY caused by vitamin B12 deficiency. For prevention of neurological damages an early diagnosis of vitamin B12 deficiency is important. Furthermore, HHCY is a factor in the pathogenesis of neural tube defects and preeclampsia.

HCY should be measured in patients with a history of atherothrombotic vessel diseases, in patients with diabetes or hyperlipidemia, in renal patients, in adipose subjects, in elderly people, in vegetarians, in postmenopausal women, and in early pregnancy.

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Clinical relevance of homocysteine monitoring in the diabetic patient

Accelerated atherosclerosis is common in diabetes mellitus, although its extent is not always related to its strong association with classical cardiovascular risk factors. Diabetic patients, especially with type 2 diabetes, are prone to cardiovascular disease which is the leading cause of death in this population. Recent clinical studies among general population have shown that an even mild increase of homocysteinemia play an important role in the progression of atherosclerosis, either in coronary or peripheral arteries. An increasing amount of in vitro data is providing evidence that excess of homocysteine has a toxic effect on the arterial wall. This aminoacid thus appears to be not only a risk marker but also an emerging cardiovascular risk factor. The measurement of plasma homocysteine contributes to the identification, among the diabetic population, of patients at high cardio-vascular risk, with the aim of improving their global management. Moreover the addition of group B vitamins provides an easy and low-cost treatment to lower hyperhomocysteinemia.

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Ovarian cancer - diagnosis

  Ovarian cancer is the most common form of reproductive cancer in women worldwide  and the leading cause of death from gynaecological cancer. If caught during the early stages, the patient has an excellent prognosis. However, in 70 % of cases, patients are diagnosed during the advanced stages of the disease when the survival rate is very poor. Only 10 – 30 % of these patients survive beyond one year. Several studies have shown that the survival rate increases when surgery is performed by a specialist  in gynaecological oncology. Currently, less than half of ovarian cancer patients have  their diagnostic surgery with a gynecologic oncologist trained in the management  of ovarian cancer.

The multiple marker assay combining CA 125 and HE4 can be used to triage patients  to the appropriate specialist.

HUMAN EPIDIDYMIS PROTEIN 4 (HE4) has been introduced in the management of Epithelial Ovarian Cancer, and the biomarker complements CA125.

• The combination of both assays raises the sensitivity for detecting Stage I/II disease.1 • HE4 and CA125 together improve the therapy monitoring of patients with Ovarian Cancer. • When used together CA125 and HE4 provide a more accurate preoperative determination of the risk of malignancy in women presenting with pelvic mass.

ROMA (RISK OF OVARIAN CANCER MALIGNANCY ALGORITHM) The combined results of HE4 and CA125 provide the physician a risk stratifi cation index for pre- and postmenopausal women presenting pelvic mass, to distinguish between a low or high risk of fi nding Epithelial Ovarian Cancer (EOC). In combination with the outcome of the current standard practices (e.g., pelvic exam, ultra sound, CT scan, biopsy etc.)

ROMA provides the physician a useful tool for the optimal treatment for the patient.

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Diagnostic tests – DVT and PE

Screening & Diagnosis

1. Chest X-ray 2. Lung scan 3. Pulmonary angiogram (gold standard/PE) 4. CT scan

Tests to Detect Blood Clots

1. D-dimer blood test 2. Ultrasound 3. Venography (gold standard/DVT) 4. MRI 5. Blood clotting tests (PT/PTT)

D-dimer serves as an aid in the clinical diagnosis and management of thrombotic disorders: Venous Thromboembolism (VTE) Deep Vein Thrombosis (DVT) Pulmonary Embolism (PE) Disseminated Intravascular Coagulation (DIC)

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Risk factors - Deep vein Thrombosis (DVT) and Pulmonary Embolism (PE)

Acquired Risk Factors: -Obesity -Cigarette Smoking -Hypertension -Immobilization (prolonged best rest) -Surgery (hip & knee replacements) -Trauma -Genetic/family history

Risk Factors: -Inactivity (air flights) -Cancer (pancreatic, ovarian, lung) -Ulcerative Colitis/Crohn’s disease -Pacemakers or venous catheters -Pregnancy & childbirth -Birth control pills

Signs and symptoms  - DVT and PE

-Sudden shortness of breath (dyspnea) -Chest pain -Cough (bloody sputum) -Excessive sweating -Rapid heartbeat (tachycardia) -Lightheadedness or fainting (syncope) -Anxiety or nervousness -Wheezing -Clammy or bluish colored skin -Leg swelling -Weak Pulse

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Deep vein Thrombosis (DVT) and Pulmonary Embolism (PE) - overview

DVT is potentially life-threatening. In it, blood clots form in the body’s deep veins, particularly veins in the legs. Sometimes the clot breaks off, travels through the bloodstream, and obstructs a vessel in the lungs, restricting blood flow. This condition is called pulmonary embolism (PE). This damages tissues and causes poor lung function, which can be fatal. The seriousness of PE depends on the size and number of emboli. A small embolus may block a small artery in the lungs, causing the death of a small piece of lung tissue (pulmonary infarction). However, a large pulmonary embolus can block all or nearly all of the blood traveling from the right side of the heart to the lungs, quickly causing death. Such massive emboli are not common, but no one can predict which case of DVT, if untreated, will lead to a massive embolus. Thus, doctors are greatly concerned about every person who has deep vein thrombosis.

A negative D-dimer result in conjunction with a pre-test probability assessment model enables the safe exclusion of the disease

D-dimer levels may be used as an aid in the diagnosis of Disseminated Intravascular Coagulation (DIC). DIC is a condition in which the clotting system is activated resulting in depletion of platelets and clotting factors needed to control bleeding. Cause, incidence, risk factors are :  -Severe tissue injury such as burns or head injury -Infection in the blood by bacteria or fungi (sepsis) -Certain pregnancy complications -Surgery -Reaction to a blood transfusion -Leukemia or disseminated cancer

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What is D-dimer?

A soluble fibrin degradation product released when cross-linked fibrin is degraded by plasmin. Plasmin formation is triggered when a fibrin clot is formed. D-dimer is the only marker of thrombotic disorders that indicates presence of stabilized fibrin. Numerous studies have indicated that EIA- based D-dimer assays can be used as reliable marker to rule out deep vein thrombosis (DVT) and pulmonary embolism (PE) in outpatients. DVT can be ruled out in approximately one third of suspected patients reducing the requirement for imaging or invasive testing D-dimer supports reducing cost and risk to the patient.

Deep vein Thrombosis (DVT) is a condition in which a blood clot forms inside a deep vein, commonly located in the calf or thigh. DVT occurs when the blood clot either partially or completely blocks the flow of blood in the vein. A major risk associated with DVT is the development of Pulmonary Embolism (PE). PE occurs when a blood clot travels to the lungs, blocking the pulmonary artery or one of its branches.

PE and DVT are collectively referred to as Venous Thrombo-Embolism (VTE). VTE has annual incidence of 1:1000 in developed countries with about 1-5% case fatality rate. There is also associated morbidity. Developing DVT after long plane rides is often called “economy-class syndrome”. People who have a history of cardiovascular disease, stroke or thrombotic episodes (blood clots) are at risk of getting blood clots in their legs during airplane flights of 10 hours or more.  But these aren’t the only people who can have this problem. DVT also can affect healthy people. Up to 75% of outpatients with suspicion of DVT do not have the disease.

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Early diagnosis of Rheumatoid Arthritis

Many patients with RA develop an immune response against proteins containing citrulline

Anti CCP2 as marker for ealry RA diagnosis is: -Sensitive and highly specific for the disease -Detectable very early in the disease -Useful for predicting disease outcome

Anti-CCP can be detected years before the first symptoms of RA Anti-CCP predicts disease progression Presence of anti-CCP in Undifferentiated Arthritis patients accurately predicts future progression to RA

European League Against Rheumatism (EULAR) recommendation :  - In every patient presenting with early arthritis to the rheumatologist, the following factors predicting persistent and erosive disease should be measured -

-Number of tender and swollen joints -ESR or CRP -Levels of rheumatoid factor and anti-CCP antibodies -Radiographic erosions

American College of Rheumatology (ACR) guidelines: "The ultimate goals in managing rheumatoid arthritis (RA) are to prevent or control joint damage, prevent loss of function, and decrease pain." To reach these goals, the ACR guidelines encourage early diagnosis of RA, patient education, and use of a variety of medicines as well as physical and occupational therapy.

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Laboratory testing - diagnosis of RA

Mostly used: *Rheumatoid factor (RF) – a marker for autoimmune activity *Erythrocyte sedimentation rate (ESR) – a marker for inflammation *C-reactive protein (CRP) – a marker for inflammation *Liver enzyme levels *Complete blood cell count (CBC), urinalysis, creatinine, and electrolyte levels

None of these tests are very specific for RA RF is present in about 80% of patients with established RA RF is present in 10 – 15% of healthy individuals RF is present in other inflammatory diseases A negative RF test does not definitively rule out RA (e.g., early disease, possible remission phase, etc.) Because RF has a high false positive rate, the specificity of this test for RA is low

There is a need for more sensitive and specific markers... Early detection and treatment is critical to improve outcomes Early detection allows early, aggressive treatment to prevent joint damage, loss of function, decrease pain

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Diagnosis and classification of RA

Diagnosis and classification of RA

Diagnosis of RA relies heavily on clinical parameters established by the American College of Rheumatology (ACR). These criteria are relatively insensitive Disease progression may be significant before a diagnosis is made

No “gold-standard” for diagnosing RA

ACR criteria for diagnosing RA -Morning stiffness > 1 hour -Arthritis of > 3 of 14 joints/joint groups -Arthritis of hand joints -Symmetric swelling of joint -Rheumatoid nodules in specific locations -Positive rheumatoid factor (RF) -Radiographic changes suggestion joint erosion

At least 4 criteria needed to establish diagnosis; 1st 4 criteria must be present for > 6 weeks

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What is Arthritis

The word “arthritis” means “joint inflammation” and it is an umbrella term referring to more than 100 different medical conditions -Osteoarthritis -Rheumatoid Arthritis -Sjogren’s syndrome -Fibromyalgia -Gout -Bursitis -Ankylosing spondylitis -Systemic lupus erythematosus -Scleroderma -Psoriatic arthritis...

All of these conditions affect the musculoskeletal system and specifically the joints Arthritis and related conditions affect millions of people around the world More common in women Prevalence will increase as the population ages Major cause of disability Cause a lot of costs in healthcare system

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Lung Cancer - tests

Affordable IVD tests that can be use a first line of test for differential             diagnosis for patients showing symptoms related to lung cancer.  Biopsy is and will remain gold standard to confirm cancer. Role of Biomarkers for Lung Cancer: 1. Aid in differential  diagnosis between NSCLC and SCLC and between lung cancer and begin lung disease 2. Monitor for recurrence after treatment 3. Estimate the disease progression 4. Distinguish the histological types

Mostly used Lung cencer tests: CEA: Carcinoembryonic Antigen SCC: Squamous Cell Carcinoma Antigen ProGRP: Progastrin releasing peptide CYFRA 21.1: Cytokeratin-19 Fragments NSE: Neuron Specific Enolase