Frank Lowy, MD
Update on Infective Endocarditis
Frank Lowy Columbia University College of Physicians & Surgreons
Topics to be Covered • • • • • •
Changing epidemiology of IE Pathogenesis of IE Clinical presentations of IE Typical cases Indications for surgery Treatment and prevention
Changing Epidemiology of Endocarditis • Increasing age of subjects (from 30‐40 to 47‐69) • Shift in nature of underlying valvular disorders • Up to 1/3 of endocarditis cases are now nosocomial ‐ both native and prosthetic valve • There is an increased risk of IE patients with intravenous catheters or on long‐term hemodialysis, among injecting drug users, diabetics and HIV‐infected patients • Change in the microbiology of cases
CHANGING EPIDEMIOLOGY OF IE
Incidence of Endocarditis by Age and Microorganism
– Increasing incidence of staphylococci – Trend toward increasingly antimicrobial‐resistant pathogens
Epidemiologic Clues for Specific Pathogens • Dental procedures, poor oral hygiene ‐ viridans streptococci, nutritionally variant streptococci, HACEK • Prosthetic valves – Early: coagulase negative staphylococci, S. aureus – Late: coagulase negative staphylococci, viridans streptococci
• Gastrointestinal or genitourinary procedures ‐ enterococci – GI lesions ‐ S. bovis (colon carcinoma)
• Injection drug use ‐ S. aureus – Depends in part on drug and drug use behavior Brouqui and Raoult, Clin Microbiol Rev, 2001 Hoen and Duval, NEJM 2013
Frank Lowy, MD
Epidemiologic Clues for Specific Pathogens • Nosocomial (i.e., IVCs ‐ S. aureus (including MRSA) >> coagulase negative staphylococci, Gram negatives, Candida species • HIV ‐ S. aureus • Animal or farm exposure: Coxiella, Chlamydia, Brucella • History of homelessness, liver disease, alcoholism (body lice): Bartonella spp. • Polymicrobial endocarditis: injection drug use, liver transplantation
PATHOGENESIS
Brouqui and Raoult, Clin Microbiol Rev, 2001
Pathogenesis of Infective Endocarditis Valvular endothelium
Mucous membranes ‐ other peripheral tissue
Congenital abnormalities, turbulent blood flow
Nonbacterial thrombus, Native valves
Trauma ‐ damage at tissue surface
Transient bacteremia
Adherence and colonization Platelet adherence, fibrin deposition ‐ vegetation formation Elaboration of bacterial enzymes, proteases
The Pathogenetic Basis for the Clinical Manifestations of Infective Endocarditis • Valvular destruction and local intracardiac complications • Bland or septic embolization of vegetations • Sustained bacteremia • Immunologic phenomena
Osler, Gulstonian Lectures, Lancet, 1885 Weinstein and Schlesinger NEJM, 1974
Diagnosis of Endocarditis • History and physical ‐ the "old fashioned way" • Laboratory studies ‐ – Microbiology ‐ sustained positive blood cultures – Other studies (adjunctive) ‐ hematologic, rheumatologic, renal
CLINICAL PRESENTATION AND DIAGNOSIS
• Echocardiography and other imaging studies – Transesophageal echocardiography
AHA Diagnosis and Management of IE and Its Complications, Circulation, 2005
Frank Lowy, MD
Clinical Manifestations
Cutaneous Manifestations of Endocarditis
• • • •
Protean illness with large variety of clinical presentations Fever: almost always present Fatigue, weight loss, anorexia Cardiac murmur ‐ uniformly present in subacute IE ‐ not so in acute IE • Additional symptoms defined by organ of involvement – Neurological symptoms are common
Splinter Hemorrhages
Embolic Phenomena in Endocarditis
Osler’s Node
Janeway Lesion
Laboratory Diagnosis: Blood Cultures in Endocarditis
Sustained bacteremia in contrast with nonendovascular infections
Classic bacteremia studies of Beeson
Beeson et al., JEM, 1945
TEE ‐ Mitral Valve Endocarditis
CT Scan of the Lung
Frank Lowy, MD
Duke Criteria* for the Diagnosis of Endocarditis • Definite: – Pathologic criteria organisms are demonstrated or cultured or there is histological evidence of active endocarditis ‐ vegetation, abscess or emboli. – Clinical criteria are 2 major, 1 major plus 3 minor or 5 minor criteria
• Possible: – 1 major, 1 minor; or 3 minor criteria
• Rejected: – Firm alternate diagnosis, resolution of infection with brief therapy (≤4 days), no pathologic evidence of endocarditis at surgery or autopsy, fails to meet criteria for possible endocarditis
Duke Criteria for the Diagnosis of Endocarditis* Major Criteria • Positive Blood Cultures (2 separate cultures ) – Typical pathogens ‐ streptococci, HACEK, S. aureus (community or hospital) or enterococci (community‐acquired, no primary focus) – Persistently positive cultures ‐ 2 sets 12h apart, all of 3, or a majority of ≥4 at least 1h apart – Coxiella burnetti ‐ single positive culture or serology
• Endocardial Involvement – Positive echocardiogram (TEE for prosthetic valves, possible IE): veget’n, paravalvular abscess, dehisced prosthetic valve – New regurgitant murmur
* Durack et al. AJM, 1994; Li et al. Clin Infect Dis, 2000, Baddour et al., Circ'n, 2007
Duke Criteria for the Diagnosis of Endocarditis ‐ Minor Criteria • Predisposition: heart disease or IDU • Fever >38.0˚C • Vascular phenomena ‐ major vessel emboli, Janeway lesions, mycotic aneurysm, septic pulmonary infarcts, intracranial hemorrhage • Immunologic phenomena ‐ glomerulonephritis, Osler's nodes, rheumatoid factor • Microbiologic evidence (not major criteria ‐ positive blood culture) or serological evidence of infection with organism associated with endocarditis (excluding coagulase negative staphylococci)
Subacute Endocarditis A 47‐year old woman with a past history of MVP presents with three weeks of low grade fevers and fatigue. On examination she has painful necrotic lesions on her fingers and evidence of a mild L‐CVA. An echo reveals a large MV vegetation. Three sets of blood cultures grow viridans streptococcus. She is treated with PCN for NVE. During the course of her antibiotic therapy she develops a morbilliform eruption. She develops refractory CHF requiring mitral valve replacement and requires valve replacement.
TYPICAL CLINICAL PRESENTATIONS
Nosocomial Endocarditis A 78 yo man has been hospitalized for 2 months following surgery for an intra‐abdominal abscess. He has received numerous courses of parenteral antibiotics with some improvement, however lately his fevers have persisted and w/u for the source of his fever has been negative. On examination he appears chronically ill, has a (?) new 1‐2/6 systolic murmur, bibasilar rales and a well healed abdominal wound. Although he has had positive blood in the past, multiple recent blood cultures have been negative
Frank Lowy, MD
Prosthetic Valve Endocarditis A 77 yo woman undergoes AVR with a mechanical valve. Surgery is complicated by bleeding requiring re‐exploration. One week after surgery she develops fever and increasing signs of left ventricular failure. A new, soft aortic insufficiency murmur is noted. Blood cultures are positive for S. epidermidis. TEE is suggestive of a myocardial abscess. Discussion ensures regarding whether she should receive medical or medical plus surgical therapy.
Intravenous Catheter‐Related IE A 73yo man s/p CABG with an uncomplicated postoperative course develops IV catheter phlebitis. The catheter is promptly removed. However multiple sets of blood cultures are subsequently positive for S. aureus
Acute IDU‐Related Endocarditis A 27yo IDU presents with a history of recent drug use. He has a small soft tissue abscess at his injection site. He appears toxic with a T104°. His respiratory rate is increased and he has pleuritic chest pain and bloody sputum production. No murmur is heard.
Culture Negative Endocarditis • Still reported to occur in 5‐10% of cases – Prior antibiotic therapy is the most common cause – Incidence likely higher in nosocomial endocarditis
• Clinical outcome is worse than in patients with an established bacteriologic diagnosis • Species include both the fastidious and nonfastidious species (e.g. coxiella, legionella, chlamydia, brucella) perhaps due to prior antibiotic treatment – Need careful and specific culture methods – Serologic assays, fungal cultures
• PCR‐based diagnosis using either resected valvular or embolic tissue is becoming an important adjunct in the diagnosis and therapy of endocarditis – T. whipplei, Bartonella spp. Breitkopf et al., Circulation, 2005
Indications/Issues Related to Surgery • Hemodynamic decompensation – Prognosis decreases with NYHA class 3 or 4 – Patients appear to do better if operated on sooner (operative mortality is less with less CHF)
• Myocardial abscess, large vegetations – anterior leaflet mitral valve veg'n
• Relapse, resistant bacteria
INDICATIONS FOR SURGERY
– Coxiella, brucella, fungi, resistant VRE – S. aureus left‐sided native valve endocarditis – Left‐sided S. aureus prosthetic valve endocarditis
• Recurrent emboli (at least one occurs in 20‐50% of patients) – Remains controversial (≥ 2 major) – Increased with: S. aureus, Abiotrophia, HACEK, Candida – Nature of vegetation (size, shape) not necessarily predictive of likelihood of emboli
Frank Lowy, MD
Principles of Therapy
TREATMENT
Antimicrobial Therapy for Enterococcal Endocardi s (1) • Standard therapy – Ampicillin (12 gm/day) plus gentamicin (1 mg/kg Q 8h) for 4‐6 wks* – Vancomycin (30 mg/kg per 24h, ≤ 2 g/24h) plus gentamicin for 4‐6 wks
• Aminoglycoside‐resistant strains** – Continuous infusion with ampicillin for 8‐12 wks – Surgery
• Bactericidal antibiotics must be used • Prolonged therapy is necessary (weeks) • Treatment is best started after multiple sets of blood cultures have been taken. • Urgency in the initiation of therapy is required for acute but not subacute endocarditis. • Synergistic combinations of antibiotics are sometimes used when available.
Antimicrobial Therapy for Enterococcal Endocarditis (2) • Beta‐lactamase ‐ producing isolates – Ampicillin ‐ sulbactam, imipenem – Vancomycin plus aminoglycosides
• Vancomycin ‐ resistant isolates – – – – –
Ampicillin ‐ if susceptible Ampicillin and gentamicin if susceptible Linezolid, synercid (E. faecium) Imipenem (or ceftriaxone) plus ampicillin (E. faecalis) Daptomycin
* Synergy requires susceptibility to gentamicin 17,000 ill returned travelers from 6 developing regions of the world
• Diseases endemic to the country of origin – Tuberculosis – Malaria – Hepatitis
• • • • •
Culturally / socially based health practices Immunization status Living and workplace conditions Risk-taking behaviors Loss of immunity to diseases in country of origin
– Significant regional differences in morbidity in 16 of 21 reported syndromes – Four major syndromes included: • Diarrheal illness (acute and chronic) • Systemic febrile illness • Dermatologic problems NEJM 2006; 354:119
Deaths Related to International Travel (2007-2009)
Patient Counseling
• From 2007-2009, 2,352 US citizens died from injuries or violence in foreign countries:
• Sufficient time for patient education and vaccinations – generally 6 weeks prior to travel
– 32% motor vehicle accidents – 18% from homicide – 14% from drowning
• Tailored to suit individual traveler: – – – – –
• US travelers are 10x more likely to die from an injury than from and infectious disease
Destination – what countries and parts of countries Time of year – seasonal risks Type of lodging – hotel, hostel, camp, etc Planned activities – business, pleasure, humanitarian, etc. Contact with local residents – relatives, project-oriented
• Assess fitness for travel – Understanding impact on existing health conditions – Advisability of destinations with respect to age and health – Prior travel experience
Patients with special needs …
Medical Issues To Address: • Medical History – Age-specific issues – Underlying illness, immunosuppression – Current medication use – Allergies
• Vaccination history • Contraindications to vaccines and medications Adapted from CDC
• • • • • •
Pregnant traveler Traveler who is breastfeeding Traveler using contraceptives HIV-infected patients Transplant patients Patients who are likely to engage in risk-taking behaviors
Adapted from CDC
Mary T. Flood, M.D., Ph.D.
Illness Prevention Depends Upon Avoiding …
Travelers’ Diarrhea • Epidemiology
• • • • • • •
Contaminated food and water Bites from mosquitoes, ticks and other insects Bites and stings from larger animals Deep vein thrombosis Altitude sickness Motion sickness Sun and cold exposure
– Most common illness in travelers to resource poor areas – 90% of travelers will make an error in what they eat or drink within several days – 50% of travelers will experience illness over the course of a 2-3 week vacation
• The illness – >2 loose stools over 24 hrs – Fever, nausea, vomiting, cramping – Duration 3-5 days T. Miller, M.D.
www.MDtravelhealth.com
Travelers’ Diarrhea
Food and Water Precautions • Advise travelers that in developing countries:
• Caused by many different organisms:
– Avoid tap water unless it has been boiled, filtered or chemically treated – Vigorous boiling for 1 min. is the most effective means of water purification; at altitudes greater than 6500 ft, boil for 3 min. – Chemical disinfection with iodine is also effective (use 2% tincture of iodine – 5 drops per liter of clear water and 10 drops for cloudy water) – Small pore water filters are also effective
– Bacteria: E.coli, Salmonella, Shigella, Campylobacter, Aeromonas, and Vibrios – Parasites: Giardia, Entamoeba histolytica, Cryptosporidium and Cyclospora
• Major complication: dehydration • Prevention: avoid questionable foods or beverages (Contaminated food is a more common source of TD than water contamination) CDC
Food and Water Precautions continued • Use bottled, boiled or filtered water • Select foods carefully – Food should be well-cooked and if meant to be eaten hot, eat it hot – Avoid: • salads, raw vegetables, unpeeled fruit, and unpasteurized dairy products • eating from street vendors • ice CDC
Treatment of Travelers’ Diarrhea • Begin taking Bismuth subsalicylate with the onset of soft stool • Start anti-diarrheal drug if significant diarrhea occurs – Ciprofloxacin 500 mg BID or Levofloxacin 500 mg qd – Azithromycin 500 mg QD – Rifaximin 200 mg TID • Do not use with fever or bloody stools • Not approved for pregnant women • Avoid if allergic to erythromycin or related antibiotics
– Bactrim 1 ds BID – generally less effective
• Adequate fluid intake – oral rehydration fluids with salt and sugar, water with plain salted crackers, or broth • Avoided dairy products until diarrhea has subsided www.MDtravelhealth.com
Mary T. Flood, M.D., Ph.D.
Cholera
Travelers’ Diarrhea • Prophylactic antibiotic use generally not recommended - prevent selection of resistant organisms • May be appropriate for situations in which diarrhea may be unusually troublesome: – – – – –
Business trip Diplomatic mission Athletic event Immunocompromised travelers Travelers with a hx of intestinal disorders
• If chemoprophylaxis is required, treatment regimens include: – Ciprofloxaxin 500 mg BID or Levofloxacin 500 mg qd – Bactrim 1 ds qd – Bismuth subsalicylate – 2 tablets or 2 oz. qid (avoid with renal disease, gout, and pregnancy; do not use with ASA or concurrent quinolones use)
• Intestinal infection caused by a bacterium known as Vibrio cholerae that causes profuse diarrhea and vomiting • Acquired through ingestion of food and water contaminated by the feces of an infected person even if the person is not symptomatic (recent outbreaks in Haiti and India) • Incubation period is 1-5 days • Rx: rehydration is the most important rx • Antibiotics: tetracycline, doxycycline, ciprofloxacin, levofloxacin and azithromycin • New oral vaccines have been developed – safe, but protection is not greater than 6 months – licensed in Canada, Australia, and European Union; not in US
www.MDtravelhealth.com
Campylobacter • Causes diarrhea, often with fever and cramps and bloody stools. • Incubation period can range anywhere from 1- 8 days, but is typically 3 - 4 days • Usually a self-limited illness • Can cause serious invasive illness, particularly in the elderly, infants and the immunocompromised • Poultry is the most common food source • Rx: Azithromycin or Fluoroquinolones • Resistant TD has been reported in Thailand and now spreading throughout SE Asia – Among military personnel in Thailand – Campylobacter is the cause of 20-60% of TD – 85% are resistant to fluoroquinolones
Typhoid • Caused by the ingestion of food or water contaminated by the bacteria Salmonella typhi • Fecal-oral transmission • Bacteria may persist in stool after signs of illness have resolved • Sxs: fever, malaise, muscle aches, dizziness, loss of appetite, nausea, abdominal pain and diarrhea or constipation • Complications: intestinal perforation, bleeding, confusion, delirium, and rarely coma • Rx: Ciprofloxacin or Levofloxacin (orally) or Ceftriaxone • Prevention: food and water precautions + vaccine • Vaccines: oral form (contains live bacteria) or injectable polysaccharide vaccine WWW.MDtravelhealth.com
Hepatitis A
Typhoid
• Viral infection of the liver found worldwide • Most common travel-related illness after travelers’ diarrhea: – – – –
Direct contact with infected person Contaminated water or ice Fish harvested from sewage-contaminated water Foods contaminated by infected food handlers
• Sxs: fever, malaise, jaundice, nausea, vomiting and abdominal pain • Dx: Hep A IgM Ab in blood; supportive therapy • Hep A vaccine recommended for all travelers to developing countries www.spmsd.co.uk
www.MDtravelhealth.com
Mary T. Flood, M.D., Ph.D.
Insect-borne Infectious Disease Risks to the Traveler • • • • • • •
Malaria • Transmitted by female Anopheles mosquitoes that generally bite between dusk and dawn • Parasitic illness of RBC’s and liver caused primarily by 4 related Plasmodium protozoan species:
Malaria* Dengue Leishmaniasis Polio Yellow Fever Japanese Encephalitis Various tick-borne illnesses
– Plasmodium falciparum – 40 to 60% of cases; 95% of deaths • Sub-Saharan Africa, Latin America, and South-East Asia
– Plasmodium vivax – 30 to 40% of cases • South-East Asia, Latin America, and Sub-Saharan Africa
– Plasmodium ovale • South-East Asia, Pacific, and East Africa
– Plasmodium malariae • West Africa, Guyana, and India
– Plasmodium knowlesi – simian malaria species – emerging public health problem in South-East Asia
• Sxs: fever, sweats, chills, headache, body aches, malaise • Complications: anemia, splenomegaly, kidney failure, pulmonary edema or ARDS, altered consciousness, seizures or coma
Adapted from CDC
Malaria Prophylaxis
3r
Drugs
Adult Dose
Advantages
Disadvantages
2 tablets weekly, begin 1 wk before travel until 4 wks after travel
Low cost; well tolerated; suitable in pregnancy or breast feeding
Inc. resistance of P.falciparum Limited usage
Mefloquine (250 mg tablets)
2 tablets weekly, begin 2 wks before travel until 4 wks after travel
Weekly dose; effective in most areas; can be used in 2nd-3rd trimesters
Neuro-psychiatric side effects; need to start 2-3 wks before departure
Atovaquone / Proguanil (200/50 mg tab)
1 tablet daily, begin 1-2d before travel and continue to 7d after travel
Well tolerated; short course; begin close to travel
Expensive
Doxycycline (100 mg tablets)
1 tablet daily, begin 1-2d before travel and continue to 4 wks after travel
Low cost; generally well tolerated; can begin close to departure
Photosensitivity; vaginal yeast infections in women
Chloroquine (250 mg tablets)
www.stanford.edu
Antiretrovirals and Antimalarials
NEJM 2008; 359:603
Drug
Protease Inhibitors
NRTI’s NtRTI’s
NNRTI’s
Mefloquine
Decreased levels No known of Ritonavir and interactions possibly other PI’s
Efavirenz and Nevirapine may dec. Mefloquine
Atovaquone / Proguanil
Reduced Inc. AZT levels; Atovaquone levels dec. Indinavir levels
No known interactions
Doxycycline
No known interactions
No known interactions
No known interactions
Chloroquine
No clinically significant interactions
No clinically significant interactions
No clinically significant interactions
Mary T. Flood, M.D., Ph.D.
Mosquito Precautions • Malaria prophylaxis • To prevent mosquito bites, wear long sleeves, long pants and shoes – especially outdoors at dawn and dusk • Insect repellents containing DEET – 25-35% protective and not toxic – Products with 30% DEET protective for about 6 hrs – High temperature, humidity, sweating, and water exposure may reduce the duration of the repellent’s effectiveness – Do not apply to eyes, mouth, cuts, wounds or open skin – Do not apply to skin under clothing www.MDtravelhealth.com
• Picaridin, a newly developed repellent, appears to be as effective as DEET when used in comparable concentrations – No odor or stickiness; can use with synthetic fibers – US: product is marketed with 7% picaridin which is comparable to 10% DEET (4 hrs protection)
• For additional protection, Picaridin-containing repellents can be applied to clothing, shoes, tents, bed linens • Sleeping quarters should be protected from mosquitoes – Windows should be screened or netted – If sleeping outdoors, use permethrin-impregnated bednets with mesh size less than 1.5 mm
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Malaria • CDC published in Annals of IM (2005) a review of all the ~150 deaths from malaria in the US over the previous 30 years: – ~70% of deaths were contributed to by health care providers (wrong chemoprophylaxis, delay in diagnosis, incorrect treatment). – Most patients either did not get expert advice or did not follow the advice for preventing malaria. – ~20% of cases were diagnosed at autopsy. – ~20% of patients who died never had a FEVER.
Dengue • Viral infection that typically causes flu-like sxs: fever, muscle aches, joint pains, headaches, nausea, vomiting and occasionally rash • Most cases are mild and resolve in a few days • Dengue hemorrhagic fever – excessive bleeding and dangerous fall in BP (dengue shock syndrome) • Transmitted by Aedes mosquitoes which bite preferentially in the daytime • Especially common in densely populated urban areas as well as rural areas • Rx: no rx except analgesics and plenty of fluids • Prevention: insect protection • Clinicians should include dengue in the differential diagnosis of acute febrile illnesses in patients who live in or have recently traveled to subtropical areas of the United States or to the tropics
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Mosquito Precautions
Malaria Treatment • Chemotherapeutic treatment regimens are complex – consult ID specialist • In US, falciparum malaria should be treated with a combination of Quinine plus Doxycycline, Clindamycin, or Sulfadoxine-Pyrimethamine (Fansidar) • Alternatively, Malarone or Mefloquine can be used – Therapeutic doses of Mefloquine may cause neuropsychiatric side effects
• Quinidine may be used for parenteral therapy • Where available, combinations of artemisinin agents (artesunate, artemether) and Mefloquine are widely used • Chloroquine can be used for susceptible malaria (caused by species other than P.falciparum) and should be followed by a course of Primaquine for infections due to P.vivax and P.ovale to eradicate the latent liver forms and prevent relapse – Test for G6PD deficiency before giving Primaquine – Primaquine should not be used in patients with G6PD deficiency because it will induce hemolysis
Dengue
Mary T. Flood, M.D., Ph.D.
Yellow Fever
Yellow Fever
• Life-threatening viral illness transmitted by mosquitoes in certain parts of Africa and South America • In urban areas, it is a disease primarily of humans and transmitted from person-to-person by the Aedes mosquitoes • Breed in man-made water containers • Except during epidemics, it is rare in urban areas • In the jungle, it is a disease of non-human primates and transmitted by a variety of mosquitoes • Incubation period: 3-6 days • Sxs: fever, chills, headache, muscle pains, backache, nausea, vomiting, and loss of appetite • Rx: supportive care • Prevention: Yellow fever vaccine
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Leishmaniasis
www.travelclinicoregon.com
Leshmaniasis
• Parasitic disease that occurs in 3 forms: – Visceral disease: fever, weight loss, anemia and enlargement of the liver and spleen developing over months to years – Cutaneous disease: nonhealing skin ulcers on the exposed parts of the body developing over weeks to months – Mucocutaneous disease: disfiguring erosions of the mouth and the membranes of the nose, mouth, and throat
• Transmitted by sandflies (1/3 size of a mosquito) – Breed in soil, old tree bark, rubbish heaps, human dwellings – Typically bite from dusk to dawn but may bite during daytime
• Protection: insect precautions; bed netting – finer mesh www.MDtravelhealth.com
Tick and Other Insect Precautions • Ticks – use the same precautions as for mosqito bites – Wear socks with pants tucked in – In rural or forested areas, do a thorough tick check at the end of each day – Ticks should be removed by grasping the tick by the head
• Sandflies – use the same precautions as for mosquito bites except bednetting must be a finer mesh (at least 18 holes to linear inch) • Tsetse flies – insect repellents are ineffective – Avoid areas infected with tsetse flies – Travelers in infected areas should wear long sleeves, long pants, socks, etc
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Meningococcal Meningitis • Life-threatening infection caused by a bacterium known as Neisseria meningitides • Person-to-person spread by exposure to secretions from nose or throat of an infected person • African Meningitis belt – major epidemics esp. in dry season (December to June) • Sxs: fever, headache, stiff neck, lethargy • Rx: Ampicillin or Ceftriaxone • Prevention: vaccination – confer protection against 4 groups of Neisseria meningitides (A/C/Y/W-135) but not group B which is often involved in epidemics
Mary T. Flood, M.D., Ph.D.
Meningococcal Meningitis Belt
Immunizations for Immmunocompromised Travelers • Yellow Fever Vaccine – Avoid in immunocompromised travelers – May consider for those with asymptomatic HIV infection if travel to high-risk areas is unavoidable
• Typhoid vaccine – inactivated injectable vaccine preferable to oral vaccine (live bacteria)
• Measles vaccine – May be given to individuals with mild immune deficiencies – Consider prophylactic injection of Ig if necessary
• Varicella Vaccine – Avoid in immunocompromised travelers www2.ncid.cdc.gov
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Travel During Pregnancy
Travel During Pregnancy • Travelers diarrhea:
• International travel should be avoided by pregnant women with underlying medical conditions: – Diabetes – High blood pressure – Hx of complications during prev. pregnancy
• Know the available medical facilities (physicians, clinics, hospitals, etc.) • Adequate travel insurance to cover medical evacuation • Second trimester is the safest time for travel abroad (14-26 weeks); third trimester is least safe
– Strict attention to food and water precautions – Many medications given for travelers’ diarrhea may not be used in pregnancy - Rx: Azithromycin and 3rd generation cephalosporins – Adequate fluid intake is essential – Iodine tablets should not be used for more than a few weeks to avoid congenital goiter – Bismuth compounds should be avoided
• Malaria – – – –
Avoid travel to malaria-endemic areas May be life-threatening illness to mother and fetus None of the prophylactic medications are 100% effective Chloroquine has the best safety record in pregnancy but not protective in many malaria infested areas
www.MDtravelhealth.com
Travel During Pregnancy • Vaccines which may be administered during pregnancy if indicated (avoid during 1st trimester) – – – – – –
Hepatitis B Rabies (human diploid cell) Inactivated polio Meningococcal meningitis Td Influenza
• Vaccines to avoid: – Measles – mumps – rubella – Varicella – Yellow fever (unless travel to high risk area unavoidable)
• Vaccines for which safety data during pregnancy not available: – Hepatitis A (immune globulin preferred) – Typhoid (Typhim Vi polysaccharide may be safest) – Japanese encephalitis (avoid travel to high risk areas) www.MDtravelhealth.com
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Deep Vein Thrombosis • DVT’s may form in the legs during long plane rides (esp. flights longer than 8-10 hrs) • Risk factors for DVT include: – – – – – – – – –
Previous hx of deep vein thrombosis Chronic swelling in legs or feet Varicose veins Use of estrogen or Raloxifene (Evista) Advanced age Cancer Obesity Stroke Recent hospitalization or surgery
www.MDtravelhelalth.com
Mary T. Flood, M.D., Ph.D.
Measures to Prevent Deep Vein Thrombosis
Bloodborne Infections and STD Precautions
• Wear loose-fitting clothing • Do not place hand luggage where it will limit leg movement • Walk around the cabin at regular intervals • Perform isometric compressions of leg muscles • Avoid crossing your legs • Drink plenty of fluids – avoid alcohol • High risk travelers should wear compression stockings
• Travelers need to be aware of the prevalence of: – STDs – Hepatitis B and C – HIV
• Risk of unprotected sexual activity • Incidence of HIV and STD’s among commercial sex workers • Dangers of tattooing, body piercing, and cosmetic surgery • Incidence of auto accident mortality • Risk of receiving blood products in developing countries • Risk of dental and surgical procedures CDC
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High Altitude Sickness (Acute Mountain Sickness or Altitude Illness) • Physiological effect of high altitude caused by acute exposure to low partial pressure of O2 at high altitude (above 1500m or 5000ft) • Sxs: HA, fatigue, dizziness, tachycardia, SOB • Prevention: slow ascent to allow acclimatization – Ascend < 600 m/day – Rest every 600 – 1200 m
• Prophylactic medication: Acetazolamide – 125 to 250 mg twice daily from one day prior to ascent until 2 days post ascent
• Rx: rest, descent, oxygen, fluids, meds • Can progress to HACE or HAPE (can be fatal)
Spectrum of Disease and Relation to Place of Exposure Among Ill Returned Travelers
Travel Emergency Kit
NEJM 2006; 354:119-130
• While diarrheal illness was more common; systemic febrile illness was generally more serious
• Copy of medical records and extra pair of glasses • Prescription medications (bring extra medicine) • Over-the counter medicines and supplies – Analgesics – Decongestant, cough suppressant – Antibiotics for travelers’ diarrhea – Pepto-Bismol – Band-Aids, gauze, tape, ace wraps – Insect repellant, sunscreen – Tweezers, scissors, thermometer
• Systemic febrile illness occurred disproportionately among those returning from sub-Saharan Africa or Southeast Asia – Malaria was one of the most frequent causes of febrile illness in travelers from every region except sub-Saharan Africa and Central America
– Dengue was more prevalent in Central America than malaria – In sub-Saharan Africa, tick-borne spotted fever occurred more frequently than typhoid or dengue • Acute bacterial diarrhea occurred mostly among those returning from south central Asia • Dermatologic problems occurred primarily in those returning from the Caribbean or Central or South America
CDC
Mary T. Flood, M.D., Ph.D.
Post-travel Consultation: The Ill-returned Traveler • Most frequent health problems in illreturned travelers: – Gastrointestinal illness (10%) – Skin lesions and rashes (8%) – Respiratory infections (5-13%) depending on the season of travel – Fever (up to 3%)
Fever Patterns in Tropical Diseases • Classic patterns: – – – –
Continuous: Rickettsia, Typhoid Remittent: Early typhoid, TB, P.falciparum malaria Recurrent: Malaria, Borreliosis Biphasic: Dengue
• Most commonly – no definite fever pattern • Fever may be absent at time of presentation
Adapted from CDC
Incubation Period for Selected Tropical Infections • 21 days: – – – – –
Viral hepatitis (A, B, C, D, E) Malaria* Tuberculosis* Acute HIV infection Amoebic liver abscess
Specific Exposures for Selected Tropical Diseases
Diseases with long latency periods seen in refugees and travelers • • • • • • •
Tuberculosis Hepatitis B and C Leprosy Malaria Many parasitic diseases Meliodosis Brucellosis
Specific Exposures for Selected Tropical Diseases Freshwater exposure
Schistosomiasis Leptospirosis
Brucellosis
Barefoot exposure
Stongyloides, CLM
Raw/undercooked meat and fish
Enteric infections, Cestodes, Trichinosis
Sexual contacts Infected persons
Animal contact
Rabies, Q fever, Tularemia, Brucellosis, Echinococcus
HIV, Hepatitis B and C Chlamydia, GC, Herpes Enteric fever, MTB, Meningococcal infection
Untreated water
Salmonella, Shigella, Hepatitis A&E, Amoebiasis
Unpasteurized dairy
Mary T. Flood, M.D., Ph.D.
Specific Vector Exposures for Selected Tropical Diseases Mosquitoes
Malaria, Dengue, JE
Ticks Reduviid bugs
Rickettsioses, Lyme, Tularemia American trypanosomiasis
Tsetse flies
African trypanosomiasis
Case History …
Case History
Question #1
• JT is a 36 yr old married businessman, HIV positive, who is going to Ghana for 6 weeks on a business project that will cause him to spend a great deal of time in the outdoors and bring him into remote rural areas and densely populated villages • JT has not had routine childhood vaccines as his parents felt his older sister’s autism was due to vaccines • He presents to his PCP about 1 month before his scheduled departure for travel recommendations • Current CD4 cell count is 560; viral load is undetectable
Which of the following vaccine(s) should not be given to JT? A. Yellow fever vaccine B. Typhoid vaccine C. Measles vaccine D. Varicella vaccine E. A, C, and D F. All of the above
Answer – Question #1
Question #2
D. Varicella vaccine should not be given to HIVinfected adults or children; its safety is currently being investigated in HIV-infected adults. Explanation: Yellow fever and measles vaccines can be given to asymptomatic HIV persons if necessary; typhoid inactivated injectable vaccine can be given to immuno-compromised persons.
JT’s current ART: Atripla (Sustiva and Truvada). What malaria prophylaxis should his PCP recommend? A. Chloroquine B. Mefloquine C. Atovaquone / Proguanil D. Doxycycline E. Advise JT not to go to Ghana
Mary T. Flood, M.D., Ph.D.
Answer – Question #2 C. Atovaquone / Proguanil – it has no known intertaction with NNRT’s (Sustiva) or with NRTI’s other than AZT and Indinavir or with NtRTI . Other options are not acceptable: Chloroquine is not protective in Ghana. Mefloquine levels are decreased by Sustiva. Doxycyline is not recommended for someone who will spend extensive time in the outdoors.
Question #3 Which of the following is not an insect – borne infectious disease risk for JT? A. B. C. D. E.
Leishmaniasis Schistosomiasis Dengue Malaria Japanese encephalitis
Answer – Question #3 B. Schistosomiasis – parasite; humans are infected by the larval form found in fresh water bodies. All of the other answers are insect-borne infectious diseases.
“There are no foreign lands. It is only the traveler who is foreign!” Robert Louis Stevenson
Jay Dobkin, M.D.
Objectives… Current Management of HIV Disease: 2013
Jay Dobkin, M.D.
Diagnosis of HIV disease Staging and prognosis Prophylactic strategies for AIDS-defining opportunistic infections Principles of anti-retroviral therapy Keys to preventing and managing resistance Immune reconstitution inflammatory syndrome
Act 1: Mono or not Mono?
A 26 year old sexually active man who has sex with men presents with fever, generalized adenopathy and severe pharyngitis. He says a friend of his had “mono” recently. His CBC is remarkable for leukopenia and atypical lymphocytosis. You send a heterophile test for mononucleosis which is negative. What test(s) are needed to establish the correct diagnosis?
DIAGNOSIS OF ACUTE HIV
Non-specific symptoms (fever, macular rash, adenopathy, pharyngitis). Lab findings suggestive of mononucleosis. Diagnosis made with negative antibody test + high level of viremia by PCR. (>500,000 copies) Risk of false positives (low level PCR) with inappropriate testing.
TEST OPTIONS 1. An HIV Elisa and Western Blot Antibody test 2. A PCR assay for HIV RNA 3. A CD4 count
CHOOSE THE BEST ANSWER A. None of these B. 1 C. 2 D. 3 E. 1+2 F. 2+3
Plasma HIV-1 RNA Level After Acute HIV-1 Infection Predicts Disease Course Patients with AIDS 5 years after infection
106 HIV-1 RNA in Plasma (copies/mL)
Act 1
62%
105
49% 104
26%
8% 103 Detection threshold 0
0.5
1.0
1.5
Years After Infection Reprinted with permission f rom Ho. Science. 1996;272:1124-1125.
2.0
Jay Dobkin, M.D.
Stratified 3 year risk of AIDS
CD4
HIV RNA
201-350
Risk
55,000
4.1% 36.4% 64.4%
>350
14.3% Source: MACS
Act 2: HIV by the Numbers
The patient you diagnosed with acute HIV infection is reluctant to identify his contact but eventually brings his partner to your office. You test him and find:
Act 2: What’s next
HIV Elisa and Western Blot positive CD4 count= 98/cu mm Viral load 17,000
Indication
Regimen
Toxoplasmosis
Seropositive+ CD495% 90-95% 80-90% 70-80% 60,000, CD4100 for 3-6 mo. No active disease
Conclusions
Web Resources
Detection of HIV infection, especially in the acute stage, remains a challenge. Proper staging by CD4 count allows effective prevention of many OI complications. Anti-retroviral therapy has transformed HIV disease into a chronic, manageable condition. Success with the initial regimen is crucial since progressive resistance accompanies failure and limits future options. If new agents become available which can overcome crossresistance excellent response is possible even in advanced, highly resistant cases.
Secondary Prophylaxis or suppression : Additional criteria
DHHS Guidelines
Stanford Resistance Database
aidsinfo.nih.gov
hivdb.stanford.edu
International AIDS Society
iasusa.org
Magdalena E. Sobieszczyk, MD, MPH
Learning Objectives
Tick Borne Diseases
• Review general principles of tick‐borne diseases • Review tick‐borne pathogens
19th Annual Update & Review of Internal Medicine June 7, 2013 Magdalena E. Sobieszczyk, MD, MPH Assistant Professor of Clinical Medicine Columbia University
• Review clinical presentation, diagnosis and treatment of several tick‐borne diseases • References and Further Reading
Tick-borne diseases
General Principles
(human tick vector) Hard Ticks
• Presentation is often very non‐specific
Lyme disease
– flu‐like: fever, headaches, myalgias
• Review travel history, consider seasonal presentations and geography • Diagnosis is clinical ‐ Treatment should be initiated before test results available • May be associated with a specific rash • Frequent abnormalities: LFT and CBC • Convergence in tick‐vectors: Co‐infections are common • DOXYCYCLINE is therapy for most common tick‐borne illnesses
Tick-borne pathogens • Bacteria: ‐ Rickettsia species ‐ Borrelia species • Parasites ‐ Protozoa • Viruses
Rocky Mountain spotted fever Babesiosis Ehrlichiosis Anaplasmosis Tularemia Endemic typhus Southern-tick associated illness (STARI) Powassan and other tick-borne encephalitis Tick typhus: African tick typhus, Mediterranean tick typhus, Quennsland tick typhus Colorado tick fever
Soft Ticks Relapsing fever
Case 1 • 62 yo woman presents with 3 week history of fever, headaches and malaise • She is otherwise healthy with a hx/o HTN treated with beta blockers • Social Hx: – Originally from Ecuador, last visit to Ecuador one month ago – lives in Queens and has a dog – Relatives on Cape Cod – frequent visits
Magdalena E. Sobieszczyk, MD, MPH
Which of the following is the most likely diagnosis
Blood smear
A. Lyme B. Colorado tick fever C. Anaplasmosis D. Babesiosis E. RMSF
Question 1
Babesiosis
Epidemiology
• Emerging infection • Ixodes tick • Intraerythrocytic protozoa Babesia • Animals as natural reservoirs ‐ White‐tailed deer perpetuate tick ‐ White‐footed mouse perpetuate Babesia
• B. microti in North‐East (NE, CT, NY, P) ‐ hundreds of cases reported • B. duncanii Washington State and Northern California (very few cases) • B. divergens: Missouri, Kentucky, Washington State • Europe: rare, B. divergens • Other routes of transmission – transfusion or vertical
Geographic Areas Where Human Babesiosis and Ixodes Tick Vectors Are Endemic
Transmission of Babesia microti by the Ixodes scapularis Tick
Vannier & Krause NEJM 2012 Vannier & Krause NEJM 2012
Magdalena E. Sobieszczyk, MD, MPH
Clinical presentation • Incubation 1 – 6 weeks • Spectrum of disease: – Mild flu‐like illness in young and healthy – Life‐threatening, malaria‐like in asplenic, immunocompromised elderly
• Most common symptoms: – Fever (intermittent or sustained), shaking chills – Fatigue, malaise, arthralgias, myalgias, SOB – Mild hepato‐splenomegaly
Slide courtesy A-C.Uhlemann
Complications of B. microti • • • • • • •
Acute respiratory failure Disseminated intravascular coagulation Congestive heart failure Renal failure Severe anemia, high parasitemia (>10%) Fatal in 5 – 10% hospitalized B. divergens: ‐ hemoglobinuria, jaundice ‐ persistent high fevers, parasitemia up to 80% Slide courtesy A-C.Uhlemann
Babesia (microti) • Deer tick Ixodes scapularis • Microscopy clues: Thin blood smear ‐ Maltese cross ‐ Varying shapes and sizes ‐ Vacuoles ‐ Lack of pigment production • PCR • Indirect immunofluorescent antibody test–
Algorithm for Diagnosis of Babesiosis Caused by Babesia microti.
– specificity 88‐96% – Symptoms precede rise in Ab by ~1week
Treatment • Not necessary in asymptomatic individuals but consider if parasites persist for >=3months • Mild B. microtii: treatment 7‐10 days – Atovaquone + azithromycin (preferred) – Quinine + clindamycin
• Severe disease B. microtii: longer course needed – IV clindamycin + quinine
• Exchange transfusions in high‐grade parasitemia (>10%), severe anemia, pulmonary/renal complications • B. divergens: – immediate complete RBC exchange transfusion – plus clindamycin and quinine
• Evaluate for Lyme’s & Human granulocytotropic anaplasmosis (same vector)
Babesiosis: Take home points • Rare protozoal disease, non‐specific febrile illness • Consider diagnosis if – Flu‐like symptoms in residents of endemic areas of travelers to endemic areas – Patients are presenting with Lyme or human granulocytic anaplasmosis (causative agents also transmitted by Ixodid Ticks)
• Acquired by humans if close to white‐footed mouse and white‐tailed deer • Severe disease in immuno‐compromised • Thin blood smear, PCR, serologies • Long treatment courses for persistant and relapsing disease, RBC exchange
Magdalena E. Sobieszczyk, MD, MPH
Case 2 • A 65 y.o avid gardener and golfer who lives in Westchester, NY presents in June with fever, myalgias, arthralgias, headache, malaise, and nausea. • Lab tests are notable for: – Leukopenia – thrombocytopenia – and elevated liver enzymes
What is the most likely diagnosis? A. B. C. D. E.
Acute CMV Rocky Mountain spotted fever Tularemia Ehrlichiosis Lyme
Question 2
Ehrlichioses – Anaplasmataceae family • Tickborne infections
Morulae, Latin for ‘mulberry’ Ehrlichia chaffeensis
Anaplasma phagocytophilum
• Ehrlichia chaffeensis causes Human Monocytic Ehrlichiosis (HME) • Anaplasma phagocytophilium causes Human Granulocytic Anaplasmosis (HGA) • Very small, obligate intracellular, Gram negative bacteria • Target either monocytes OR granulocytes and are named accordingly
Incidence by State
CDC.gov
CID 2007: 45 Dumler
Incidence by Age Group, Ehrlichiosis
CDC.gov
Magdalena E. Sobieszczyk, MD, MPH
HME--Epidemiology
HGA--Epidemiology • NE, mid‐Atlantic, Upper Midwest, Pacific NW states + internationally • Vector: Ixodes ticks (hard ticks)
• S. Central, SE, mid‐Atlantic states • Vector: Ixodes ticks (hard ticks) – Lone Star tick (Amblyomma americanum)
– I. scapularis (aka blacklegged tick or deer tick) or Western Blacklegged tick
• Reservoir: white‐tailed deer
• Reservoir: small mammals (esp. white‐ footed mice)
CDC.gov
Clinical Presentation
CDC.gov
Clinical Presentation: similar to rickettsial diseases, but less likely to get a rash
• Wide spectrum of disease – Ranges from mild illness/asymptomatic to a severe, fatal infection (up to 3%)
• Risk factors for more severe disease: Immunocompromised status (HIV, asplenic, on steroids/chemotherapy)
Diagnosis and Treatment • Clinical suspicion (fever/flu symptoms) in endemic region during tick season • PCR—acutely, diagnostic tool of choice – May not be available
• Serologic—look for 4x rise in antibodies – Most sensitive test
• Examination of peripheral blood for morulae – Clumps of organisms in the cytoplasm of the Monocyte (HME) or granulocyte (HGA) – very low yield
• Treatment: Doxycycline
Case 3 • 52 y.o man reports spending a weekend hiking on Long Island. This morning he discovered a tick on his leg which he promptly removed (easily extracted) but is wondering whether or not he should do anything else.
Magdalena E. Sobieszczyk, MD, MPH
Which of the following statements is most appropriate in this situation? A. Since the tick was removed promptly, no further action is needed B. You recommend 14 day course of Doxycycline C. You recommend a single dose of Doxycycline D. You recommend a single dose of Amoxicillin
I. scapularis
• The I. scapularis nymphal ticks that spread B. burgdorferi are very small!
Question 3
Removing the Tick per the CDC:
• Remove a tick from your skin as soon as you notice it. Use fine-tipped tweezers to firmly grasp the tick very close to your skin. With a steady motion, pull the tick’s body away from your skin. Then clean your skin with soap and warm water. Throw the dead tick away with your household trash. • Avoid crushing the tick’s body. Do not be alarmed if the tick’s mouthparts remain in the skin. Once the mouthparts are removed from the rest of the tick, it can no longer transmit the Lyme disease bacteria. If you accidentally crush the tick, clean your skin with soap and warm water or alcohol. • Don’t use petroleum jelly, a hot match, nail polish, or other products to remove a tick.
Case 3 continued • The patient fails to fill the prescription and does not take Doxycycline. • About 10 days later he emails you this picture, reports o a mild headache and a temperature of 100.2 F
Prophylactic antibiotics after tick bites? • Epidemiology – what to prevent? • NE – Lyme disease • Transmission: – 5cm), 3 – 30d – Early: may also have fever, flu‐symptoms
• Early neurologic disease: days to weeks – Meningitis or radiculopathy – Cranial nerve palsy
• Cardiac disease: – Heart block, myopericarditis
• Late Disease: weeks to years – Arthritis (can occur earlier), CNS or PNS disease
CDC.gov
Magdalena E. Sobieszczyk, MD, MPH
Two-Tiered Testing for Lyme Disease
Diagnosis • If there is erythema migrans, diagnosis can be clinical • Acute/convalescent antibodies** – Not useful acutely, sensitivity/specificity issues
• CSF examination may be indicated – CSF profile: Lymphocytosis, elevated protein, normal glucose – Test for antibodies
• Co‐infection with HGA and Babesia may occur (same vector!)
Indication, route, and duration of therapy for Lyme disease INDICATION
ROUTE
REGIMEN
DURATION
Erythema migrans
Oral
14 d (14-21d)
Cranial nerve palsy
Oral*
Preferred: Doxycycline, Amoxicillin, Cefuroxime axetil Alternative: Azithromycin, Clarithromycin, Erythromycin
Meningitis
IV
Cardiac
14 d (1421d)
Preferred: Ceftriaxone (2g daily) 14 d (10Alternative: Cefotaxime, Penicillin G 28d) IV or Oral
28 d
Arthritis no neurologic disease
Oral
28 d
Recurrent arthritis after oral regimen
IV or Oral
28 d
Antibioticrefractory arthritis
Symptomatic (eg NSAIDS), no antibiotics
Lyme-associated dementia
IV
Post–Lyme disease syndrome
Consider and evaluate other potential causes of symptoms; if none is found, then administer symptomatic therapy
Treatment Essentials • Doxycycline (or alternative) for erythema migrans • Oral regimen may also be used for isolated Bell’s palsy, mild cardiac disease, arthritis • IV Ceftriaxone (3rd gen cephalosporin) for heart block, symptomatic cardiac disease, other PNS/CNS disease
28 d
“Post Lyme Disease Syndrome” • No accepted definition • Chronic symptoms after receiving standard treatment regimens • May be an autoimmune issue without ongoing infection • Additional antibiotics not recommended • Re‐infection can occur
Lyme: Take home points • 80% of patients with Lyme disease develop EM, 5‐14 days after inoculation; systemic presents may or may not be present • Serologic testing is often negative in patients with early Lyme • Lyme carditis most often consist of transient heart block • Lyme arthritis typically presents as a mono‐ or oligoarthritis most commonly involving the knees • Seroreactivity often persists for at least months after antibiotic treatment of early infection and for years after treatment of late infection
Magdalena E. Sobieszczyk, MD, MPH
Case 4 • It’s July and a 57 y.o. woman is evaluated for 1 day of fever, mylagia, frontal headache. Past medical hx/o negative • Reports recent travel 2‐week camping trip in Virginia and close to home. She returned 11 days ago and does not recall any insect/bug bites • Has a dog and two cats o • On exam: mildly ill, temp 101.6 F • BP 125/65, HR 90/min • No lymphadenopathy or rash. Cardiopulmonary and abdominal exam normal • Labs:
Which of the following is the most appropriate next step A. Doxycycline B. Oseltamivir C. Postpone treatment until we have results of diagnostic test D. Vancomycin and cefriaxone
– Normal Hgb, platelets at 110,000/μL; Elevated AST/ALT – Sodium 130
Rocky Mountain Spotted Fever (RMSF)
Question 5
RMSF • The most severe rickettsial disease in U.S. • Transmitted to humans via tick bite (60% recall a bite) • Hard ticks (Ixodidae family) are both the reservoir and vector for RMSF – Dermacentor species: American dog tick, brown dog tick or RM wood tick, depending on location in U.S.
• Caused by Rickettsia rickettsii, small gram‐negative coccobacilli (need special stain to see) • Belongs to the spotted fever group of Rickettsiae • Obligate intracellular bacteria (cell culture)
Some thoughts about ticks
• Hosts: various mammals‐‐depends on tick and stage of development
“Rocky Mountain” is now a Misnomer: most common in SE/S.Central states, 2010
• By 1996: 869 species or subspecies! • Two major families ‐ Ixodidae (hard ticks): most infections ‐ Argasidae (soft ticks): brief meals from host and drop off; rarely recalled, rodent infested cabins in Western US ‐> Tick‐borne relapsing fever • Basic life stages: larva, nymph, adult • Second to mosquitos as vectors of human infections
www.cdc.gov
Slide courtesy of A-C. Uhlemann
•Also has wide Geographic distribution in the Western hemisphere
Magdalena E. Sobieszczyk, MD, MPH
RMSF in the US, cases/year 1920-2010
Decreasing fatality: 28% case fatality in 1944 to 60 and male gender Chronic alcohol abuse Non‐tetracycline use Delayed initiation of treatment (>5 days illness) Black race (rash can be missed)
Diagnosis • Clinical Suspicion • Immunohistochemistry on a skin biopsy • Serologic tests (IFA)* and PCR available – results take time
• Shell vial cell culture (not usually done) • Alternative stains (not usually done)
Magdalena E. Sobieszczyk, MD, MPH
RMSF Treatment • Doxycycline • Treatment should not be delayed while awaiting laboratory confirmation – Prompt treatment associated with better outcome: mortality rate increases from 6.5% to >20% when treatment is initiated more than 5 days after onset of symptoms
Additional References • Wormser et al. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases 2006; 43:1089–134 • Chapman AS et al. Tickborne Rickettsial Disease Working Group. MMWR Recomm Rep. 2005; 55:1‐27 • Halperin JJ, Golightly M. Lyme borreliosis in Bell’s palsy. Long Island. Neuroborreliosis Collaborative Study Group. Neurology 1992; 42: 1268–70 • Krause PJ et al. Disease‐specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis. 2002;34(9):1184. • Vannier E et al. Human babesiosis. N Engl J Med. 2012 Jun;366(25):2397‐ 407.
RMSF: Take home points • Rash: characterized by blanching erythema around wrists, ankles – Lesions spread centripetally and become petechial
• Rash may occur in only 15% of patients on presentation but appears in majority by day 4 of illness • Prompt treatment is key
Karen Brudney, MD
EPIDEMIOLOGY: SLOW DECREASE in TB since 2006 • M. TUBERCULOSIS INFECTS 1/3 WORLD’S POPULATION= 2 BILLION PEOPLE • 8.7 MILLION NEW TB CASES 2011 • 12.0 MILLION PREVALENT TB CASES 2010 • 1.1 MILLION TB DEATHS IN HIV-NEG 2010 • 350,000 TB DEATHS IN HIV-POS 2010 • 2ND TO HIV AS CAUSE OF DEATH FROM INFECTIOUS DISEASE
HIV/TB DEADLY COMBINATION 30,000 25,000 No. of Cases
• TB=LEADING CAUSE OF DEATH IN PEOPLE WITH HIV IN AFRICA • 1 IN 4 PEOPLE WITH HIV DIE DUE TO TB • 1.4 MILLION HIV POSITIVE TB PATIENTS GLOBALLY IN 2008 OF WHOM 78% LIVE IN SUB-SAHARAN AFRICA • PEOPLE INFECTED WITH BOTH HIV & TB 20-30 TIMES MORE LIKELY TO DEVELOP ACTIVE TB THAN THOSE WITHOUT HIV
Reported TB Cases United States, 1982–2011*
20,000 15,000 10,000 5,000 0
Year *Updated as of June 25, 2012.
Karen Brudney, MD
TB Case Rates by Race/Ethnicity* United States, 2003–2011**
Reported TB Cases by Race/Ethnicity* United States, 2011
35.0
Black or African American (23%)
25.0
Hispanic or Latino (29%)
20.0 15.0
American Indian or Alaska Native (1%)
10.0 5.0
Native Hawaiian or Other Pacific Islander (1%)
0.0 2003
2004
2005
2006
Hispanic or Latino Asian Native Hawaiian or Other Pacific Islander
2007
2008
2009
2010
2011
American Indian or Alaska Native Black or African American White
Asian (30%)
White (16%)
*All races are non-Hispanic. Persons reporting two or more races accounted for less than 1% of all cases.
*All races are non-Hispanic. **Updated as of June 25, 2012.
TB Morbidity in the US, 2005-2011
Countries of Birth of Foreign-born Persons Reported with TB, United States, 2011 YEAR
NUMBER
RATE
2005
14,068
4.8
2006
13,727
4.6
2007
13,278
4.4
2008
12,895
4.2
2009
11,528
3.8
2010
11,171
3.6
2011
10,528
3.4
Mexico (22%)
Other Countries 39% Philippines (11%)
Haiti (3%) Guatemala China (3%) (6%)
Vietnam India
(8%)
(8%)
Number of TB Cases in U.S.-born vs. Foreign-born Persons United States, 1993–2011*
TB Case Rates,* United States, 2011 20,000
D.C.
No. of Cases
Cases per 100,000
30.0
15,000 10,000 5,000 0
< 3.4 (2011 national average)
U.S.-born
>3.4 *Cases per 100,000.
*Updated as of June 25, 2012.
Foreign-born
Karen Brudney, MD
Trends in TB Cases in Foreign-born Persons United States, 1991 – 2011* No. of Cases
Percentage 70
10,000 9,000 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 0
60
2001
2011
50 40 30 20
DC
DC
10 0
Number of Cases *Updated as of June 25, 2012.
Percentage of TB Cases Among Foreign-born Persons, United States*
Percentage of Total Cases
*Updated as of June 25, 2012.
>50% 25%–49% M) Incidences rises in men after age 50 50% of women will have a UTI by age 32 years Cystitis recurrence rate in women is 25% by 6 months Hospital-acquired UTI is the most prevalent nosocomial infection (40% of the total) Catheter associated UTI is associated with a 2.8 fold increase in mortality
The scope of the problem Asymptomatic bacteriuria Cystitis and pyelonephritis in nonpregnant, otherwise healthy premenopausal women Resistant organisms
A case……. A 35 yr old asymptomatic, nonpregnant woman who has never had a UTI calls to report that she went to her gynecologist for a routine check-up last week. She had a UA and C&S done. UA revealed that she had 35 WBC/HPF. Urine culture grew 105 cfu/ml E. Coli.
As her internist you recommend: Her gynecologist has recommended a 5 day course of ciprofloxacin. She does not want to take antibiotics since she feels completely well.
A. she should take the cipro for 5 days because she will most likely become symptomatic if she does not take it B. that the urine culture should be repeated with plans to treat if the culture has the same organism C. she should be treated only if she develops symptoms
Ellen A. B. Morrison, M.D., M.P.H.
As her internist you recommend:
Asymptomatic bacteriuria (ASB)
A. she should take the cipro for 5 days because she will most likely become symptomatic if she does not take it B. that the urine culture should be repeated with plans to treat if the culture has the same organism
In younger women, ASB is often related to sexual activity Incidence increases with age in women As high as 20% of healthy women over 80 years of age living in the community Higher in diabetics Rare in men until after 50 years of age Is a major risk for symptomatic UTI
C. she should be treated only if she develops symptoms
Old approach= treat if the patient has pyuria
ASB: Why not treat?
New approach = treat if the patient has symptoms
ASB is usually transient (particularly in young women) 50% recurrence by 1 year Rx does not prevent UTI Rx associated with antibiotic resistance Other concerns: C dif, vaginal Candidiasis, resistant organisms, cost
ASB
Urinary Tract Infection (UTI)
Screening and treatment indicated:
Usually E. coli or other gram negatives In women: colonization of the vaginal introitus and periurethral area with uropathogenic organisms, ascent of the organism into the bladder, inflammatory response In men: longer urethra decreases the chance that organisms will ascend, urinary stasis from BPH provides culture media Risk factors: gender, sexual activity, BPH, genetics, spermicide use, estrogen deficiency, urinary catheters, structural abnormalities, prior UTI
In early pregnancy Before TURP or other urological procedures that result in mucosal bleeding Possibly in women who have catheter associated bacteriuria that persists 48 hrs after removal of the catheter ? Renal transplant patients
Ellen A. B. Morrison, M.D., M.P.H.
Prior UTI as a risk factor
Symptomatic UTI
A proxy for all of the other risk factors ? Increased vulnerability after a treated UTI 20% recurrence rate of symptomatic UTI by 6 months after UTI treatment Possibly related to colonization with a uropathogenic strain ? Use of antibiotics disturbs normal flora
Cystitis vs pyelonephritis
IDSA/ESCMID Guidelines
IDSA/ESCMID Guidelines
International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of American and the European Society for Microbiology and Infectious Diseases
Co-sponsored by:
Clinical Infectious Diseases 2011:52
Fever, flank pain, systemic illness
Uncomplicated vs complicated UTI Complicated = urological abnormalities, significant medical comorbidities, longer duration of symptoms
American Congress of Obstetricians and Gynecologists American Urological Association Association of Medical Microbiology and Infectious Diseases-Canada Society for Academic Emergency Medicine
These guidelines:
Another case…….
Address premenopausal, nonpregnant women with no known urological abnormalities or medical comorbidities Do not address recurrent UTIs, postmenopausal women, diabetics, etc. Consider collateral damage and in vitro resistance prevalence Literature review, weighting of the evidence, grade of the recommendations
A 25 year old woman presents to you with complaint of 24 hours of urinary frequency, burning, and hematuria. She has no nausea and no history of allergies. She has no medical comorbidities. She is afebrile and has no CVAT.
Ellen A. B. Morrison, M.D., M.P.H.
Preferred first line antibiotics for this UTI include:
A. B. C. D. E. F. G.
Ciprofloxacin Fosfomycin trometamol Nitrofurantoin monohydrate Amoxicillin Trimethoprim-sulfamethoxazole All of the above B, C, and E
Preferred first line antibiotics for this UTI include:
A. B. C. D. E. F.
Ciprofloxacin Fosfomycin trometamol Nitrofurantoin monohydrate Amoxicillin Trimethoprim-sulfamethoxazole All of the above
G. B, C, and E
Trimethoprim-sulfamethoxazole (TMP/SMX)
Amoxicillin or ampicillin
BID tab bid for 3 days unless local resistance pattern is known to exceed 20%+
Removed from recommended regimens in 1999 due to high rates of resistance and treatment failure
90-95% case of cystitis will be cured 40% of resistant uropathogens will be cured
Factors predicting resistance Receiving TMP/SMX in the prior 3-6 months Travel outside the U.S. + at NYP 65% OPD E. coli were S in 2011
Nitrofurantoin
Fosfomycin
100 mg bid for 5 days Comparable efficacy to TMP/SMX or cipro in clinical trials Clinical cure rates of 88-93% Minimal resistance in the U.S. Less efficacious for pyelonephritis
3 gm single dose Limited use in U.S., but > 20 yrs experience abroad Available IV in Europe
Bactericidal Inhibits uridine diphosphate-GlcNAc enol-pyruvyltransferase (MurA) Novel mechanism of action – little potential for cross resistance
Ellen A. B. Morrison, M.D., M.P.H.
Fosfomycin
Fosfomycin
Broad gram positive (including E fecalis) and gram negative enteric flora
Does your local pharmacy carry this? Is it on your patient’s pharmacy plan antibiotic formulary?
E. coli are 97-99% susceptible worldwide +/- against Pseudomonas aeruginosa and not active against Acinetobacter sp
Long half life Great tissue penetration NOT RECOMMENDED FOR PYELONEPHRITIS (as a single dose)
Other B-lactams (amoxicillinclavulanate, cefdinir, cefaclor, etc.)
Fluoroquinolones+ Highly efficacious in 3 day regimens Clinical cure rates of 85-98% Considered an alternative because of concerns about collateral damage
Less clinical data Lower efficacy Less effective at eliminating vaginal colonization Cefpodoxime-proxetil Hooton, et al. JAMA clinical efficacy 82%
+70% OPD E.coli were S to levaquin at NYP 2011
Costs of Cystitis Treatment Average wholesale prices of treatment course
Fosfomycin Nitrofurantoin Trimethoprim-sulfamethoxazole Ciprofloxacin Levafloxacin
$51 $19 $7 $28 $26
Significant potential for collateral damage
Ellen A. B. Morrison, M.D., M.P.H.
After obtaining urine for C & S, you could treat her empirically with:
Another case…… A 35 y/o woman presents with fever and flank pain. She had mild dysuria for 2 days before becoming ill. She is hemodynamically stable and tolerating oral intake.
After obtaining urine for C & S you could treat her empirically with:
A. Bactrim alone B. Bactrim + ceftriaxone or aminoglycoside C. Fluoroquinolone + ceftriaxone or aminoglycoside D. Nitrofurantoin or fosfomycin E. An oral B-lactam
F. B or C
Pyelonephritis:
preferred regimens for
susceptible organisms
Bactrim DS bid for 14 days Fluoroquinolones for 5-7 days Oral B-lactams are inferior to these regimens
A. Bactrim alone B. Bactrim + ceftriaxone or aminoglycoside C. Fluoroquinolone + ceftriaxone or aminoglycoside D. Nitrofurantoin or fosfomycin E. An oral B-lactam F. B or C
Pyelonephritis Get a culture before treatment and adjust therapy when results are available Less room for error Initial dose of ceftriaxone or aminoglycoside with bactrim with fluoroquinolone (if rate of resistance >10%) with oral B-lactams
Nasty Bugs (highly resistant) More likely if pt is known to be colonized or previously infected with nasty bugs More likely if pt has recently received antibiotics Associated with foreign travel
Ellen A. B. Morrison, M.D., M.P.H.
Nasty Bugs
Nasty Bugs
Ertapenem is a once daily carbapenem
Fosfomycin has activity against VRE, MRSA, and ESBL-producing gram negatives Nitrofurantoin also has broad activity Both are inferior to TMP/SMX or quinolones for pyelonephritis
Less activity against Pseudomonas and Acinetobacter than other carbapenems Can be given IM or IV
Aminoglycosides can be given once daily, IM or IV
Does the urinalysis have value? Pyuria is not an indication for treatment if patient is asymptomatic On the other hand, if the patient’s symptoms are from a UTI, most will have pyuria the absence of pyuria should cause you to question the diagnosis Exception: neutropenic patients
Arun Swaminath, MD
Question 1 CUMC Annual Update and Intensive Review of Internal Medicine 2012: Inflammatory Bowel Disease
Arun Swaminath, MD
•
Using GWAS testing, we have identified over 100 genes that overlap in IBD (UC/CD). A 25 yo Female comes to you for “genetic testing” because her maternal grandmother had Crohn’s. You…. A) Get her tested for all the associated gene mutations
[email protected]
Assistant Professor of Clinical Medicine Division of Digestive and Liver Diseases
B) Tell her genetic testing isn’t currently recommended, but you’ll test her for the 2 most important (NOD2, ATG16) C) Tell Genetic testing is not currently recommended and is unlikely to benefit her.
Question 2 •
Which one of the following steps is necessary before initiation of biologic agents/Anti-TNF such as adalimumab for the treatment of moderate to severe Crohn’s disease? A) B) C) D) E)
Assessment of TB exposure with PPD and CXR Hepatitis B serology Checking thiopurine methyltransferase (TPMT) levels Baseline DEXA scan A&B
Outline of today’s talk 1. Epidemiology of CD/UC 2. Pathogenesis 3. Disease Distribution; localization 4. Symptomatic Presentations to the hospital; 5. Relevant parts of hx/pex (incl EIM's) to know before calling the consult! 6. Assessing disease severity --> pex findings/ CDAI/ HBI/UCDAI/Endoscopy indices 7. Labs/tests/imaging/procedures to order 8. Treatment options 9. Colorectal cancer in IBD
IBD Epidemiology
Epidemiology of IBD
• Family History: Greatest risk factor • 1.4 Million cases of IBD in the U.S. • Approximately 10,000 new cases dx annually • Peak onset: 15 to 25 years of age – 25% diagnosed by age 18yr
• Approximately equal between males and females • Incidence increased in industrialized nations from 1970
– – – – – –
15-20% of patients have a (+) family history Risk to offspring of affected patients: ~9% Risk to siblings of affected patients: ~9% Risk to parents of affected patient: 3.5% Risk to offspring if both parents affected - ~35% Concordance in monozygotic twins: CD (27-58%), UC (4%)
• Jewish > Non-Jewish populations: – Crohn’s 3-8x more likely, Ulcerative colitis 2-4x more likely
to 1990 • Caucasian > African American
Arun Swaminath, MD
Inflammatory Bowel Disease Geographic Distribution
Outline of today’s talk 1. Epidemiology of CD/UC 2. Pathogenesis 3. Disease Distribution; localization 4. Symptomatic Presentations to the hospital; 5. Relevant parts of hx/pex (incl EIM's) to know before calling the consult! 6. Assessing disease severity --> pex findings/ CDAI/ HBI/UCDAI/Endoscopy indices 7. Labs/tests/imaging/procedures to order 8. Current treatment options 9. Colorectal cancer in IBD
IBD – Interaction of Genetic Susceptibility, Immune Dysregulation, and Environmental Triggers
Overview of IBD Pathogenesis Bacterial Products or Environmental exposure?
Genetic Susceptibility
Chronic Inflammation = IBD
Immune Dysregulation
IBD Environmental Triggers
-microbiome
Moderately Acutely Inflamed Normal Gut
Pathogenesis: Environmental Triggers Infections
Antibiotics
NSAIDs
IBD
Diet
Smoking Stress
Normal Gut Mildly Inflamed
Pathogenesis: Genetic associations
Arun Swaminath, MD
Allelic Variants of NOD2 Are Associated with Crohn’s Disease 1, 2 NBD
CARD1 CARD2
P268S SNP5
PATHOGENEIS: MICROBIOTA Spatial and temporal aspects of intestinal microbiota composition.
LRR R702W G908R 1007fs SNP8 SNP12 SNP13
Carriage of NOD2 allelic variants 1-6: – Crohn’s disease – Control population – UC population
27-39% 14-16% 12-14%
5
Carriage of 2 mutations is estimated to carry absolute risk of CD of 3% 1) Hugot JP et al. Nature 2001;411: 599 2) Ogura Y et al. Nature 2001;411: 603 3) Hampe J et al. Lancet 2001;357:1925
4) Lesage S et al. Am J Hum Genet 2002;70: 845 5) Cuthbert AP et al. Gastro 2002;122: 867 6) Ahmad T et al. Gastro 2002;122: 854
The interplay between the host microbiota and host genetics
A paradigm for risk of IBD in family of affected patients
Gut 2012;61:311e318. doi:10.1136/gut.2011.238568
Outline of today’s talk 1. Epidemiology of CD/UC 2. Pathogenesis 3. Disease Distribution; localization 4. Symptomatic Presentations to the hospital; 5. Relevant parts of hx/pex (incl EIM's) to know 6. Assessing disease severity --> pex findings/ CDAI/ HBI/UCDAI/Endoscopy indices 7. Labs/tests/imaging/procedures to order 8. Treatment Options 9. Colorectal cancer in IBD
Crohn’s Disease 40/30/25
Ulcerative Colitis
Arun Swaminath, MD
NORMAL COLON: Endoscopic Appearance And Histology
IBD Symptoms
Inflammatory Bowel Disease Systemic Complications Eye inflammation
Crohn’s Disease
Ulcerative Colitis
• Diarrhea Growth failure in children
•Abdominal pain •Weight loss/Food avoidance
Lower bone density* Kidney stones
Liver and bile duct inflammation Gallstones
Subfertility*
Skin lesions*
Arthritis and joint pains
*Increased in women.
Natural History of CD
•Bloody Diarrhea
(after meals)
•Abdominal distention/Nausea/ vomiting
•Fever •Weight loss •Urgency •Fecal Incontinence
•Recurrent UTI’s Pneumaturia, psoas abscess, perianal pain/drainage
Natural History of UC
APT 2002
Gastro 1994
Arun Swaminath, MD
Outline of today’s talk
Diagnostic Testing • Endoscopy
1. Epidemiology of CD/UC 2. Pathogenesis 3. Disease Distribution; localization 4. Symptomatic Presentations to the hospital; 5. Relevant parts of hx/pex (incl EIM's) 6. Assessing disease severity --> CDAI/ HBI/UCDAI/Endoscopy indices 7. Labs/tests/imaging/procedures to order – Serology; Imaging; 8. Treatment options 9. Colorectal cancer in IBD
– – – – –
Flexible sigmoidoscopy Colonoscopy Upper endoscopy Endoscopic U/S Capsule
• Tissue Biopsy • CT scan (try to minimize) • Blood Tests
Evolving Areas of Diagnosis and Therapy in IBD
ASCA/ANCA/OmpC CBir
Th2
Imaging in IBD
Th1 NOD2, OCTN, DLG Others
Genetic profile
Biologic Immune Suppression, Innate Immune Augmentation
Cytokine profile
Antibody profile
The future of small bowel Imaging --30-year-old woman with normal CT findings at enterography
Macari, M. et al. Am. J. Roentgenol. 2007;188:1344-1355
Copyright © 2007 by the American Roentgen Ray Society
Small Intestinal Crohn’s Disease as Seen by Wireless Capsule Endoscopy
Arun Swaminath, MD
FDG-PET/CT: structure and function
Imaging in IBD-Down Side
PNA
GASTROENTEROLOGY 2008;135:1055–1078
Medical Therapies for IBD
Outline of today’s talk 1. Epidemiology of CD/UC 2. Pathogenesis 3. Disease Distribution; localization 4. Symptomatic Presentations to the hospital; 5. Relevant parts of hx/pex (incl EIM's) to know 6. Assessing disease severity --> CDAI/ HBI/UCDAI/Endoscopy indices 7. Labs/tests/imaging/procedures to order – Serology; Imaging 8. Treatment Options 9. Colorectal cancer in IBD
Ulcerative Colitis: Treatment Algorithm
• • • • • • • •
Crohn’s Disease 5-Aminosalicylates Corticosteroids 6-MP/AZA Infliximab Adalimumab Antibiotics Methotrexate Natalizumab
• • • • • •
Ulcerative Colitis 5-Aminosalicylates Corticosteroids 6-MP/AZA Infliximab Adalimumab Cyclosporine
Crohn’s disease: Treatment Algorithm 5-ASA trial in the US
Arun Swaminath, MD
Role of Corticosteroids •Effective in acute disease -UC and Crohn’s •Tapering regimen -40 mg prednisone 6-8 weeks •Steroid dependence -small subset remain in remission on low dose steroids. •Long term treatment -do not reliably prevent relapses
Healing of Colonic Ulceration With Infliximab
Immunomodulators • • •
Azathioprine (AZA)/6-Mercaptopurine (6-MP) 6-Thioguanine (6TG) Methotrexate
•
Cyclosporine
Toxicity of immunomodulators • • • • • • •
Leukopenia (necessitates frequent cbc’s) Total marrow suppression Pancreatitis (4%) Infectious complications Allergic reactions Drug hepatitis ?Birth defects-associated with preconception use by men or women
Pretreatment
4 Weeks posttreatment
Reprinted with permission of van Dullemen HM et al. Gastroenterology. 1995;109:129.
INFLIXIMAB: Crohn’s Disease And Ulcerative Colitis Remission Data
Adverse Events with Anti-TNF Agents Tolerability ● Infusion reactions ● Injection-site reactions ● Delayed hypersensitivity reactions
ACCENT I
ACT 1
Week 2 Responders
Clinical Remission at Week 54 P ro p o rtio n o f P a tie n ts (% )
Clinical Remission at Week 54 100 90 80 70 60 50 40 30 20 10 0
*p = 0.001
Infection
34.7
*
34.4
*
16.5
Placebo
Development of autoimmunity
Lymphoma Congestive heart failure
5 mg/kg Infliximab
10 mg/kg Infliximab
Demyelinating illness
Arun Swaminath, MD
Outline of today’s talk “a physician who sees no patients, makes no diagnoses, and offers no treatments would have a perfect safety record, while doing no one any good at all.”
1. Epidemiology of CD/UC 2. Pathogenesis 3. Disease Distribution; localization 4. Symptomatic Presentations to the hospital; 5. Relevant parts of hx/pex (incl EIM's) to know 6. Assessing disease severity --> CDAI/ HBI/UCDAI/Endoscopy indices 7. Labs/tests/imaging/procedures to order – Serology; Imaging 8. Treatment Options 9. Colorectal cancer in IBD
Amnon Sonnenberg, Charles Boardman Am J of Gastro 2013; 108: 183-175
•
Largest long term study of CD patients with extensive colitis >7yrs
•
Cumulative risk of neoplasia was 22% at 4th exam in this cohort and 25% at 10th exam (LDG, HGD, CA).
•
This parallels the risk of CA within ulcerative colitis cohorts. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6:993–998
Colorectal Cancer in IBD • Increased incidence-after 8-10 years. True rate not certain • Similar risk UC and CD have similar rate of Colon carcinoma. • CD associated with wide spread GI carcinoma • CD has increased rate of squamous CA in perineal disease
• Risk Factors long duration, extensive disease, severity of disease, •
dysplasia on biopsies
• Characteristics arise in flat mucosa, often multiple, anaplastic • Surveillance-colonoscopy every 1-2 years for high risk groups – – –
Pancolitis: At 8yrs L sided Colitis- At 10 yrs PSC with Colitis: No delay! Start surveillance at time of diagnosis
FINAL QUESTION
Arun Swaminath, MD
In which of the following situations is a colonoscopy NOT required? A. 24 yo F with intermittent bloody diarrhea x 5 months with 10lb wt loss. B. 60 yo M with quiescent UC diagnosed when he was 25 years old. C. A 30 yo M with PSC diagnosed with colitis 1 year ago. D. An 18 yo M with ileocolonic crohn’s disease dx 1yr ago who is asymptomatic on pentasa.
Abby Siegel, MD MS
Estimated New Cancer Cases* in the US in 2013
Gastrointestinal Malignancies Abby Siegel, MD MS Assistant Professor of Clinical Medicine
• • • •
Colon cancer Gastric cancer Pancreatic cancer Hepatobiliary cancers
• • • •
Colon cancer Gastric cancer Pancreatic cancer Hepatobiliary cancers
Epidemiology of Colorectal Cancer
Risk of Colorectal Cancer 6%
General population Personal history of colorectal neoplasia
Sporadic (65%–85%)
15%–20%
Inflammatory bowel disease
Familial (10%–20%)
15%–40% 70%–80%
Lynch Syndrome
>95%
FAP 0
20
40
60
Lifetime risk (%)
80
Hereditary CRC syndromes (6%)
100 Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996
Abby Siegel, MD MS
Factors Associated With CRC Risk factors Strong (RR > 4.0) Advanced age FAP / HNPCC Long-standing UC/Crohn’s colitis Moderate (RR 2.1 - 4.0) High red meat diet Previous adenoma or cancer Family history of adenoma or cancer Modest (RR 1.1 - 2.0) High fat diet Smoking and alcohol consumption Obesity Cholecystectomy
Hereditary Colorectal Cancer Syndromes
Protective factors Moderate (RR < 0.6) High physical activity Aspirin / NSAID use
Familial Adenomatous Polyposis (FAP) Lynch (HNPCC) Syndrome
Modest (RR 0.9 - 0.6) High vegetable / fruit diet High fiber diet High folate / methionine intake High calcium intake Postmenopausal hormone therapy
CRC tumor progression in sporadic and hereditary CRC syndromes
Both involve germline inheritance of gene mutations
Clinical Features of FAP
1% of all CRC 100‐1000s of adenomas APC gene mutations Risk of extracolonic tumors (desmoids, duodenal cancer thyroid, brain)
Risk of CRC=100% if untreated
HNPCC/Lynch Syndrome
Lynch Syndrome
Most common hereditary CRC syndrome 5% of all CRC
Defective DNA Mismatch Repair Mutations in MLH1, MSH2, MSH6, PMS2
Lifetime risk of CRC = 70‐80% Risk is markedly lower if colonoscopies begin early
Vasen et al. Dis Colon Rect 1991 34:424‐5. Lindor et al. JAMA 2005; 293:1979‐85.
Abby Siegel, MD MS
Lynch Syndrome Clinical Features
Survival probabilities according to stage of disease
Striking family history affecting multiple generations
Early (but variable) age at CRC diagnosis (mean 45 years)
Multiple primary cancers Extracolonic cancers: Endometrium Ovary Urinary tract Stomach Small bowel Sebaceous carcinomas of skin
pT: Stage:
Stage 1 Colorectal Cancer • 25% of colorectal CA • Cancer has grown through the mucosa and invades the muscularis • Treatment: surgery to remove the tumor and some surrounding lymph nodes • Survival: 90%
Adapted from www.plwc.org, 2007
Stage 3 Colorectal Cancer • 25% of CRC • CRC has spread to the regional lymph nodes • Treatment (colon): surgery and adjuvant chemotherapy! • Treatment (rectal): surgery, radiation and chemotherapy • Survival: 40 to 80% Adapted from www.plwc.org, 2007
TisN0
T1N0
T2N0
T3/4N0
0
I
I
II
T2N1 III
T3/4N1 III
Stage 2 Colorectal Cancer • 30% of colorectal CA • Cancer grows beyond the muscularis of the colon or rectum but has not spread to the lymph nodes • Treatment (colon): surgery +/‐ adjuvant chemotherapy • Survival: 70 to 85% • Treatment (rectal): surgery, radiation and chemo
Adapted from www.plwc.org, 2007
Surveillance after resection • See physician every 3‐6 months for 3 yrs, every six months during years 4 and 5, then yearly • CEA at each follow‐up visit for at least the first three years after primary resection, even if preoperative CEA levels were normal • Colo at/around surgery, at 1 year, 3 and 5 yrs • Scans yearly for 3 years if might be a surgical candidate
Abby Siegel, MD MS
Lifestyle modification
Stage 4 Colorectal Cancer
• “Western” compared with “prudent” diet triples risk of recurrence and doubles rate of death from colon cancer • Walking 6 or more hours per week lowers risk of recurrence and death by up to 50% • Observational studies suggest aspirin is beneficial, but awaiting randomized trials
• 20% of CRC • CRC has spread to other areas of the body • Treatment: chemotherapy • Surgery to remove metastases (liver/lung) in carefully selected patients • Survival: evolving
Molecularly Targeted Therapy
TREATMENT: Pharmaceuticals
5‐Fluorouracil ‐ pyrimidine antimetabolite
Irinotecan ‐ topoisomerase inhibitor prevents re‐ligation after cleavage of DNA by topoisomerase I
Oxaliplatin ‐ alkylating agent, causes formation of bulky DNA adducts Modified from Siegel et al, Hepatology 52:360-369, 2010
Correlating Survival With Skin Rash
EGFR inhibition and rash
P = .0008*
P = .0007*
14 12
P = .04*
Survival
10 8
G0 G1 G2 G3
P = .0002*
6 4 2 0 Colon
Colon
Head and Neck
* Log‐rank P value, grade 0 vs. grades 1‐3 Saltz L et al. Proc Am Soc Clin Oncol 2003; 22:204 (abstract 817) Slide courtesy of Josep Tabernero, MD
Pancreas
Abby Siegel, MD MS
Hazard Ratios for Progression‐free and Overall Survival and Odds Ratios with Tumor Response, According to the Mutation Status of KRAS in the Tumor
How is resectability of liver metastases defined? (Slide Courtesy of Dr. Wells Messersmith)
1) Capability of resecting all evident disease (R0). 2) Sufficient hepatic remnant: at least 2 contiguous remaining segments adequate inflow and outflow adequate hepatic function and volume
Surgical Planning: Characterization of “future liver remnant” compared to total liver volume (>20% desirable)
Van Cutsem E et al. N Engl J Med 2009;360:1408‐1417
Trends in the Median Survival of Patients with Advanced Colorectal Cancer • • • • •
Colon cancer Gastric cancer Pancreatic cancer Esophageal cancer Hepatobiliary cancers
Meyerhardt, J. A. et al. N Engl J Med 2005;352:476‐487
Age adjusted gastric cancer incidence per 100,000
Risk factors for Gastric adenocarcinoma
slide courtesy of Deirdre Cohen MD
• Definite and Surveillance Suggested • • • •
High‐grade dysplasia Familial adenomatous polyposis Adenomas Barrett’s esophagus (cardia and gastroesophageal junction)
• Definite • • • •
Intestinal metaplasia Chronic atrophic gastritis H pylori infection Hereditary nonpolyposis colorectal cancer
Slide courtesy of Deirdre Cohen MD
29
30
Abby Siegel, MD MS
Workup and treatment • Symptoms and signs: – Abdominal pain, early satiety, non‐healing ulcer
• Determine if potentially resectable: – Stage with EUS, CT, PET – Distant metastases and invasion of a major vascular structure make unresectable
• Need either adjuvant chemoRT or periop chemo (or adjuvant chemo in Asia)
Post‐treatment surveillance • Exam every 3‐6 months for 2 years, then every 6‐12 months for 3 more years, then annually • Imaging and scoping as indicated • Follow vitamin B12, iron, folate and calcium as well as bone density
Metastatic disease • No standard chemotherapy; several regimens possible • Data now for second line therapy
• • • •
Colon cancer Gastric cancer Pancreatic cancer Hepatobiliary cancers
• New data of importance of checking for HER‐2 expression, like in breast cancer
Risk Factors • • • • •
Cigarette Smoking Diabetes – cause and effect Obesity/physical activity Chronic Pancreatitis Inherited syndromes – – – – – – –
BRCA2 – relative risk Familial atypical multiple mole‐melanoma syndrome Peutz‐Jeghers (STK11/LKB1) Familial pancreatitis (PRSS1) HNPCC Ataxia‐telangiectasia (ATM gene) FAP
Presentation and workup • • • •
Abdominal pain (particularly radiating to back) Jaundice for head masses EUS/CT scans used for workup EUS guided biopsy less risky for peritoneal seeding than CT‐guided
Abby Siegel, MD MS
Pancreaticoduodenectomy mortality
Treatment
based on hospital volume (1994‐1999) 18
< 1/yr.
No. Operations 1-2/yr 3-5/yr 6-16/yr
1,563
2,757
>16
16 14
% mortality
12 10 8 6 4 2 0
1,885 No. Patients
2,166
2,159
• After resection, can give either chemo or chemoRT • For advanced disease, gemcitabine was approved based on “clinical benefit” of 42% even though response rate was only about 5% • Erlotinib approved based on small statistically significant survival benefit of about 2 weeks • Two new options: FOLFIRINOX and gemcitabine/abraxane
Birkmeyer, NEJM 2002;346:1128 Slide courtesy of Dr. Steve Cohen
Overall Survival Gem/abraxane
FOLFIRINOX: Pancreatic cancer
OS, months
1.0 Events/N (%)
Proportion of Survival
0.9
Median (95% CI)
75th Percentile
0.8
nab-P + Gem 333/431 (77)
8.5 (7.89–9.53)
14.8
0.7
Gem
6.7 (6.01–7.23)
11.4
359/430 (83)
0.6 0.5 0.4
HR = 0.72 95% CI (0.617–0.835) P = 0.000015
0.3 0.2 0.1 0.0 0
3
6
9
12
15
18
21
24
27
30
33
36
39
16 7
9 3
4 1
1 0
1 0
0 0
Months Pts at Risk nab-P + Gem: 431 Gem: 430
357 340
269 220
169 124
108 69
67 40
40 26
27 15
Conroy T et al. N Engl J Med 2011;364:1817-1825. Von Hoff et al., ASCO GI 2013 LBA148 Slide Courtesy of Dr. Steve Cohen
Liver Cancer Worldwide El‐Serag, NEJM 2011; 365:1118‐27
• • • •
Colon cancer Gastric cancer Pancreatic cancer Hepatobiliary cancers
40
Abby Siegel, MD MS
HCC Risk Factors
Who should be screened: • Anyone who is cirrhotic
• Exposures – HCV, ETOH, Aflatoxin – HBV • HBV viral load>104 copies/ml, genotype C, e antigen positive
• Asian male HBV carriers over age 40
• Genetic susceptibility – hereditary hemochromatosis, alpha‐1 antitrypsin deficiency, Wilson’s disease
• Metabolic factors
• Asian female HBV carriers over age 50 • African/North American AA with HBV
– NASH, metabolic syndrome
• Demographics
• HBV carrier with family history of HCC
• Older age, male sex
Barcelona Clinic Liver Cancer (BCLC) staging classification and treatment schedule
Milan Criteria for liver transplantation • If only one tumor, it must be 5 cm or less • 3 or fewer tumors, each 3 cm or less • No gross vascular invasion Mazzafero et al. NEJM 1996, 334:693‐700
Llovet et al. J. Natl. Cancer Inst. 2008
Molecularly Targeted Therapy for HCC
Sorafenib Improves overall survival from 7.9 to 10.7 months Llovet, NEJM 2008
Modified from Siegel et al, Hepatology 52:360-369, 2010
Abby Siegel, MD MS
Biliary Anatomy
Epidemiology • Differs according to subtype, and by geographic location – Gallbladder: • US: and Chile: gallstones • India: salmonella/chronic typhoid
– Bile duct cancers: • US: PSC, metabolic syndrome, hepatitis C • Asia: liver flukes Adapted from De Groen et al, NEJM 1999 Oct 28;341(18):1368‐78
Preparation of a meal of Koi‐Pla using uncooked fish infected with O. viverrini
Surgical options • Resection – Gallbladder • Extended surgery if tumor invades muscularis (T2) • Resection of liver segments IVb and V, and lymph node dissection of the hepatoduodenal ligament
– Bile duct
Sripa B, Kaewkes S, Sithithaworn P, Mairiang E, et al. (2007) Liver Fluke Induces Cholangiocarcinoma. PLoS Med 4(7): e201. doi:10.1371/journal.pmed.0040201
• Wide excision • Can involve portal vein embolization to increase size of remnant
Biliary Tract Cancer: Gemcitabine Alone versus Cisplatin plus Gemcitabine
Liver transplantation • • • • •
Piloted at Mayo, Nebraska and Columbia Very select patient population Extrahepatic, =30
3.6
0 benefit
I. No recommendation. Insufficient evidence to weigh risks and benefits.
Deepu Gowda, MD, MPH
Cervical Cancer Trends Cervical Cancer Screening
Effectiveness of Pap Testing
When to Begin Cervical Cancer Screening
• No trials evaluating benefit of pap • Ecological data – Implementation of pap in previously pap naïve populations: 60‐ 90% reduction of incidence in 3 yrs. – Studies in North America and Europe with 20‐60% relative reduction in Cervical CA mortality after the introduction of screening.
• High rates of HPV clearance in women 50 – Current UK RCT women in 40s. Interim: non‐significant trend toward decreased mortality.
• More likely to have false positive results • Psychological harms, time spent and inconvenience, pain and risks of biopsies and further testing
Humphrey LL et al. Breast cancer screening; a summary of the evidence for the USPSTF. Annals Int Med 2002;137:347‐ 60.
Step 1. Risk Stratification of Women 40‐49 ACP Recommendations
Decision to screen in a given patient
1. Risk stratify 2. Patient’s values re: potential harms and benefits
• • • • • • •
Age. At population level, 40 different from 49 ½ yo. Older age at first childbirth (>30) Younger menarche (75 yo
• ACOG
Grade I
Grade D
• Mammogram exam in women 40 “breast awareness”, but not self breast exam >75, talk with your doctor
Deepu Gowda, MD, MPH
Trends in Prostate Cancer: Population Level Data
Prostate Cancer Screening
Evidence for Benefit of Prostate Cancer Screening • Prior evidence poor and with varying results • 2 RCTs interim results published in NEJM March, 2009
Mortality and late stage disease decline
PSA introduced
RCTs: March 2009 NEJM • PLCO: Prostate, Lung, Colorectal, and Ovarian. Cancer Screening Trial (United States) • ERSPC: European Randomized Study of Screening for Prostate Cancer • Outcomes: Prostate cancer mortality
Mortality Results from a Randomized Prostate Cancer Screening Trial [PLCO] • 76,693 men randomized – aged 55‐74
PLCO Compliance and Contamination
• Screening group – 85% PSA and 86% DRE compliance
• Screening – annual PSA x 6 yrs (4 ng/ml cut‐off) – DRE x 4 yrs • Control – Usual care – Could include screening Gerald L. Andriole et al. PLCO Project Team NEJM March 26, 2009. 1310‐1319.
• Control – 52% got PSA by 6th year
Deepu Gowda, MD, MPH
PCLO Results Prostate Cancer Incidence
• 22% increase in diagnosis of prostate cancer in the screened group [rate ratio: 1.22 (1.16 to 1.29)].
Considerations
PLCO Prostate Cancer Mortality
• Intention to screen analysis – No difference in Prostate Cancer Mortality. Rate ratio: 1.13 (0.75 to 1.70)
Screening and Prostate‐Cancer Mortality in a Randomized European Study [ERSPC]. Fritz H. Schröder, M.D.et al. NEJM March 26, 2009. 1320‐1328.
• Contamination: are two arms too similar? • Yet 22% increase in diagnosis in screened group.
• Cutoff of 4 ng/ml; ERSPC used avg of 3 ng/ml • Longer follow‐up period
Results • Screening group: – 82% accepted screening – Cumulative incidence of prostate cancer 8.2%
• Control group – Cumulative incidence 4.8%
• 182,000 men between 50‐74 • 7 European countries • Randomized to PSA avg of every 4 yrs or control • Avg 8 yrs follow‐up
Results • Intention to screen analysis • 20% reduction in prostate cancer mortality for screening group vs. control at 8.8 yrs: Rate ratio 0.80 (0.65‐0.98 and P=0.04) • Absolute risk difference 0.71 deaths/1000 men • 1410 men screened and 48 cases treated to save 1 life
Deepu Gowda, MD, MPH
ERSPC Authors’ Discussion • “Overdiagnosis and overtreatment are probably the most important adverse effects of prostate‐cancer screening and are vastly more common than in screening for breast, colorectal, or cervical cancer.” • Overdiagnosis/Overtreatment: Diagnosis/treatment of a disease in persons who would not have gone on to develop clinical symptoms.
Remaining questions • Quality of life assessments are currently being studied in both PLCO and ERSPC • Cost • Cost‐Effectiveness • Race/ethnicity
Headlines
USPSTF (March 2012): Prostate Cancer Screening
• “Prostate Test Found to Save Few Lives” • New York Times. March 19, 2009
• “Study: Prostate Screenings Don’t Reduce Cancer Deaths”
Grade D Recommend against
• CNN. March 18, 2009
• “No Definitive Answers from Initial Results of Prostate Screening Trials” • NCI Cancer Bulletin. March 24th, 2009
American Cancer Society – Research has not yet proven that the potential benefits of testing outweigh the harms of testing and treatment. – Talk with doctor about pros and cons when >50 or if AA or family history, talk with doctor >45 yo
Informed and shared decision‐making • Difficult but important conversation • Has not been shown to save lives. We may find cancers that would have never harmed you. • Especially in older people.
Deepu Gowda, MD, MPH
Final thoughts • Guidelines are for guidance, not to be blindly followed. They are meant to be integrated with the patient’s values and your own understanding of the literature. • For category C and I, we must slow down to consider the patient’s risk profile, comorbidities, and their values.
Thank you Deepu Gowda, MD, MPH
[email protected]
• We are better at appreciating the risk of missing a diagnosis. • It is more difficult for physicians and patients alike to understand the risks of overdiagnosis and overtreatment.
Feel free to contact me!
Charles Halasz, MD, FAAD, FACP
Dermatology #1 reason for OV Readers Digest April 2013
Primary Care Office Dermatology 19th Annual Update & Intensive Review of Internal Medicine
Skin disorders 43%
Charles Halasz, MD, FAAD, FACP June 2013 Note: slides by permission of NEJM, AAD, and my personal collection, to be used for teaching purposes only
Primary lesion morphology (high power) Small < 1 cm
Large > 1 cm larger
Macule
Patch
Papule
Plaque
Vesicle
Bulla
Pustule
Abscess
Petechiae Telangectasi a Wheal
Purpura
Erosion
Ulcer
Nodule
Secondary lesions (high power) (manipulation or evolution of 10 lesion)
•Scale
Flakey, keratotic surface
•Crust
Dry serous, hemorrhagic, pussy Thinned
•Atrophy
Ecchymosis
Urticaria
•Lichenification
•Excoriation
Arrangement, or how grouped (Medium power)
Annular: tinea, erythema migrans, sarcoid, granuloma annulare, leprosy
Extensor: psoriasis
Flexor: atopic eczema
Follicular: Staph
Nummular (coin-shaped): eczema
Scalloped border: herpes
Accentuated, thickened, skin markings- from itching, rubbing
Pattern (Low power)
Acral: RMSF, erythema multiforme, 2o syphillis
Dermatomal:
Linear: contact d.
Reticular (net-like): livedo reticularis
Symmetric: Pityriasis rosea
Unilateral: zoster
zoster
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Charles Halasz, MD, FAAD, FACP
Papules
Neuropathic Ulceration
What’s the primary lesion?
Pearly penile papules
Vestibular Papillomatosis
Foreign body
Bylaite M, Ruzicka T. N Engl J Med 2007;357:691-691.
Chan C, Chiu H. N Engl J Med 2008;358:1495-1495.
Teelucksingh S, Naraynsingh V. N Engl J Med 2010;362:
ARS Image Challenge: Papulosquamous
Papulosquamous 1)
Psoriasis
2)
Lichen planus
3)
CTCL (mycosis fungoides)
4)
Tinea corporis & versicolor
5)
Pityriasis rosea
6)
Syphillis- the great imitator
Q: What is the diagnosis? 1. Lichen planus 2. Mycosis fungoides 3. Ostraceous psoriasis 4. Paraneoplastic pemphigoid 5. Staphylococcal scalded skin syndrome
Image Challenge
Psoriasis
Q: What is the diagnosis?
Answer: 3. Ostraceous psoriasis
Papulosquamous
These sharply demarcated, erythematous, well-defined limpet-like plaques covered with scales and crust are most consistent with ostraceous psoriasis.
Silvery scale
Read More: N Engl J Med 2010;362:155
Extensor
Elbows, Knees
Scalp, Gluteal cleft
Seroneg. Arthritis
Nail dystrophy
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Charles Halasz, MD, FAAD, FACP
Image Challenge: Papulosquamous
From: Systemic and Vascular Inflammation in Patients With Moderate to Severe Psoriasis as Measured by [18F]Fluorodeoxyglucose Positron Emission Tomography –Computed Tomography (FDG-PET/CT): A Pilot Study Arch Dermatol. 2011;147(9):1031-1039. doi:10.1001/archdermatol.2011.119 Nehal Patel
Figure 2. [18F]-Fluorodeoxyglucose positron emission tomography-computed tomographic (FDG-PET/CT) imaging. † Increased FDG uptake throughout the liver consistent with increased hepatic inflammation. ‡ Diffuse FDG uptake in the aortic and the femoral arterial tree, consistent with vascular inflammation. § Focal areas of FDG uptake in skin consistent with inflammation in thick plaques in lower extremities.
Date of download: 9/5/2012
37 yof: itchy polygonal purple papules on wrists & ankles x 1 mo What’s the dx? 1. Psoriasis 2. Secondary syphilis 3. Lichen planus 4. Erythema multiforme
Copyright © 2012 American Medical Association. All rights reserved.
Image Challenge: Papulosquamous 37 yof: itchy polygonal purple papules on wrists & ankles x 1 mo What’s the dx? 1. Psoriasis 2. Secondary syphilis 3. Lichen planus 4. Erythema multiforme
Papulosquamous Challenge
ARS: What is the next step?
Itchy eruption on trunk & proximal extremities for several weeks Started on right shoulder
ARS: What is the next step?
1. ✓ oral mucosae
2. ✓ for adenopathy
1. ✓ oral mucosae
3. ✓ VDRL, or RPR
2. ✓ for adenopathy
4. All the above
3. ✓ VDRL, or RPR
4. All the above
Pityriasis rosea
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Charles Halasz, MD, FAAD, FACP
ARS: What is the next step?
Papulosquamous Challenge
27 yo f 5 yr hx pink patches on trunk
1. Topical steroid
2. Antihistamine
New spots coming up
4. Skin biopsy
Scalp, elbows, knees not involved
ARS: What is the next step?
1. Topical steroid
2. Antihistamine
3. Mild soap & moisturizer
Papulosquamous Challenge 80 yo diabetic m with myeloma & prostate ca applying Elidel to nonpruritic rash
3. Mild soap & moisturizer
4. Skin biopsy
CTCL
ARS: What’s the next step?
ARS: What’s the next step?
1. KOH smear
1. KOH smear
2. ✓ toenails
2. ✓ toenails
3. Order topical or systemic antifungal 4. All of the above
3. Order topical or systemic antifungal
4. All of the above
Tinea corporis
4
Charles Halasz, MD, FAAD, FACP
Papulosquamous Rash Associated with Secondary Syphilis
Condylomata Lata of Secondary Syphilis
Acral involvement Badri T, Ben Jennet S. N Engl J Med 2011;364:71-71.
Oral Manifestations of Secondary Syphilis
Check peri-anal mucosae Begovac J, Lukas D. N Engl J Med 2005;352:708-708.
Secondary syphillis
Check oral mucosae Ulmer A, Fierlbeck G. N Engl J Med 2002;347:1677-1677.
ARS: Image Challenge
Blistering disorders & dermatitis: Poison ivy dermatitis
Contact dermatitis
Linear
Red
Itchy
Spongiotic dermatitis
Vesicles, bullae
Q: What is the diagnosis? 1. Contact dermatitis 2. Discoid lupus erythematosus 3. Melanoma 4. Nummular eczema 5. Tinea corporis
5
Charles Halasz, MD, FAAD, FACP
Image Challenge
Atopic dermatitis
Q: What is the diagnosis?
Answer:
4. Nummular eczema The image illustrates discoid (nummular) eczema in an infant. This pattern of eczema is frequently associated with atopic dermatitis and is often confused with ringworm infection.
Flexures Face, neck
Intertrigo (dermatitis in skin fold)
contact or irritant
Inverse psoriasis
Candida
atopic
Scaley dermatitis
Secondary Staph infect.
Palmar
Also spongiotic
Dorsum
= Itchy + Red
Hand dermatitis
Eczema= dermatitis
26 yo m Itchy scaley red patches on face & scalp “long time” Comes & goes Patient otherwise healthy, no fever, or arthralgias
Irritant bacterial overgrowth
What’s the next step?
1. Check ANA
2. Check ESR
3. Check RF
4. Prescribe topical antifungal, or mild topical steroid
6
Charles Halasz, MD, FAAD, FACP
What’s the next step?
1. Check ANA
2. Check ESR
3. Check RF
Blistering disorders: Herpes Herpetiform
4. Prescribe topical antifungal, or mild topical steroid
simplex
Zosteriform
shingles
Seborrheic dermatitis
Blistering disorders Pemphigoid vs. Pemphigus
Autoimmune dermatoses
Tense bullae
Anti-basement membrane Ab’s Pemphigoid
Acute SLE
Flaccid bullae
40 yof red papules & pustules on face x 45 mos. What’s the dx?
butterfly rash
+ANA
fever, arthritis
Anti-epidermal desmosomal Ab’s Pemphigus
Autoimmune dermatoses SLE?
Autoimmune dermatoses SLE?
40 yof red papules & pustules on face x 45 mos. What’s the dx?
1. Acne vulgaris
2. Acne rosacea
2. Acne rosacea
3. Perioral dermatitis
1. Acne vulgaris 3. Perioral dermatitis
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Charles Halasz, MD, FAAD, FACP
Image Challenge
Image Challenge Q: What laboratory evaluation is most likely to be abnormal in this 10-year-old patient who also had discrete facial erythema?
Answer: 2. Creatine kinase Multiple hyperkeratotic, erythematous, flat papules with central atrophy are notable on the dorsum of the metacarpophalangeal and interphalangeal joints, consistent with Gottron's papules. Though muscle-strength examination was normal, laboratory evaluation revealed an elevated level of creatine kinase suggestive of dermatomyositis. Q: What laboratory evaluation is most likely to be abnormal in this 10-year-old patient who also had discrete facial erythema?
Read More: N Engl J Med 2010;363:e17
1. CD4 count 2. Creatine kinase 3. Rheumatoid factor 4. Thyrotropin 5. Zinc
Acne
Peds
Bad foods:
Skim milk
Sugars, carbs
Good foods:
Cholocate
Fish
Measles
Rosacea from steroid inhaler
Morbilliform = maculopapular
An African child with severe mesles on day 10 of the disease.
Cough, coryza, conjunctivities Fever, Koplik spots
Measles Outbreak Hits UK
Mulholland EK et al. N Engl J Med 2012;366:1755-1757.
Qvar
8
Charles Halasz, MD, FAAD, FACP
Image Challenge
Hand-foot-mouth
Coxsackie A16, 6
EV-71
Q: This 4-year-old boy presented with a 5-day history of mild fever and malaise and a 3-day history of rash. What is the diagnosis? 1. Erythema infectiosum (5th disease, or Parvovirus B19) 2. Hand, foot, and mouth disease 3. Kawasaki disease 4. Measles 5. Pityriasis rosea
Image Challenge
Hand foot mouth in adult
Q: This 4-year-old boy presented with a 5-day history of mild fever and malaise and a 3-day history of rash. What is the diagnosis?
Answer: 2. Hand, foot, and mouth disease This clinical picture is highly characteristic of hand, foot, and mouth disease, a self-limiting viral disease that is usually caused by coxsackievirus A16 or enterovirus 71. Typical skin lesions are elliptical vesicles surrounded by an erythematous halo. The patient was treated supportively at home without medication and recovered.
HFM: Coxsackie A16, A6, Enterovirus 71
Erythema infectiosum
Parvovirus B19
Slapped cheek
Arthalgias in adults
Hydrops fetalis
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Charles Halasz, MD, FAAD, FACP
ARS: Image Challenge
Scarlet fever
Strep
Pastia’s lines
-vesicles, -pustules -papules
Q: What is the diagnosis? 1. Bullous pemphigoid 2. Dermatitis herpetiformis 3. Impetigo 4. Syphilis 5. Varicella
Image Challenge Q: What is the diagnosis?
Answer:
Additional common disorders in children and adults
5. Varicella This polymorphic rash with vesicles, pustules, and crusty lesions is most consistent with varicella infection. Read More: N Engl J Med 2010;362:1227
PUPPP Polymorphic eruption of pregnancy
Pruritic urticarial papules & plaques of pregnancy
Starts in striae
Itchy dermatitis
3rd trimester
Primigravida
Alopecia areata
Non-scarring
Common
Usually grows back
Check TFT’s
10
Charles Halasz, MD, FAAD, FACP
Vitiligo
Depigmented patches: vitiligo
Inflammatory
Periorificial, over boney prominences Thyroid & autoimmune associations Depigmentation w/ c-kit tyrosinase kinase inhibitors like imatinib
Erythema nodosum
Painful subcutaneous nodules on shins Panniculitis Sarcoid, IBD, Granulomatous infections: TB, Strep, coccidio Drugs: BCP, sulfa
Erythema multiforme Target lesions Violaceous center with a pink halo, separated by a pale ring
Urticaria
Transient wheals (hrs.)
Halo of pallor a clue
Often resolve in 2-4 wks
Triggers:
foods (shellfish, nuts, berries)
Prescription med’s
OTC (ASA & NSAID’s)
Autoimmune (anti-TPO, TG Ab’s
ARS: Image Challenge
Usually herpes or Mycoplasma pneumonia
Q: Serum levels of which one of the following laboratory tests would be expected to be most abnormal in this patient? 1. 17-hydroxyprogesterone 2. Angiotensin-converting enzyme 3. Anti-tissue transglutaminase antibody 4. Prolactin 5. Vitamin B6
Acral
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Charles Halasz, MD, FAAD, FACP
Image Challenge Q: Serum levels of which one of the following laboratory tests would be expected to be most abnormal in this patient?
Answer:
Infections
2. Angiotensin-converting enzyme Lupus pernio is a manifestation of sarcoidosis that involves the nasal bridge and cheeks. Serum levels of the angiotensin-converting enzyme are elevated in the majority of patients with untreated sarcoidosis.
Bacterial
Impetigo
Honey crusts
Staph or strep
Lyme d.
> 5 cm
Erythema migrans
Kerion Celsi
Infections
Pustules
Fungal Enlarged node
Proudfoot LE, Morris-Jones R. N Engl J Med 2012;366:1142-1142.
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Charles Halasz, MD, FAAD, FACP
Tinea capitis- nuchal region
Tinea faciei
Image Challenge
Infections
Viral
Q: What is the diagnosis? 1. Dermatitis herpetiformis 2. Impetigo 3. Measles 4. Secondary syphilis 5. Varicella
Image Challenge
Herpes Zoster (Unilateral & Painful)
Q: What is the diagnosis?
Answer: 5. Varicella This unvaccinated adolescent had fever and a classic, extensive varicella rash characterized by pruritic vesicular lesions with erythematous bases.
Shingles vaccine! Wills CP, River G. N Engl J Med 2010;362:1128-1128.
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Charles Halasz, MD, FAAD, FACP
Bedbug Bites Cimex lectularius
Infections
Parasites
Stucki A, Ludwig R. N Engl J Med 2008;359:1047-1047.
Image Challenge
Image Challenge Q: What is the diagnosis?
Answer: 4. Scabies The image shows a typical, specific, scabious, linear burrow with a tiny vesicle at the distal end. Such an obvious lesion is rarely seen, because it is usually obscured by eczema, impetigo, or both. Q: What is the diagnosis? 1. Eczema 2. Herpetic whitlow 3. Impetigo 4. Scabies 5. Tinea pedis
Image Challenge
Image Challenge Q: This patient had multiple myeloma. What diagnosis is suggested from this image of the axilla?
Answer: 2. Crusted scabies The thick, leathery, gray skin was intensely pruritic. A specimen obtained showed scabies mites and eggs, confirming the diagnosis of crusted scabies. Patients with crusted scabies have a very high burden of mites and are extremely infectious. Q: This patient had multiple myeloma. What diagnosis is suggested from this image of the axilla? 1. Acanthosis nigricans 2. Crusted scabies 3. Erysipelas 4. Malacoplakia 5. Psoriasis
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Charles Halasz, MD, FAAD, FACP
TK inhibitor- acneform rash Iressa (gefitinib) for lung ca Oncology
New drug rashes
TK inhibitor- paronychia Tykerb (lapatinib) for breast ca Neoplasms
Molecular Pathogenesis of Basal-Cell Carcinoma
Basal cell ca features
Pink
Pearly border
Waxy
Rodent Ulcer
Sonic hedgehog (SHH) pathway Blocked by new drug: vismodegib (Erivedge inhibits SMO)
suppresor
May be pigmented in darker skin types
Rubin AI et al. N Engl J Med 2005;353:2262-2269.
15
Charles Halasz, MD, FAAD, FACP
Image Challenge
Image Challenge Q: What is the diagnosis?
Answer: 5. Squamous-cell carcinoma The lesion is exophytic and hyperkeratotic with central ulceration, features that are most typical of a squamous-cell carcinoma.
Q: What is the diagnosis? 1. Basal-cell carcinoma 2. Granuloma fissuratum 3. Melanoma 4. Seborrheic keratosis 5. Squamous-cell carcinoma
“Easy” Pigmented Neoplasms
Melanocytic nevi
Seborrheic keratoses
stuck-on
tan
uniform
A 26-Year-Old Man with Atypical Nevi
Common:
symmetrical
uniform
defined borders
Dysplastic:
larger (> 6 mm)
variable pigmentation
Fading border
Metastatic melanoma
Naeyaert J and Brochez L. N Engl J Med 2003;349:2233-2240
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Charles Halasz, MD, FAAD, FACP
Melanoma risk factors
Zelboraf (vemurafenib)
BRAF is a protein kinase in the RAS-RAF signaling mitogenactivated protein kinase pathway
large number nevi + fam. hx fair skin blistering sunburns in childhood
For BRAF mutations at position V600 4 month mproved progression-free survival vs dacarbazine
Signature nevi
ABCDE’s of melanoma Brown
Asymmetry
Border irregularity
Color variegation
Pink
Irregular, jagged, fading
Diameter > 6 mm (pencil eraser)
Evolving: changing size
Ugly duckling sign
Suh K-I, Bolognia JL: Signature nevi.JAAD:60:508-514,2009
Signature nevi
Signature nevi
Eclipse & Cockade/Cockarde (rim & flying saucer)
Halo nevus
Fried egg pattern
Perifollicular hypopigmentation Suh K-I, Bolognia JL: Signature nevi.JAAD:60:508-514,2009
Suh K-I, Bolognia JL: Signature nevi.JAAD:60:508-514,2009
17
Charles Halasz, MD, FAAD, FACP
Dermoscopy
Signature nevi
Dermatoscope
Cheetah
Nl nevus- reticular pattern
Suh K-I, Bolognia JL: Signature nevi.JAAD:60:508-514,2009 http://www.dermnetnz.org/lesions/moles.html
Necrobiosis Lipoidica Diabeticorum
Atrophic nontender ulcerating plaques
Metabolic Endocrine/ Nutritional
Wake N, Fang JC. N Engl J Med 2006;355:
Pseudospectacles in Familial Hypercholesterolemia TUBEROUS XANTHOMAS LDL
Girish M, Gupta MD. N Engl J Med 2005;352:2424-2424.
Eruptive Xanthomas Associated with Hypertriglyceridemia and New-Onset Diabetes Mellitus
Nayak KR, Daly RG. N Engl J Med 2004;350:1235-1235.
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Charles Halasz, MD, FAAD, FACP
Scurvy
Dermopathy of Graves' Disease
Leggett J, Convery R. N Engl J Med 2001;345:1818-1818.
Cheng S, Liu C. N Engl J Med 2005;352:918-918.
Image Challenge
Image Challenge Q: What is the diagnosis?
Answer: 2. Gout The patient's serum uric acid level was elevated. Multiple bright-yellow needle-shaped crystals, consistent with gout, were visible in a skin scraping. Read More: N Engl J Med 2002;346:1714
Q: What is the diagnosis? 1. Digital pilonidal sinus 2. Gout 3. Paronychia 4. Scabies 5. Xanthomata
Calcinosis Cutis in Systemic Sclerosis
Pigmented lesion case
76 yof dark irregular nevus chest ?duration Noted by internist on routine physical
Makol A, Ytterberg SR. N Engl J Med 2011;364:2245-2245.
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Charles Halasz, MD, FAAD, FACP
Recommended references
What is next step?
1. Recheck patient in six mos.
2. Tell patient not to worry about it.
3. Tell patient to wear sunscreen. 4. Arrange for skin biopsy
Allen, HB: Dermatology Terminology, New York, Springer, 2010. Elewski BE, et al: Differential Diagnosis in Dermatology, Philadelphia, Mosby, 2005 Goodheart HP: Photoguide to Common Skin Disorders, New York, Wolters KluwerLippincott Williams & Wilkins, 2009 Ferri, FF: Fast Facts in Dermatology, Saunders, Philadelphia, 2011
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