July 29, 2014 Grand Rounds

Case # 1. A 19 year old man with diffuse macular rash, bilateral red eyes, fever, headache, abdominal pain, diarrhea, elevated liver enzymes and leukocytosis secondary to acute leptospirosis

 http://0101.nccdn.net/1_5/317/170/030/leptospira.jpg

1. Remember that not all patients with leptospirosis present with the deadliest form of the infection called Weil's syndrome (i.e. profound jaundice with total bilirubin out of proportion to the liver enzyme elevation, renal failure, pulmonary hemorrhage, hemorrhagic diathesis). Majority of patients present with the anicteric form of the disease.

2. There are usually two phases of anicteric leptospirosis (although, an overlap between the two commonly occurs):

     A. Septicemic phase.  Characterized by abrupt onset of fever, headache, chills, myalgia, conjunctival suffusion, nausea, vomiting, diarrhea, and rash. Lasts for 5-7 days.

• Conjunctival suffusion. Manifests as bilateral conjunctivitis without eye discharge (eyes appear "wet"). Although not specific for leptospirosis, its presence in a patient with nonspecific symptoms should raise suspicion for leptospirosis. In fact, the World Health Organization (WHO) includes this in its scoring system for diagnosing leptospirosis (read here).
• Myalgia is also a predominant symptom. Calf tenderness is most often cited in the literature and is also included in the WHO scoring system.
• Rash occurs in 8-12% of patients. It is usually transient. Can appear as urticarial, macular, maculopapular, or purpuric.

     B. Immune phase. Characterized  by aseptic meningitis in 80% of patients. Uveitis, renal insufficiency, respiratory symptoms, and hepatosplenomegaly may occur.

3. The icteric form of leptospirosis (Weil's syndrome) is not usually biphasic. It usually manifests with persistent fever and abrupt onset of jaundice and profound renal failure.

4. The diagnosis rests on serologic testing. The CDC defines a positive serology as a titer of >/= 1:200 by the microscopic agglutination test (MAT). At Barnes-Jewish Hospital, the samples are sent to the Mayo Clinic which uses indirect hemagglutination assay (IHA) for diagnosing leptospirosis. For this test, the cut-off of a positive result is a titer of at least 1:50. A single titer of >/= 1:100 is suggestive of active or recent leptospirosis. The IHA is 100% sensitive and 97% specific for leptospirosis compared with the MAT.

Case # 2. A 3 year old girl coming from a trip to Cameroon, presents with fever, abdominal pain, vomiting, and diarrhea secondary to non-typhoidal Salmonella infection

 http://images.gizmag.com/hero/salmonella.png

1. Non-typhoidal Salmonella is the most common cause of bacteremia in Africa according to one study.

2. Non-typhoidal Salmonella infection is usually self-limited. Treatment is required for patients with severe symptoms (e.g high fever, prolonged diarrhea needing hospitalization), for immunocompromised patients (e.g. AIDS, organ transplant, use of steroids or other immunosuppressive agents, sickle cell or other hemoglobinopathies), patients > 50 years, and those with prosthesis or severe valvular heart disease.

Case # 3. A 24 year old man who presented with a 1 month history of diffuse erythrodermic scaly rash, fever, weight loss, night sweats, arthralgia, leukocytosis, and diffuse lymphadenopathy mistaken for an infectious process and Still's disease; an excision biopsy of an enlarged inguinal lymph node revealed classic Hodgkin lymphoma

 http://hematopathology.stanford.edu/images/HP-Home-Image.jpg

1. In a patient with symptoms consistent with lymphoma and unrevealing infectious disease work-up, always pursue excisional lymph node biopsy. Fine needle aspiration biopsy is inferior to excisional biopsy for diagnosing lymphoma. Lymphoma is a great mimic! There are many cases reported in the literature of occult lymphoma diagnosed only with several excisional lymph node biopsies.

ID GRAND ROUNDS: July 22, 2014

Case #1. A 20-day old girl with fever, irritation, elevated liver enzymes, and tachycardia secondary to human parechovirus infection.

Taken from http://jvi.asm.org/content/85/3/F1.medium.gif

1. Human parechovirus (HPeV) is genetically and phenotypically similar to enterovirus. Its clinical presentation is also indistinguishable from enterovirus. However, it is not detected by routine enterovirus PCR testing. In a child with enterovirus-like clinical disease but the enterovirus PCR is negative, suspect HPeV infection.

2. It commonly affects children < 2 years (only a few case reports of infection in children > 10 years). Most commonly manifests as meningoencephalitis, sepsis, hepatitis, and mycocarditis.

3. Treatment is supportive. Pleconaril does not have activity against HPeV. IVIG, which has been shown to be beneficial in some cases of enterovirus infection (e.g. myocarditis), has not been studied in HPeV infection. Pocapovir is a new agent against HPeV currently being studied.

Case # 2. A 64 year old woman from New Mexico, with end-stage liver disease, s/p orthotopic liver transplantation 2 months prior to admission, who presents with fever, chills, malaise, nausea, and vomiting; found to have pancytopenia secondary to Ehrlichia infection

Taken from  https://ahdc.vet.cornell.edu/sects/ClinPath/modules/CaseMonth/images/June2012/Figure%204.jpg

1. In a case series of 15 solid organ transplant recipients with ehrlichiosis, transplant patients experienced less rash and had lower liver enzymes compared to immunocompetent patients. However, they had more leucopenia and renal dysfunction. There were no deaths in this case series because doxycycline was administered within 48 hours of presentation. Read more on this here.

Case # 3. A 70 year old woman with leukemia, s/p stem cell transplantation 7 months prior to admission, who presents with refractory CMV disease and viremia secondary to multi-drug resistance

1. Ganciclovir, in order to be active against CMV, has to undergo several steps of phosphorylation by enzymes produced by CMV. Let's review CMV antiviral resistance.

    A. UL97 phosphotransferase mutation (inhibits initial step of ganciclovir phosphorylation); it is the most commonly seen CMV mutation; confers resistance to ganciclovir

    B. UL54 DNA polymerase mutation (inhibits succeeding steps of ganciclovir phosphorylation); it is less commonly seen compared to UL97 mutation; confers various combination of resistance to not only ganciclovir but also to foscarnet, and/or cidovir.

   C. The presence of both UL97 and UL54 mutations usually confers high-level resistance to ganciclovir. Isolated UL54 mutation (in the absence of UL97 mutation) is very uncommon.

2. It is important to monitor CMV viremia during treatment with ganciclovir. You should expect a twofold drop in viremia per day or at least a tenfold drop in 1 week. Significant log drop should be expected in 2 weeks. CMV viremia not responding to ganciclovir should be checked for UL97 and UL54 genotypic mutations.

3. Treatment options for drug-resistant CMV (adapted from Deepali Kumar's AST Handbook of Transplant Infections, 2011):

   A. Reduce immunosuppression. Sirolimus maybe used to replace other calcineurin inhibitors as it has been shown to have some degree of activity against CMV.

  B. CMV with only UL97 mutation. For low-level mutation, can use high dose ganciclovir. For high-level resistance, can use foscarnet alone or in combination with ganciclovir.

  C. CMV with UL54 mutation (again, this is usually associated with UL97 mutation). Can use foscarnet +/- CMV immunoglobulin. The other agent that can be used include CMX-001, leflunomide, artesunate, and maribavir.

4. Letermovir is a new drug against CMV infection (read here) currently being studied in phase II trials (for CMV prophylaxis, read here). It is a promising agent since it has a novel mechanism of action (inhibits CMV pUL56 gene thereby disrupting the viral terminase complex necessary for viral replication) and has low toxicity, good oral bioavailability, and low potential for drug-drug interactions.

July 15, 2014 Grand Rounds

Case 1: A 70 year old immunocompetent woman presenting with 4 weeks of generalized body weakness and gram positive bacilli that grew on 4 culture bottles on admission.

Taken from: http://www.easynotecards.com/uploads/977/95/69c3b13a_13a8788d737__8000_00000081.jpg

1. The gram positive bacilli in this case was later identified as Bacillus sp. (not anthracis). The same blood cultures also showed growth of methicillin-susceptible Staphylococcus aureus and Staphylococcus hominis.

2. Let's review the different clinically important gram positive bacilli (look here). Our laboratory routinely reports branching filamentous organisms (BFO). It is important to note that some gram positive bacilli are also AFB positive. As you can see from the diagram, the clinically significant gram positive bacilli are diverse and are responsible for a wide spectrum of illnesses.

3. Can Bacillus (not athracis) cause clinically significant infection? The answer is yes. Bacillus cereus is known to cause serious endophthalmitis. It has also been reported as a cause of endocarditis (see here, kuddos to our very own Ben Thomas). Bacillus bacteremia have been reported among intravenous drug users, preterm neonates, and those with long-term indwelling catheters.

Case 2: A 14 year old boy presenting with acute frontal head swelling and pain, rhinorrhea, cough, fever, and post-nasal discharge secondary to Streptococcus angionosus Pott's puffy tumor.

Taken from: http://www.asnr2.org/neurographics/8/3/68/What%27s%20in%20a%20Name_files/slide0029_image128.jpg

1. Pott's puffy tumor refers to frontal bone subperiosteal abscess associated with frontal bone osteomyelitis. It occurs as a complication of frontal sinusitis or trauma. Most patients with Pott's puffy tumor are immunocompetent. All patients present with frontal head swelling. Complications include intracranial extension (80%) and orbital cellulitis (30%).

2. Common etiologic agents for Pott's puffy tumor include Streptococcus (pneumoniae, angionosus, Group A), Staphylococcus (aureus usually), and anaerobes (Fusobacterium, Propionebacterium). Cultures can be polymicrobial or sterile as well.

3. Streptococcus angionosus group (once known as Streptococcus milleri) include Streptococcus angionosus, Streptococcus intermedius, and Streptococcus constellatus. They have a characteristic butterscotch smell on culture media. They are associated with abscess formation.

Case 3: This is a management case

A 22 year old man with paraplegia presenting with sepsis secondary to osteomyelitis and soft tissue infection from multi-drug resistant organisms (vancomycin-resistant Enterococcus; methicillin-susceptible Staphylococcus aureus; Pseudomonas aeruginosa susceptible only to colistin, amikacin, gentamicin, and tobramycin; and Candida lusitaniae)

1. The main point that was emphasized is that, management of chronic osteomyelitis in paraplegic patients is very challenging and one that requires a multidisciplinary approach. Antibiotics alone will not be sufficient.

July 8, 2014 Grand Rounds

Case # 1. A 24 year old man from Arkansas with no significant past medical history who presented with 9 days of fever, nausea, vomiting, diarrhea, abdominal pain, cholecystitis, and elevated liver enzymes secondary to acute histoplasmosis

Taken from http://wwwnc.cdc.gov/eid/article/17/9/10-1987-f1

1. Gastrointestinal (GI) histoplasmosis as a presenting symptoms of acute histoplasmosis is rare but is actually found in 70% of disseminated histoplasmosis on autopsy. It should be considered in the differential diagnosis of a patient with acute progressive gastroenteritis. The geographic distribution of histoplasmosis cases in the US is shown in the diagram.

2. Most common presentation of GI histoplasmosis include mucosal ulcers and abdominal lymphadenopathy. It can also present as ileitis that mimic inflammatory bowel disease (can add this in the differential diagnoses of infectious etiologies that cause ileitis such as tuberculosis, amoebiasis, Yersinia/Salmonella infection, and actinomycosis among others).

3. A negative Histoplasma antigen test does not rule out disseminated histoplasmosis. The urine Histoplasma antigen test is more informative in the immunocompromised host compared to the immunocompetent patient (read here).

4. Histoplasma antibody testing is more informative in immunocompetent hosts compared to immunocompromised patients where it can be falsely negative.

Case 2. A 2 week old preterm and small for gestational age infant with persistent methicillin-susceptible Staphylococcus aureus bacteremia

1. An aggressive search for any focus of infection is a priority in patients with persistent staphylococcal bacteremia. Have a low threshold for draining localized areas of fluid collections.

Case 3. A 59 year old woman with alcoholic cirrhosis, CMV colitis, recurrent profuse diarrhea,  respiratory failure, and pancytopenia who was found to have Pneumocycstis jirovecii pneumonia (PCP)

Taken from http://bestpractice.bmj.com/best-practice/images/bp/en-gb/19-4_default.jpg

1. Cirrhosis and severe malnutrition are enough to make one immunocompromised. Infection with opportunistic infections secondary to CMV and PCP have been reported in cirrhotic and malnourished patients. Include PCP in the differential diagnoses of refractory pneumonia even in non-AIDS and non-translant patients.

2. The presence of cystic lung disease and pneumatoceles, although not specific for any etiologic agent for pneumonia, is an  underrecognized radiolographic manifestation of PCP.

July 1, 2014 Grand Rounds

Case 1. 60 year old man with acute onset fever, confusion, renal failure, progressive pancytopenia, respiratory distress, and septic shock secondary to Heartland virus infection.

 (Picture taken from: http://upload.wikimedia.org/wikipedia/commons/2/29/Amblyomma_americanum_tick.jpg)

1. Heartland virus is a newly discovered phlebovirus (family Bunyaviridae) first described in 2009 in a farmer from northwestern Missouri who presented with fever, thrombocytopenia, and leucopenia. It is also transmitted by the Lone Star tick (Amblyomma americanum), the main vector of ehrlichiosis, tularemia, and Southern Tick Associated Rash Illness (STARI).

2. A patient who presents with fever, leucopenia, thrombocytopenia, and transaminitis but has repeatedly negative tests for Ehrlichia should be tested for Heartland virus infection (contact Dr. George Turabelidze at george.turabelidze@health.mo.gov of the Missouri Health Department). Heartland virus is diagnosed by a positive Heartland virus RNA or a fourfold rise of antibody titers between acute and convalescent samples.

3. The Heartland virus will not respond to doxycycline. No therapy is available.

4. Heartland virus infection can be lethal. Our case represents the 3rd mortality in the US (first mortality was from Tennessee, second mortality was from Oklahoma).

5. Heartland virus closely resembles the severe fever with thrombocytopenia syndrome virus recently described from China in 2007.

Case 2: A 15 year old male with acute abdominal pain, fever, and hypotension secondary to Campylobacter jejuni infection

1.This patient eventually developed diarrhea during his hospital stay. Patients with fever and diarrhea should always have a stool culture to rule out invasive bacterial infection secondary to Salmonella, Shigella, and Campylobacter. Other causes of fever and diarrhea include rotavirus, norovirus and Clostridium difficile infection.

2. Campylobacter infection can be associated with reactive arthritis (3% of cases), Guillain-Barre syndrome (<1% of cases), and bacteremia (<1% of cases). Reactive arthritis and Guillain-Barre syndrome usually manifest 1-2 weeks (occasionally several weeks) after onset of diarrhea.

Case 3. This is a management case. 

Patient with acute myelogenous leukemia who presents with multi-drug resistant Enterococcus infection (vancomycin resistant, susceptible only to linezolid and daptomycin), Candida glabrata (susceptible only to fluctosine, no susceptibility break point for amphotericin), and Stenotrophomonas maltophilia (susceptible only to minocycline).

1. Patient was treated with minocyline, amphotericin, and linezolid. Amphotericin-resistant Candida is exceedingly rare (except for Candida lusitaniae).