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.