EUH Dressler Conference: What are HIV elite controllers and HIV long-term nonprogressors?

The Bottom Line: Long-term nonprogressors (LTNP) account for 1-5% of HIV-infected individuals characterized by documented infection for more than 7-10 years, a stable CD4+ T cell count over 500/mm3 and low viremia in the absence of antiretroviral treatment. They are able to remain clinically health for more than 10 years in the absence of ART (Lugue et al, 2014).

Elite controllers (EC) are a small number of untreated HIV-1-postivite patients (approx. 1 in 300 infected people) who have undetectable viral loads in commercial PCR assays. Most definitions of EC require HIV-1 replication to be below the level of detection on at least three occasions during a 12-month period. Epidemiological studies have shown that the spontaneous control of HIV-1 replications can last more than 30 years, although loss of immune control is observed in some individuals (Walker and Yu, 2013).

References: Luque MC, Santos CC, Mairena EC, Wilkinson P, et al. Gene expression profile in long-term non progressor HIV infected patients: In search of potential resistance factors. Mol Immunol. 2014 Nov;62(1):63-70. doi:10.1016/j.molimm.2014.05.016.

Walker BD and Yu XG. Unravelling the mechanisms of durable control of HIV-1. Nat Rev Immunol. 2013 Jul;13(7):487-98. doi:10.1038/nri3478.

Summary: From “Genetics of HIV” [chapter 84] in Clinical Genomics: Practical Applications in Adult Patient Care (via AccessMedicine):

Long-term Nonprogressors: A significant number of studies have evaluated this population and among this group, the CCR5 mutations are most well characterized in terms of their ability to prevent HIV acquisition and delay AIDS progression through impaired HIV entry into cells. The Δ32 variant is the most prevalent mutation in this population and has been demonstrated to have prevalence in these individuals of 30%. It is on the basis of this understanding that the entry inhibitor class of antiretrovirals has been developed. By contrast, some mutations that interact or inhibit or downregulate CCR5 are associated with accelerated progression to AIDS. HLA typing subsets have also been implicated in this group, specifically related to individuals with the HLA-B*5705 and HLA-B*2705 who demonstrate substantially longer HIV course before progression to AIDS. In small sample sizes greater than 80% of LTNPs posses these alleles compared with approximately 10% of chronic progressors. An additional class of LTNPs has been identified who suppress viral progression on the basis of antibodies to HIV surface proteins including gp120 and gp41.

Elite Controllers/Suppressors: The APOBEC group of genes is important in the study of long-term nonprogressors and elite controllers, as mutations in APOBEC3G have been shown to relate to delayed AIDS progression. This group of proteins is made up of cytidine deaminases that catalyze the deamination of cytosine to uracil in the nascent viral DNA causing mutations that are lethal for the virus. HLA complex P5 (HCP5) has been implicated as associated with 1% of HIV patients who demonstrate slowed progression of disease. The HCP5 gene is located on chromosome 6, and the associated variant is known to be in high linkage disequilibrium with the HLA allele B*5701. HLA-B*57 and B*58 are associated with low viral load that is thought to boost cytotoxic T-lymphocyte activity. KIR3DS1 or KIR3DL1 allele and HLA class I alleles that encode an isoleucine at position 80 (HLA-Bw480I) had the slowest rates of progression to AIDS.

For additional reading: Madhavi V, Wines BD, Amin J, Emery S, et al. HIV Env- and Vpu-specific antibody-dependent cellular cytotoxicity responses associated with elite control of HIV.  J Virol. 2017 Aug 24; 91(18): pii:e00700-17. doi:10.1128/JVI.0700-17.

Pereyra F, Addo MM, Kaufman DE, Liu Y, et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis. 2008 Feb 15;197(4):563-71. doi:10.1086/526786.


EUH Dressler Conference: What is the most appropriate timeframe for administering IV fluids to patients with sepsis or septic shock?

The Bottom Line: The Surviving Sepsis Guideline states 30cc/kg within first 3 hours for sepsis or shock, as defined by new Sepsis definitions (Singer et al, 2016).

References: Leisman D, Wie B, Doerfler M, Bianculli A, et al. Association of fluid resuscitation initiation within 30 minutes of severe sepsis and septic shock recognition with reduced mortality and length of stay. Annals of Emergency Medicine. 2016 Sep;68(3):298-311. doi:10.1016./j.annemergmed.2016.02.044.

Seymour CW, Gesten F, Prescott HC, Friedrich ME, et al. Time to treatment and mortality during mandated emergency care for sepsis. NEJM. 2017 Jun 8;376(23):2235-2244. doi:10.1056/NEJMoa1703058.

Singer, M, Deutschman CS, Seymour CW. The Third International Consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287.

Summary: While some of the recent data on timing of IVFs (Seymour et al, 2017) suggest that completion of the initial IVF bolus within the first 3 hours is not associated with mortality improvement compared to completion of the initial IVF bolus beyond 3 hours, other data (Leisman et al, 2016) suggest that the earlier initiation of IVFs (within the first 30 minutes) is associated with improved mortality and reduced hospital length of stay.

The current guidelines, as listed in DynaMed Plus, call for fluids within 3 hours.

EUH Dressler Conference: How a differential diagnosis tool held up to Emory minds.

The Bottom Line: Isabel, a differential diagnosis generator, was used by a clinical informationist as residents and faculty talked through a case study. The ultimate diagnosis, Hodgkin’s lymphoma, was listed in Isabel’s #2 spot of possible diagnoses (see screenshot below). Emory residents were able to specify the diagnosis as nodular sclerosis Hodgkin’s lymphoma. It must be noted that the residents and faculty were not aware of Isabel’s participation until after they reached the final diagnosis.

Screen Shot 2017-04-13 at 2.11.58 PM

Summary: Isabel is a differential diagnosis support tool designed to help physicians construct or broaden their differential. In this case study, the clinical features presented as the chief complaint were entered and a list of possible diagnoses was generated. As the case progressed, additional clinical features were added when appropriate.

To access Isabel, go to the WHSC Library’s Clinical Resources page. Isabel is listed under “Point of Care.” Tell us what you think of Isabel! Click here to provide feedback on this tool.

What information can I learn from looking at an ROC curve?

Receiver operating characteristic curves graph the true positive rate against the false positive rate for the possible cutpoints of a diagnostic test.  Use ROC curve to…

  1. Compare accuracy of test at different cutpoints.  Curve close to left and upper border of ROC graph=more accurate test.  Curve closer to 45° diagonal of ROC graph=less accurate test.
  2. Compare the accuracy of two tests by comparing the two curves.
  3. VIsualize the trade offs of sens and spec of various cutpoints of a test (i.e., any ↑ in sens will be accompanied by a ↓ in spec.)
  4. The slope of the tangent line at a cutpoint gives the likelihood ratio for that test value.

See example of ROC curve In User’s Guide to the Medical Literature.

Review of pulmonary hypertension

Holger, M. Nef.  Pulmonary Hypertension: Updated classification and management of pulmonary hypertension Heart 2010;96:552-559 doi:10.1136/hrt.2008.156299

Pulmonary arterial hypertension is characterised by a progressive increase of pulmonary pressure and resistance leading to right heart failure.

Pulmonary hypertension is categorised into five main groups: group 1, PAH; group 2, PH associated with left sided heart diseases; group 3, PH
associated with lung disease and/or hypoxaemia; group 4,PHdue to chronic thrombotic and/or embolic disease; and group 5, miscellaneous

Without treatment, the prognosis for patients is poor with a reported median life expectancy of 2.8 years from the diagnosis.

Table 1 New thresholds of pulmonary hypertension determined at the 4th World Symposium held in Dana Point 2008  page 553

Figure 1 Updated clinical classification of pulmonary hypertension according to the proposals of the 4th World Symposium on Pulmonary hypertension held in Dana Point 2008.  page 556

Figure 5 Treatment algorithm of pulmonary arterial hypertension (PAH) following the recommendation of the 4th World Symposium on PAH held in Dana Point 2008  page 557

*Original posting date 04/22/10. Reposted by kbradford

Diabetic ketoacidosis (DKA) & hyperglycemic hyperosmolar non-ketotic syndrome (HHNK)

Umpierrez GEMD, Khajavi MMD, Kitabchi AEPMD. Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Nonketotic Syndrome. American Journal of the Medical Sciences. 1996;311(5):225-233.

Umpierrez GE, Smiley D, Kitabchi AE. Narrative review: ketosis-prone type 2 diabetes mellitus. Ann Intern Med. 2006 Mar 7;144(5):350-7.

Palmer BF. Approach to fluid and electrolyte disorders and acid-base problems. Primary Care: Clinics in Office Practice. 2008;35(2):195-213.

Seifter JL. Acid Base Disorders In: Goldman-Cecil Medicine, 25th edition. Saunders, 2016.

Skorecki K, Ausiello D. Disorders of Sodium and Water Homeostasis. In: Goldman-Cecil Medicine, 25th edition. Saunders, 2016.
Includes discussion of hypovolemia, euvolemia, and hypervolemia.