Blog Mon, 24 Apr 2017 10:21:54 -0400 Joomla! - Open Source Content Management en-gb Foodborne Illnesses in 2016

Foodborne illness remains a substantial public health concern in the United States. FoodNet is a collaboration among CDC, 10 state health departments, the U.S. Department of Agriculture’s Food Safety and Inspection Service, and the Food and Drug Administration. FoodNet conducts active, population-based surveillance for laboratory-diagnosed infections caused by nine enteric pathogens including; Campylobacter, Cryptosporidium, Cyclospora, Listeria, Salmonella, Shiga toxin-producing Escherichia coli (STEC), Shigella, Vibrio, and Yersinia. Surveillance covers 10 sites representing approximately 15% of the U.S. population.

During 2016, FoodNet identified 24,029 cases, 5,512 hospitalizations, and 98 deaths attributed to foodborne illness. Infections were detected by culture or culture-independent diagnostic tests (CIDT). Parasitic infections were detected in clinical specimens by direct fluorescent antibody test, polymerase chain reaction, enzyme immunoassay, or light microscopy. CIDTs included tests for bacterial antigens, nucleic acid sequences, or Shiga toxin in a stool specimen or enrichment broth. The largest number of culture confirmed or CIDT positive–only infections in 2016 was reported for Campylobacter (8,547), followed by Salmonella (8,172), Shigella (2,913), STEC (1,845), Cryptosporidium (1,816), Yersinia (302), Vibrio (252), Listeria (127), and Cyclospora (55).

The number of infections detected by CIDT has been steadily increasing compared to culture. Increased use of CIDT may account for the increased incidence of Cryptosporidium, STEC, and Yersinia, and slight but not significant increases in incidence of Campylobacter, Salmonella, Shigella, and Vibrio. More widespread adoption of CIDT is likely to improve detection of foodborne illness.


Marder EP, Cieslak PR, Cronquist AB, et al. Incidence and Trends of Infections with Pathogens Transmitted Commonly Through Food and the Effect of Increasing Use of Culture-Independent Diagnostic Tests on Surveillance — Foodborne Diseases Active Surveillance Network, 10 U.S. Sites, 2013–2016. MMWR Morb Mortal Wkly Rep 2017;66:397–403. DOI:

]]> (Fred Plapp) Blog Sun, 23 Apr 2017 20:21:08 -0400
CMV Infection Risk in Newborns

Transfusion acquired cytomegalovirus (CMV) can cause serious complications and even death in very low birth weight infants. Because of this risk, transfusion services provide CMV negative blood components for fetal and intrauterine transfusions and for very low birth weight premature infants. When infants become infected with CMV, neonatologists often suspect that transfusion is the source of the infection. A donor with a recent CMV infection can harbor virus in their plasma or white blood cells even though they test negative for antibodies. The window period for CMV infection is estimated to be 6 to 8 weeks.

A prospective multicenter study sought to determine the source of postnatal CMV infection during the first 90 days after birth in 539 very low birth weight infants. Postnatal CMV infection was detected in 29 infants by both serological and nucleic acid tests. More than half of these infants had been transfused with cellular blood components that were CMV seronegative and leukocyte reduced. Testing of donors revealed that non of the infections were associated with transfusion. Instead, all of the infections were transmitted by CMV positive breast milk.

The findings of this study suggest that the risk of CMV transmission by blood transfusion is negligible when CMV seronegative and leukocyte reduced blood components are transfused. However, CMV transmission by breast milk from CMV-positive donors remains a serious risk.


Josephson CD, Caliendo AM, Easley KA, Knezevic A, Shenvi N, Hinkes MT, Patel RM, Hillyer CD, Roback JD. Blood Transfusion and Breast Milk Transmission of Cytomegalovirus in Very Low-Birth-Weight Infants: A Prospective Cohort Study. JAMA Pediatr 2014;168(11):1054-62.

]]> (Fred Plapp) Blog Sun, 09 Apr 2017 20:56:45 -0400
Screening for Celiac Disease

Celiac disease is an autoimmune disease that occurs in genetically predisposed adults and children after exposure to dietary gluten. Classic celiac disease is associated with symptoms of malabsorption. However, many patients experience other symptoms such as anemia, osteoporosis, fatigue, peripheral neuropathy, ataxia, stomatitis, dermatitis herpetiformis, infertility, fetal loss or short stature. The estimated prevalence of celiac disease in the United States is 0.71% in adults and 0.76% in children. Most celiac disease in believed to be undetected despite the widespread availability of noninvasive serologic tests such as anti-tissue transglutaminase IgA antibody. Individuals with atypical or nonspecific symptoms may not be diagnosed for many years.

Screening of the general population might enable earlier detection and treatment. However, a recent review by The United States Preventive Services Task Force (USPSTF) concluded that there is insufficient evidence to support screening for celiac disease in asymptomatic persons. USPSTF found no studies on the benefits of treatment of screen-detected celiac disease compared to treatment that is initiated after clinical diagnosis.


US Preventive Services Task Force, Screening for Celiac Disease: US Preventive Services Task Force Recommendation Statement, JAMA 2017;317:1252-57.

Choung RS and Murray JA. The US Preventive Task Force Recommendation on Screening for Asymptomatic Celiac Disease: A Dearth of Evidence. JAMA 2017;317:1221-23.

]]> (Fred Plapp) Blog Sun, 02 Apr 2017 20:45:59 -0400
Hashtags for Clinical Pathology

Twitter has become a very active social media site for all subspecialties of Pathology.  Recently, Symplur published a list of Pathology Tag Ontology, which was developed by the USCAP Social Media Subcommittee. Pathology Tag Ontology is a standardized list of social media communication descriptors.

Originally, individuals interested in Pathology could just follow the #pathology hashtag. However, Pathology is an incredibly diverse specialty with many subspecialties and the content within a single hashtag became too voluminous to follow. This new list contains standardized hashtags for most subspecialties of pathology and laboratory medicine. Now it is much easier to follow specific disciplines and collaborate with your peers.  Below, I have listed the standardized hashtags that have been created for clinical pathology and laboratory medicine.

#labmed for laboratory medicine

#ClinPath for Clinical Pathology

#BloodBank for blood banking and transfusion medicine

#HemePath for Hematopathology

#MolDx for Molecular Pathology

#pathinformatics for Pathology Informatics

The complete list of standardized hashtags for Pathology can be found at:

Although they were not included in the standardized list, I also follow:





]]> (Fred Plapp) Blog Sun, 26 Mar 2017 21:36:41 -0400
Metabolic Syndrome

The metabolic syndrome is defined as the co-occurrence of metabolic risk factors for both type 2 diabetes and cardiovascular disease. These risk factors include abdominal obesity, hyperglycemia, dyslipidemia, and hypertension. All of them are related to insulin resistance. Other names for this syndrome include the dysmetabolic Syndrome, Syndrome X, Insulin Resistance Syndrome , or the obesity dyslipidemia syndrome.

Several medical organizations have published definitions for the metabolic syndrome. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) is the most widely used in the United States. ATPIII criteria for diagnosis of the metabolic syndrome include the presence of any three of the parameters summarized in the following table.






>102 cm

>80 cm


>102 cm

>80 cm





>94 cm

>80 cm
















Triglycerides >150 >150 >150 >150














   2h OGTT












20 ug/min

30 mg/g


NCEP: National Cholesterol Education Program; IDF: International Diabetes Federation;  WHO: World Health Organization; AACE: American Association of Clinical Endocrinologists


The major difference between these criteria is in the tests for glucose intolerance. Both the AACE and WHO recommend an oral glucose tolerance test (OGTT), even in patients without an elevated fasting glucose. ATP III does not recommend OGTT in such persons, because they believe that the increased sensitivity does not outweigh the increased cost and inconvenience. WHO includes elevated microalbumin in their diagnostic criteria, but the other 2 organizations do not.

NCEP requires 3 of 5 abnormalities for diagnosis of insulin resistance syndrome. WHO requires evidence of glucose intolerance plus 2 more abnormalities. AACE does not specify a defined number of abnormalities and leaves the diagnosis to clinical judgment. IDF requires increased waist circumference, with ethnic-specific waist circumference cut-points plus two of the other criteria.

Using NCEP criteria, data from the National Health and Nutrition Survey (NHANES) from 1999 to 2002 indicated that 34.5% of adults in the United States have the metabolic syndrome. Identification of the metabolic syndrome is important because it is a significant risk factor for diabetes and cardiovascular disease.

]]> (Fred Plapp) Blog Sun, 19 Mar 2017 21:08:32 -0400
Laboratory Tests to Assess Nutrition

Hospitalized patients are often assessed for nutritional status prior to or at the time of admission. This may include a history, an interview by a dietician, and laboratory tests. Of particular concern for patients undergoing surgery are the risks of postoperative infection and poor wound healing. If the results of these tests indicate possible nutritional deficits, patients may be provided nutritional supplementation prior to a surgery or procedure and be monitored regularly during recovery.

Three different plasma proteins are measured to assess protein status. Each of them has a different circulating half-life. They reflect severity of illness and are used in conjunction with other clinical data to determine therapy.

Serum albumin is synthesized in the liver and has the longest half-life at 18 to 20 days. It is an indicator of dietary intake during the preceding three weeks. Low serum albumin (<2.2 g/dL) is a marker of a negative catabolic state, and a predictor of poor outcome. Many other conditions affect serum albumin levels. Serum albumin is not a good nutritional marker in the setting of disorders causing large protein losses from the circulation, such as ascites, protein losing enteropathy, proteinuria, liver disease, or extensive burns and inflammation. Serum albumin concentration gradually returns to normal after initiation of nutritional therapy, but this may take up to three weeks.

Serum transferrin has an intermediate half-life of eight to nine days, reflecting protein status over the past two to four weeks. Transferrin also reflects iron status, and low transferrin should be considered an indicator of protein status only in the setting of normal serum iron.

Prealbumin (also called transthyretin) is a plasma protein that is synthesized in the liver. Prealbumin is turned over rapidly with a half-life of two to three days. Serum prealbumin concentrations fall rapidly in patients with poor dietary intake and rise to low-normal values within 10 days of initiation of nutritional therapy and adequate refeeding. Thus, prealbumin is a good predictor of protein and energy adequacy of the diet in the days prior to testing, and can serve as a marker of an acute reduction in food consumption. However, it is a negative acute-phase reactant, meaning that concentrations fall in the presence of inflammation. Inflammatory cytokines decrease prealbumin synthesis by the liver. Prealbumin can also be decreased in patients with renal and hepatic diseases. Therefore, prealbumin levels do not accurately reflect nutrition status in patients with these conditions.

In addition to assessing protein status, a few other laboratory studies may be helpful. Electrolytes, glucose, BUN and creatinine help assess overall clinical and fluid volume status and need to be obtained if parenteral (intravenous) nutrition is a possibility. Plasma calcium, magnesium, and phosphorous concentrations should also be assessed periodically, particularly in the setting of poor oral intake or diarrhea. They are monitored regularly in patients receiving parenteral nutrition.

A complete blood cell count (CBC) can be used to identify patients with nutritional deficiencies of iron, folate, or vitamin B12. A macrocytic anemia suggests folic acid and/or vitamin B12 deficiency. Iron deficiency anemia, associated with hypochromic, microcytic red cell morphology, is the most common nutritional deficiency. Plasma ferritin is the most sensitive measure of the adequacy of body iron status, but it is an acute-phase reactant and may be elevated during infectious or inflammatory diseases. Additional tests that are useful in the evaluation of microcytic anemia include serum iron, total iron-binding capacity, and transferrin.

Testing for specific vitamin deficiencies may be necessary in patients who have gastrointestinal malabsorption. Serum concentrations of vitamins A, E, and 25-hydroxyvitamin D can be measured directly. Prothrombin time can be used to assess vitamin K adequacy.

Vitamin A is a lipid soluble vitamin that is also called retinoic acid. Vitamin A plays an essential role in light detection by the retina and cellular differentiation of epithelial tissues. Together with carotenoids, vitamin A enhances immune function.

Vitamin A deficiency is rare in the United States, but is a common nutritional deficiency in underdeveloped countries. In the United States, vitamin A deficiency may be seen with disorders causing fat malabsorption such as biliary cholangitis, Crohn disease, and bariatric surgery. Night blindness is an early symptom that may be followed by xerophthalmia, corneal ulcers, scarring, and blindness.

Vitamin D is the hormone that enhances intestinal absorption of calcium and insures healthy bone formation. Vitamin D metabolism is dependent on sunlight exposure, intestinal absorption, and liver and kidney function. Vitamin D malabsorption may be associated with several GI disorders including Crohn disease, celiac disease, and pancreatic insufficiency. Severe vitamin D deficiency causes increased secretion of parathyroid hormone (PTH), which promotes calcium absorption from bone. Vitamin D deficiency is a major risk factor for bone loss, weakness and fracture. 

Vitamin E is a tocopherol that functions as an antioxidant, protecting the integrity of lipid membranes and preventing oxidative damage to retinol.Vitamin E deficiency can be caused by conditions that cause fat malabsorption such as cholestatic liver disease, pancreatic insufficiency and small intestinal resection or disease. Deficiency of Vitamin E in adults and children causes reversible neuropathy and hemolysis.

Deficiency of water-soluble vitamins is less common, and levels should be measured only when clinically indicated. Water soluble vitamins (in addition to folate and vitamin B12) include vitamins C, B1 (thiamin), B2 (riboflavin), B3 (niacin) and B6 (pyridoxine).

Vitamin C deficiency results in scurvy. Generalized symptoms of scurvy include fatigue, myalgias, arthralgias, weakness, anorexia, weight loss, and irritability. Although a low plasma vitamin C level is specific for the diagnosis of scurvy, plasma vitamin C levels quickly normalize with enteral intake of ascorbic acid and do not reflect tissue levels.

Thiamine (Vitamin B1) deficiency causes Wernicke's encephalopathy, which is characterized by the classic triad of mental confusion, oculomotor dysfunction, and gait ataxia. Thiamine diphosphate is the active form of thiamine. It is present predominantly in erythrocytes, with very little occurring in plasma. Measurement of thiamine diphosphate in whole blood by liquid chromatography and mass spectrometry is the preferred method for determining nutritional status. Riboflavin is quantitated in plasma using high performance liquid chromatography and tandem mass spectrometry.

Riboflavin is also called Vitamin B2. Deficiency is called ariboflavinosis and is usually caused by reduced dietary intake. Symptoms include sore throat, cheilosis, angular stomatitis, glossitis, corneal vascularization, dermatitis, and normocytic, normochromic anemia.

Vitamin B3 (niacin) deficiency predisposes to pellagra. Pellagra is extremely uncommon in the western world except as a complication of alcoholism, anorexia nervosa, or malabsorption. The most characteristic finding is a symmetric hyperpigmented rash on sun exposed areas of skin. Other clinical findings include red tongue, diarrhea and vomiting. Neurologic symptoms include insomnia, anxiety, disorientation, delusions, dementia, and encephalopathy.

The primary reason for ordering vitamin B6 is to diagnose pyridoxine deficiency, which has been associated with microcytic hypochromic anemia, dermatitis, neuritis, stomatitis and cheliosis. Pyridoxal-5- phosphate is the active form of vitamin B6 in the body. It is the vitamer that is measured in serum or plasma to determine vitamin B6 levels.

]]> (Fred Plapp) Blog Sun, 12 Mar 2017 20:59:54 -0400
Distinguishing Daratumumab from Monoclonal Proteins

Protein electrophoresis and immunofixation (IFE) are widely used to monitor monoclonal proteins (M-proteins) in patients with multiple myeloma. The approval of daratumumab (Darzalex) by the FDA in November 2015 for treatment of refractory or relapsed multiple myeloma has increased the difficulty of distinguishing residual disease from circulating therapeutic monoclonal antibody.

Daratumumab is a human monoclonal IgG kappa antibody that kills myeloma cells by binding with high affinity to CD38. Daratumumab is administered at high enough doses to be detected by serum protein electrophoresis and immunofixation. The mean peak concentration at the completion of dosing is 915 ug/mL (0.09 g/dL) and the mean trough concentration is 573 ug/mL (0.06 g/dL). The limit of detection of M-proteins is 0.1 g/dL by protein electrophoresis and 0.02 g/dL by IFE. In patients with treatment- associated hypogammaglobulinemia, IFE can detect M-proteins concentrations below 0.01 g/dL. Therefore, during treatment and several months after infusion of the last dose, there is a strong likelihood that daratumumab will be detected by IFE.

The International Myeloma Working Group definition of a complete clinical response requires that patients have no detectable M-protein by either protein electrophoresis or IFE. The presence of detectable daratumumab could cause patients to be misclassified due to an inability to differentiate residual disease from therapeutic monoclonal antibody.

Daratumumab is a human IgG kappa antibody. Detection of another isotype excludes it as the cause of a monoclonal spike. Because IgG kappa is the most common isotype produce by patients with multiple myeloma, other methods are needed. One possibility is measuring the migration distance of daratumumab on capillary electrophoresis and comparing it to the position of each patient’s IgG kappa M-protein. Other methods such as daratumumab specific immunofixation electrophoresis reflex assay (DIRA) and mass spectrometry have been described but are not available in most hospital laboratories.

Until more robust methods become available, a few other precautions can be taken:

  • Ask physicians to order a trough specimen for protein electrophoresis and IFE, just before the next dose, to minimize the possibility of detecting daratumumab.
  • Educate phlebotomists and nurses not to draw samples from patients being infused with daratumumab.
  • Recommend that pathologists check the electronic medical record on patients with small, suspicious IgG kappa M-proteins.


Keren DF. Therapeutic complications: A caveat for M-protein detection. J Appl Lab Med. 2017;01:342-45.

Mills JR & Murray DL. Identification of Friend or Foe: The laboratory challenge of differentiating M-proteins from monoclonal antibody therapies. J Appl Lab Med. 2017;01:421-31.

]]> (Fred Plapp) Blog Sun, 05 Mar 2017 19:42:58 -0500
Updated Sepsis Guidelines Continue to Recommend Plasma Lactate Measurement

A consensus committee of 55 international experts representing 25 international organizations was convened in 2016 to provide an update to the 2012 Surviving Sepsis Campaign guidelines for the management of severe sepsis and septic shock.

Mean arterial pressure (MAP) is the driving pressure of tissue perfusion. Below a threshold MAP, perfusion of critical organs such as the brain or kidney becomes inadequate. Plasma lactate is not a direct measure of tissue perfusion. Increases in plasma lactate concentration may represent tissue hypoxia, accelerated aerobic glycolysis driven by excess beta-adrenergic stimulation, or other causes such as liver failure. Regardless of the source, increased lactate levels are associated with worse outcomes.

Five randomized controlled trials (647 patients) have evaluated lactate-guided resuscitation of patients with septic shock. A significant reduction in mortality was seen in lactate-guided resuscitation compared to resuscitation without lactate monitoring (RR 0.67; 95% CI 0.53–0.84; low quality). There was no evidence for difference in ICU length of stay (mean difference −1.51 days; 95% CI −3.65 to 0.62; low quality). Two other meta-analyses of these same 647 patients demonstrated moderate evidence for reduction in mortality when an early lactate clearance strategy was used, compared with either usual care or with a Scvo2 normalization strategy.

Based on this evidence, updated Surviving Sepsis guidelines continue to recommend measurement of plasma lactate levels to guide resuscitation.



Rhodes, A., Evans, L.E., Alhazzani, W. et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med (2017). doi:10.1007/s00134-017-4683-6

Levy B (2006) Lactate and shock state: the metabolic view. Curr Opin Crit Care. 12(4):315–321

Casserly B, Phillips GS, Schorr C et al (2015) Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med 43(3):567–573

]]> (Fred Plapp) Blog Sun, 26 Feb 2017 18:17:15 -0500
Popular Cancer Gene Panels Give Widely Discordant Results

Hospital laboratories have been inundated with requests to send out specimens for next generation sequencing to identify cancer-associated mutations in the hope that an effective targeted therapy is available. These popular tests cost thousands of dollars but their clinical value has not been systematically studied. 

Recently, investigators from the University of Washington in Seattle sent specimens from 9 patients with advanced cancer to two different laboratories for analysis. Five patients had breast cancer and four other patients had pancreatic, lung, salivary gland, and thymic cancer. The two laboratories were Foundation Medicine and Guardant Health. FoundationOne sequences the exons of 315 cancer-associated genes and introns from 28 genes using tumor tissue. Guardant360 sequences 70 genes using cell-free circulating DNA. The investigators limited comparisons to alterations identifiable by both FoundationOne and Guardant360 testing.

The genomic alterations reported by both laboratories were compared for each patient. The results were also assessed to compare the recommended drugs. Unfortunately, this study revealed widely discordant results in the same patient. One patient had no genetic alteration identified by using either platform. The other 8 patients had 45 alterations, but only 10 (22%) were concordant between the platforms. Furthermore, for 2 of these 8 patients, there was zero concordance among the described alterations.

For the 8 patients, a total of 36 drugs were recommended. However, only 9 drugs (25%) were recommended for the same patients by both platforms. In 5 patients, there was no overlap between the drugs recommended by the FoundationOne test and those recommended by the Guardant360 test. In the majority of the patients, there was zero concordance in terms of drug recommendations.

Despite having a small sample size, this study was clinically relevant since both tests are performed in thousands of patients with cancer each year.  This study casts significant doubt on the benefit of genetic analysis of tumors for precision oncology.

Many critics have called for clinical trials to determine whether the rapidly expanding industry of cancer genetics testing actually improves patient outcomes. Treatments based on the results of these tests are almost never curative. They certainly do drive up health care costs.

Kuderer, NM et al. Comparison of 2 commercially available next-generation sequencing platforms in oncology. JAMA Oncol. Published online December 15, 2016. doi:10.1001/jamaoncol.2016.4983  Abstract

]]> (Fred Plapp) Blog Sun, 19 Feb 2017 21:17:08 -0500