Seven percent of Medicare hospital DRGs: That is, potentially, how much Medicare reimbursement will be in play from CMS' hospital value-based purchasing (HVBP) quality initiatives by Fiscal Year 2017, Nell Buhlman, MBA, vice president of clinical products for Press Ganey Associates, said during a Sunday pre-course at SHM 2012. How many of you know your hospital’s profit margin on Medicare?” she posed to the audience. “Is it 7%?”

Buhlman outlined various components of CMS’ quality initiatives for hospitals, which could add up to millions of dollars per year for an average-sized hospital. By 2017 quality measures impacting on reimbursement will include the HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems), core clinical measures, penalties for higher-than-expected 30-day readmission rates, and meaningful-use reductions.

Hospitals are capable of significant quality improvement, “but the importance of hitting the hospital quality targets every single time will grow,” she said.

“Improving quality is fantastic, but even better is improving faster than everyone else,” Buhlman said, adding that the smallest things can sometimes make a big difference on outcomes scores. She offered the example of giving a notepad and pen to hospitalized patients so they can write down the questions they want to ask their doctor for the next visit.

Seven percent of Medicare hospital DRGs: That is, potentially, how much Medicare reimbursement will be in play from CMS' hospital value-based purchasing (HVBP) quality initiatives by Fiscal Year 2017, Nell Buhlman, MBA, vice president of clinical products for Press Ganey Associates, said during a Sunday pre-course at SHM 2012. How many of you know your hospital’s profit margin on Medicare?” she posed to the audience. “Is it 7%?”

Buhlman outlined various components of CMS’ quality initiatives for hospitals, which could add up to millions of dollars per year for an average-sized hospital. By 2017 quality measures impacting on reimbursement will include the HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems), core clinical measures, penalties for higher-than-expected 30-day readmission rates, and meaningful-use reductions.

Hospitals are capable of significant quality improvement, “but the importance of hitting the hospital quality targets every single time will grow,” she said.

“Improving quality is fantastic, but even better is improving faster than everyone else,” Buhlman said, adding that the smallest things can sometimes make a big difference on outcomes scores. She offered the example of giving a notepad and pen to hospitalized patients so they can write down the questions they want to ask their doctor for the next visit.

Seven percent of Medicare hospital DRGs: That is, potentially, how much Medicare reimbursement will be in play from CMS' hospital value-based purchasing (HVBP) quality initiatives by Fiscal Year 2017, Nell Buhlman, MBA, vice president of clinical products for Press Ganey Associates, said during a Sunday pre-course at SHM 2012. How many of you know your hospital’s profit margin on Medicare?” she posed to the audience. “Is it 7%?”

Buhlman outlined various components of CMS’ quality initiatives for hospitals, which could add up to millions of dollars per year for an average-sized hospital. By 2017 quality measures impacting on reimbursement will include the HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems), core clinical measures, penalties for higher-than-expected 30-day readmission rates, and meaningful-use reductions.

Hospitals are capable of significant quality improvement, “but the importance of hitting the hospital quality targets every single time will grow,” she said.

“Improving quality is fantastic, but even better is improving faster than everyone else,” Buhlman said, adding that the smallest things can sometimes make a big difference on outcomes scores. She offered the example of giving a notepad and pen to hospitalized patients so they can write down the questions they want to ask their doctor for the next visit.

Sitting in the back of a conference room at the San Diego Convention Center on Sunday morning, Benjamin Frizner, MD, listens intently as a panel of HM experts debates the finer points of how best to implement and manage multidisciplinary rounds. The conversation, one of dozens to be tackled at a daylong pre-course on practice management, gave Dr. Frizner and dozens of physicians around him applicable advice, new viewpoints, and time to think about the big picture.

Welcome to HM12.

"The topics are focused to a lot of the problems we are facing," says Dr. Frizner, director of the hospitalist program at Saint Agnes Hospital in Baltimore. "It really gives us the whole day to just focus."

Of course, the four-day meeting is only just starting. Sunday is dedicated to eight pre-courses that offer CME credits, including a new session, "How to Improve Performance in CMS' Value-Based Purchasing Program." Other pre-courses dealt with ABIM Maintenance of Certification, critical care, perioperative care, and hands-on training in ultrasound and other medical procedures.

The annual meeting continues Monday, April 2, and includes the Research, Innovations, and Clinical Vignettes (RIV) poster competition and plenary addresses from Patrick Conway, MD, MSc, FAAP, SFHM, a pediatric hospitalist and chief medical officer of the Centers for Medicare & Medicaid Services (CMS); political commentator Norman Ornstein, PhD, MA, BA; and HM pioneer Robert Wachter, MD, MHM.

"This is the best meeting I've ever been to," says Madonna Ringswald, DO, medical director of the hospitalist program at Baptist Hospital Northeast in La Grange, Ky., who attended the practice management pre-course. "If you can’t find a lecture [that appeals to you], there’s something wrong with you."

Sitting in the back of a conference room at the San Diego Convention Center on Sunday morning, Benjamin Frizner, MD, listens intently as a panel of HM experts debates the finer points of how best to implement and manage multidisciplinary rounds. The conversation, one of dozens to be tackled at a daylong pre-course on practice management, gave Dr. Frizner and dozens of physicians around him applicable advice, new viewpoints, and time to think about the big picture.

Welcome to HM12.

"The topics are focused to a lot of the problems we are facing," says Dr. Frizner, director of the hospitalist program at Saint Agnes Hospital in Baltimore. "It really gives us the whole day to just focus."

Of course, the four-day meeting is only just starting. Sunday is dedicated to eight pre-courses that offer CME credits, including a new session, "How to Improve Performance in CMS' Value-Based Purchasing Program." Other pre-courses dealt with ABIM Maintenance of Certification, critical care, perioperative care, and hands-on training in ultrasound and other medical procedures.

The annual meeting continues Monday, April 2, and includes the Research, Innovations, and Clinical Vignettes (RIV) poster competition and plenary addresses from Patrick Conway, MD, MSc, FAAP, SFHM, a pediatric hospitalist and chief medical officer of the Centers for Medicare & Medicaid Services (CMS); political commentator Norman Ornstein, PhD, MA, BA; and HM pioneer Robert Wachter, MD, MHM.

"This is the best meeting I've ever been to," says Madonna Ringswald, DO, medical director of the hospitalist program at Baptist Hospital Northeast in La Grange, Ky., who attended the practice management pre-course. "If you can’t find a lecture [that appeals to you], there’s something wrong with you."

Sitting in the back of a conference room at the San Diego Convention Center on Sunday morning, Benjamin Frizner, MD, listens intently as a panel of HM experts debates the finer points of how best to implement and manage multidisciplinary rounds. The conversation, one of dozens to be tackled at a daylong pre-course on practice management, gave Dr. Frizner and dozens of physicians around him applicable advice, new viewpoints, and time to think about the big picture.

Welcome to HM12.

"The topics are focused to a lot of the problems we are facing," says Dr. Frizner, director of the hospitalist program at Saint Agnes Hospital in Baltimore. "It really gives us the whole day to just focus."

Of course, the four-day meeting is only just starting. Sunday is dedicated to eight pre-courses that offer CME credits, including a new session, "How to Improve Performance in CMS' Value-Based Purchasing Program." Other pre-courses dealt with ABIM Maintenance of Certification, critical care, perioperative care, and hands-on training in ultrasound and other medical procedures.

The annual meeting continues Monday, April 2, and includes the Research, Innovations, and Clinical Vignettes (RIV) poster competition and plenary addresses from Patrick Conway, MD, MSc, FAAP, SFHM, a pediatric hospitalist and chief medical officer of the Centers for Medicare & Medicaid Services (CMS); political commentator Norman Ornstein, PhD, MA, BA; and HM pioneer Robert Wachter, MD, MHM.

"This is the best meeting I've ever been to," says Madonna Ringswald, DO, medical director of the hospitalist program at Baptist Hospital Northeast in La Grange, Ky., who attended the practice management pre-course. "If you can’t find a lecture [that appeals to you], there’s something wrong with you."

Recertification is a fact of life for physicians. But at today’s ABIM Maintenance of Certification pre-course, the conversation is about more than just answers. It’s about the questions.

“When you take the actual recertification exam, it’s an exam,” Ethan Cumbler, MD, FACP, of University of Colorado Denver, says between leading question-and-answer sessions at the Hm12 pre-course this afternoon. “You find out whether it’s pass or fail. But when you go through this process of getting to look at the questions, look at all the answers, ask questions, discuss it as a group for the controversies - that’s an entirely different process."

Dr. Cumbler also tells pre-course attendees that the MOC is more than an evaluation.

“What this is is a learning process," he says, "and I think the people who come want to be part of that."

Recertification is a fact of life for physicians. But at today’s ABIM Maintenance of Certification pre-course, the conversation is about more than just answers. It’s about the questions.

“When you take the actual recertification exam, it’s an exam,” Ethan Cumbler, MD, FACP, of University of Colorado Denver, says between leading question-and-answer sessions at the Hm12 pre-course this afternoon. “You find out whether it’s pass or fail. But when you go through this process of getting to look at the questions, look at all the answers, ask questions, discuss it as a group for the controversies - that’s an entirely different process."

Dr. Cumbler also tells pre-course attendees that the MOC is more than an evaluation.

“What this is is a learning process," he says, "and I think the people who come want to be part of that."

Recertification is a fact of life for physicians. But at today’s ABIM Maintenance of Certification pre-course, the conversation is about more than just answers. It’s about the questions.

“When you take the actual recertification exam, it’s an exam,” Ethan Cumbler, MD, FACP, of University of Colorado Denver, says between leading question-and-answer sessions at the Hm12 pre-course this afternoon. “You find out whether it’s pass or fail. But when you go through this process of getting to look at the questions, look at all the answers, ask questions, discuss it as a group for the controversies - that’s an entirely different process."

Dr. Cumbler also tells pre-course attendees that the MOC is more than an evaluation.

“What this is is a learning process," he says, "and I think the people who come want to be part of that."

With pre-course participants finishing up lunch today, four hospitalists from three hospitals are talking shop. Two of the hospitals are in the process of implementing computerized physician order entry (CPOE), and the third hospital is on track to do the same but got delayed. Each of the hospitalists expresses cautious optimism about the outcomes.

“It’s a necessary evil,” says Gaurav T. Parikh, MD, a Cogent HMG hospitalist practicing at City Hospital in Martinsburg, W.V. “Once we start using it—if it really makes things easier—then it should give us more flexibility. You can use it anywhere in the hospital.

"Sometimes I leave a patient’s room and go to another patient, and then remember, gee, I forget to order something for that first patient.”

With CPOE, Dr. Parikh can enter the additional prescription at a computer terminal or try to reach a nurse on that floor by phone, who then places the order.

Jaydeep Patel, MD, MBA, hospitalist at Grant Medical Center in Columbus,Ohio, says he used CPOE in residency and eagerly is awaiting its implementation at Grant. “I really liked it. There’s just less chance for error, as opposed to 15 charts on the rack,” he says.

Dr. Parikh says his hospital tried for two years to get physicians to enter the date and time on prescriptions. “It didn’t happen,” he says, noting CPOE puts an electronic signature on every prescription. He also says the hospital will have an easier time pulling data on practice. “In a time of increased demands for data and quality, it will help you big time," he adds. "But it won’t necessarily save us time.”

Larry Beresford is a freelance writer covering HM12.

With pre-course participants finishing up lunch today, four hospitalists from three hospitals are talking shop. Two of the hospitals are in the process of implementing computerized physician order entry (CPOE), and the third hospital is on track to do the same but got delayed. Each of the hospitalists expresses cautious optimism about the outcomes.

“It’s a necessary evil,” says Gaurav T. Parikh, MD, a Cogent HMG hospitalist practicing at City Hospital in Martinsburg, W.V. “Once we start using it—if it really makes things easier—then it should give us more flexibility. You can use it anywhere in the hospital.

"Sometimes I leave a patient’s room and go to another patient, and then remember, gee, I forget to order something for that first patient.”

With CPOE, Dr. Parikh can enter the additional prescription at a computer terminal or try to reach a nurse on that floor by phone, who then places the order.

Jaydeep Patel, MD, MBA, hospitalist at Grant Medical Center in Columbus,Ohio, says he used CPOE in residency and eagerly is awaiting its implementation at Grant. “I really liked it. There’s just less chance for error, as opposed to 15 charts on the rack,” he says.

Dr. Parikh says his hospital tried for two years to get physicians to enter the date and time on prescriptions. “It didn’t happen,” he says, noting CPOE puts an electronic signature on every prescription. He also says the hospital will have an easier time pulling data on practice. “In a time of increased demands for data and quality, it will help you big time," he adds. "But it won’t necessarily save us time.”

Larry Beresford is a freelance writer covering HM12.

With pre-course participants finishing up lunch today, four hospitalists from three hospitals are talking shop. Two of the hospitals are in the process of implementing computerized physician order entry (CPOE), and the third hospital is on track to do the same but got delayed. Each of the hospitalists expresses cautious optimism about the outcomes.

“It’s a necessary evil,” says Gaurav T. Parikh, MD, a Cogent HMG hospitalist practicing at City Hospital in Martinsburg, W.V. “Once we start using it—if it really makes things easier—then it should give us more flexibility. You can use it anywhere in the hospital.

"Sometimes I leave a patient’s room and go to another patient, and then remember, gee, I forget to order something for that first patient.”

With CPOE, Dr. Parikh can enter the additional prescription at a computer terminal or try to reach a nurse on that floor by phone, who then places the order.

Jaydeep Patel, MD, MBA, hospitalist at Grant Medical Center in Columbus,Ohio, says he used CPOE in residency and eagerly is awaiting its implementation at Grant. “I really liked it. There’s just less chance for error, as opposed to 15 charts on the rack,” he says.

Dr. Parikh says his hospital tried for two years to get physicians to enter the date and time on prescriptions. “It didn’t happen,” he says, noting CPOE puts an electronic signature on every prescription. He also says the hospital will have an easier time pulling data on practice. “In a time of increased demands for data and quality, it will help you big time," he adds. "But it won’t necessarily save us time.”

Larry Beresford is a freelance writer covering HM12.

HM12 kicked off this morning with hundreds attending eight pre-courses and many more registering for the annual meeting. SHM expects more than 3,000 to attend the four-day gathering at the San Diego Convention Center.

The Hospitalist will be delivering daily news updates and analysis throughout the annual meeting. Check back or download the HM12 at Hand web application to stay abreast of the latest news.

Today's pre-courses are as follows:

• 
  ABIM MOC learning session, 6.5 credits;
• Advanced Interactive Critical Care, 7.75 credits;
• CMS’s Value-Based Purchasing Program, 3.75 credits;
• Medical Procedures, 7.5 credits;
• Portable Ultrasounds, 3.75 credits;
• Perioperative Medicine, 7.75 credits; and
• Practice Management, 7.5 credits.

HM12 kicked off this morning with hundreds attending eight pre-courses and many more registering for the annual meeting. SHM expects more than 3,000 to attend the four-day gathering at the San Diego Convention Center.

The Hospitalist will be delivering daily news updates and analysis throughout the annual meeting. Check back or download the HM12 at Hand web application to stay abreast of the latest news.

Today's pre-courses are as follows:

• 
  ABIM MOC learning session, 6.5 credits;
• Advanced Interactive Critical Care, 7.75 credits;
• CMS’s Value-Based Purchasing Program, 3.75 credits;
• Medical Procedures, 7.5 credits;
• Portable Ultrasounds, 3.75 credits;
• Perioperative Medicine, 7.75 credits; and
• Practice Management, 7.5 credits.

HM12 kicked off this morning with hundreds attending eight pre-courses and many more registering for the annual meeting. SHM expects more than 3,000 to attend the four-day gathering at the San Diego Convention Center.

The Hospitalist will be delivering daily news updates and analysis throughout the annual meeting. Check back or download the HM12 at Hand web application to stay abreast of the latest news.

Today's pre-courses are as follows:

• 
  ABIM MOC learning session, 6.5 credits;
• Advanced Interactive Critical Care, 7.75 credits;
• CMS’s Value-Based Purchasing Program, 3.75 credits;
• Medical Procedures, 7.5 credits;
• Portable Ultrasounds, 3.75 credits;
• Perioperative Medicine, 7.75 credits; and
• Practice Management, 7.5 credits.

Supplement Editor:
Kathryn Teng, MD

Contents

Building an innovative model for personalized healthcare
Kathryn Teng, MD; Charis Eng, MD, PhD; Caryl A. Hess, PhD, MBA; Meredith A. Holt, MBA; Rocio T. Moran, MD; Richard R. Sharp, PhD; and Elias I. Traboulsi, MD

Supplement Editor:
Kathryn Teng, MD

Contents

Building an innovative model for personalized healthcare
Kathryn Teng, MD; Charis Eng, MD, PhD; Caryl A. Hess, PhD, MBA; Meredith A. Holt, MBA; Rocio T. Moran, MD; Richard R. Sharp, PhD; and Elias I. Traboulsi, MD

Supplement Editor:
Kathryn Teng, MD

Contents

Building an innovative model for personalized healthcare
Kathryn Teng, MD; Charis Eng, MD, PhD; Caryl A. Hess, PhD, MBA; Meredith A. Holt, MBA; Rocio T. Moran, MD; Richard R. Sharp, PhD; and Elias I. Traboulsi, MD

Personalized healthcare is the tailoring of medical management and patient care to the individual characteristics of each patient. This is achieved by incorporating the genetic and genomic makeup of an individual and his or her family medical history, environment, health-related behaviors, culture, and values into a complete health picture that can be used to customize care. Another level of personalization, often called personalized medicine, involves the selection of drug therapy through the use of tests to determine the genes and gene interactions that can reliably predict an individual’s response to a given therapy. This white paper focuses largely on the use of personalized healthcare as a risk prediction tool.

CURRENT STATUS OF PERSONALIZED HEALTHCARE

The case for personalized healthcare: Seeking value

To fully appreciate the need to advance the adoption of personalized healthcare into the delivery of medicine, one must consider the operation of our current healthcare system and its inefficiencies in terms of delivery and cost, its imprecision in the selection of therapies, and its inability to optimize outcomes. The framework of the US healthcare system as it is now constructed is expensive, disease-directed (instead of health- and wellness-directed), fragmented, and complex. While gross domestic product (GDP) in the United States has increased by approximately 3% per year,² the compounded growth rate of healthcare expenditures is 6.1% per year. Healthcare in the aggregate now represents 17.6% of GDP and 27% of spending by the federal government and consumes 28% of the average household’s discretionary spending, surpassed only by housing.³

Personalized healthcare can potentially address the need for value consistent with the healthcare system’s prominent share of the US economy. The growth in healthcare spending is certain to be a target of the newly created Joint Select Committee on Deficit Reduction (created by the Budget Control Act of 2011), which is tasked with deficit reduction of at least $1.5 trillion over a 10-year period.

The need to address healthcare costs has been recognized in the Patient Protection and Affordable Care Act, a central feature of which is the creation of integrated health systems that pay for value based on quality, cost containment, and consumer experience. The legislation was enacted to transform healthcare in a variety of ways to make it more sustainable. The Patient Protection and Affordable Care Act seeks to end fragmentation by expanding the use of information technology to reorganize the delivery system and to prevent errors, shifting from volume-based incentives to incentives based on performance and outcomes, and rewarding effective healthcare delivery measures and good patient outcomes.

A shift from reactive to proactive

The premise behind personalized healthcare is the potential for more efficient healthcare, with the assumption that efficiency translates to lower cost and improved patient care.

Although healthcare reform is most often referred to in the context of improving access to care through insurance coverage mandates, true healthcare reform shifts current healthcare models from the practice of reactive medicine to the practice of proactive medicine, in which the tools of personalized healthcare (ie, genetics, genomics, and other molecular diagnostics) enable not only better quality of care but also less expensive care.

Several personalized tools have long been accepted into mainstream medicine. Two examples are the family history, which is the least expensive and most available genetic evaluation tool, and ABO blood typing for safe transfusions (as ABO blood types are alleles of a gene). In fact, much of what is now considered mainstream medical management was at one time considered new. To allow further evolution of medical practice, our challenge is to open our minds to the possibility that personalized proactive medicine can improve healthcare.

The new vision: More precise management

The trial-and-error approach to treating disease is inefficient and costly. Many drugs are effective for only about 50% of patients, often leading to switching or intensification of therapy that requires multiple patient visits.

Personalized medicine considers pharmacokinetic and other characteristics in selection of drug dosages. Genomic testing has the potential to provide clearer insight into the more successful use of currently available medicines. Treatment decisions (ie, drug and drug dosage choice) made on the basis of pharmacogenomic testing should increase adherence through greater effectiveness and fewer adverse drug reactions.

A massive amount of waste is related to pharmaceutical nonadherence and noncompliance. The New England Healthcare Institute has estimated that medication nonadherence costs the healthcare system $290 billion annually.⁴ Methodologies targeted at individual patients to improve adherence to drug regimens could save the healthcare system a tremendous amount of money.

Cancer management as a model for personalized healthcare. Personalization of therapy is especially suited to cancer management, given that the response to nonspecific cancer chemotherapy is suboptimal in most patients yet exposes them to adverse effects.⁵ Large-scale sequencing of human cancer genomes is rapidly changing the understanding of cancer biology and is identifying new targets in difficult-to-treat diseases and causes of drug resistance. Applying this information can achieve cost savings by avoiding the use of treatments that are ineffective in particular patients.

Overexpression of genetic mutations renders some cancers less susceptible to certain treatments, but has opened the door to individualized molecularly guided treatment strategies. For example, among patients with non–small cell lung cancer, mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain predict response to EGFR tyrosine kinase inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors induce response in patients harboring a mutation in EML4-ALK genes. The recognition that human epidermal growth factor receptor (HER)-2 overexpression as a result of ERBB2 gene amplification occurs in as many as 20% of human breast cancers paved the way for the development of HER-2–targeted therapies. Patients with advanced colorectal cancer whose tumors express the KRAS gene mutation do not benefit from an EGFR inhibitor, whereas those with wild-type KRAS have improved survival with EGFR inhibitor treatment.⁶

BARRIERS TO THE APPLICATION OF PERSONALIZED HEALTHCARE

The availability and potential of personalized healthcare services and technology is not universally recognized or appreciated by consumers and clinicians. This lack of awareness contributes to a shortage of public support and limited demand for such services. Other barriers include misperceptions regarding the impact of personalized healthcare on disease management, limited incentives to use the available technology, and a knowledge gap among healthcare providers.

Lack of awareness and support

As applications of personalized healthcare advance to the point of clinical relevance, it is important to consider strategies for effective implementation into healthcare practice. Personalized healthcare, when more fully implemented, promises to accelerate the progress that healthcare reform hopes to achieve.

A major challenge to widespread adoption of personalized healthcare is limited recognition by the public and some healthcare providers that personalized healthcare can help to achieve better value. For personalized medicine to be embraced, the concept of “helix to health,” or translation of knowledge to the clinical setting, must resonate with the general public. Despite lack of public and provider awareness, the Personalized Medicine Coalition (PMC) has documented the existence of 56 personalized treatment and diagnostic products. Further, more than 200 product labels now recommend genetic testing prior to use to identify likely responders or inform of the influence of genetic variation on safety and effectiveness.

Consumers’ confidence in the efficacy and safety of medicines they take might contribute to the absence of public support for personalized healthcare. Similarly, despite the availability of genomic tests and tools, many physicians who might be advocates for personalized healthcare do not see the relevance of genomic medicine to their practices in terms of direct benefit to patient care.⁷

Apart from clinicians and consumers, support is also weak among health insurers and employers, even though the return on investment for personalized healthcare may be profound. Payers await the economic outcomes data that are crucial for their commitment to personalized healthcare. In addition, some have concerns about the ethical implications of personalized healthcare (see “Managing Genomic Information Responsibly”).

Perception of impact on treatment and prevention

A frequent criticism of genomics in medicine is that a genetic diagnosis does not help with patient management. In fact, surveillance and management of patients and family members often changes in response to a genetic diagnosis; knowing which gene is involved personalizes medical management. An example is the management of hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, which is the most common form of hereditary colon cancer. For a person with HNPCC, the lifetime risk of developing colorectal cancer is approximately 80%. Lynch syndrome is caused by germline mutations in one of three major mismatch repair (MMR) genes (MLH1, MSH2, and MSH6), and it predisposes to other cancers—uterine, stomach, and ovarian—as well. In women with Lynch syndrome, the lifetime risk for uterine cancer is 40%, compared with 4% in the general population.

At least 90% of patients with Lynch syndrome can be detected through MMR testing via microsatellite instability (MSI) or immunohistochemistry (IHC).⁸ MSI is a cellular phenotype that indicates a deficiency in at least one DNA MMR protein.

Although 5-fluorouracil–based chemo therapy is the standard of care for treatment of colorectal cancer, it confers no survival advantage in patients with MMR-IHC null (lack of expression of the gene) or MSI-high sporadic colorectal cancer.^9,10 Knowing the status of MMR proteins, therefore, would alter the decision regarding neoadjuvant and adjuvant chemotherapy.

Perception of value

Implementation of pharmacogenomics into clinical practice has lagged. One major reason is the lack of an obvious business model for a product that may only be required once in an individual patient’s lifetime.¹¹

A second barrier to integration lies in the limited demand for pharmacogenomics from physicians. This may be related partly to limited expertise in genetics among many physicians and to significant pushback from payers against today’s costs. Without reimbursement, little incentive exists for pharmacogenomics diagnostics. The incentive for physicians is further depressed, perhaps appropriately, when randomized controlled studies fail to demonstrate improved clinical outcomes with the use of pharmacogenomicbased treatment strategies. Two such examples are genotype-guided warfarin dosing, which failed in a randomized controlled trial to improve the proportion of international normalized ratios in the therapeutic range,¹² and dosing of clopidogrel based on platelet reactivity, which did not improve outcomes after percutaneous coronary intervention compared with standard dosing in a randomized double-blind clinical trial.¹³

A significant delay in obtaining the results of pharmacogenomics testing, which also postpones the prescribing encounter, is another major drawback.

A knowledge gap persists

At present, delivery of personalized healthcare is not part of the usual training of physicians and other healthcare providers who are the gatekeepers of medicine. Few medical schools incorporate human and medical genetics, genomics, and pharmacogenomics into their curricula. Genetics is inadequately emphasized in residency curricula outside of pediatrics, family medicine, and obstetrics/gynecology.

The resulting knowledge gap is a fundamental factor in the lack of interest in using genomics in clinical medicine. Educating consumers and physicians at all levels, including specialty societies as well as insurers, will be key to expanding utilization of personalized healthcare. Educating payers and providing them with more data on economic outcomes associated with personalized healthcare will be necessary for adoption into clinical practice; implementation will lag as long as reimbursement decisions do not support personalized approaches to medicine.

As DNA sequencing technology has become less expensive and more powerful, companies have begun to market personal genomic testing. As a result, patients who use these services will increasingly want to discuss the results with their physicians. A significant number of clinicians are unfamiliar with personal genomic testing and emerging genetic testing options. In one survey of physicians who attended educational sessions that discussed recent developments in clinical genetics, only 37% indicated that they were familiar with recent genetic research that affected their patients.¹⁴

Targeted education will enhance physicians’ understanding of probabilities and risk estimates from the use of genomic testing; it will also improve recognition of potential causes of patient anxiety, gene variants of unknown significance, and follow-up tests and procedures that can add to expense. Nonphysician healthcare providers (ie, nurses and physician assistants) of direct care also will benefit from education.

INTEGRATING PERSONALIZED HEALTHCARE INTO CLINICAL PRACTICE

Practice standardization and an overhaul of the health information technology (HIT) infrastructure are needed if we are to reap the potential benefits of personalized healthcare. Creative approaches to practitioner education, which are being used in some institutions, must become more widespread. Similarly, the models for successful integration of personalized healthcare that have been achieved in some settings also can be implemented in other institutions.

Data collection and integration must be prioritized

Personalized healthcare can be both predictive and preventive, but moving past the disruptive phase of personalized healthcare will require a radical transformation of the healthcare “ecosystem” and HIT infrastructure.

Although data collection in the current system is extensive, data sharing and data management are inadequate. The pace at which HIT links clinical and genetic information must be accelerated. HIT will expedite innovation and implementation of personalized healthcare, allowing greater integration of data to permit improved data analysis capability. The ultimate goal is to create an interoperable system that connects these data across hospitals and clinicians to help clinicians interpret genomic and other risk information to better inform patient care.

Fully integrated health systems support better coordination of care and optimize the treatment of individual patients: linking research findings, treatment guidelines, treatment outcomes based on genetic profiles, and the individual patient’s own genetic profile will help to personalize treatments. Genomic information added to an individual’s electronic medical record along with improved data-sharing will facilitate clinicians’ ability to retrieve outcomes data based on patient characteristics.

Care models must be standardized, evidence-based practices must be executed, and care must be coordinated yet decentralized. In this way, clinicians can use the electronic medical record as an interoperable patient record to determine a personalized pathway to patient management. Standardization reduces variability in practice and permits seamless execution of care. Automation is imperative to achieving standardization, irrespective of the care supervisor. Investments must therefore be made to stimulate electronic medical record decision support.

In addition, larger data sets will be needed to identify the types of patients likely to respond to a treatment. Ideal data sets would be large enough to have adequate statistical power, be publicly available, standardize the collection of data with respect to response to therapy and toxicity, and contain data on concomitant collections of biologic samples.

Reimbursement must keep pace with medical advances

Payer willingness to reimburse for genomic tests and treatments will determine the pace of integration of personalized healthcare into clinical practice. Evidence that enhanced value can be derived from personalized approaches to medicine must be generated before personalized healthcare gains widespread acceptance by payers.

In addition, care-coordinated models must be developed to promote a value-based agenda that facilitates physician accountability and encourages clinical integration.

Innovative approaches are needed to educate providers

Development of point-of-care tools. Because information overload and lack of time are obstacles to clinicians’ efforts to incorporate genomic information into clinical practice, emphasis must be placed on genomic applications that have demonstrated utility. Engaging busy clinicians with point-of-care tools will maximize the relevance of the genomic information they receive and encourage effective use of their time. Decision-making should be supported through automatic risk assessment and management recommendations.

Educational tools. The National Coalition for Health Professional Education in Genetics (NCHPEG) was borne out of the recognition that the pace of genomic discovery far exceeds the pace at which healthcare providers can be educated. Its vision is to improve healthcare through informed use of genomic resources. NCHPEG is a member-based organization whose stakeholders include professional societies, hospitals, advocacy groups, and industry; it attempts to identify the specific educational needs for particular target audiences and then address these needs. It achieves its goals through the use of point-of-care tools and educational programs for continuing medical education credit.

One NCHPEG tool is the Pregnancy and Health Profile, which is a risk assessment and screening tool that attempts to improve the identification of women and babies at risk of developing genetic disease. It collects personal and family history information, performs a risk assessment for the clinician, and provides clinical decision support and education.

Another example of an educational tool is the “Genes to Society” curriculum initiated by The Johns Hopkins University School of Medicine in August 2009. The curriculum is being used as “the foundation for the scientific and clinical career development of future physicians.”¹⁵

Using personal genomic testing for education. The number of direct-to-consumer genomic tests is growing, and their market penetration will only increase as the cost of supplying a personal genome continues to decline. Whole genome scanning is being offered with the promise of identifying genetic predisposition to multiple diseases.

Participation in personal genomic testing may be a useful educational tool. Medical students, residents, and practicing physicians who participate in testing may be better equipped to advise patients about the processes involved and the potential utility and limitations of direct-to-consumer genotyping.¹⁴

Some companies that offer direct-to-consumer genomic testing provide telephone support from genetic counselors to help clients and their healthcare providers manage genetic information. Counselor services include identifying hereditary risks and reviewing diagnostic, preventive, and early-detection options.

Implementing pharmacogenomics into practice: Decision support systems are needed

A genomic decision support system that guides medication prescribing is needed to implement pharmacogenomic diagnostics. For such a system to achieve the goal of selecting the best medication for each individual, it must do the following:

• Test all polymorphisms relevant to the prescribing of any medication
• Be completed with no out-of-pocket cost to the patient
• Be performed before the patient requires the medication
• Provide results that will be interpreted as part of an individualized pharmacogenomics consult.¹¹

The 1200 Patients Project, a pilot research study under way at the Center for Personalized Therapeutics at the University of Chicago, is attempting to demonstrate the feasibility of incorporating pharmacogenomic testing into routine clinical practice for medication treatment decisions. DNA samples from patients who are taking at least one prescription medication are being tested for differences in genes that may suggest greater effectiveness or an increased risk of side effects from certain medications.

Cleveland Clinic’s genetics-based management of Lynch syndrome, the integration of genetics services during patient appointments at Cleveland Clinic, and a coordinated approach at The Ohio State University Medical Center are examples of practical applications of personalized healthcare.

Colorectal cancer management. One example of a personalized approach to medicine that improves health outcome while achieving cost savings is the genetics-based approach to HNPCC (Lynch syndrome) at Cleveland Clinic.

Early identification of Lynch syndrome by screening all colorectal cancer patients has been shown to save $250,000 per life-year gained in the United States.¹⁶ All colorectal cancers resected at the Cleveland Clinic main campus are routinely screened for MSI and IHC, and the process is embedded into the routine pathology workflow. With the patients’ foreknowledge, a gastrointestinal cancer genetics counselor scans the list of MSI and IHC results each week. Patients who are MSI-high or IHC-null are invited to receive genetic counseling and consider germline single-gene testing guided by the IHC results. With this active approach, patient uptake is 80%; in comparison, with a passive approach (MSI/IHC results are placed in the pathology report), the uptake is 14%¹⁷ (B. Leach and C. Eng, unpublished data, 2011).The successful application of the active approach requires the close cooperation of multiple disciplines, including members of the Cleveland Clinic Genomic Medicine, Pathology & Laboratory Medicine, and Digestive Disease Institutes.¹⁸

Integrating genetics-based care at Cleveland Clinic. Time delays for genetics services and limited collaboration with managing physicians who are not genetics specialists reduces genetics-based access and availability. Broad access to genetics clinical services is a means of clinical integration of genetics-enabled care. Providing patients and healthcare providers with easy access and short wait times is vital for clinical integration of genetics-enabled personalized healthcare.

As part of a patient-centered focus on medicine, clinical genetics services have been integrated throughout Cleveland Clinic. The system has two genetics clinics at its main campus and has embedded multiple genetics satellites within its nongenetics clinics, easing access. Genetics counselors are stationed in the same areas of practice as referring providers. Although patient encounters have increased at the medical genetics clinic in the Genomic Medicine Institute, genetics consultations no longer require an extra trip to the clinic since they are integrated into existing appointments. With this approach, large numbers of patients can be seen with no wait times.

Coordinated care at The Ohio State University Medical Center. The Center for Personalized Health Care at The Ohio State University Medical Center (OSUMC) embraces a systems-based care-coordinated model that improves care by executing standardized processes and automating routine tasks. The Institute for Systems Biology, which was established to develop genomics, wellness, and chronic disease biomarkers, collaborates with OSUMC on pilot projects in chronic disease, including cancer.

The OSUMC has a closed system in which it is the payer, employer, and provider of healthcare. This closed system serves as an ideal testing ground for reform. Goals include intervention in disease before symptoms appear and maintenance of wellness. The data from these demonstration projects should facilitate adoption of personalized healthcare by improving physician acceptance of personalized approaches and satisfying payers that personalized healthcare is cost-effective.

Personalized healthcare is the tailoring of medical management and patient care to the individual characteristics of each patient. This is achieved by incorporating the genetic and genomic makeup of an individual and his or her family medical history, environment, health-related behaviors, culture, and values into a complete health picture that can be used to customize care. Another level of personalization, often called personalized medicine, involves the selection of drug therapy through the use of tests to determine the genes and gene interactions that can reliably predict an individual’s response to a given therapy. This white paper focuses largely on the use of personalized healthcare as a risk prediction tool.

CURRENT STATUS OF PERSONALIZED HEALTHCARE

The case for personalized healthcare: Seeking value

To fully appreciate the need to advance the adoption of personalized healthcare into the delivery of medicine, one must consider the operation of our current healthcare system and its inefficiencies in terms of delivery and cost, its imprecision in the selection of therapies, and its inability to optimize outcomes. The framework of the US healthcare system as it is now constructed is expensive, disease-directed (instead of health- and wellness-directed), fragmented, and complex. While gross domestic product (GDP) in the United States has increased by approximately 3% per year,² the compounded growth rate of healthcare expenditures is 6.1% per year. Healthcare in the aggregate now represents 17.6% of GDP and 27% of spending by the federal government and consumes 28% of the average household’s discretionary spending, surpassed only by housing.³

Personalized healthcare can potentially address the need for value consistent with the healthcare system’s prominent share of the US economy. The growth in healthcare spending is certain to be a target of the newly created Joint Select Committee on Deficit Reduction (created by the Budget Control Act of 2011), which is tasked with deficit reduction of at least $1.5 trillion over a 10-year period.

The need to address healthcare costs has been recognized in the Patient Protection and Affordable Care Act, a central feature of which is the creation of integrated health systems that pay for value based on quality, cost containment, and consumer experience. The legislation was enacted to transform healthcare in a variety of ways to make it more sustainable. The Patient Protection and Affordable Care Act seeks to end fragmentation by expanding the use of information technology to reorganize the delivery system and to prevent errors, shifting from volume-based incentives to incentives based on performance and outcomes, and rewarding effective healthcare delivery measures and good patient outcomes.

A shift from reactive to proactive

The premise behind personalized healthcare is the potential for more efficient healthcare, with the assumption that efficiency translates to lower cost and improved patient care.

Although healthcare reform is most often referred to in the context of improving access to care through insurance coverage mandates, true healthcare reform shifts current healthcare models from the practice of reactive medicine to the practice of proactive medicine, in which the tools of personalized healthcare (ie, genetics, genomics, and other molecular diagnostics) enable not only better quality of care but also less expensive care.

Several personalized tools have long been accepted into mainstream medicine. Two examples are the family history, which is the least expensive and most available genetic evaluation tool, and ABO blood typing for safe transfusions (as ABO blood types are alleles of a gene). In fact, much of what is now considered mainstream medical management was at one time considered new. To allow further evolution of medical practice, our challenge is to open our minds to the possibility that personalized proactive medicine can improve healthcare.

The new vision: More precise management

The trial-and-error approach to treating disease is inefficient and costly. Many drugs are effective for only about 50% of patients, often leading to switching or intensification of therapy that requires multiple patient visits.

Personalized medicine considers pharmacokinetic and other characteristics in selection of drug dosages. Genomic testing has the potential to provide clearer insight into the more successful use of currently available medicines. Treatment decisions (ie, drug and drug dosage choice) made on the basis of pharmacogenomic testing should increase adherence through greater effectiveness and fewer adverse drug reactions.

A massive amount of waste is related to pharmaceutical nonadherence and noncompliance. The New England Healthcare Institute has estimated that medication nonadherence costs the healthcare system $290 billion annually.⁴ Methodologies targeted at individual patients to improve adherence to drug regimens could save the healthcare system a tremendous amount of money.

Cancer management as a model for personalized healthcare. Personalization of therapy is especially suited to cancer management, given that the response to nonspecific cancer chemotherapy is suboptimal in most patients yet exposes them to adverse effects.⁵ Large-scale sequencing of human cancer genomes is rapidly changing the understanding of cancer biology and is identifying new targets in difficult-to-treat diseases and causes of drug resistance. Applying this information can achieve cost savings by avoiding the use of treatments that are ineffective in particular patients.

Overexpression of genetic mutations renders some cancers less susceptible to certain treatments, but has opened the door to individualized molecularly guided treatment strategies. For example, among patients with non–small cell lung cancer, mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain predict response to EGFR tyrosine kinase inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors induce response in patients harboring a mutation in EML4-ALK genes. The recognition that human epidermal growth factor receptor (HER)-2 overexpression as a result of ERBB2 gene amplification occurs in as many as 20% of human breast cancers paved the way for the development of HER-2–targeted therapies. Patients with advanced colorectal cancer whose tumors express the KRAS gene mutation do not benefit from an EGFR inhibitor, whereas those with wild-type KRAS have improved survival with EGFR inhibitor treatment.⁶

BARRIERS TO THE APPLICATION OF PERSONALIZED HEALTHCARE

The availability and potential of personalized healthcare services and technology is not universally recognized or appreciated by consumers and clinicians. This lack of awareness contributes to a shortage of public support and limited demand for such services. Other barriers include misperceptions regarding the impact of personalized healthcare on disease management, limited incentives to use the available technology, and a knowledge gap among healthcare providers.

Lack of awareness and support

As applications of personalized healthcare advance to the point of clinical relevance, it is important to consider strategies for effective implementation into healthcare practice. Personalized healthcare, when more fully implemented, promises to accelerate the progress that healthcare reform hopes to achieve.

A major challenge to widespread adoption of personalized healthcare is limited recognition by the public and some healthcare providers that personalized healthcare can help to achieve better value. For personalized medicine to be embraced, the concept of “helix to health,” or translation of knowledge to the clinical setting, must resonate with the general public. Despite lack of public and provider awareness, the Personalized Medicine Coalition (PMC) has documented the existence of 56 personalized treatment and diagnostic products. Further, more than 200 product labels now recommend genetic testing prior to use to identify likely responders or inform of the influence of genetic variation on safety and effectiveness.

Consumers’ confidence in the efficacy and safety of medicines they take might contribute to the absence of public support for personalized healthcare. Similarly, despite the availability of genomic tests and tools, many physicians who might be advocates for personalized healthcare do not see the relevance of genomic medicine to their practices in terms of direct benefit to patient care.⁷

Apart from clinicians and consumers, support is also weak among health insurers and employers, even though the return on investment for personalized healthcare may be profound. Payers await the economic outcomes data that are crucial for their commitment to personalized healthcare. In addition, some have concerns about the ethical implications of personalized healthcare (see “Managing Genomic Information Responsibly”).

Perception of impact on treatment and prevention

A frequent criticism of genomics in medicine is that a genetic diagnosis does not help with patient management. In fact, surveillance and management of patients and family members often changes in response to a genetic diagnosis; knowing which gene is involved personalizes medical management. An example is the management of hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, which is the most common form of hereditary colon cancer. For a person with HNPCC, the lifetime risk of developing colorectal cancer is approximately 80%. Lynch syndrome is caused by germline mutations in one of three major mismatch repair (MMR) genes (MLH1, MSH2, and MSH6), and it predisposes to other cancers—uterine, stomach, and ovarian—as well. In women with Lynch syndrome, the lifetime risk for uterine cancer is 40%, compared with 4% in the general population.

At least 90% of patients with Lynch syndrome can be detected through MMR testing via microsatellite instability (MSI) or immunohistochemistry (IHC).⁸ MSI is a cellular phenotype that indicates a deficiency in at least one DNA MMR protein.

Although 5-fluorouracil–based chemo therapy is the standard of care for treatment of colorectal cancer, it confers no survival advantage in patients with MMR-IHC null (lack of expression of the gene) or MSI-high sporadic colorectal cancer.^9,10 Knowing the status of MMR proteins, therefore, would alter the decision regarding neoadjuvant and adjuvant chemotherapy.

Perception of value

Implementation of pharmacogenomics into clinical practice has lagged. One major reason is the lack of an obvious business model for a product that may only be required once in an individual patient’s lifetime.¹¹

A second barrier to integration lies in the limited demand for pharmacogenomics from physicians. This may be related partly to limited expertise in genetics among many physicians and to significant pushback from payers against today’s costs. Without reimbursement, little incentive exists for pharmacogenomics diagnostics. The incentive for physicians is further depressed, perhaps appropriately, when randomized controlled studies fail to demonstrate improved clinical outcomes with the use of pharmacogenomicbased treatment strategies. Two such examples are genotype-guided warfarin dosing, which failed in a randomized controlled trial to improve the proportion of international normalized ratios in the therapeutic range,¹² and dosing of clopidogrel based on platelet reactivity, which did not improve outcomes after percutaneous coronary intervention compared with standard dosing in a randomized double-blind clinical trial.¹³

A significant delay in obtaining the results of pharmacogenomics testing, which also postpones the prescribing encounter, is another major drawback.

A knowledge gap persists

At present, delivery of personalized healthcare is not part of the usual training of physicians and other healthcare providers who are the gatekeepers of medicine. Few medical schools incorporate human and medical genetics, genomics, and pharmacogenomics into their curricula. Genetics is inadequately emphasized in residency curricula outside of pediatrics, family medicine, and obstetrics/gynecology.

The resulting knowledge gap is a fundamental factor in the lack of interest in using genomics in clinical medicine. Educating consumers and physicians at all levels, including specialty societies as well as insurers, will be key to expanding utilization of personalized healthcare. Educating payers and providing them with more data on economic outcomes associated with personalized healthcare will be necessary for adoption into clinical practice; implementation will lag as long as reimbursement decisions do not support personalized approaches to medicine.

As DNA sequencing technology has become less expensive and more powerful, companies have begun to market personal genomic testing. As a result, patients who use these services will increasingly want to discuss the results with their physicians. A significant number of clinicians are unfamiliar with personal genomic testing and emerging genetic testing options. In one survey of physicians who attended educational sessions that discussed recent developments in clinical genetics, only 37% indicated that they were familiar with recent genetic research that affected their patients.¹⁴

Targeted education will enhance physicians’ understanding of probabilities and risk estimates from the use of genomic testing; it will also improve recognition of potential causes of patient anxiety, gene variants of unknown significance, and follow-up tests and procedures that can add to expense. Nonphysician healthcare providers (ie, nurses and physician assistants) of direct care also will benefit from education.

INTEGRATING PERSONALIZED HEALTHCARE INTO CLINICAL PRACTICE

Practice standardization and an overhaul of the health information technology (HIT) infrastructure are needed if we are to reap the potential benefits of personalized healthcare. Creative approaches to practitioner education, which are being used in some institutions, must become more widespread. Similarly, the models for successful integration of personalized healthcare that have been achieved in some settings also can be implemented in other institutions.

Data collection and integration must be prioritized

Personalized healthcare can be both predictive and preventive, but moving past the disruptive phase of personalized healthcare will require a radical transformation of the healthcare “ecosystem” and HIT infrastructure.

Although data collection in the current system is extensive, data sharing and data management are inadequate. The pace at which HIT links clinical and genetic information must be accelerated. HIT will expedite innovation and implementation of personalized healthcare, allowing greater integration of data to permit improved data analysis capability. The ultimate goal is to create an interoperable system that connects these data across hospitals and clinicians to help clinicians interpret genomic and other risk information to better inform patient care.

Fully integrated health systems support better coordination of care and optimize the treatment of individual patients: linking research findings, treatment guidelines, treatment outcomes based on genetic profiles, and the individual patient’s own genetic profile will help to personalize treatments. Genomic information added to an individual’s electronic medical record along with improved data-sharing will facilitate clinicians’ ability to retrieve outcomes data based on patient characteristics.

Care models must be standardized, evidence-based practices must be executed, and care must be coordinated yet decentralized. In this way, clinicians can use the electronic medical record as an interoperable patient record to determine a personalized pathway to patient management. Standardization reduces variability in practice and permits seamless execution of care. Automation is imperative to achieving standardization, irrespective of the care supervisor. Investments must therefore be made to stimulate electronic medical record decision support.

In addition, larger data sets will be needed to identify the types of patients likely to respond to a treatment. Ideal data sets would be large enough to have adequate statistical power, be publicly available, standardize the collection of data with respect to response to therapy and toxicity, and contain data on concomitant collections of biologic samples.

Reimbursement must keep pace with medical advances

Payer willingness to reimburse for genomic tests and treatments will determine the pace of integration of personalized healthcare into clinical practice. Evidence that enhanced value can be derived from personalized approaches to medicine must be generated before personalized healthcare gains widespread acceptance by payers.

In addition, care-coordinated models must be developed to promote a value-based agenda that facilitates physician accountability and encourages clinical integration.

Innovative approaches are needed to educate providers

Development of point-of-care tools. Because information overload and lack of time are obstacles to clinicians’ efforts to incorporate genomic information into clinical practice, emphasis must be placed on genomic applications that have demonstrated utility. Engaging busy clinicians with point-of-care tools will maximize the relevance of the genomic information they receive and encourage effective use of their time. Decision-making should be supported through automatic risk assessment and management recommendations.

Educational tools. The National Coalition for Health Professional Education in Genetics (NCHPEG) was borne out of the recognition that the pace of genomic discovery far exceeds the pace at which healthcare providers can be educated. Its vision is to improve healthcare through informed use of genomic resources. NCHPEG is a member-based organization whose stakeholders include professional societies, hospitals, advocacy groups, and industry; it attempts to identify the specific educational needs for particular target audiences and then address these needs. It achieves its goals through the use of point-of-care tools and educational programs for continuing medical education credit.

One NCHPEG tool is the Pregnancy and Health Profile, which is a risk assessment and screening tool that attempts to improve the identification of women and babies at risk of developing genetic disease. It collects personal and family history information, performs a risk assessment for the clinician, and provides clinical decision support and education.

Another example of an educational tool is the “Genes to Society” curriculum initiated by The Johns Hopkins University School of Medicine in August 2009. The curriculum is being used as “the foundation for the scientific and clinical career development of future physicians.”¹⁵

Using personal genomic testing for education. The number of direct-to-consumer genomic tests is growing, and their market penetration will only increase as the cost of supplying a personal genome continues to decline. Whole genome scanning is being offered with the promise of identifying genetic predisposition to multiple diseases.

Participation in personal genomic testing may be a useful educational tool. Medical students, residents, and practicing physicians who participate in testing may be better equipped to advise patients about the processes involved and the potential utility and limitations of direct-to-consumer genotyping.¹⁴

Some companies that offer direct-to-consumer genomic testing provide telephone support from genetic counselors to help clients and their healthcare providers manage genetic information. Counselor services include identifying hereditary risks and reviewing diagnostic, preventive, and early-detection options.

Implementing pharmacogenomics into practice: Decision support systems are needed

A genomic decision support system that guides medication prescribing is needed to implement pharmacogenomic diagnostics. For such a system to achieve the goal of selecting the best medication for each individual, it must do the following:

• Test all polymorphisms relevant to the prescribing of any medication
• Be completed with no out-of-pocket cost to the patient
• Be performed before the patient requires the medication
• Provide results that will be interpreted as part of an individualized pharmacogenomics consult.¹¹

The 1200 Patients Project, a pilot research study under way at the Center for Personalized Therapeutics at the University of Chicago, is attempting to demonstrate the feasibility of incorporating pharmacogenomic testing into routine clinical practice for medication treatment decisions. DNA samples from patients who are taking at least one prescription medication are being tested for differences in genes that may suggest greater effectiveness or an increased risk of side effects from certain medications.

Cleveland Clinic’s genetics-based management of Lynch syndrome, the integration of genetics services during patient appointments at Cleveland Clinic, and a coordinated approach at The Ohio State University Medical Center are examples of practical applications of personalized healthcare.

Colorectal cancer management. One example of a personalized approach to medicine that improves health outcome while achieving cost savings is the genetics-based approach to HNPCC (Lynch syndrome) at Cleveland Clinic.

Early identification of Lynch syndrome by screening all colorectal cancer patients has been shown to save $250,000 per life-year gained in the United States.¹⁶ All colorectal cancers resected at the Cleveland Clinic main campus are routinely screened for MSI and IHC, and the process is embedded into the routine pathology workflow. With the patients’ foreknowledge, a gastrointestinal cancer genetics counselor scans the list of MSI and IHC results each week. Patients who are MSI-high or IHC-null are invited to receive genetic counseling and consider germline single-gene testing guided by the IHC results. With this active approach, patient uptake is 80%; in comparison, with a passive approach (MSI/IHC results are placed in the pathology report), the uptake is 14%¹⁷ (B. Leach and C. Eng, unpublished data, 2011).The successful application of the active approach requires the close cooperation of multiple disciplines, including members of the Cleveland Clinic Genomic Medicine, Pathology & Laboratory Medicine, and Digestive Disease Institutes.¹⁸

Integrating genetics-based care at Cleveland Clinic. Time delays for genetics services and limited collaboration with managing physicians who are not genetics specialists reduces genetics-based access and availability. Broad access to genetics clinical services is a means of clinical integration of genetics-enabled care. Providing patients and healthcare providers with easy access and short wait times is vital for clinical integration of genetics-enabled personalized healthcare.

As part of a patient-centered focus on medicine, clinical genetics services have been integrated throughout Cleveland Clinic. The system has two genetics clinics at its main campus and has embedded multiple genetics satellites within its nongenetics clinics, easing access. Genetics counselors are stationed in the same areas of practice as referring providers. Although patient encounters have increased at the medical genetics clinic in the Genomic Medicine Institute, genetics consultations no longer require an extra trip to the clinic since they are integrated into existing appointments. With this approach, large numbers of patients can be seen with no wait times.

Coordinated care at The Ohio State University Medical Center. The Center for Personalized Health Care at The Ohio State University Medical Center (OSUMC) embraces a systems-based care-coordinated model that improves care by executing standardized processes and automating routine tasks. The Institute for Systems Biology, which was established to develop genomics, wellness, and chronic disease biomarkers, collaborates with OSUMC on pilot projects in chronic disease, including cancer.

The OSUMC has a closed system in which it is the payer, employer, and provider of healthcare. This closed system serves as an ideal testing ground for reform. Goals include intervention in disease before symptoms appear and maintenance of wellness. The data from these demonstration projects should facilitate adoption of personalized healthcare by improving physician acceptance of personalized approaches and satisfying payers that personalized healthcare is cost-effective.

Personalized healthcare is the tailoring of medical management and patient care to the individual characteristics of each patient. This is achieved by incorporating the genetic and genomic makeup of an individual and his or her family medical history, environment, health-related behaviors, culture, and values into a complete health picture that can be used to customize care. Another level of personalization, often called personalized medicine, involves the selection of drug therapy through the use of tests to determine the genes and gene interactions that can reliably predict an individual’s response to a given therapy. This white paper focuses largely on the use of personalized healthcare as a risk prediction tool.

CURRENT STATUS OF PERSONALIZED HEALTHCARE

The case for personalized healthcare: Seeking value

To fully appreciate the need to advance the adoption of personalized healthcare into the delivery of medicine, one must consider the operation of our current healthcare system and its inefficiencies in terms of delivery and cost, its imprecision in the selection of therapies, and its inability to optimize outcomes. The framework of the US healthcare system as it is now constructed is expensive, disease-directed (instead of health- and wellness-directed), fragmented, and complex. While gross domestic product (GDP) in the United States has increased by approximately 3% per year,² the compounded growth rate of healthcare expenditures is 6.1% per year. Healthcare in the aggregate now represents 17.6% of GDP and 27% of spending by the federal government and consumes 28% of the average household’s discretionary spending, surpassed only by housing.³

Personalized healthcare can potentially address the need for value consistent with the healthcare system’s prominent share of the US economy. The growth in healthcare spending is certain to be a target of the newly created Joint Select Committee on Deficit Reduction (created by the Budget Control Act of 2011), which is tasked with deficit reduction of at least $1.5 trillion over a 10-year period.

The need to address healthcare costs has been recognized in the Patient Protection and Affordable Care Act, a central feature of which is the creation of integrated health systems that pay for value based on quality, cost containment, and consumer experience. The legislation was enacted to transform healthcare in a variety of ways to make it more sustainable. The Patient Protection and Affordable Care Act seeks to end fragmentation by expanding the use of information technology to reorganize the delivery system and to prevent errors, shifting from volume-based incentives to incentives based on performance and outcomes, and rewarding effective healthcare delivery measures and good patient outcomes.

A shift from reactive to proactive

The premise behind personalized healthcare is the potential for more efficient healthcare, with the assumption that efficiency translates to lower cost and improved patient care.

Although healthcare reform is most often referred to in the context of improving access to care through insurance coverage mandates, true healthcare reform shifts current healthcare models from the practice of reactive medicine to the practice of proactive medicine, in which the tools of personalized healthcare (ie, genetics, genomics, and other molecular diagnostics) enable not only better quality of care but also less expensive care.

Several personalized tools have long been accepted into mainstream medicine. Two examples are the family history, which is the least expensive and most available genetic evaluation tool, and ABO blood typing for safe transfusions (as ABO blood types are alleles of a gene). In fact, much of what is now considered mainstream medical management was at one time considered new. To allow further evolution of medical practice, our challenge is to open our minds to the possibility that personalized proactive medicine can improve healthcare.

The new vision: More precise management

The trial-and-error approach to treating disease is inefficient and costly. Many drugs are effective for only about 50% of patients, often leading to switching or intensification of therapy that requires multiple patient visits.

Personalized medicine considers pharmacokinetic and other characteristics in selection of drug dosages. Genomic testing has the potential to provide clearer insight into the more successful use of currently available medicines. Treatment decisions (ie, drug and drug dosage choice) made on the basis of pharmacogenomic testing should increase adherence through greater effectiveness and fewer adverse drug reactions.

A massive amount of waste is related to pharmaceutical nonadherence and noncompliance. The New England Healthcare Institute has estimated that medication nonadherence costs the healthcare system $290 billion annually.⁴ Methodologies targeted at individual patients to improve adherence to drug regimens could save the healthcare system a tremendous amount of money.

Cancer management as a model for personalized healthcare. Personalization of therapy is especially suited to cancer management, given that the response to nonspecific cancer chemotherapy is suboptimal in most patients yet exposes them to adverse effects.⁵ Large-scale sequencing of human cancer genomes is rapidly changing the understanding of cancer biology and is identifying new targets in difficult-to-treat diseases and causes of drug resistance. Applying this information can achieve cost savings by avoiding the use of treatments that are ineffective in particular patients.

Overexpression of genetic mutations renders some cancers less susceptible to certain treatments, but has opened the door to individualized molecularly guided treatment strategies. For example, among patients with non–small cell lung cancer, mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain predict response to EGFR tyrosine kinase inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors induce response in patients harboring a mutation in EML4-ALK genes. The recognition that human epidermal growth factor receptor (HER)-2 overexpression as a result of ERBB2 gene amplification occurs in as many as 20% of human breast cancers paved the way for the development of HER-2–targeted therapies. Patients with advanced colorectal cancer whose tumors express the KRAS gene mutation do not benefit from an EGFR inhibitor, whereas those with wild-type KRAS have improved survival with EGFR inhibitor treatment.⁶

BARRIERS TO THE APPLICATION OF PERSONALIZED HEALTHCARE

The availability and potential of personalized healthcare services and technology is not universally recognized or appreciated by consumers and clinicians. This lack of awareness contributes to a shortage of public support and limited demand for such services. Other barriers include misperceptions regarding the impact of personalized healthcare on disease management, limited incentives to use the available technology, and a knowledge gap among healthcare providers.

Lack of awareness and support

As applications of personalized healthcare advance to the point of clinical relevance, it is important to consider strategies for effective implementation into healthcare practice. Personalized healthcare, when more fully implemented, promises to accelerate the progress that healthcare reform hopes to achieve.

A major challenge to widespread adoption of personalized healthcare is limited recognition by the public and some healthcare providers that personalized healthcare can help to achieve better value. For personalized medicine to be embraced, the concept of “helix to health,” or translation of knowledge to the clinical setting, must resonate with the general public. Despite lack of public and provider awareness, the Personalized Medicine Coalition (PMC) has documented the existence of 56 personalized treatment and diagnostic products. Further, more than 200 product labels now recommend genetic testing prior to use to identify likely responders or inform of the influence of genetic variation on safety and effectiveness.

Consumers’ confidence in the efficacy and safety of medicines they take might contribute to the absence of public support for personalized healthcare. Similarly, despite the availability of genomic tests and tools, many physicians who might be advocates for personalized healthcare do not see the relevance of genomic medicine to their practices in terms of direct benefit to patient care.⁷

Apart from clinicians and consumers, support is also weak among health insurers and employers, even though the return on investment for personalized healthcare may be profound. Payers await the economic outcomes data that are crucial for their commitment to personalized healthcare. In addition, some have concerns about the ethical implications of personalized healthcare (see “Managing Genomic Information Responsibly”).

Perception of impact on treatment and prevention

A frequent criticism of genomics in medicine is that a genetic diagnosis does not help with patient management. In fact, surveillance and management of patients and family members often changes in response to a genetic diagnosis; knowing which gene is involved personalizes medical management. An example is the management of hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, which is the most common form of hereditary colon cancer. For a person with HNPCC, the lifetime risk of developing colorectal cancer is approximately 80%. Lynch syndrome is caused by germline mutations in one of three major mismatch repair (MMR) genes (MLH1, MSH2, and MSH6), and it predisposes to other cancers—uterine, stomach, and ovarian—as well. In women with Lynch syndrome, the lifetime risk for uterine cancer is 40%, compared with 4% in the general population.

At least 90% of patients with Lynch syndrome can be detected through MMR testing via microsatellite instability (MSI) or immunohistochemistry (IHC).⁸ MSI is a cellular phenotype that indicates a deficiency in at least one DNA MMR protein.

Although 5-fluorouracil–based chemo therapy is the standard of care for treatment of colorectal cancer, it confers no survival advantage in patients with MMR-IHC null (lack of expression of the gene) or MSI-high sporadic colorectal cancer.^9,10 Knowing the status of MMR proteins, therefore, would alter the decision regarding neoadjuvant and adjuvant chemotherapy.

Perception of value

Implementation of pharmacogenomics into clinical practice has lagged. One major reason is the lack of an obvious business model for a product that may only be required once in an individual patient’s lifetime.¹¹

A second barrier to integration lies in the limited demand for pharmacogenomics from physicians. This may be related partly to limited expertise in genetics among many physicians and to significant pushback from payers against today’s costs. Without reimbursement, little incentive exists for pharmacogenomics diagnostics. The incentive for physicians is further depressed, perhaps appropriately, when randomized controlled studies fail to demonstrate improved clinical outcomes with the use of pharmacogenomicbased treatment strategies. Two such examples are genotype-guided warfarin dosing, which failed in a randomized controlled trial to improve the proportion of international normalized ratios in the therapeutic range,¹² and dosing of clopidogrel based on platelet reactivity, which did not improve outcomes after percutaneous coronary intervention compared with standard dosing in a randomized double-blind clinical trial.¹³

A significant delay in obtaining the results of pharmacogenomics testing, which also postpones the prescribing encounter, is another major drawback.

A knowledge gap persists

At present, delivery of personalized healthcare is not part of the usual training of physicians and other healthcare providers who are the gatekeepers of medicine. Few medical schools incorporate human and medical genetics, genomics, and pharmacogenomics into their curricula. Genetics is inadequately emphasized in residency curricula outside of pediatrics, family medicine, and obstetrics/gynecology.

The resulting knowledge gap is a fundamental factor in the lack of interest in using genomics in clinical medicine. Educating consumers and physicians at all levels, including specialty societies as well as insurers, will be key to expanding utilization of personalized healthcare. Educating payers and providing them with more data on economic outcomes associated with personalized healthcare will be necessary for adoption into clinical practice; implementation will lag as long as reimbursement decisions do not support personalized approaches to medicine.

As DNA sequencing technology has become less expensive and more powerful, companies have begun to market personal genomic testing. As a result, patients who use these services will increasingly want to discuss the results with their physicians. A significant number of clinicians are unfamiliar with personal genomic testing and emerging genetic testing options. In one survey of physicians who attended educational sessions that discussed recent developments in clinical genetics, only 37% indicated that they were familiar with recent genetic research that affected their patients.¹⁴

Targeted education will enhance physicians’ understanding of probabilities and risk estimates from the use of genomic testing; it will also improve recognition of potential causes of patient anxiety, gene variants of unknown significance, and follow-up tests and procedures that can add to expense. Nonphysician healthcare providers (ie, nurses and physician assistants) of direct care also will benefit from education.

INTEGRATING PERSONALIZED HEALTHCARE INTO CLINICAL PRACTICE

Practice standardization and an overhaul of the health information technology (HIT) infrastructure are needed if we are to reap the potential benefits of personalized healthcare. Creative approaches to practitioner education, which are being used in some institutions, must become more widespread. Similarly, the models for successful integration of personalized healthcare that have been achieved in some settings also can be implemented in other institutions.

Data collection and integration must be prioritized

Personalized healthcare can be both predictive and preventive, but moving past the disruptive phase of personalized healthcare will require a radical transformation of the healthcare “ecosystem” and HIT infrastructure.

Although data collection in the current system is extensive, data sharing and data management are inadequate. The pace at which HIT links clinical and genetic information must be accelerated. HIT will expedite innovation and implementation of personalized healthcare, allowing greater integration of data to permit improved data analysis capability. The ultimate goal is to create an interoperable system that connects these data across hospitals and clinicians to help clinicians interpret genomic and other risk information to better inform patient care.

Fully integrated health systems support better coordination of care and optimize the treatment of individual patients: linking research findings, treatment guidelines, treatment outcomes based on genetic profiles, and the individual patient’s own genetic profile will help to personalize treatments. Genomic information added to an individual’s electronic medical record along with improved data-sharing will facilitate clinicians’ ability to retrieve outcomes data based on patient characteristics.

Care models must be standardized, evidence-based practices must be executed, and care must be coordinated yet decentralized. In this way, clinicians can use the electronic medical record as an interoperable patient record to determine a personalized pathway to patient management. Standardization reduces variability in practice and permits seamless execution of care. Automation is imperative to achieving standardization, irrespective of the care supervisor. Investments must therefore be made to stimulate electronic medical record decision support.

In addition, larger data sets will be needed to identify the types of patients likely to respond to a treatment. Ideal data sets would be large enough to have adequate statistical power, be publicly available, standardize the collection of data with respect to response to therapy and toxicity, and contain data on concomitant collections of biologic samples.

Reimbursement must keep pace with medical advances

Payer willingness to reimburse for genomic tests and treatments will determine the pace of integration of personalized healthcare into clinical practice. Evidence that enhanced value can be derived from personalized approaches to medicine must be generated before personalized healthcare gains widespread acceptance by payers.

In addition, care-coordinated models must be developed to promote a value-based agenda that facilitates physician accountability and encourages clinical integration.

Innovative approaches are needed to educate providers

Development of point-of-care tools. Because information overload and lack of time are obstacles to clinicians’ efforts to incorporate genomic information into clinical practice, emphasis must be placed on genomic applications that have demonstrated utility. Engaging busy clinicians with point-of-care tools will maximize the relevance of the genomic information they receive and encourage effective use of their time. Decision-making should be supported through automatic risk assessment and management recommendations.

Educational tools. The National Coalition for Health Professional Education in Genetics (NCHPEG) was borne out of the recognition that the pace of genomic discovery far exceeds the pace at which healthcare providers can be educated. Its vision is to improve healthcare through informed use of genomic resources. NCHPEG is a member-based organization whose stakeholders include professional societies, hospitals, advocacy groups, and industry; it attempts to identify the specific educational needs for particular target audiences and then address these needs. It achieves its goals through the use of point-of-care tools and educational programs for continuing medical education credit.

One NCHPEG tool is the Pregnancy and Health Profile, which is a risk assessment and screening tool that attempts to improve the identification of women and babies at risk of developing genetic disease. It collects personal and family history information, performs a risk assessment for the clinician, and provides clinical decision support and education.

Another example of an educational tool is the “Genes to Society” curriculum initiated by The Johns Hopkins University School of Medicine in August 2009. The curriculum is being used as “the foundation for the scientific and clinical career development of future physicians.”¹⁵

Using personal genomic testing for education. The number of direct-to-consumer genomic tests is growing, and their market penetration will only increase as the cost of supplying a personal genome continues to decline. Whole genome scanning is being offered with the promise of identifying genetic predisposition to multiple diseases.

Participation in personal genomic testing may be a useful educational tool. Medical students, residents, and practicing physicians who participate in testing may be better equipped to advise patients about the processes involved and the potential utility and limitations of direct-to-consumer genotyping.¹⁴

Some companies that offer direct-to-consumer genomic testing provide telephone support from genetic counselors to help clients and their healthcare providers manage genetic information. Counselor services include identifying hereditary risks and reviewing diagnostic, preventive, and early-detection options.

Implementing pharmacogenomics into practice: Decision support systems are needed

A genomic decision support system that guides medication prescribing is needed to implement pharmacogenomic diagnostics. For such a system to achieve the goal of selecting the best medication for each individual, it must do the following:

• Test all polymorphisms relevant to the prescribing of any medication
• Be completed with no out-of-pocket cost to the patient
• Be performed before the patient requires the medication
• Provide results that will be interpreted as part of an individualized pharmacogenomics consult.¹¹

The 1200 Patients Project, a pilot research study under way at the Center for Personalized Therapeutics at the University of Chicago, is attempting to demonstrate the feasibility of incorporating pharmacogenomic testing into routine clinical practice for medication treatment decisions. DNA samples from patients who are taking at least one prescription medication are being tested for differences in genes that may suggest greater effectiveness or an increased risk of side effects from certain medications.

Cleveland Clinic’s genetics-based management of Lynch syndrome, the integration of genetics services during patient appointments at Cleveland Clinic, and a coordinated approach at The Ohio State University Medical Center are examples of practical applications of personalized healthcare.

Colorectal cancer management. One example of a personalized approach to medicine that improves health outcome while achieving cost savings is the genetics-based approach to HNPCC (Lynch syndrome) at Cleveland Clinic.

Early identification of Lynch syndrome by screening all colorectal cancer patients has been shown to save $250,000 per life-year gained in the United States.¹⁶ All colorectal cancers resected at the Cleveland Clinic main campus are routinely screened for MSI and IHC, and the process is embedded into the routine pathology workflow. With the patients’ foreknowledge, a gastrointestinal cancer genetics counselor scans the list of MSI and IHC results each week. Patients who are MSI-high or IHC-null are invited to receive genetic counseling and consider germline single-gene testing guided by the IHC results. With this active approach, patient uptake is 80%; in comparison, with a passive approach (MSI/IHC results are placed in the pathology report), the uptake is 14%¹⁷ (B. Leach and C. Eng, unpublished data, 2011).The successful application of the active approach requires the close cooperation of multiple disciplines, including members of the Cleveland Clinic Genomic Medicine, Pathology & Laboratory Medicine, and Digestive Disease Institutes.¹⁸

Integrating genetics-based care at Cleveland Clinic. Time delays for genetics services and limited collaboration with managing physicians who are not genetics specialists reduces genetics-based access and availability. Broad access to genetics clinical services is a means of clinical integration of genetics-enabled care. Providing patients and healthcare providers with easy access and short wait times is vital for clinical integration of genetics-enabled personalized healthcare.

As part of a patient-centered focus on medicine, clinical genetics services have been integrated throughout Cleveland Clinic. The system has two genetics clinics at its main campus and has embedded multiple genetics satellites within its nongenetics clinics, easing access. Genetics counselors are stationed in the same areas of practice as referring providers. Although patient encounters have increased at the medical genetics clinic in the Genomic Medicine Institute, genetics consultations no longer require an extra trip to the clinic since they are integrated into existing appointments. With this approach, large numbers of patients can be seen with no wait times.

Coordinated care at The Ohio State University Medical Center. The Center for Personalized Health Care at The Ohio State University Medical Center (OSUMC) embraces a systems-based care-coordinated model that improves care by executing standardized processes and automating routine tasks. The Institute for Systems Biology, which was established to develop genomics, wellness, and chronic disease biomarkers, collaborates with OSUMC on pilot projects in chronic disease, including cancer.

The OSUMC has a closed system in which it is the payer, employer, and provider of healthcare. This closed system serves as an ideal testing ground for reform. Goals include intervention in disease before symptoms appear and maintenance of wellness. The data from these demonstration projects should facilitate adoption of personalized healthcare by improving physician acceptance of personalized approaches and satisfying payers that personalized healthcare is cost-effective.

A 55-year-old woman has come to the clinic because of clear rhinorrhea and nasal congestion, which occur year-round but are worse in the winter. She reports that at times her nose runs continuously. Nasal symptoms have been present for 4 to 5 years but are worsening. The clear discharge is not associated with sneezing or itching. Though she lives with a cat, her symptoms are not exacerbated by close contact with it.

One year ago, an allergist performed skin testing but found no evidence of allergies as a cause of her rhinitis. A short course of intranasal steroids did not seem to improve her nasal symptoms.

The patient also has hypertension, hypothyroidism, and hot flashes due to menopause; these conditions are well controlled with lisinopril (Zestril), levothyroxine (Synthroid), and estrogen replacement. She has no history of asthma and has had no allergies to drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs.)

How should this patient be evaluated and treated?

COMMON, OFTEN OVERLOOKED

Many patients suffer from rhinitis, but this problem can be overshadowed by other chronic diseases seen in a medical clinic, especially during a brief office visit. When a patient presents with rhinitis, a key question is whether it is allergic or nonallergic.

This review will discuss the different forms of nonallergic rhinitis and their causes, and give recommendations about therapy.

RHINITIS: ALLERGIC OR NONALLERGIC?

While allergic rhinitis affects 30 and 60 million Americans annually, or between 10% to 30% of US adults,¹ how many have nonallergic rhinitis has been difficult to determine.

In a study in allergy clinics, 23% of patients with rhinitis had the nonallergic form, 43% had the allergic form, and 34% had both forms (mixed rhinitis).² Other studies have suggested that up to 52% of patients presenting to allergy clinics with rhinitis have nonallergic rhinitis.³

Over time, patients may not stay in the same category. One study found that 24% of patients originally diagnosed with nonallergic rhinitis developed positive allergy tests when retested 3 or more years after their initial evaluation.⁴

Regardless of the type, untreated or uncontrolled symptoms of rhinitis can significantly affect the quality of life.

All forms of rhinitis are characterized by one or more of the following symptoms: nasal congestion, clear rhinorrhea, sneezing, and itching. These symptoms can be episodic or chronic and can range from mild to debilitating. In addition, rhinitis can lead to systemic symptoms of fatigue, headache, sleep disturbance, and cognitive impairment and can be associated with respiratory symptoms such as sinusitis and asthma.¹

Mechanisms are mostly unknown

While allergic rhinitis leads to symptoms when airborne allergens bind with specific immunoglobulin E (IgE) in the nose, the etiology of most forms of nonallergic rhinitis is unknown. However, several mechanisms have been proposed. These include entopy (local nasal IgE synthesis with negative skin tests),⁵ nocioceptive dysfunction (hyperactive sensory receptors),⁶ and autonomic nervous system abnormalities (hypoactive or hyperactive dysfunction of sympathetic or parasympathetic nerves in the nose).⁷

Does this patient have an allergic cause of rhinitis?

When considering a patient with rhinitis, the most important question is, “Does this patient have an allergic cause of rhinitis?” Allergic and nonallergic rhinitis have similar symptoms, making them difficult to distinguish. However, their mechanisms and treatment differ. By categorizing a patient’s type of rhinitis, the physician can make specific recommendations for avoidance and can initiate treatment with the most appropriate therapy. Misclassification can lead to treatment failure, multiple visits, poor adherence, and frustration for patients with uncontrolled symptoms.

Patients for whom an allergic cause cannot be found by allergy skin testing or serum specific IgE immunoassay (Immunocap/RAST) for environmental aeroallergens are classified as having nonallergic rhinitis.

CLUES POINTING TO NONALLERGIC VS ALLERGIC RHINITIS

Nonallergic rhinitis encompasses a range of syndromes with overlapping symptoms. While tools such as the Rhinitis Diagnostic Worksheet are available to help differentiate allergic from nonallergic rhinitis, debate continues about whether it is necessary to characterize different forms of rhinitis before initiating treatment.⁸

The diagnosis of nonallergic rhinitis depends on a thorough history and physical examination. Key questions relate to the triggers that bring on the rhinitis, which will assist the clinician in determining which subtype of rhinitis a patient may be experiencing and therefore how to manage it. Clues:

• Patients with nonallergic rhinitis more often report nasal congestion and rhinorrhea, rather than sneezing and itching, which are predominant symptoms of allergic rhinitis.
• Patients with nonallergic rhinitis tend to develop symptoms at a later age.
• Common triggers of nonallergic rhinitis are changes in weather and temperature, food, perfumes, odors, smoke, and fumes. Animal exposure does not lead to symptoms.
• Patients with nonallergic rhinitis have few complaints of concomitant symptoms of allergic conjunctivitis (itching, watering, redness, and swelling).
• Many patients with nonallergic rhinitis find that antihistamines have no benefit. Also, they do not have other atopic diseases such as eczema or food allergies and have no family history of atopy.

PHYSICAL FINDINGS

Some findings on physical examination may help distinguish allergic from nonallergic rhinitis.

• Patients with long-standing allergic rhinitis may have an “allergic crease,” ie, a horizontal wrinkle near the tip of the nose caused by frequent upward wiping. Another sign may be a gothic arch, which is a narrowing of the hard palate occurring as a child.
• In allergic rhinitis, the turbinates are often pale, moist, and boggy with a bluish tinge.
• 
  Findings such as a deviated nasal septum, discolored nasal discharge, atrophic nasal mucosa, or nasal polyps should prompt consideration of the several subtypes of nonallergic rhinitis (Table 1).

CASE CONTINUED

Our patient’s symptoms can be caused by many different factors. Allergic triggers for rhinitis include both indoor and outdoor sources. The most common allergens include cat, dog, dust mite, cockroach, mold, and pollen allergens. The absence of acute sneezing and itching when around her cat and her recent negative skin-prick tests confirm that the rhinitis symptoms are not allergic.

In this patient, who has symptoms throughout the year but no allergic triggers, consideration of the different subtypes of nonallergic rhinitis may help guide further therapy.

SUBTYPES OF NONALLERGIC RHINITIS

Vasomotor rhinitis

Vasomotor rhinitis is thought to be caused by a variety of neural and vascular triggers, often without an inflammatory cause. These triggers lead to symptoms involving nasal congestion and clear rhinorrhea more than sneezing and itching. The symptoms can be sporadic, with acute onset in relation to identifiable nonallergic triggers, or chronic, with no clear trigger.

Gustatory rhinitis, for example, is a form of vasomotor rhinitis in which clear rhinorrhea occurs suddenly while eating or while drinking alcohol. It may be prevented by using nasal ipratropium (Atrovent) before meals.

Irritant-sensitive vasomotor rhinitis. In some patients, acute vasomotor rhinitis symptoms are brought on by strong odors, cigarette smoke, air pollution, or perfume. When asked, most patients easily identify which of these irritant triggers cause symptoms.

Weather- or temperature-sensitive vasomotor rhinitis. In other patients, a change in temperature, humidity, or barometric pressure or exposure to cold or dry air can cause nasal symptoms.⁹ These triggers are often hard to identify. Weather- or temperature-sensitive vasomotor rhinitis is often mistaken for seasonal allergic rhinitis because weather changes occur in close relation to the peak allergy seasons in the spring and fall. However, this subtype does not respond as well to intranasal steroids.⁹

Other nonallergic triggers of vasomotor rhinitis may include exercise, emotion, and sexual arousal (honeymoon rhinitis).¹⁰

Some triggers, such as tobacco smoke and perfume, are easy to avoid. Other triggers, such as weather changes, are unavoidable. If avoidance measures fail or are inadequate, medications (described below) can be used for prophylaxis and symptomatic treatment.

Drug-induced rhinitis

Drugs of various classes are known to cause either acute or chronic rhinitis. Drug-induced rhinitis has been divided into different types based on the mechanism involved.¹¹

The local inflammatory type occurs in aspirin-exacerbated respiratory disease, which is characterized by nasal polyposis with chronic rhinosinusitis, hyposmia, and moderate to severe persistent asthma. Aspirin and other NSAIDs induce an acute local inflammation, leading to severe rhinitis and asthma symptoms. Avoiding all NSAID products is recommended; aspirin desensitization may lead to improvement in rhinosinusitis and asthma control.

The neurogenic type of drug-induced rhinitis can occur with sympatholytic drugs such as alpha receptor agonists (eg, clonidine [Cat-apres]) and antagonists (eg, prazosin [Minipress]).¹¹ Vasodilators, including phosphodiesterase-5 inhibitors such as sildenafil (Viagra), can lead to acute rhinitis symptoms (“anniversary rhinitis”).

Unknown mechanisms. Many other medications can lead to rhinitis by unknown mechanisms, usually with normal findings on physical examination. These include beta-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, exogenous estrogens, oral contraceptives, antipsychotics, and gabapentin (Neurontin).

Correlating the initiation of a drug with the onset of rhinitis can help identify offending medications. Stopping the suspected medication, if feasible, is the first-line treatment.

Rhinitis medicamentosa, typically caused by overuse of over-the-counter topical nasal decongestants, is also classified under drug-induced rhinitis. Patients may not think of nasal decongestants as medications, and the physician may need to ask specifically about their use.

On examination, the nasal mucosa appears beefy red without mucous. Once a diagnosis is made, the physician should identify and treat the original etiology of the nasal congestion that led the patient to self-treat.

Patients with rhinitis medicamentosa often have difficulty discontinuing use of topical decongestants. They should be educated that the withdrawal symptoms can be severe and that more than one attempt at quitting may be needed. To break the cycle of rebound congestion, topical intranasal steroids should be used, though 5 to 7 days of oral steroids may be necessary.¹

Cocaine is a potent vasoconstrictor. Its illicit use should be suspected, especially if the patient presents with symptoms of chronic irritation such as frequent nosebleeds, crusting, and scabbing.¹²

Infectious rhinitis

One of the most common causes of acute rhinitis is upper respiratory infection.

Acute viral upper respiratory infection often presents with thick nasal discharge, sneezing, and nasal obstruction that usually clears in 7 to 10 days but can last up to 3 weeks. Acute bacterial sinusitis can follow, typically in fewer than 2% of patients, with symptoms of persistent nasal congestion, discolored mucus, facial pain, cough, and sometimes fever.

Chronic rhinosinusitis is a syndrome with sinus mucosal inflammation with multiple causes. It is clinically defined as persistent nasal and sinus symptoms lasting longer than 12 weeks and confirmed with computed tomography (CT).¹³ The CT findings of chronic rhinosinusitis include thickening of the lining of the sinus cavities or complete opacification of the pneumatized sinuses.

Major symptoms to consider for diagnosis include facial pain, congestion, obstruction, purulent discharge on examination, and changes in olfaction. Minor symptoms are cough, fatigue, headache, halitosis, fever, ear symptoms, and dental pain.

Treatment may involve 3 or more weeks of an oral antibiotic and a short course of an oral steroid, a daily nasal steroid spray, or both oral and nasal steroids. Most patients can be managed in the primary care setting, but they can be referred to an ear, nose, and throat specialist, an allergist, or an immunologist if their symptoms do not respond to initial therapy.

Patients with nonallergic rhinitis eosinophilic syndrome (NARES) are typically middle-aged and have perennial symptoms of sneezing, itching, and rhinorrhea with intermittent exacerbations. They occasionally have associated hyposmia (impaired sense of smell).¹ The diagnosis is made when eosinophils account for more than 5% of cells on a nasal smear and allergy testing is negative.

Patients may develop nasal polyposis and aspirin sensitivity.¹ Entopy has been described in some.¹⁴

Because of the eosinophilic inflammation, this form of nonallergic rhinitis responds well to intranasal steroids.

Immunologic causes

Systemic diseases can affect the nose and cause variable nasal symptoms that can be mistaken for rhinitis. Wegener granulomatosis, sarcoidosis, relapsing polychondritis, midline granulomas, Churg-Strauss syndrome, and amyloidosis can all affect the structures in the nose even before manifesting systemic symptoms. Granulomatous infections in the nose may lead to crusting, bleeding, and nasal obstruction.¹

A lack of a response to intranasal steroids or oral antibiotics should lead to consideration of these conditions, and treatment should be tailored to the specific disease.

Occupational rhinitis

Occupational exposure to chemicals, biologic aerosols, flour, and latex can lead to rhinitis, typically through an inflammatory mechanism. Many patients present with associated occupational asthma. The symptoms improve when the patient is away from work and worsen throughout the work week.

Avoiding the triggering agent is necessary to treat these symptoms.

Hormonal rhinitis

Hormonal rhinitis, ie, rhinitis related to metabolic and endocrine conditions, is most commonly associated with high estrogen states. Nasal congestion has been reported with pregnancy, menses, menarche, and the use of oral contraceptives.¹⁵ The mechanism for congestion in these conditions still needs clarification.

When considering drug therapy, only intranasal budesonide (Rhinocort) has a pregnancy category B rating.

While hypothyroidism and acromegaly have been mentioned in reviews of nonallergic rhinitis, evidence that these disorders cause nonallergic rhinitis is not strong.^16,17

Structurally related rhinitis

Anatomic abnormalities that can cause persistent nasal congestion include nasal septal deviation, turbinate hypertrophy, enlarged adenoids, tumors, and foreign bodies. These can be visualized by simple anterior nasal examination, nasal endoscopy, or radiologic studies. If structural causes lead to impaired quality of life or chronic rhinosinusitis, then consider referral to a specialist for possible surgical treatment.

Clear spontaneous rhinorrhea, with or without trauma, can be caused by cerebrospinal fluid leaking into the nasal cavity.¹⁸ A salty, metallic taste in the mouth can be a clue that the fluid is cerebrospinal fluid. A definitive diagnosis of cerebrospinal fluid leak is made by finding beta-2-transferrin in nasal secretions.

Atrophic rhinitis

Atrophic rhinitis is categorized as primary or secondary.

Primary (idiopathic) atrophic rhinitis is characterized by atrophy of the nasal mucosa and mucosal colonization with Klebsiella ozaenae associated with a foul-smelling nasal discharge.^19,20 This disorder has been primarily reported in young people who present with nasal obstruction, dryness, crusting, and epistaxis. They are from areas with warm climates, such as the Middle East, Southeast Asia, India, Africa, and the Mediterranean.

Secondary atrophic rhinitis can be a complication of nasal or sinus surgery, trauma, granulomatous disease, or exposure to radiation.²¹ This disorder is typically diagnosed with nasal endoscopy and treated with daily saline rinses with or without topical antibiotics.²¹

CASE CONTINUED

Questioned further, our patient says her symptoms are worse when her husband smokes, but that she continues to have congestion and rhinorrhea when he is away on business trips. She notes that her symptoms are often worse on airplanes (dry air with an acute change in barometric pressure), with weather changes, and in cold, dry environments. Symptoms are not induced by eating.

We note that she started taking lisinopril 2 years ago and conjugated equine estrogens 8 years ago. Review of systems reveals no history of facial or head trauma, polyps, or hyposmia.

The rhinitis and congestion are bilateral, and she denies headaches, acid reflux, and conjunctivitis. She has a mild throat-clearing cough that she attributes to postnasal drip.

On physical examination, her blood pressure is 118/76 mm Hg and her pulse is 64. Her turbinates are congested with clear rhinorrhea. The rest of the examination is normal.

AVOID TRIGGERS, PRETREAT BEFORE EXPOSURE

People with known environmental, non-immunologic, and irritant triggers should be reminded to avoid these exposures if possible.

If triggers are unavoidable, patients can pretreat themselves with topical nasal sprays before exposure. For example, if symptoms occur while on airplanes, then intranasal steroids or antihistamine sprays should be used before getting on the plane.

Fortunately, many effective drugs are available to treat nonallergic rhinitis. These have few adverse effects or drug interactions.

Intranasal steroid sprays are considered first-line therapy, as there are studies demonstrating effectiveness in nonallergic rhinitis.²² Intranasal fluticasone propionate (Flonase) and beclomethasone dipropionate (Beconase AQ) are approved by the US Food and Drug Administration (FDA) for treating nonallergic rhinitis. Intranasal mometasone (Nasonex) is approved for treating nasal polyps.

Nasal steroid sprays are most effective if the dominant nasal symptom is congestion, but they have also shown benefit for rhinorrhea, sneezing, and itching.

Side effects of nasal steroid sprays include nasal irritation (dryness, burning, and stinging) and epistaxis, the latter occurring in 5% to 10% of patients.²³

Intranasal antihistamines include azelastine (Astelin, Astepro) and olopatadine (Patanase). They are particularly useful for treating sneezing, congestion, and rhinorrhea.²⁴ Astelin is the only intranasal antihistamine with FDA approval for nonallergic rhinitis.

Side effects of this drug class include bitter taste (with Astelin), sweet taste (with Astepro), headache, and somnolence.

Oral antihistamines such as loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) are now available over the counter, and many patients try them before seeking medical care. These drugs may be helpful for those bothered by sneezing. However, no study has demonstrated their effectiveness for nonallergic rhinitis.²⁵ First-generation antihistamines may help with rhinorrhea via their anticholinergic effects.

Ipratropium, an antimuscarinic agent, decreases secretions by inhibiting the nasal parasympathetic mucous glands. Intranasal ipratropium 0.03% (Atrovent 0.03%) should be considered first-line if the dominant symptom is rhinorrhea. Higher-dose ipratropium 0.06% is approved for rhinorrhea related to the common cold or allergic rhinitis. Because it is used topically, little is absorbed. Its major side effect is nasal dryness.

Decongestants, either oral or topical, can relieve the symptoms of congestion and rhinorrhea in nonallergic rhinitis. They should only be used short-term, as there is little evidence to support their chronic use.

Phenylpropanolamine, a decongestant previously found in over-the-counter cough medicines, was withdrawn from the market in 2000 owing to concern that the drug, especially when used for weight suppression, was linked to hemorrhagic stroke in young women.^26,27 Other oral decongestants, ie, pseudoephedrine and phenylephrine, are still available, but there are no definitive guidelines for their use. Their side effects include tachycardia, increase in blood pressure, and insomnia.

Nasal saline irrigation has been used for centuries to treat rhinitis and sinusitis, despite limited evidence of benefit. A Cochrane review concluded that saline irrigation was well tolerated, had minor side effects, and could provide some relief of rhinosinusitis symptoms either as the sole therapeutic measure or as adjunctive treatment.²⁸ Hypertonic saline solutions, while possibly more effective than isotonic saline in improving mucociliary clearance, are not as well tolerated since they can cause nasal burning and irritation. Presumed benefits of saline irrigation are clearance of nasal secretions, improvement of nasociliary function, and removal of irritants and pollen from the nose.

A strategy

Imaging the sinuses with CT, which has replaced standard nasal radiography, may help if one is concerned about chronic rhinosinusitis, nasal polyps, or other anatomic condition that could contribute to persistent symptoms. Cost and radiation exposure should enter into the decision to obtain this study because a diagnosis based on the patient’s report of symptoms may be equally accurate.^29,30

CASE CONTINUED

Our patient has a number of potential causes of her symptoms. Exposure to second-hand tobacco smoke at home and to the air in airplanes could be acute triggers. Weather and temperature changes could explain her chronic symptoms in the spring and fall. Use of an angiotensin-converting enzyme inhibitor (in her case, lisinopril) and estrogen replacement therapy may contribute to perennial symptoms, but the onset of her nonallergic rhinitis does not correlate with the use of these drugs. There are no symptoms to suggest chronic rhinosinusitis or anatomic causes of her symptoms.

This case is typical of vasomotor rhinitis of the weather- or temperature-sensitive type. This diagnosis may explain her lack of improvement with intranasal steroids, though adherence and spray technique should be assessed. At this point, we would recommend trying topical antihistamines daily when chronic symptoms are present or as needed for acute symptoms.

A 55-year-old woman has come to the clinic because of clear rhinorrhea and nasal congestion, which occur year-round but are worse in the winter. She reports that at times her nose runs continuously. Nasal symptoms have been present for 4 to 5 years but are worsening. The clear discharge is not associated with sneezing or itching. Though she lives with a cat, her symptoms are not exacerbated by close contact with it.

One year ago, an allergist performed skin testing but found no evidence of allergies as a cause of her rhinitis. A short course of intranasal steroids did not seem to improve her nasal symptoms.

The patient also has hypertension, hypothyroidism, and hot flashes due to menopause; these conditions are well controlled with lisinopril (Zestril), levothyroxine (Synthroid), and estrogen replacement. She has no history of asthma and has had no allergies to drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs.)

How should this patient be evaluated and treated?

COMMON, OFTEN OVERLOOKED

Many patients suffer from rhinitis, but this problem can be overshadowed by other chronic diseases seen in a medical clinic, especially during a brief office visit. When a patient presents with rhinitis, a key question is whether it is allergic or nonallergic.

This review will discuss the different forms of nonallergic rhinitis and their causes, and give recommendations about therapy.

RHINITIS: ALLERGIC OR NONALLERGIC?

While allergic rhinitis affects 30 and 60 million Americans annually, or between 10% to 30% of US adults,¹ how many have nonallergic rhinitis has been difficult to determine.

In a study in allergy clinics, 23% of patients with rhinitis had the nonallergic form, 43% had the allergic form, and 34% had both forms (mixed rhinitis).² Other studies have suggested that up to 52% of patients presenting to allergy clinics with rhinitis have nonallergic rhinitis.³

Over time, patients may not stay in the same category. One study found that 24% of patients originally diagnosed with nonallergic rhinitis developed positive allergy tests when retested 3 or more years after their initial evaluation.⁴

Regardless of the type, untreated or uncontrolled symptoms of rhinitis can significantly affect the quality of life.

All forms of rhinitis are characterized by one or more of the following symptoms: nasal congestion, clear rhinorrhea, sneezing, and itching. These symptoms can be episodic or chronic and can range from mild to debilitating. In addition, rhinitis can lead to systemic symptoms of fatigue, headache, sleep disturbance, and cognitive impairment and can be associated with respiratory symptoms such as sinusitis and asthma.¹

Mechanisms are mostly unknown

While allergic rhinitis leads to symptoms when airborne allergens bind with specific immunoglobulin E (IgE) in the nose, the etiology of most forms of nonallergic rhinitis is unknown. However, several mechanisms have been proposed. These include entopy (local nasal IgE synthesis with negative skin tests),⁵ nocioceptive dysfunction (hyperactive sensory receptors),⁶ and autonomic nervous system abnormalities (hypoactive or hyperactive dysfunction of sympathetic or parasympathetic nerves in the nose).⁷

Does this patient have an allergic cause of rhinitis?

When considering a patient with rhinitis, the most important question is, “Does this patient have an allergic cause of rhinitis?” Allergic and nonallergic rhinitis have similar symptoms, making them difficult to distinguish. However, their mechanisms and treatment differ. By categorizing a patient’s type of rhinitis, the physician can make specific recommendations for avoidance and can initiate treatment with the most appropriate therapy. Misclassification can lead to treatment failure, multiple visits, poor adherence, and frustration for patients with uncontrolled symptoms.

Patients for whom an allergic cause cannot be found by allergy skin testing or serum specific IgE immunoassay (Immunocap/RAST) for environmental aeroallergens are classified as having nonallergic rhinitis.

CLUES POINTING TO NONALLERGIC VS ALLERGIC RHINITIS

Nonallergic rhinitis encompasses a range of syndromes with overlapping symptoms. While tools such as the Rhinitis Diagnostic Worksheet are available to help differentiate allergic from nonallergic rhinitis, debate continues about whether it is necessary to characterize different forms of rhinitis before initiating treatment.⁸

The diagnosis of nonallergic rhinitis depends on a thorough history and physical examination. Key questions relate to the triggers that bring on the rhinitis, which will assist the clinician in determining which subtype of rhinitis a patient may be experiencing and therefore how to manage it. Clues:

• Patients with nonallergic rhinitis more often report nasal congestion and rhinorrhea, rather than sneezing and itching, which are predominant symptoms of allergic rhinitis.
• Patients with nonallergic rhinitis tend to develop symptoms at a later age.
• Common triggers of nonallergic rhinitis are changes in weather and temperature, food, perfumes, odors, smoke, and fumes. Animal exposure does not lead to symptoms.
• Patients with nonallergic rhinitis have few complaints of concomitant symptoms of allergic conjunctivitis (itching, watering, redness, and swelling).
• Many patients with nonallergic rhinitis find that antihistamines have no benefit. Also, they do not have other atopic diseases such as eczema or food allergies and have no family history of atopy.

PHYSICAL FINDINGS

Some findings on physical examination may help distinguish allergic from nonallergic rhinitis.

• Patients with long-standing allergic rhinitis may have an “allergic crease,” ie, a horizontal wrinkle near the tip of the nose caused by frequent upward wiping. Another sign may be a gothic arch, which is a narrowing of the hard palate occurring as a child.
• In allergic rhinitis, the turbinates are often pale, moist, and boggy with a bluish tinge.
• 
  Findings such as a deviated nasal septum, discolored nasal discharge, atrophic nasal mucosa, or nasal polyps should prompt consideration of the several subtypes of nonallergic rhinitis (Table 1).

CASE CONTINUED

Our patient’s symptoms can be caused by many different factors. Allergic triggers for rhinitis include both indoor and outdoor sources. The most common allergens include cat, dog, dust mite, cockroach, mold, and pollen allergens. The absence of acute sneezing and itching when around her cat and her recent negative skin-prick tests confirm that the rhinitis symptoms are not allergic.

In this patient, who has symptoms throughout the year but no allergic triggers, consideration of the different subtypes of nonallergic rhinitis may help guide further therapy.

SUBTYPES OF NONALLERGIC RHINITIS

Vasomotor rhinitis

Vasomotor rhinitis is thought to be caused by a variety of neural and vascular triggers, often without an inflammatory cause. These triggers lead to symptoms involving nasal congestion and clear rhinorrhea more than sneezing and itching. The symptoms can be sporadic, with acute onset in relation to identifiable nonallergic triggers, or chronic, with no clear trigger.

Gustatory rhinitis, for example, is a form of vasomotor rhinitis in which clear rhinorrhea occurs suddenly while eating or while drinking alcohol. It may be prevented by using nasal ipratropium (Atrovent) before meals.

Irritant-sensitive vasomotor rhinitis. In some patients, acute vasomotor rhinitis symptoms are brought on by strong odors, cigarette smoke, air pollution, or perfume. When asked, most patients easily identify which of these irritant triggers cause symptoms.

Weather- or temperature-sensitive vasomotor rhinitis. In other patients, a change in temperature, humidity, or barometric pressure or exposure to cold or dry air can cause nasal symptoms.⁹ These triggers are often hard to identify. Weather- or temperature-sensitive vasomotor rhinitis is often mistaken for seasonal allergic rhinitis because weather changes occur in close relation to the peak allergy seasons in the spring and fall. However, this subtype does not respond as well to intranasal steroids.⁹

Other nonallergic triggers of vasomotor rhinitis may include exercise, emotion, and sexual arousal (honeymoon rhinitis).¹⁰

Some triggers, such as tobacco smoke and perfume, are easy to avoid. Other triggers, such as weather changes, are unavoidable. If avoidance measures fail or are inadequate, medications (described below) can be used for prophylaxis and symptomatic treatment.

Drug-induced rhinitis

Drugs of various classes are known to cause either acute or chronic rhinitis. Drug-induced rhinitis has been divided into different types based on the mechanism involved.¹¹

The local inflammatory type occurs in aspirin-exacerbated respiratory disease, which is characterized by nasal polyposis with chronic rhinosinusitis, hyposmia, and moderate to severe persistent asthma. Aspirin and other NSAIDs induce an acute local inflammation, leading to severe rhinitis and asthma symptoms. Avoiding all NSAID products is recommended; aspirin desensitization may lead to improvement in rhinosinusitis and asthma control.

The neurogenic type of drug-induced rhinitis can occur with sympatholytic drugs such as alpha receptor agonists (eg, clonidine [Cat-apres]) and antagonists (eg, prazosin [Minipress]).¹¹ Vasodilators, including phosphodiesterase-5 inhibitors such as sildenafil (Viagra), can lead to acute rhinitis symptoms (“anniversary rhinitis”).

Unknown mechanisms. Many other medications can lead to rhinitis by unknown mechanisms, usually with normal findings on physical examination. These include beta-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, exogenous estrogens, oral contraceptives, antipsychotics, and gabapentin (Neurontin).

Correlating the initiation of a drug with the onset of rhinitis can help identify offending medications. Stopping the suspected medication, if feasible, is the first-line treatment.

Rhinitis medicamentosa, typically caused by overuse of over-the-counter topical nasal decongestants, is also classified under drug-induced rhinitis. Patients may not think of nasal decongestants as medications, and the physician may need to ask specifically about their use.

On examination, the nasal mucosa appears beefy red without mucous. Once a diagnosis is made, the physician should identify and treat the original etiology of the nasal congestion that led the patient to self-treat.

Patients with rhinitis medicamentosa often have difficulty discontinuing use of topical decongestants. They should be educated that the withdrawal symptoms can be severe and that more than one attempt at quitting may be needed. To break the cycle of rebound congestion, topical intranasal steroids should be used, though 5 to 7 days of oral steroids may be necessary.¹

Cocaine is a potent vasoconstrictor. Its illicit use should be suspected, especially if the patient presents with symptoms of chronic irritation such as frequent nosebleeds, crusting, and scabbing.¹²

Infectious rhinitis

One of the most common causes of acute rhinitis is upper respiratory infection.

Acute viral upper respiratory infection often presents with thick nasal discharge, sneezing, and nasal obstruction that usually clears in 7 to 10 days but can last up to 3 weeks. Acute bacterial sinusitis can follow, typically in fewer than 2% of patients, with symptoms of persistent nasal congestion, discolored mucus, facial pain, cough, and sometimes fever.

Chronic rhinosinusitis is a syndrome with sinus mucosal inflammation with multiple causes. It is clinically defined as persistent nasal and sinus symptoms lasting longer than 12 weeks and confirmed with computed tomography (CT).¹³ The CT findings of chronic rhinosinusitis include thickening of the lining of the sinus cavities or complete opacification of the pneumatized sinuses.

Major symptoms to consider for diagnosis include facial pain, congestion, obstruction, purulent discharge on examination, and changes in olfaction. Minor symptoms are cough, fatigue, headache, halitosis, fever, ear symptoms, and dental pain.

Treatment may involve 3 or more weeks of an oral antibiotic and a short course of an oral steroid, a daily nasal steroid spray, or both oral and nasal steroids. Most patients can be managed in the primary care setting, but they can be referred to an ear, nose, and throat specialist, an allergist, or an immunologist if their symptoms do not respond to initial therapy.

Patients with nonallergic rhinitis eosinophilic syndrome (NARES) are typically middle-aged and have perennial symptoms of sneezing, itching, and rhinorrhea with intermittent exacerbations. They occasionally have associated hyposmia (impaired sense of smell).¹ The diagnosis is made when eosinophils account for more than 5% of cells on a nasal smear and allergy testing is negative.

Patients may develop nasal polyposis and aspirin sensitivity.¹ Entopy has been described in some.¹⁴

Because of the eosinophilic inflammation, this form of nonallergic rhinitis responds well to intranasal steroids.

Immunologic causes

Systemic diseases can affect the nose and cause variable nasal symptoms that can be mistaken for rhinitis. Wegener granulomatosis, sarcoidosis, relapsing polychondritis, midline granulomas, Churg-Strauss syndrome, and amyloidosis can all affect the structures in the nose even before manifesting systemic symptoms. Granulomatous infections in the nose may lead to crusting, bleeding, and nasal obstruction.¹

A lack of a response to intranasal steroids or oral antibiotics should lead to consideration of these conditions, and treatment should be tailored to the specific disease.

Occupational rhinitis

Occupational exposure to chemicals, biologic aerosols, flour, and latex can lead to rhinitis, typically through an inflammatory mechanism. Many patients present with associated occupational asthma. The symptoms improve when the patient is away from work and worsen throughout the work week.

Avoiding the triggering agent is necessary to treat these symptoms.

Hormonal rhinitis

Hormonal rhinitis, ie, rhinitis related to metabolic and endocrine conditions, is most commonly associated with high estrogen states. Nasal congestion has been reported with pregnancy, menses, menarche, and the use of oral contraceptives.¹⁵ The mechanism for congestion in these conditions still needs clarification.

When considering drug therapy, only intranasal budesonide (Rhinocort) has a pregnancy category B rating.

While hypothyroidism and acromegaly have been mentioned in reviews of nonallergic rhinitis, evidence that these disorders cause nonallergic rhinitis is not strong.^16,17

Structurally related rhinitis

Anatomic abnormalities that can cause persistent nasal congestion include nasal septal deviation, turbinate hypertrophy, enlarged adenoids, tumors, and foreign bodies. These can be visualized by simple anterior nasal examination, nasal endoscopy, or radiologic studies. If structural causes lead to impaired quality of life or chronic rhinosinusitis, then consider referral to a specialist for possible surgical treatment.

Clear spontaneous rhinorrhea, with or without trauma, can be caused by cerebrospinal fluid leaking into the nasal cavity.¹⁸ A salty, metallic taste in the mouth can be a clue that the fluid is cerebrospinal fluid. A definitive diagnosis of cerebrospinal fluid leak is made by finding beta-2-transferrin in nasal secretions.

Atrophic rhinitis

Atrophic rhinitis is categorized as primary or secondary.

Primary (idiopathic) atrophic rhinitis is characterized by atrophy of the nasal mucosa and mucosal colonization with Klebsiella ozaenae associated with a foul-smelling nasal discharge.^19,20 This disorder has been primarily reported in young people who present with nasal obstruction, dryness, crusting, and epistaxis. They are from areas with warm climates, such as the Middle East, Southeast Asia, India, Africa, and the Mediterranean.

Secondary atrophic rhinitis can be a complication of nasal or sinus surgery, trauma, granulomatous disease, or exposure to radiation.²¹ This disorder is typically diagnosed with nasal endoscopy and treated with daily saline rinses with or without topical antibiotics.²¹

CASE CONTINUED

Questioned further, our patient says her symptoms are worse when her husband smokes, but that she continues to have congestion and rhinorrhea when he is away on business trips. She notes that her symptoms are often worse on airplanes (dry air with an acute change in barometric pressure), with weather changes, and in cold, dry environments. Symptoms are not induced by eating.

We note that she started taking lisinopril 2 years ago and conjugated equine estrogens 8 years ago. Review of systems reveals no history of facial or head trauma, polyps, or hyposmia.

The rhinitis and congestion are bilateral, and she denies headaches, acid reflux, and conjunctivitis. She has a mild throat-clearing cough that she attributes to postnasal drip.

On physical examination, her blood pressure is 118/76 mm Hg and her pulse is 64. Her turbinates are congested with clear rhinorrhea. The rest of the examination is normal.

AVOID TRIGGERS, PRETREAT BEFORE EXPOSURE

People with known environmental, non-immunologic, and irritant triggers should be reminded to avoid these exposures if possible.

If triggers are unavoidable, patients can pretreat themselves with topical nasal sprays before exposure. For example, if symptoms occur while on airplanes, then intranasal steroids or antihistamine sprays should be used before getting on the plane.

Fortunately, many effective drugs are available to treat nonallergic rhinitis. These have few adverse effects or drug interactions.

Intranasal steroid sprays are considered first-line therapy, as there are studies demonstrating effectiveness in nonallergic rhinitis.²² Intranasal fluticasone propionate (Flonase) and beclomethasone dipropionate (Beconase AQ) are approved by the US Food and Drug Administration (FDA) for treating nonallergic rhinitis. Intranasal mometasone (Nasonex) is approved for treating nasal polyps.

Nasal steroid sprays are most effective if the dominant nasal symptom is congestion, but they have also shown benefit for rhinorrhea, sneezing, and itching.

Side effects of nasal steroid sprays include nasal irritation (dryness, burning, and stinging) and epistaxis, the latter occurring in 5% to 10% of patients.²³

Intranasal antihistamines include azelastine (Astelin, Astepro) and olopatadine (Patanase). They are particularly useful for treating sneezing, congestion, and rhinorrhea.²⁴ Astelin is the only intranasal antihistamine with FDA approval for nonallergic rhinitis.

Side effects of this drug class include bitter taste (with Astelin), sweet taste (with Astepro), headache, and somnolence.

Oral antihistamines such as loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) are now available over the counter, and many patients try them before seeking medical care. These drugs may be helpful for those bothered by sneezing. However, no study has demonstrated their effectiveness for nonallergic rhinitis.²⁵ First-generation antihistamines may help with rhinorrhea via their anticholinergic effects.

Ipratropium, an antimuscarinic agent, decreases secretions by inhibiting the nasal parasympathetic mucous glands. Intranasal ipratropium 0.03% (Atrovent 0.03%) should be considered first-line if the dominant symptom is rhinorrhea. Higher-dose ipratropium 0.06% is approved for rhinorrhea related to the common cold or allergic rhinitis. Because it is used topically, little is absorbed. Its major side effect is nasal dryness.

Decongestants, either oral or topical, can relieve the symptoms of congestion and rhinorrhea in nonallergic rhinitis. They should only be used short-term, as there is little evidence to support their chronic use.

Phenylpropanolamine, a decongestant previously found in over-the-counter cough medicines, was withdrawn from the market in 2000 owing to concern that the drug, especially when used for weight suppression, was linked to hemorrhagic stroke in young women.^26,27 Other oral decongestants, ie, pseudoephedrine and phenylephrine, are still available, but there are no definitive guidelines for their use. Their side effects include tachycardia, increase in blood pressure, and insomnia.

Nasal saline irrigation has been used for centuries to treat rhinitis and sinusitis, despite limited evidence of benefit. A Cochrane review concluded that saline irrigation was well tolerated, had minor side effects, and could provide some relief of rhinosinusitis symptoms either as the sole therapeutic measure or as adjunctive treatment.²⁸ Hypertonic saline solutions, while possibly more effective than isotonic saline in improving mucociliary clearance, are not as well tolerated since they can cause nasal burning and irritation. Presumed benefits of saline irrigation are clearance of nasal secretions, improvement of nasociliary function, and removal of irritants and pollen from the nose.

A strategy

Imaging the sinuses with CT, which has replaced standard nasal radiography, may help if one is concerned about chronic rhinosinusitis, nasal polyps, or other anatomic condition that could contribute to persistent symptoms. Cost and radiation exposure should enter into the decision to obtain this study because a diagnosis based on the patient’s report of symptoms may be equally accurate.^29,30

CASE CONTINUED

Our patient has a number of potential causes of her symptoms. Exposure to second-hand tobacco smoke at home and to the air in airplanes could be acute triggers. Weather and temperature changes could explain her chronic symptoms in the spring and fall. Use of an angiotensin-converting enzyme inhibitor (in her case, lisinopril) and estrogen replacement therapy may contribute to perennial symptoms, but the onset of her nonallergic rhinitis does not correlate with the use of these drugs. There are no symptoms to suggest chronic rhinosinusitis or anatomic causes of her symptoms.

This case is typical of vasomotor rhinitis of the weather- or temperature-sensitive type. This diagnosis may explain her lack of improvement with intranasal steroids, though adherence and spray technique should be assessed. At this point, we would recommend trying topical antihistamines daily when chronic symptoms are present or as needed for acute symptoms.

A 55-year-old woman has come to the clinic because of clear rhinorrhea and nasal congestion, which occur year-round but are worse in the winter. She reports that at times her nose runs continuously. Nasal symptoms have been present for 4 to 5 years but are worsening. The clear discharge is not associated with sneezing or itching. Though she lives with a cat, her symptoms are not exacerbated by close contact with it.

One year ago, an allergist performed skin testing but found no evidence of allergies as a cause of her rhinitis. A short course of intranasal steroids did not seem to improve her nasal symptoms.

The patient also has hypertension, hypothyroidism, and hot flashes due to menopause; these conditions are well controlled with lisinopril (Zestril), levothyroxine (Synthroid), and estrogen replacement. She has no history of asthma and has had no allergies to drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs.)

How should this patient be evaluated and treated?

COMMON, OFTEN OVERLOOKED

Many patients suffer from rhinitis, but this problem can be overshadowed by other chronic diseases seen in a medical clinic, especially during a brief office visit. When a patient presents with rhinitis, a key question is whether it is allergic or nonallergic.

This review will discuss the different forms of nonallergic rhinitis and their causes, and give recommendations about therapy.

RHINITIS: ALLERGIC OR NONALLERGIC?

While allergic rhinitis affects 30 and 60 million Americans annually, or between 10% to 30% of US adults,¹ how many have nonallergic rhinitis has been difficult to determine.

In a study in allergy clinics, 23% of patients with rhinitis had the nonallergic form, 43% had the allergic form, and 34% had both forms (mixed rhinitis).² Other studies have suggested that up to 52% of patients presenting to allergy clinics with rhinitis have nonallergic rhinitis.³

Over time, patients may not stay in the same category. One study found that 24% of patients originally diagnosed with nonallergic rhinitis developed positive allergy tests when retested 3 or more years after their initial evaluation.⁴

Regardless of the type, untreated or uncontrolled symptoms of rhinitis can significantly affect the quality of life.

All forms of rhinitis are characterized by one or more of the following symptoms: nasal congestion, clear rhinorrhea, sneezing, and itching. These symptoms can be episodic or chronic and can range from mild to debilitating. In addition, rhinitis can lead to systemic symptoms of fatigue, headache, sleep disturbance, and cognitive impairment and can be associated with respiratory symptoms such as sinusitis and asthma.¹

Mechanisms are mostly unknown

While allergic rhinitis leads to symptoms when airborne allergens bind with specific immunoglobulin E (IgE) in the nose, the etiology of most forms of nonallergic rhinitis is unknown. However, several mechanisms have been proposed. These include entopy (local nasal IgE synthesis with negative skin tests),⁵ nocioceptive dysfunction (hyperactive sensory receptors),⁶ and autonomic nervous system abnormalities (hypoactive or hyperactive dysfunction of sympathetic or parasympathetic nerves in the nose).⁷

Does this patient have an allergic cause of rhinitis?

When considering a patient with rhinitis, the most important question is, “Does this patient have an allergic cause of rhinitis?” Allergic and nonallergic rhinitis have similar symptoms, making them difficult to distinguish. However, their mechanisms and treatment differ. By categorizing a patient’s type of rhinitis, the physician can make specific recommendations for avoidance and can initiate treatment with the most appropriate therapy. Misclassification can lead to treatment failure, multiple visits, poor adherence, and frustration for patients with uncontrolled symptoms.

Patients for whom an allergic cause cannot be found by allergy skin testing or serum specific IgE immunoassay (Immunocap/RAST) for environmental aeroallergens are classified as having nonallergic rhinitis.

CLUES POINTING TO NONALLERGIC VS ALLERGIC RHINITIS

Nonallergic rhinitis encompasses a range of syndromes with overlapping symptoms. While tools such as the Rhinitis Diagnostic Worksheet are available to help differentiate allergic from nonallergic rhinitis, debate continues about whether it is necessary to characterize different forms of rhinitis before initiating treatment.⁸

The diagnosis of nonallergic rhinitis depends on a thorough history and physical examination. Key questions relate to the triggers that bring on the rhinitis, which will assist the clinician in determining which subtype of rhinitis a patient may be experiencing and therefore how to manage it. Clues:

• Patients with nonallergic rhinitis more often report nasal congestion and rhinorrhea, rather than sneezing and itching, which are predominant symptoms of allergic rhinitis.
• Patients with nonallergic rhinitis tend to develop symptoms at a later age.
• Common triggers of nonallergic rhinitis are changes in weather and temperature, food, perfumes, odors, smoke, and fumes. Animal exposure does not lead to symptoms.
• Patients with nonallergic rhinitis have few complaints of concomitant symptoms of allergic conjunctivitis (itching, watering, redness, and swelling).
• Many patients with nonallergic rhinitis find that antihistamines have no benefit. Also, they do not have other atopic diseases such as eczema or food allergies and have no family history of atopy.

PHYSICAL FINDINGS

Some findings on physical examination may help distinguish allergic from nonallergic rhinitis.

• Patients with long-standing allergic rhinitis may have an “allergic crease,” ie, a horizontal wrinkle near the tip of the nose caused by frequent upward wiping. Another sign may be a gothic arch, which is a narrowing of the hard palate occurring as a child.
• In allergic rhinitis, the turbinates are often pale, moist, and boggy with a bluish tinge.
• 
  Findings such as a deviated nasal septum, discolored nasal discharge, atrophic nasal mucosa, or nasal polyps should prompt consideration of the several subtypes of nonallergic rhinitis (Table 1).

CASE CONTINUED

Our patient’s symptoms can be caused by many different factors. Allergic triggers for rhinitis include both indoor and outdoor sources. The most common allergens include cat, dog, dust mite, cockroach, mold, and pollen allergens. The absence of acute sneezing and itching when around her cat and her recent negative skin-prick tests confirm that the rhinitis symptoms are not allergic.

In this patient, who has symptoms throughout the year but no allergic triggers, consideration of the different subtypes of nonallergic rhinitis may help guide further therapy.

SUBTYPES OF NONALLERGIC RHINITIS

Vasomotor rhinitis

Vasomotor rhinitis is thought to be caused by a variety of neural and vascular triggers, often without an inflammatory cause. These triggers lead to symptoms involving nasal congestion and clear rhinorrhea more than sneezing and itching. The symptoms can be sporadic, with acute onset in relation to identifiable nonallergic triggers, or chronic, with no clear trigger.

Gustatory rhinitis, for example, is a form of vasomotor rhinitis in which clear rhinorrhea occurs suddenly while eating or while drinking alcohol. It may be prevented by using nasal ipratropium (Atrovent) before meals.

Irritant-sensitive vasomotor rhinitis. In some patients, acute vasomotor rhinitis symptoms are brought on by strong odors, cigarette smoke, air pollution, or perfume. When asked, most patients easily identify which of these irritant triggers cause symptoms.

Weather- or temperature-sensitive vasomotor rhinitis. In other patients, a change in temperature, humidity, or barometric pressure or exposure to cold or dry air can cause nasal symptoms.⁹ These triggers are often hard to identify. Weather- or temperature-sensitive vasomotor rhinitis is often mistaken for seasonal allergic rhinitis because weather changes occur in close relation to the peak allergy seasons in the spring and fall. However, this subtype does not respond as well to intranasal steroids.⁹

Other nonallergic triggers of vasomotor rhinitis may include exercise, emotion, and sexual arousal (honeymoon rhinitis).¹⁰

Some triggers, such as tobacco smoke and perfume, are easy to avoid. Other triggers, such as weather changes, are unavoidable. If avoidance measures fail or are inadequate, medications (described below) can be used for prophylaxis and symptomatic treatment.

Drug-induced rhinitis

Drugs of various classes are known to cause either acute or chronic rhinitis. Drug-induced rhinitis has been divided into different types based on the mechanism involved.¹¹

The local inflammatory type occurs in aspirin-exacerbated respiratory disease, which is characterized by nasal polyposis with chronic rhinosinusitis, hyposmia, and moderate to severe persistent asthma. Aspirin and other NSAIDs induce an acute local inflammation, leading to severe rhinitis and asthma symptoms. Avoiding all NSAID products is recommended; aspirin desensitization may lead to improvement in rhinosinusitis and asthma control.

The neurogenic type of drug-induced rhinitis can occur with sympatholytic drugs such as alpha receptor agonists (eg, clonidine [Cat-apres]) and antagonists (eg, prazosin [Minipress]).¹¹ Vasodilators, including phosphodiesterase-5 inhibitors such as sildenafil (Viagra), can lead to acute rhinitis symptoms (“anniversary rhinitis”).

Unknown mechanisms. Many other medications can lead to rhinitis by unknown mechanisms, usually with normal findings on physical examination. These include beta-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, exogenous estrogens, oral contraceptives, antipsychotics, and gabapentin (Neurontin).

Correlating the initiation of a drug with the onset of rhinitis can help identify offending medications. Stopping the suspected medication, if feasible, is the first-line treatment.

Rhinitis medicamentosa, typically caused by overuse of over-the-counter topical nasal decongestants, is also classified under drug-induced rhinitis. Patients may not think of nasal decongestants as medications, and the physician may need to ask specifically about their use.

On examination, the nasal mucosa appears beefy red without mucous. Once a diagnosis is made, the physician should identify and treat the original etiology of the nasal congestion that led the patient to self-treat.

Patients with rhinitis medicamentosa often have difficulty discontinuing use of topical decongestants. They should be educated that the withdrawal symptoms can be severe and that more than one attempt at quitting may be needed. To break the cycle of rebound congestion, topical intranasal steroids should be used, though 5 to 7 days of oral steroids may be necessary.¹

Cocaine is a potent vasoconstrictor. Its illicit use should be suspected, especially if the patient presents with symptoms of chronic irritation such as frequent nosebleeds, crusting, and scabbing.¹²

Infectious rhinitis

One of the most common causes of acute rhinitis is upper respiratory infection.

Acute viral upper respiratory infection often presents with thick nasal discharge, sneezing, and nasal obstruction that usually clears in 7 to 10 days but can last up to 3 weeks. Acute bacterial sinusitis can follow, typically in fewer than 2% of patients, with symptoms of persistent nasal congestion, discolored mucus, facial pain, cough, and sometimes fever.

Chronic rhinosinusitis is a syndrome with sinus mucosal inflammation with multiple causes. It is clinically defined as persistent nasal and sinus symptoms lasting longer than 12 weeks and confirmed with computed tomography (CT).¹³ The CT findings of chronic rhinosinusitis include thickening of the lining of the sinus cavities or complete opacification of the pneumatized sinuses.

Major symptoms to consider for diagnosis include facial pain, congestion, obstruction, purulent discharge on examination, and changes in olfaction. Minor symptoms are cough, fatigue, headache, halitosis, fever, ear symptoms, and dental pain.

Treatment may involve 3 or more weeks of an oral antibiotic and a short course of an oral steroid, a daily nasal steroid spray, or both oral and nasal steroids. Most patients can be managed in the primary care setting, but they can be referred to an ear, nose, and throat specialist, an allergist, or an immunologist if their symptoms do not respond to initial therapy.

Patients with nonallergic rhinitis eosinophilic syndrome (NARES) are typically middle-aged and have perennial symptoms of sneezing, itching, and rhinorrhea with intermittent exacerbations. They occasionally have associated hyposmia (impaired sense of smell).¹ The diagnosis is made when eosinophils account for more than 5% of cells on a nasal smear and allergy testing is negative.

Patients may develop nasal polyposis and aspirin sensitivity.¹ Entopy has been described in some.¹⁴

Because of the eosinophilic inflammation, this form of nonallergic rhinitis responds well to intranasal steroids.

Immunologic causes

Systemic diseases can affect the nose and cause variable nasal symptoms that can be mistaken for rhinitis. Wegener granulomatosis, sarcoidosis, relapsing polychondritis, midline granulomas, Churg-Strauss syndrome, and amyloidosis can all affect the structures in the nose even before manifesting systemic symptoms. Granulomatous infections in the nose may lead to crusting, bleeding, and nasal obstruction.¹

A lack of a response to intranasal steroids or oral antibiotics should lead to consideration of these conditions, and treatment should be tailored to the specific disease.

Occupational rhinitis

Occupational exposure to chemicals, biologic aerosols, flour, and latex can lead to rhinitis, typically through an inflammatory mechanism. Many patients present with associated occupational asthma. The symptoms improve when the patient is away from work and worsen throughout the work week.

Avoiding the triggering agent is necessary to treat these symptoms.

Hormonal rhinitis

Hormonal rhinitis, ie, rhinitis related to metabolic and endocrine conditions, is most commonly associated with high estrogen states. Nasal congestion has been reported with pregnancy, menses, menarche, and the use of oral contraceptives.¹⁵ The mechanism for congestion in these conditions still needs clarification.

When considering drug therapy, only intranasal budesonide (Rhinocort) has a pregnancy category B rating.

While hypothyroidism and acromegaly have been mentioned in reviews of nonallergic rhinitis, evidence that these disorders cause nonallergic rhinitis is not strong.^16,17

Structurally related rhinitis

Anatomic abnormalities that can cause persistent nasal congestion include nasal septal deviation, turbinate hypertrophy, enlarged adenoids, tumors, and foreign bodies. These can be visualized by simple anterior nasal examination, nasal endoscopy, or radiologic studies. If structural causes lead to impaired quality of life or chronic rhinosinusitis, then consider referral to a specialist for possible surgical treatment.

Clear spontaneous rhinorrhea, with or without trauma, can be caused by cerebrospinal fluid leaking into the nasal cavity.¹⁸ A salty, metallic taste in the mouth can be a clue that the fluid is cerebrospinal fluid. A definitive diagnosis of cerebrospinal fluid leak is made by finding beta-2-transferrin in nasal secretions.

Atrophic rhinitis

Atrophic rhinitis is categorized as primary or secondary.

Primary (idiopathic) atrophic rhinitis is characterized by atrophy of the nasal mucosa and mucosal colonization with Klebsiella ozaenae associated with a foul-smelling nasal discharge.^19,20 This disorder has been primarily reported in young people who present with nasal obstruction, dryness, crusting, and epistaxis. They are from areas with warm climates, such as the Middle East, Southeast Asia, India, Africa, and the Mediterranean.

Secondary atrophic rhinitis can be a complication of nasal or sinus surgery, trauma, granulomatous disease, or exposure to radiation.²¹ This disorder is typically diagnosed with nasal endoscopy and treated with daily saline rinses with or without topical antibiotics.²¹

CASE CONTINUED

Questioned further, our patient says her symptoms are worse when her husband smokes, but that she continues to have congestion and rhinorrhea when he is away on business trips. She notes that her symptoms are often worse on airplanes (dry air with an acute change in barometric pressure), with weather changes, and in cold, dry environments. Symptoms are not induced by eating.

We note that she started taking lisinopril 2 years ago and conjugated equine estrogens 8 years ago. Review of systems reveals no history of facial or head trauma, polyps, or hyposmia.

The rhinitis and congestion are bilateral, and she denies headaches, acid reflux, and conjunctivitis. She has a mild throat-clearing cough that she attributes to postnasal drip.

On physical examination, her blood pressure is 118/76 mm Hg and her pulse is 64. Her turbinates are congested with clear rhinorrhea. The rest of the examination is normal.

AVOID TRIGGERS, PRETREAT BEFORE EXPOSURE

People with known environmental, non-immunologic, and irritant triggers should be reminded to avoid these exposures if possible.

If triggers are unavoidable, patients can pretreat themselves with topical nasal sprays before exposure. For example, if symptoms occur while on airplanes, then intranasal steroids or antihistamine sprays should be used before getting on the plane.

Fortunately, many effective drugs are available to treat nonallergic rhinitis. These have few adverse effects or drug interactions.

Intranasal steroid sprays are considered first-line therapy, as there are studies demonstrating effectiveness in nonallergic rhinitis.²² Intranasal fluticasone propionate (Flonase) and beclomethasone dipropionate (Beconase AQ) are approved by the US Food and Drug Administration (FDA) for treating nonallergic rhinitis. Intranasal mometasone (Nasonex) is approved for treating nasal polyps.

Nasal steroid sprays are most effective if the dominant nasal symptom is congestion, but they have also shown benefit for rhinorrhea, sneezing, and itching.

Side effects of nasal steroid sprays include nasal irritation (dryness, burning, and stinging) and epistaxis, the latter occurring in 5% to 10% of patients.²³

Intranasal antihistamines include azelastine (Astelin, Astepro) and olopatadine (Patanase). They are particularly useful for treating sneezing, congestion, and rhinorrhea.²⁴ Astelin is the only intranasal antihistamine with FDA approval for nonallergic rhinitis.

Side effects of this drug class include bitter taste (with Astelin), sweet taste (with Astepro), headache, and somnolence.

Oral antihistamines such as loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) are now available over the counter, and many patients try them before seeking medical care. These drugs may be helpful for those bothered by sneezing. However, no study has demonstrated their effectiveness for nonallergic rhinitis.²⁵ First-generation antihistamines may help with rhinorrhea via their anticholinergic effects.

Ipratropium, an antimuscarinic agent, decreases secretions by inhibiting the nasal parasympathetic mucous glands. Intranasal ipratropium 0.03% (Atrovent 0.03%) should be considered first-line if the dominant symptom is rhinorrhea. Higher-dose ipratropium 0.06% is approved for rhinorrhea related to the common cold or allergic rhinitis. Because it is used topically, little is absorbed. Its major side effect is nasal dryness.

Decongestants, either oral or topical, can relieve the symptoms of congestion and rhinorrhea in nonallergic rhinitis. They should only be used short-term, as there is little evidence to support their chronic use.

Phenylpropanolamine, a decongestant previously found in over-the-counter cough medicines, was withdrawn from the market in 2000 owing to concern that the drug, especially when used for weight suppression, was linked to hemorrhagic stroke in young women.^26,27 Other oral decongestants, ie, pseudoephedrine and phenylephrine, are still available, but there are no definitive guidelines for their use. Their side effects include tachycardia, increase in blood pressure, and insomnia.

Nasal saline irrigation has been used for centuries to treat rhinitis and sinusitis, despite limited evidence of benefit. A Cochrane review concluded that saline irrigation was well tolerated, had minor side effects, and could provide some relief of rhinosinusitis symptoms either as the sole therapeutic measure or as adjunctive treatment.²⁸ Hypertonic saline solutions, while possibly more effective than isotonic saline in improving mucociliary clearance, are not as well tolerated since they can cause nasal burning and irritation. Presumed benefits of saline irrigation are clearance of nasal secretions, improvement of nasociliary function, and removal of irritants and pollen from the nose.

A strategy

Imaging the sinuses with CT, which has replaced standard nasal radiography, may help if one is concerned about chronic rhinosinusitis, nasal polyps, or other anatomic condition that could contribute to persistent symptoms. Cost and radiation exposure should enter into the decision to obtain this study because a diagnosis based on the patient’s report of symptoms may be equally accurate.^29,30

CASE CONTINUED

Our patient has a number of potential causes of her symptoms. Exposure to second-hand tobacco smoke at home and to the air in airplanes could be acute triggers. Weather and temperature changes could explain her chronic symptoms in the spring and fall. Use of an angiotensin-converting enzyme inhibitor (in her case, lisinopril) and estrogen replacement therapy may contribute to perennial symptoms, but the onset of her nonallergic rhinitis does not correlate with the use of these drugs. There are no symptoms to suggest chronic rhinosinusitis or anatomic causes of her symptoms.

This case is typical of vasomotor rhinitis of the weather- or temperature-sensitive type. This diagnosis may explain her lack of improvement with intranasal steroids, though adherence and spray technique should be assessed. At this point, we would recommend trying topical antihistamines daily when chronic symptoms are present or as needed for acute symptoms.