Editorials

Primary Care and Primary Immunodeficiencies

KATHLEEN E. SULLIVAN, M.D., PH.D.
Division of Immunology, Children's Hospital of Philadelphia

See article on page 2001.

In this issue of American Family Physician, Cooper and associates¹ provide a timely review of the diagnostic considerations of common primary immunodeficiencies. This is an exciting time in the field of immunology. It is worth reflecting on a few recent advances and highlighting the importance of maintaining a high index of suspicion for immunodeficiencies.

In 1997, the World Health Organization listed 60 primary immunodeficiencies.² An update in 1999 listed 71 defects of immunologic function and another 39 disorders in which immunodeficiency was a component.³ Since that time, the genetic defects for most immunodeficiencies have been identified, and new disorders have been recognized at a rate of one to two per year.

The improved understanding of signaling pathways and mechanisms of host defense also has led to the development of interventions for primary immunodeficiencies. The most dramatic new management strategy is gene therapy for adenosine deaminase­deficient and X-linked forms of severe combined immunodeficiency.⁴ The use of gene therapy remains somewhat controversial, but further refinements should improve its safety. Yet, the article by Cooper and colleagues¹ is a reminder that treatment advances are not helpful unless physicians can make the diagnosis early.

There is as yet no national database on primary immunodeficiencies. The most common diagnosis is IgA deficiency, with an estimated frequency of approximately one case per 500 white persons.⁵ Excluding developmental delay of immunoglobulin production (transient hypogammaglobulinemia of infancy, which occurs in an estimated one of every 1,000 infants⁵), the next most common primary immunodeficiency is chromosome 22q11.2 deletion syndrome (DiGeorge syndrome). This syndrome occurs with an estimated frequency of one case per 3,000 live births,⁶ regardless of ethnic or racial background.

Most family physicians can expect to encounter patients with primary immunodeficiencies. The most common primary immunodeficiencies would be seen in most large clinical practices. However, to ensure timely diagnosis, the family physician also should be familiar with the less common immunodeficiency disorders.

The article by Cooper and associates is important because it reminds the family physician to be alert to clinical presentations. With more than 70 disorders classified as congenital immunodeficiencies and other syndromes in which immunodeficiency is a significant component, it is somewhat overwhelming to attempt a thorough cataloging. Instead, it is helpful to remember that nearly all immunodeficiencies can be categorized according to the effector "arm" of the immune system that is impaired.

Patients with disorders of antibody production or function nearly always present with common recurrent infections. Each infection is unremarkable, but the frequency of the infections is excessive. Patients with common variable immunodeficiency (which becomes apparent later in life than other primary immunodeficiency disorders) typically present with new-onset recurrent sinusitis or bronchitis. Patients with antibody deficiencies usually do not look chronically ill.

The diagnosis of a disorder of antibody production or function nearly always will be suspected by the family physician, who has insight into a patient's pattern of visits for acute illnesses. Screening laboratory tests are readily obtainable and usually consist of immunoglobulin determinations and measurements of antibody responses to immunizations. Timely diagnosis of antibody defects is important, because untreated patients develop progressive end-organ damage and are at risk for life-threatening enteroviral infections.

Unlike patients with antibody disorders, who generally have typical infections, patients with T-cell defects often have unusual infections or atypical infections with common organisms. In children, T-cell defects are less common than antibody defects. In adults, T-cell defects (other than those resulting from human immunodeficiency virus [HIV] infection) seldom will be new diagnoses.

Recognition of patients with significant T-cell deficiencies is imperative, because delay of therapy adversely affects outcome. In infants, the frequencies of HIV infection and severe combined immunodeficiency are nearly the same. Thus, in most situations where HIV testing would be considered, primary T-cell defects also should be considered.

Although severe combined immunodeficiency may have various presentations, one key characteristic is the persistence of infection. In the absence of T-cell function, a simple upper respiratory tract infection progresses inexorably over one to two months. Hence, the family physician should be suspicious when an infant has an infection with a prolonged or atypical course.

A helpful finding is that most infants with severe combined immunodeficiency have diminished lymphocyte counts (less than 2,800 cells per mm³ [2.8 3 10⁹ per L]). An infant with chronic diarrhea, chronic wheezing, or recurrent Candida and a low lymphocyte count should be seen immediately by an immunologist. Urgent intervention is required for patients with severe combined immunodeficiency. Generally, the first step in analyzing these patients is to obtain lymphocyte counts, which often suggest the diagnosis of severe combined immunodeficiency.

Severe combined immunodeficiency nearly always is treated with stem cell transplantation. Polyethylene glycol­modified adenosine deaminase and gene therapy constitute reasonable experimental alternatives in certain patients. The success of all three treatments depends greatly on the status of the child at the time therapy is initiated. While stem cell transplantation or gene therapy is curative, an infant with severe end-organ compromise is less likely to survive the procedure.⁷

The primary immunodeficiencies with the least definable presentations are the phagocytic disorders. Most neutrophil disorders result in increased susceptibility to staphylococcal infections, whereas most macrophage activation disorders result in increased susceptibility to atypical mycobacterial infections. In addition, patients with neutrophil disorders often are predisposed to fungal and unusual bacterial infections. There are no easily obtainable screening tests for phagocytic disorders. Each disorder has its own specific diagnostic test.

The family physician is particularly well placed to recognize an abnormal infection pattern in a patient and initiate a work-up for suspected immunodeficiency disorder. Management of the patient with a primary immunodeficiency disorder requires a meticulous approach. Infections must be treated aggressively, and surveillance for unusual infections, malignancy, or autoimmune disease is critical. With appropriate medical support, the patient with a primary immunodeficiency disorder can be expected to lead a full and productive life.

Resources for patients, physicians, and caregivers are available through two organizations: the Immune Deficiency Foundation (http://www.primaryimmune.org) and The Jeffrey Modell Foundation (http://www.jmfworld. com).

REFERENCES

1. Cooper MA, Pommering TL, Korányi K. Primary immunodeficiencies. Am Fam Physician 2003;68: 2001-8,2011.
2. Primary immunodeficiency diseases. Report of a WHO scientific group. Clin Exp Immunol 1997; 109(suppl 1):1-28.
3. Primary immunodeficiency diseases. Report of an IUIS scientific committee. International Union of Immunological Societies. Clin Exp Immunol 1999; 118(suppl 1):1-28.
4. Fischer A, Hacein-Bey S, Le Deist F, de Saint Basile G, Cavazzana-Calvo M. Gene therapy for human severe combined immunodeficiencies. Immunity 2001;15:1-4.
5. Stiehm ER. Immunologic disorders in infants and children. 4th ed. Philadelphia: Saunders, 1996.
6. Devriendt K, Fryns JP, Mortier G, van Thienen MN, Keymolen K. The annual incidence of DiGeorge/ velocardiofacial syndrome. J Med Genet 1998; 35:789-90.
7. Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW, Myers LA, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999;340:508-16.

Kathleen E. Sullivan, M.D., Ph.D., is director of the immunology clinic at The Children's Hospital of Philadelphia.

Address correspondence to Kathleen E. Sullivan, M.D., Ph.D., Division of Immunology, The Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104. Reprints are not available from the author.

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Public Health--the Role of Family Physicians

THOMAS L. SCHWENK, M.D.
University of Michigan Health System
Ann Arbor, Michigan

In its recent report on educating health professionals to keep the public healthy, the Institute of Medicine (IOM) produced a thorough and scholarly assessment of public health problems and proposed educational solutions.¹ The following are paraphrased examples of some of the IOM's recommendations:

• Schools of public health and medicine should collaborate in community-based research on the prevention and care of chronic disease.
• All medical students should receive basic training in a population-based approach geared toward health promotion and disease prevention.
• A significant proportion of medical school graduates should receive advanced training at the Master of Public Health level to take an ecologic approach to population health.
• Schools of nursing should provide community-based training in an ecologic approach to health, in close collaboration with schools of public health.

In 281 pages, the IOM lays out an educational framework for the experiences and training necessary for several types of health professionals to enhance the public health system and protect the health of the public. Unfortunately, this framework is laid on the foundation of a health care system that is shaky, at best. Irrespective of the education of health professionals, the system itself is not designed to improve the health of populations--rather just the opposite. It focuses on the numerator (patients seen by health care professionals) rather than the denominator (patients in need, but not seen) in most quality measures.

Managed care systems manage finances rather than care, and rarely on a true population basis. An increasing number of patients are uninsured and underinsured,² with increasing exclusionary conditions; cost shifting to patients; restricted access; inadequate support for routine and preventive care; and poor care for patients with disabilities, chronic disease, terminal illness, and mental illness. Our political and social systems lack a commitment to the concept that basic health care is a right for all rather than a privilege dependent on employment status and income.

The health system is essentially unaddressed in the IOM report, and the system will need to change before these educational recommendations will find a fertile ground on which to grow and thrive. In addition, the medical care and public health systems have grown far apart in the United States during the past century.

Given all this, why would family physicians have any interest other than intellectual or theoretic in educating public health professionals to keep the public healthy?

The answer lies in the IOM report. Buried in the report are several critical concepts that family physicians intuitively understand and value: an ecologic approach to understanding health care, population-based medical informatics, a commitment to health promotion and disease prevention, cultural competence, community-based participatory research, and ethical dilemmas arising from the competing needs of individual patients and their communities.

The American Academy of Family Physicians, in its recent call for health care access and insurance for all Americans,³ bases its plan on several of these concepts. Despite the lack of a functional and effective health care system committed to public health, family physicians contribute to the health of our communities and practice populations by adapting their practices to these concepts in subtle, but effective, ways.

Family physicians might ask themselves specific questions about the health of the public as they work through their schedule of individual patients. For example:

• How much do I know about the major health threats to the specific patient populations for which I care?
• What kinds of medical care and educational programs could I design to respond to these threats?
• How much effort and energy do I or my office staff put into health promotion, such as smoking cessation, exercise promotion, and seat-belt use?
• How often do I ask my patients about interpersonal violence, hidden substance abuse, and the risk of sexually transmitted diseases?
• How would my practice fare in an immunization audit (e.g., for influenza or hepatitis B) compared with national benchmarks?
• What is the rate of postmyocardial infarction use of aspirin and beta blockers in my patients?
• If I do not know the answers to these questions, how could I find out?

The willingness of family physicians to ask and answer these questions will contribute in a large and tangible way to our specialty making a legitimate claim as the foundation of a health care system truly committed to the health of the public.

REFERENCES

1. 1. Who will keep the public healthy? Institute of Medicine. Accessed October, 2003 at: http://www.iom.edu/project.asp?id=4307.
2. 2. Committee on the Consequences of Uninsurance. Care without coverage. Institute of Medicine. Accessed October, 2003 at: http://www.iom.edu/project.asp?id=4660.
3. 3. Assuring health care coverage for all: a plan by the American Academy of Family Physicians. Accessible online at: http://www.aafp.org/unicov.xml.

Dr. Schwenk is professor and chair of the Department of Family Medicine at the University of Michigan Health System, Ann Arbor.

Address correspondence to Thomas L. Schwenk, M.D. Dept. of Family Medicine, University of Michigan Health System, L2003 Womens, Box 0239, Ann Arbor, MI 48109.

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DNA, Nobel Prizes, and Succinct Writing

JAY SIWEK, M.D.
Georgetown University Medical Center
Washington, D.C.

Fifty years ago, Watson and Crick¹ reported the double-helical structure of DNA that would eventually earn them the Nobel Prize. Given the far-reaching implications of their report, it was notable in its brevity--occupying a single page in Nature,¹ and weighing in at only 903 words.

A frequent lament I hear from authors is that their topics require more space than our standard guideline for length (about 2,000 words). When this happens, I think about the scene from the film, A River Runs Through It, in which the stern father looks over the homework essay of his young son, who must finish this task before he can go fly-fishing. More than once, he tells his son to go back to work and cut it in half. I also recall the quote: "I would have written you a shorter letter, but I didn't have time." Now, I'm going to add Watson and Crick's pithy piece to this Trifecta of calls for brevity in writing.

Every author should keep readers foremost in mind--how much time do they want to spend reading a clinical review? Readers value articles that are short and readable, and that readily convey the important points. And isn't the point in writing an article to actually have it read?

Watson and Crick's report shows that even complex topics and scientific breakthroughs do not have to be dense or verbose. They can and should be conveyed in plain, straightforward language, without unnecessary detail. In fact, looking over their report, I found about 50 words that could easily be cut without losing meaning. So, next time you set out to write, think short--think DNA--think Nobel Prize.

REFERENCE

1. 1. Watson JD, Crick FHC. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature 1953;171:737. Reprinted in: Ann Intern Med 2003;138:581. Also accessible at: http://www.nature.com/genomics/human/watson-crick.

Jay Siwek, M.D., is editor of American Family Physician. He is professor and chair of the Department of Family Medicine, Georgetown University Medical Center, Washington, D.C.

Address correspondence to Jay Siwek, M.D., Department of Family Medicine, 212 Kober-Cogan Hall, Georgetown University Medical Center, 3800 Reservoir Rd., N.W., Washington, DC 20007. Reprints are not available from the author.

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