Chest ACCP Member Benefits
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (25)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yaari, E.
Right arrow Articles by Kerem, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yaari, E.
Right arrow Articles by Kerem, E.
(Chest. 1999;115:1254-1258.)
© 1999 American College of Chest Physicians

Clinical Manifestations of Bordetella pertussis Infection in Immunized Children and Young Adults*

Einat Yaari, MD; Yael Yafe-Zimerman, MD; Shepard B. Schwartz, MD; Paul E. Slater, MD, MPH; Pesach Shvartzman, MD; Nachum Andoren, PhD; David Branski, MD and Eitan Kerem, MD

* From the Department of Pediatrics (Drs. Yaari, Yafe-Zimerman, Schwartz, Branski, and Kerem) and Unit of Pediatric Respiratory Medicine (Dr. Kerem), Shaare Zedek Medical Center, Jerusalem, Israel; Department of Epidemiology (Dr. Slater), Israel Ministry of Health, Jerusalem, Israel; Department of Family Medicine (Dr. Shvartzman), Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel; and Government Central Laboratories (Dr. Andoren), Israel Ministry of Health, Jerusalem, Israel.

Correspondence to: Eitan Kerem, MD, Pediatric Respiratory Medicine, Shaare Zedek Medical Center, PO Box 3235, Jerusalem 91031, Israel; e-mail: ek{at}cc.huji.ac.il


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: The incidence and prevalence of pertussis in adults have increased in recent years. It has been shown that previously immunized adults and adolescents are the main sources of transmission of Bordetella pertussis. The aim of this study was to describe the clinical presentation and the clinical course of pertussis in children and young adults who were immunized previously against B pertussis.

Design: Retrospective study.

Subjects: Children and young adults who were reported by local physicians to the Department of Epidemiology in the Israeli Ministry of Health with serologically confirmed pertussis and who were immunized previously were included. Information sought included personal data, epidemiologic data, signs and symptoms, laboratory results, initial diagnosis, and treatment.

Results: In the 95 previously immunized patients with serologically confirmed pertussis (mean age [± SD], 8.9 ± 4.4 years old; range, 5 to 30 years old), the mean duration from onset of symptoms until the final diagnosis of pertussis was 23 ± 15 days. The disease was usually atypical and generally mild. All the described patients had cough, usually prolonged, lasting 4 ± 3.6 weeks. Only 6% had the classic whoop. The mean WBC count was 8.7 ± 2.6 cells/mm6, and the lymphocyte count was 40 ± 12%. Two patients were admitted to the hospital for severe pneumonia. Among the reported cases, the proportion of patients between the ages of 10 and 45 years increased from 6.5% during the period from 1971 to 1980, to 26% during the period from 1980 to 1990, and to 38% during a 1989 outbreak.

Conclusions: Pertussis in previously immunized individuals is usually characterized by an atypical and relatively mild clinical course. Patients suffer mainly from a prolonged and persistent cough. Early diagnosis may lead to prompt administration of therapy. Prophylaxis of exposed persons might be effective in decreasing both severity and transmission of the disease.

Key Words: pertussis, clinical course • pertussis, epidemiology • pertussis, immunization


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Pertussis is an acute disease of the respiratory tract caused by Bordetella pertussis and characterized by progressive, repetitive, and paroxysmal coughing. It is regarded as a vaccine-preventable childhood illness. Classic pertussis lasts for 6 to 8 weeks, and it may be divided into three stages of clinical illness: catarrhal, paroxysmal, and convalescent. Whooping cough, cyanotic spells, and brief apnea episodes may also occur. Leukocytosis (20,000 to 100,000 cells/µL) with absolute lymphocytosis is characteristic. A chronic cough may persist for several months.1 Since the introduction of routine childhood immunization, pertussis morbidity and mortality have declined markedly.2 However, despite widespread vaccination, the disease was not eradicated, and an increased incidence rate has been reported in the last 2 decades.3 Cases have been reported primarily in nonimmunized or underimmunized populations,3 4 although outbreaks in well-immunized populations have also occurred. Several reports of pertussis outbreaks have been documented recently among older children and young adults who were previously immunized by vaccination.5 6 7 8 9 10 Furthermore, the incidence and prevalence of pertussis in adults are far higher than previously reported.11 12 13 14 15 Investigations of outbreaks have documented that adults develop infection with B pertussis and transmit the organism to susceptible children or other adults. Thus, previously immunized adults and adolescents are the main sources of transmission of B pertussis.15 16

The period of immunity induced by the pertussis vaccine tends to wane within 5 to 10 years and is shorter than that induced by the disease itself.17 Although the number of susceptible adults is increasing, it is difficult to determine the true incidence of pertussis in adults. Studies of adults with prolonged cough have found that 20 to 25% have serologic evidence of recent pertussis infection.11 12 13 14 18 19 20 However, adults may have an atypical presentation of pertussis with a modified clinical course.18 19 20 Because the signs and symptoms are usually nonspecific, pertussis is rarely considered in adults. This may lead to underdiagnosis and lack of, or a delay in, treatment. Furthermore, in vaccinated populations, adults maintain the ability to transmit B pertussis and are now the primary source of infection to susceptible children who may develop severe disease. Several studies on a small number of adult patients with pertussis reported the association between pertussis and chronic cough. However, to the best of our knowledge, the disease in previously immunized children and adults was documented in a limited number of patients. Therefore, the aim of this study was to investigate the clinical presentation and the course of the disease in previously immunized patients suffering from B pertussis infection.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Data regarding pertussis cases were obtained from the reports of local physicians of the Israel Ministry of Health. In Israel, physicians are required to report all cases of pertussis. Retrospectively, we analyzed all serologically confirmed cases between the years of 1986 and 1991 among individuals between the ages of 5 and 30 years old whose medical records were accessible.

In all cases, the Pertussis Laboratory of the Ministry of Health Central Laboratories confirmed the diagnosis of pertussis. For the purpose of this study, serologic confirmation of pertussis required an agglutination titer >= 1:640, or a fourfold rise in agglutination titers obtained 2 to 3 weeks apart, or positive pertussis IgM levels determined by enzyme-linked immunosorbent assay method.21 As cutoff, negative, and positive control, we used in-house standards calibrated by using a pertussis kit (Virotech GmbH; Russelsheim, Germany). Cultures were not taken.

The reporting physicians were contacted and asked to complete a questionnaire based on the patient's medical records. Information sought included personal data, epidemiologic data, signs and symptoms, laboratory results, initial diagnosis, treatment, and complications.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Since 1956, when pertussis immunization was first introduced in Israel, the number of yearly cases has declined from > 10,000 in 1955 to < 100 in 1996 (data reported by Israel Ministry of Health). Nonetheless, outbreaks of pertussis were reported between 1980 and 1990.9

Of the 1,091 cases reported between the years 1971 and 1980, the percentage of cases in the group aged 10 to 45 years was 6.5%. This figure increased during the next decade to 26% of the 754 reported cases. In 1989, 38% of the 219 reported cases occurred among individuals between the ages of 10 and 45 years.

Of the 552 cases of pertussis reported to the Ministry of Health from January 1986 to December 1991, 283 were children and young adults between the ages of 5 and 30 years (mean age, 10.4 ± 4.3 years old; median, 10 years old). Only 180 patients completed pertussis vaccination during childhood (63%). Clinical information was available for 95 individuals (39% were male) aged 5 to 30 years (mean age, 8.9 ± 4.4 years old; median, 9 years old). Seventy patients were 5 to 10 years old, 16 were 11 to 14 years old, and 9 were 15 to 30 years old. In 66% of these 95 patients, a history of contact with other individuals with pertussis was documented.

The mean duration from onset of symptoms until the final diagnosis of pertussis was 23 ± 15 days (range, 7 to 90 days; median, 14 days). In 46% of the cases, pertussis was the initial diagnosis; most of the patients who developed the disease were diagnosed in a small kibbutz community during a pertussis outbreak after the diagnosis of a first case. Various incorrect diagnoses were ascribed until the diagnosis of pertussis was established. Mycoplasma pneumoniae infection was the most common initial diagnosis (17%). Other initial diagnoses included sinusitis (7%), upper respiratory tract infection (4%), asthma (4%), laryngitis (3%), and suspected cystic fibrosis (1%).

Table 1 shows the frequency of symptoms in the 95 vaccinated patients with serologically confirmed pertussis. The disease in these patients was atypical, because the clinical course was generally mild. All the described patients had cough, usually prolonged, lasting 4 ± 3.6 weeks (range, 1 to 24 weeks; median 3 weeks). The cough was productive in 7% of the patients, whereas the rest had a dry cough; only 6% had the classic whoop. Of the patients, 13% had temperature > 37.5°C. Five of the patients visited an emergency department due to severe cough and dyspnea. Two required hospitalization: a 5-year-old girl with hypoxemia and a 10-year-old boy who developed secondary pneumonia with a small pleural effusion (pleurocentesis was not performed).


View this table:
[in this window]
[in a new window]

  		Table 1. Rate of Symptoms of Pertussis Among Previously Immunized Patients (n = 95)

 
CBC count was taken in 63 patients (66%). The mean WBC count was 8,700 ± 2,600/mm3 (range, 3,950 to 24,500/mm3; median, 8,600/mm3), and the lymphocyte count was 40 ± 12% (range, 10 to 68%; median, 38%). A chest radiograph was performed on 41 patients (42%) and disclosed abnormalities in 8 (20%). Four radiographs showed enhanced interstitial markings, two revealed bilateral perihilar shadows, one showed a right lower lobe infiltrate with a small amount of pleural effusion that could not be tapped, and one showed a right middle lobe infiltrate.

Sixty-eight patients (71%) received antibiotic therapy before the diagnosis of pertussis was made. The majority (78% of treated patients) received erythromycin, while others were treated with penicillin, amoxicillin, or doxycycline. In most patients there was no apparent clinical improvement with antibiotic therapy.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, the clinical presentation of pertussis in previously immunized children and young adults was found to be relatively mild yet protracted. The three typical stages of pertussis were absent. All patients had a prolonged cough that lasted for several weeks. The classic whooping cough was found in only a few patients, and lymphocytosis was generally absent. Thus, besides the long duration of cough, there may be no typical symptoms and signs that would alert the physician to consider the diagnosis of pertussis. Therefore, a heightened index of suspicion needs to be maintained. Considering the highly contagious potential of B pertussis, the history should be evaluated carefully to search for the presence of contacts suffering from similar symptoms. Many patients in our study were diagnosed in a small community during a pertussis outbreak after the diagnosis of the first case in an infant. Pertussis is rarely considered in adults until a child contact develops classic symptoms of the disease.22 Long et al23 underscored this fact in their study of the silent transmission of pertussis in families. Fifty percent of the contacts of pertussis had serologic evidence of a recent infection. Many had onset of illness before that of the index case. Most of the actual primary cases were > 14 years old. Thus, adults are the most important source of pertussis infection in the community.

Pertussis is much more common in adults than previously believed. In Israel, the proportion of adolescents and young adults among the reported pertussis cases increased dramatically from 6.5% from 1971 to 1980 to 26% from 1980 to 1990 and 38% during the 1989 outbreak. This trend is similar to that reported by the Centers for Disease Control and Prevention in the United States,24 which found that the proportion of pertussis cases occurring in patients > 10 years old increased from 15% from 1977 to 1978 to 28% during the time from 1992 to 1994. Before the vaccination era, the majority of pertussis cases occurred among infants. At that time, most of the population was exposed to pertussis and acquired natural immunity during the first years of life. Subsequent exposure to other infants and young children with pertussis served to boost immunity. However, the immunity induced by the whole-cell vaccination is shorter than the immunity induced by the disease itself, and tends to wane within 5 to 10 years.17 Thus, several decades after the introduction of the pertussis vaccine, many adults became susceptible to pertussis. Although the vaccine has been very effective in controlling the disease, the transmission of B pertussis has not been eliminated by vaccination and still causes morbidity, even in the vaccinated population.25 The 1993 pertussis outbreak in Cincinnati6 occurred primarily among immunized children, demonstrating that the vaccine did not give full protection against the disease. It is now appreciated that adults are a major reservoir for the spread of the infection to infants.15 16 20 Pertussis was also isolated from adults infected with HIV who complained of persistent cough.26

Yet, many physicians are unaware that adults may themselves develop pertussis.27 This, in addition to the nonspecific or relative lack of symptoms among adults with pertussis, has led to under-recognition of the disease in this age category.18

The only typical finding of pertussis in our study was a prolonged and disturbing cough that lasted from several weeks to several months. Only 5% had whoop. Similarly, Wright et al12 reported that cough was found in > 85% of the immunized adults with pertussis. Whoop and lymphocytosis were not observed. Prospective studies suggested that 20 to 25% of adults with persistent cough might have pertussis.3 19 Therefore, epidemiologic studies are needed to determine the incidence of pertussis in adults with respiratory illness.

In our study, the duration of time until the final diagnosis was 23 ± 15 days. This delay in diagnosis may be critical, because initiation of therapy after 3 weeks will not shorten the course of the disease or prevent its spread.28 Early diagnosis of pertussis relies on clinical suspicion, and the definitive diagnosis of pertussis relies on laboratory tests. Cultures are difficult to obtain and need to be taken early in the course of the disease.29 The percentage of positive cultures changes precipitously from 67 to 81% shortly after exposure to 25%, 14%, and 0% during the 3rd, 4th, and 5th weeks, respectively. Compared with cultures, direct fluorescent antigen detection is not more sensitive, and it is much less specific. Determination of antibody titer IgA and IgG to lymphocytosis promoting factor, filamentous hemagglutinin, and agglutinogens (antibodies against various virulent factors of B pertussis) is currently the most sensitive diagnostic test.29 30 Polymerase chain reaction, using a specific probe for B pertussis, may offer an early diagnosis of pertussis with high specificity and sensitivity.31 32 33

Pertussis in immunized children and young adults may be associated with morbidity. Five percent of the patients in our study visited an emergency department, and 2% were hospitalized. In addition, many patients had unnecessary and costly diagnostic evaluations and may have suffered from anxiety because of the undiagnosed chronic and protracted cough. Patients may experience loss of time from work or school due to the persistent cough of pertussis. Although the clinical presentation in immunized children and young adults is atypical and the course is usually benign, as shown in our study, pertussis may still cause morbidity.

In conclusion, pertussis should be considered in the differential diagnosis of persistent cough in previously immunized children and adults. Given the relative unavailability of accurate diagnostic tests and the usual absence of whoop or lymphocytosis, a recommendation for prompt administration of erythromycin in patients presenting with persistent cough and the prophylaxis of exposed persons before culture or serologic results are available should be considered. This would be effective in decreasing both disease severity and transmission of B pertussis.34 Because pertussis is not a life-threatening illness in adults, pertussis vaccination is not currently recommended in persons > 6 years of age. However, the availability of the less reactogenic acellular vaccine may allow booster immunization and should be thoughtfully considered.

Received for publication May 12, 1998. Accepted for publication December 3, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Beherman RE, Kliegman R, eds. Nelson's textbook of pediatrics. 15th ed. Philadelphia, PA: WB Saunders, 1996; 779–784
  2. Cherry, JD (1984) The epidemiology of pertussis and pertussis immunization in the United Kingdom and the United States: a comparative study. Curr Probl Pediatr 14,1-78[Medline]
  3. Black, S (1997) Epidemiology of pertussis. Pediatr Infect Dis J 16(4 suppl),S85-S89[CrossRef][ISI][Medline]
  4. Isaacson, J, Trollfors, B, Taranger, J, et al (1993) How common is whooping cough in a nonvaccinating country? Pediatr Infect Dis J 12,284-288[ISI][Medline]
  5. Halperin, SA, Bortolussi, R, MacLean, D, et al (1989) Persistence of pertussis in an immunized population: results of the Nova Scotia Enhanced Surveillance Program. J Pediatr 115,686-693[CrossRef][ISI][Medline]
  6. Christie, CD, Marx, ML, Marchant, CD, et al (1994) The 1993 epidemic of pertussis in Cincinnati: resurgence of disease in a highly immunized population of children. N Engl J Med 331,16-21[Abstract/Free Full Text]
  7. Mink, CA, Sirota, NM, Nugent, S (1994) Outbreak of pertussis in a fully immunized adolescent and adult population. Arch Pediatr Adolesc Med 148,153-157[Abstract]
  8. Rosenthal, S, Strebel, P, Cassiday, P, et al (1995) Pertussis infection in young adults during the 1993 outbreak in Chicago. J Infect Dis 171,1650-1652[ISI][Medline]
  9. Shvartzman, P, Swartz, T, Stopler, T, et al (1991) Outbreak of pertussis in a closed population with a high vaccination rate. Isr J Med Sci 27,137-140[ISI][Medline]
  10. de-Melker, HE, Conyn Van Spaendonck, MA, Rumke, HC, et al (1997) Pertussis in the Netherlands: an outbreak despite high levels of immunization with whole-cell vaccine. Emerg Infect Dis 3,175-178[ISI][Medline]
  11. Nenning, ME, Shinefield, HR, Edwards, KM, et al (1996) Prevalence and incidence of pertussis in an urban population. JAMA 275,1672-1674[Abstract]
  12. Wright, SW, Edwards, KM, Decker, MD, et al (1995) Pertussis infection in adults with persistent cough. JAMA 273,1044-1046[Abstract]
  13. Mink, CM, Cherry, JD, Christenson, P, et al (1992) A search for Bordetella pertussis infection in university students. Clin Infect Dis 14,464-471[ISI][Medline]
  14. Robertson, PW, Goldberg, H, Jarvie, BH, et al (1987) Bordetella pertussis infection. Med J Aust 147,522-525
  15. Cherry, JD, Baraff, LJ, Hewlett, E (1989) The past, present, and future of pertussis: the role of adults in epidemiology and future control. West J Med 150,319-328[ISI][Medline]
  16. Nelson, JD (1978) The changing epidemiology of pertussis in young infants: the role of adults as reservoirs of infection. Am J Dis Child 132,371-373[Abstract]
  17. Jenkinson, D (1988) Duration of effectiveness of pertussis vaccine: evidence from a 10-year community study BMJ (Clin Res Ed) 296,612-614
  18. Aoyama, T, Takeuchi, Y, Goto, A, et al (1992) Pertussis in adults. Am J Dis Child 146,163-166[Abstract]
  19. Herwaldt, LA (1991) Pertussis in adults: what physicians need to know. Arch Intern Med 151,1510-1512[Abstract]
  20. Cromer, BA, Boydos, J, Hackell, J, et al (1993) Unrecognized pertussis infection in adolescents. Am J Dis Child 147,575-577[Abstract]
  21. Mertsola, J, Ruuskanen, O, Kuronen, T, et al (1983) Serologic diagnosis of pertussis: comparison of enzyme-linked immunosorbent assay and bacterial agglutination. J Infect Dis 147,252-257[ISI][Medline]
  22. Deen, JL, Mink, CA, Cherry, JD, et al (1995) Household contact study of Bordetella pertussis infections. Clin Infect Dis 21,1211-1219[ISI][Medline]
  23. Long, SS, Welkon, CJ, Clark, JL (1990) Widespread silent transmission of pertussis in families: antibody correlates of infection and symptomatology. J Infect Dis 161,480-486[ISI][Medline]
  24. . Centers for Disease Control (1994) Reported vaccine-preventable diseases: United States, 1993, and the Childhood Immunization Initiative. MMWR Morb Mortal Wkly Rep 43,57-60[Medline]
  25. Fine, PEM, Clarkson, JA (1982) The recurrence of whooping cough: possible implications for assessment of vaccine efficacy. Lancet 1,666-669[ISI][Medline]
  26. Colebunders, R, Vael, C, Blot, K, et al (1994) Bordetella pertussis as a cause of chronic respiratory infection in an AIDS patient. Eur J Clin Microbiol Infect Dis 13,313-315[CrossRef][ISI][Medline]
  27. Linneman, CC, Jr, Nasenbeny, J (1977) Pertussis in the adult. Annu Rev Med 28,179-185[CrossRef][ISI][Medline]
  28. Hewlett, EL (1995) Bordetella species. Mandell, GI Bennett, JE Dolin, R eds. Mandell, Douglas and Bennett's principles and practice of infectious diseases 4th ed. ,2078-2084 Churchill Livingstone New York, NY.
  29. Steketee, RW, Wassilak, SGF, Adkins, WN, Jr, et al (1988) Evidence for a high attack rate and efficacy of erythromycin prophylaxis in a pertussis outbreak facility for the developmentally disabled. J Infect Dis 157,434-440[ISI][Medline]
  30. Muller, FM, Hoppe, JE, Von Konig, W (1997) Laboratory of pertussis: state of the art 1997. J Clin Microbiol 35,2435-2443[ISI][Medline]
  31. Huard, S, Hackel, C, Herzog, A, et al (1989) Specific identification of Bordetella pertussis by the polymerase chain reaction. Res Microbiol 140,477-487[Medline]
  32. Glare, EM, Paton, JC, Premier, RR, et al (1990) Analysis of repetitive DNA sequence from Bordetella pertussis and its application to diagnosis of pertussis using the polymerase chain reaction. J Clin Microbiol 28,1982-1987[Abstract/Free Full Text]
  33. Wadowsky, RM, Michaels, RH, Libert, T, et al (1996) Multiplex PCR-based assay for detection of Bordetella pertussis in nasopharyngeal swab specimens. J Clin Microbiol 34,2645-2649[Abstract]
  34. Bass, JW (1986) Erythromycin for treatment and prevention of pertussis. J Pediatr Infect Dis 5,154-157



This article has been cited by other articles:


Home page
 Arch Intern MedHome page
S. Schafer, H. Gillette, K. Hedberg, and P. Cieslak
A Community-wide Pertussis Outbreak: An Argument for Universal Booster Vaccination.
Arch Intern Med, June 26, 2006; 166(12): 1317 - 1321.
[Abstract] [Full Text] [PDF]

Home page
 CMAJHome page
A. E. Tozzi, L. Pastore Celentano, M. L. Ciofi degli Atti, and S. Salmaso
Diagnosis and management of pertussis
Can. Med. Assoc. J., February 15, 2005; 172(4): 509 - 515.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
A. E. Tozzi, L. Rava, M. L. Ciofi degli Atti, S. Salmaso, and the Progetto Pertosse Working Group
Clinical Presentation of Pertussis in Unvaccinated and Vaccinated Children in the First Six Years of Life
Pediatrics, November 1, 2003; 112(5): 1069 - 1075.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
R. S. Irwin and J. M. Madison
The Diagnosis and Treatment of Cough
N. Engl. J. Med., December 7, 2000; 343(23): 1715 - 1721.
[Full Text] [PDF]

Home page
 JWatch GeneralHome page
Atypical Presentation of Pertussis
Journal Watch (General), June 4, 1999; 1999(604): 5 - 5.
[Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (25)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yaari, E.
Right arrow Articles by Kerem, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yaari, E.
Right arrow Articles by Kerem, E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS