Psychiatric Times.
No. 14
Psychiatric Aspects of the Impending Avian Flu Pandemic
By David J. Rissmiller, DO and Robert A. Steer |
December 1, 2007
Dr Rissmiller is associate professor and chair,
department of psychiatry, and Dr Steer is professor
of psychiatry, both at the University of
Medicine and Dentistry of New Jersey School of
Osteopathic Medicine in Cherry Hill. The authors
report no conflicts of interest concerning the
subject matter of this article.
Community mental health resources will also be heavily burdened. FluSurge 2.0 predicts that the hospital admission surge will lead to 273,665 hospital deaths. If we assume 2 survivors for each avian flu hospital death, using Piper and colleagues'19 20% rate of complicated grief among outpatients with bereavement, 109,466 new cases of pathological grief will be generated. This does not take into account cases of somatic reaction to fears of exposure or exposure-related PTSD. Psychiatrists will be called on to provide psycho-pharmacological support to mental health outreach workers trying to provide psychiatric first aid, which will be helpful in preventing the development of future psychiatric disorders.
Public response to a virulent pandemic will greatly influence the magnitude of psychological comorbidity. A unified perception of shared disaster will reduce psychiatric casualties. Alternatively, a perceived bias in pandemic resource allocation, such as hospital respirators and beds (the supply of which is predicted to run out in less than 1 week)20 will fuel a fractious response that will amplify psychiatric suffering.
Do psychological factors play a role in influenza susceptibility?
In the multifaceted connection between mental and physical disease, a significant body of research has established that various psychosocial stress factors affect susceptibility to influenza infection. Starting in the early 1990s, studies showed that laboratory stressed mice were immunologically suppressed and more susceptible to infection with the influenza A virus.21,22
Stress-mediated influenza vulnerability also affects humans. Cohen and colleagues23 rated 193 patients for a positive or negative attitude and then exposed them intranasally to influenza virus. Significantly fewer infections developed in subjects who scored high for positive attitude. In a sample of 608 persons stressed by serious mental illness, the death rate from serious medical disorders was more than 3 times the rate expected for the general US population.24 Multiple studies have demonstrated that depressive symptoms,25 high neuroticism scores,26 widowhood,27 increased loneliness/poor social network,28 hostility,29 and the stress of caring for a spouse with dementia30 all independently correlate with diminished antibody response to influenza vaccine. Finally, Vedhara and colleagues31 established that intervention with cognitive-behavioral therapy alleviates a stress-induced diminished immune response to vaccination.
Antiviral medications
Psychiatrists will also need to be familiar with the neuropsychiatric effects of antiviral treatments (Table 2). Since there is no human immunity to H5N1, all persons will require vaccination to prevent infection. The FDA approved the first H5N1 influenza vaccine in the spring of 2007, and it is now being nationally stockpiled (for further information, see http://www.cdc.gov/flu/avian/gen-info/qa.htm). It is hoped that this vaccine will ameliorate the impact of a pandemic until a more specific vaccine can be developed.
Influenza immunization is recommended for health care workers, adults aged 50 years or older, healthy children aged 6 to 59 months, and individuals with a chronic medical condition. In patients with AIDS, there is poor response to influenza vaccine if CD4+ cell counts are less than 200/µL. The only significant neurological reaction to influenza vaccination is an increased risk for Guillain-Barré syndrome, although its prevalence has decreased 4-fold from a high of 0.17 per 100,000 vaccinations in 1993-1994 to 0.04 in 2002-2003.
Amantadine, familiar to psychiatrists for treating neuroleptic-induced parkinsonism, and rimantadine are antiviral adamantane derivatives that have historically proved effective against influenza. However, recent resistant viral strains have been developing at an alarming rate. Approximately 30% of patients treated shed resistant variants within 5 days, and these resistant strains can easily infect others.32 In the United States, the frequency of adamantine resistance increased from 1.9% during the 2003-2004 influenza season to 11% during the 2004-2005 season.33 Adamantane derivatives also have not been effective against H5N1. In 2005, the CDC recommended that these agents no longer be used for treatment of or as prophylaxis against influenza outbreaks.
The neuraminidase inhibitors oseltamivir(Drug information on oseltamivir) and zanamivir(Drug information on zanamivir) block influenza A incursion into respiratory cells. Oseltamivir is given as a tablet, and zanamivir is administered via aerosol to patients free of lung conditions. When startedwithin 30 to 48 hours of the onset of influenza symptoms, neuraminidase inhibitors can reduce the duration of influenza by 1 day and reduce the risk of pneumonia, the need for antibiotics, hospitalization, and mortality. Development of viral strains resistant to neuraminidase inhibitors is rare,34 and adverse effects are similar to those with placebo. However, psychiatrists should be aware that recently the Japanese Ministry for Health, Labour, and Welfare issued a warning to doctors not to prescribe oseltamivir phosphate for adolescents aged 10 to 19 years because of 54 deaths of people taking the drug (16 of these in children or adolescents), many of which occurred by suicide. Because the preponderance of cases arose in 1 country the link remains uncertain.35
Long-term psychiatric effects
The final psychiatric sequelae of an avian flu pandemic may not occur for decades. Multiple studies have demonstrated a link between schizophrenia and mothers infected with influenza in their first or second trimester. Using epidemiological data, influenza epidemics have been statistically linked to an increased incidence of schizophrenia in Australia,36 Denmark,37 France,38 Great Britain,39-41 Finland,42 Japan,43 Poland,44 and the United States.45 The effect is especially prominent in female offspring.
One hypothesis posits that maternal influenza antibodies cross the fetal blood-brain barrier, causing the autoimmune system of the newborn to malfunction. Over time, autoantibodies attack specific infant brain structures, setting the stage for later schizophrenia. This theory has significant animal model support.46,47 In the most recent study on influenza and schizophrenia, Brown and colleagues48 followed serologically confirmed exposed mothers and found between a 3- and 7-fold increase in births of infants in whom schizophrenia subsequently developed. The influenza-schizophrenia link has been challenged by some authors on methodological grounds,49,50 and replication studies have not always confirmed the statistical rise in schizophrenia following influenza epidemics.51-53
To date there have been 5 reports studying the effect of influenza infection in pregnancy on the subsequent development of mood disorders in offspring. Findings were inconclusive: 2 of the studies showed a positive correlation, 2 showed a negative correlation, and 1 showed no correlation.54
Conclusion
Psychiatrists will play a key role in a collaborative response to any future avian influenza pandemic. It is critical that psychiatric, public health, and government agencies think through how they will respond to the dilemmas inherent to such a pandemic. To read more about preparedness, psychiatrists can access the referenced resources listed in the Additional Resources box that follows the reference list.
References
1. Mercer C. TV and radio.
The Frederick Post. Frederick, Md; Friday, March 23, 1956.
2. Arabi Y, Gomersall CD, Ahmed QA, et al. The critically ill avian influenza A (H5N1) patient.
Crit Care Med. 2007; 35:1397-1403.
3. Keawcharoen J, Oraveerakul K, Kuiken T, et al. Avian influenza H5N1 in tigers and leopards.
Emerg Infect Dis. 2004;10:2189-2191.
4. Update: WHO-confirmed human cases of avian influenza A (H5N1) infection, 25 November 2003-24 November 2006.
Wkly Epidemiol Rec. 2007;82:41-48. Available at:
http://www.who.int/wer/2007/wer8206.pdf. Accessed October 9, 2007.
5. Shives LR, ed.
Basic Concepts of Psychiatric-Mental Health Nursing. 6th ed. Anxiety Disorders. Philadelphia: Lippincott Williams & Wilkins; 2005:chap 6.
6. Grace SL, Hershenfield K, Robertson E, Stewart DE. The occupational and psychosocial impact of SARS on academic physicians in three affected hospitals.
Psychosomatics. 2005;46:385-391.
7. Hawryluck L, Gold WL, Robinson S, et al. SARS control and psychological effects of quarantine, Toronto, Canada.
Emerg Infect Dis. 2004;10:1206-1212.
8. Styra R. Ongoing distress in patients who have recovered from SARS. Presented at: the 45th ICAAC meeting of the American Society for Microbiology; December 16-19, 2005; Washington, DC. Available at:
http://www.asm.org/Media/index.asp?bid=39229. Accessed October 9, 2007.
9. Straus SE, Wilson K, Rambaldini G, et al. Severe acute respiratory syndrome and its impact on professionalism: qualitative study of physicians' behaviour during an emerging healthcare crisis.
BMJ. 2004;329:83.
10. Zhang X, Meltzer MI, Wortley P. FluSurge 2.0 (Beta test version). Centers for Disease Control and Prevention, US Department of Health and Human Services; 2005. Available at:
http://www.cdc.gov/flu/flusurge.htm. Accessed June 13, 2007.
11. United States Census Bureau. Projections of the total resident population by 5-year age groups and sex with special age categories, middle series, 2006 to 2010. National population projections. I. Summary files. Washington, DC: US Census Bureau, January 2000 (NP-T3-C).
12. American Hospital Association. Fast facts on US hospitals. Available at:
http://www.aha.org/aha/resource-center/Statistics-and-Studies/fast-facts.html. Accessed June 13, 2007.
13. Study: 25% of hospital patients have mental illness. Available at:
http://www.fiercehealthcare.com/story/study25-of-hospital-patients-have-mental-illness/2007-04-11. Accessed June 18, 2007.
14. Aladjem AD. Consultation-Liaison Psychiatry. In: Sadock BJ, Sadock VA, eds.
Kaplan & Sadock's Comprehensive Textbook of Psychiatry. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2005.
15. Koskiniemi M, Rantalaiho T, Piiparinen H, et al. Infections of the central nervous system of suspected viral origin: a collaborative study from Finland.
J Neurovirol. 2001;7:400-408.
16. Madjid M, Miller CC, Zarubaev VV, et al. Influenza epidemics and acute respiratory disease activity are associated with a surge in autopsy-confirmed coronary heart disease death: results from 8 years of autopsies in 34 892 subjects.
Eur Heart J. 2007;28:1205-1210.
17. Field TS, Zhu H, Tarrant M, et al. Relationship between supra-annual trends in influenza rates and stroke occurrence.
Neuroepidemiology. 2004;23:228-235.
18. Sokol DK. Virulent epidemics and scope of duty of care.
Policy Rev. 2006;12:1238-1241.
19. Piper WE, Ogrodniczuk JS, Azim HF, Weideman R. Prevalence of loss and complicated grief among psychiatric outpatients.
Psychiatric Serv. 2001;52:1069-1074.
20. Novation survey on pandemic flu preparedness shows hospitals will run out of supplies in less than one week.
Infection Control Today. Posted on June 14, 2007. Available at:
http://www.infectioncontroltoday.com/hotnews/76h148311751046.html. Accessed June 25, 2007.
21. Hermann G, Tovar CA, Beck FM. Restraint stress differentially affects the pathogenesis of an experimental influenza viral infection in three inbred strains of mice.
J Neuroimmunol. 1994;47:83-94.
22. Sheridan JF, Feng NG, Bonneau RH, et al. Restraint stress differentially affects anti-viral cellular and humoral immune responses in mice.
J Neuroimmunol. 1991;31: 245-255.
23. Cohen S, Alper CM, Doyle WJ, et al. Positive emotional style predicts resistance to illness after experimental exposure to rhinovirus or influenza A virus.
Psychosom Med. 2006;68:809-815.
24. Miller BJ, Paschall CB, Svendsen DP. Mortality and medical comorbidity among patients with serious mental illness.
Psychiatr Serv. 2006;57:1482-1487.
25. Glaser R, Robles TF, Sheridan J, et al. Mild depressive symptoms are associated with amplified and prolonged inflammatory responses after influenza virus vaccination in older adults.
Arch Gen Psychiatry. 2003;60:1009-1014.
26. Phillips AC, Carroll D, Burns VE, Drayson M. Neuroticism, cortisol reactivity, and antibody response to vaccination.
Psychophysiology. 2005;42:232-238.
27. Bartlett JA, Irwin M. Developmental aspects of psychoneuroimmunology. In: Lewis M, ed.
Child and Adolescent Psychiatry. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2002.
28. Pressman SD, Cohen S, Miller GE, et al. Loneliness, social network size, and immune response to influenza vaccination in college freshmen.
Health Psychol. 2005; 24:297-306.
29. Gidron Y, Hassid A, Yisrael H, Biderman A. Do psychological factors predict occurrence of influenza-like symptoms in vaccinated elderly residents of a sheltered home?
Br J Health Psychol. 2005;10:411-420.
30. Vedhara K, Cox NK, Wilcock GK, et al. Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination.
Lancet. 1999;353:627-631.
31. Vedhara K, Bennett PD, Clark S, et al. Enhancement of antibody responses to influenza vaccination in the elderly following a cognitive-behavioral stress management intervention.
Psychother Psychosom. 2003;72: 245-252.
32. Crumpacker C. Antiviral Therapy. In: Knipe DM, Howley PM, Griffin DE, et al, eds.
Field's Virology. Philadelphia: Lippincott Williams & Wilkins; 2001.
33. Centers for Disease Control and Prevention. High levels of adamantane resistance among influenza A (H3N2) viruses and interim guidelines for use of antiviral agents—United States, 2005-06 influenza season.
MMWR. 2006;55:44-46.
34. Moscona A. Neuraminidase inhibitors for influenza.
N Engl J Med. 2005;353:1363-1373.
35. New concerns about oseltamivir.
Lancet. 2007;369: 1056.
36. McGrath JJ, Pemberton MR, Welham JL, Murray RM. Schizophrenia and the influenza epidemics of 1954, 1957 and 1959: a southern hemisphere study.
Schizophr Res. 1994;14:1-8.
37. Barr CE, Mednick SA, Munk-Jorgensen P. Exposure to influenza epidemics during gestation and adult schizophrenia: a 40-year study.
Arch Gen Psychiatry. 1990;47: 869-874.
38. Limosin F, Rouillon F, Payan C, et al. Prenatal exposure to influenza as a risk factor for adult schizophrenia.
Acta Psychiatr Scand. 2003;107:331-335.
39. O'Callaghan E, Sham P, Takei N, et al. Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic.
Lancet. 1991;25:1248-1250.
40. Sham PC, O'Callaghan E, Takei N, et al. Schizophrenia following pre-natal exposure to influenza epidemics between 1939 and 1960.
Br J Psychiatry. 1992;160:461-466.
41. Cooper SJ. Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic.
Br J Psychiatry. 1992;160: 461-466.
42. Mednick SA, Machon RA, Huttunen MO, Bonett D. Adult schizophrenia following prenatal exposure to an influenza epidemic.
Arch Gen Psychiatry. 1988;45:189-192.
43. Kunugi H, Nanko S, Takei N, et al. Schizophrenia following prenatal exposure to influenza during second trimester [in Japanese].
Seishin Shinkeigaku Zasshi. 1993;95:453-462.
44. Bembenek A. Could the fetus' exposure to influenza increase the risk of schizophrenia in adult life [in Polish]?
Psychiatria Polska. 2005;39:271-283.
45. Watson CG, Kucala T, Tilleskjor C, Jacobs L. Schizophrenic birth seasonality in relation to the incidence of infectious diseases and temperature extremes.
Arch Gen Psychiatry. 1984;41:85-90.
46. Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring.
J Neurosci. 2003; 23:297-302.
47. Fatemi SH, Pearce DA, Brooks AI, Sidwell RW. Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: a potential animal model for schizophrenia and autism.
Synapse. 2005;57:91-99.
48. Brown AS, Begg MD, Gravenstein S, et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia.
Arch Gen Psychiatry. 2004;61:774-780.
49. Kendell RE, Kemp IW. Maternal influenza in the etiology of schizophrenia.
Arch Gen Psychiatry. 1989;46:878-882.
50. Crow TJ, Done DJ. Prenatal exposure to influenza does not cause schizophrenia.
Br J Psychiatry. 1992;161: 390-393.
51. Susser E, Lin SP, Brown AS, et al. No relation between risk of schizophrenia and prenatal exposure to influenza in Holland.
Am J Psychiatry. 1994;151:922-924.
52. Erlenmeyer-Kimling L, Folnegovic Z, Hrabak-Zerjavic V, et al. Schizophrenia and prenatal exposure to the 1957 A2 influenza epidemic in Croatia.
Am J Psychiatry. 1994;151:1496-1498.
53. Cannon M, Cotter D, Coffey VP, et al. Prenatal exposure to the 1957 influenza epidemic and adult schizophrenia: a follow-up study.
Br J Psychiatry. 1996;168: 368-371.
54. Mino Y, Oshima I, Okagami K. Mood disorders and influenza epidemics in Japan.
Psychiatry Clin Neurosci. 2000;54:59-65.
