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I was taken ill with the flu. They gave me up. The paper had my obit set in type. . . . My hair turned white and then it fell out. The first time I tried to rise to a sitting position I fell and broke an arm. I had phlebitis in one leg and they said I'd never walk again.
The 1918 influenza epidemic, in a period of a few months, reduced the average life span in the United States by 10 years. Since then, 2 lesser pandemics have occurred, the last more than 40 years ago. Many scientists believe that conditions are ripe today for a pandemic of avian influenza. In addition to the other challenges physicians and the public health system will face in dealing with such a pandemic, psychiatrists must be prepared to address the mental health consequences. This article provides essential information psychiatrists will need if the anticipated pandemic occurs.
Orthomyxoviridae are a family of viruses named for their ability to bind to mucous cells (Greek: myxa, "mucous"). Prominent among them is the influenza A virus. To infect a human respiratory cell, the outer membrane of the influenza virus must chemically merge with a respiratory cell membrane. Once the membranes are fused, the virus invades the respiratory cell, takes over its reproductive mechanism, and uses it to replicate new viruses, killing the respiratory cell in the process.
Nucleotide sequencing of the Spanish influenza virus indicates that it began as an avian influenza and mutated into a strain transmissible between humans.2 Of the 140 forms of avian influenza viruses, to date only 3 have mutated into a human-to-human contagious form. Some of the other strains cause pandemics among birds, but many thrive asymptomatically within the intestines of ducks, quail, geese, and swans. The viruses are excreted in the water fowls' feces, globalizing viral distribution and making eradication virtually impossible. Mammals, including humans, pigs, horses, ferrets, whales, seals, and cats, can be directly infected through contact with carrier poultry or feces.3 The avian influenza H5N1, which first appeared in 1997, has directly infected more than 300 humans and has an overall fatality rate of 60%; the fatality rate in patients older than 50 years is 40%; and for those aged 10 to 19 years it is 76%.4
When H5N1 directly infects humans it is not transmissible. However, if H5N1 and an influenza virus capable of human-to-human transmission should simultaneously infect the same human host, a new transmissible hybrid virus could be created through interviral mixing of genes (genetic shift). Given enough time, this shift and a resulting pandemic are inevitable.
Psychiatrists' role in a pandemic
The substantial risk of a modern pandemic mandates planning for the distribution of resources that will be needed for psychiatric sequelae. We know through published reports that globally, mental health casualties among survivors are intrinsic to all natural disasters.5 Those at highest risk for traumatic reactions are women, the elderly, those with premorbid psychopathology and high direct or indirect trauma exposure, and those with poor social supports and low socioeconomic and educational backgrounds.5
Most published natural disaster reports (eg, earthquakes, hurricanes, tsunamis) citing psychiatric comorbidity from outside the United States are not particularly helpful in predicting the surge that will occur if an influenza pandemic should take place in this country. Unlike flu pandemics, most natural disasters begin abruptly, last for a short period, and cause substantial homelessness and need for relocation. In addition, most reports emanate from countries where there is less response capacity, poorer dissemination of public health information, and dissimilar family and community infrastructure, leading to stress and grief reactions that are culturally distinct.
We have no internal data available since there were no psychiatric surge data kept during the 1918 US pandemic. There are some comparable surge data available from the severe acute respiratory syndrome (SARS) outbreak that occurred in Toronto in 2003. SARS, like avian influenza, arose from an animal virus that mutated to a human-to-human transmissible form. Like the anticipated influenza pandemic, it caused significant public distress, lacked an effective treatment or vaccine, had a high mortality rate, and caused tremendous strain on the health care system.6
Hawryluck and colleagues7 examined the psychological effects on 129 patients quarantined during the SARS epidemic and found that 28.9% met criteria for posttraumatic stress disorder (PTSD) and 31.2% for clinical depression. Styra8 found that of 124 hospitalized SARS patients, 35% had clinical depression and 47% had symptoms of PTSD 3 months after discharge. Among those afflicted, there was a high rate of failure to return to work and carry out daily responsibilities at home.8
Significant psychological distress was also observed among physicians who provided care to patients with SARS (45.7%) compared with those who did not (17.5%).6 The reasons included the necessity of wearing protective R-95 inhalators for protracted periods, the exposure to the morbidity and mortality of coworkers, and the fear of infecting family members. The physicians found that evaluating patients and establishing any semblance of therapeutic alliance was challenging. "You are toiling under the most stressful clinical time in your professional career. You have a headache, the mask hurts, you're sweating, and it's impossible to establish any of the usual nonverbal clues with patients."9
Recently, the CDC has developed software (FluSurge 2.0) to estimate the number of hospital admissions and deaths that will occur during an avian flu pandemic.10 This, along with SARS psychiatric data may help to predict the magnitude of psychiatric surge in a future pandemic.
On the basis of a US population of 301,140,000,11 950,00012 hospital beds, an attack rate of 35%, and a duration of 12 weeks, FluSurge 2.0 predicts that there will be 1,396,768 new hospital admissions. Many of these patients will have significant psychiatric comorbidity. Under normal circumstances, there is a 25% rate of mental illness in patients admitted to hospitals for medical indications.13 In contrast, there was a mean rate of 36% among patients admitted with SARS.7 Using these rates as end points, we calculate that there would be 349,192 to 502,829 admissions of patients with significant mental illness during a severe influenza pandemic (Table 1).
A surge in patients with psychiatric sequelae means a significant increase in psychiatric consultations. Under nonpandemic conditions, psychiatric consultations are ordered for 0.6% to 12% of hospital admissions.14 If, during a severe pandemic, 5% of admitted patients were referred, 69,837 additional psychiatric consultations would be generated during the first 12 weeks of the pandemic.
During the initial influenza phase, psychiatrists will be treating influenza-related delirium from high fevers. Encephalopathies and Reye syndrome will affect about 7% of infected children.15 Visitors will be restricted from visiting quarantined patients, causing increased isolation and psychiatric comorbidity.
As occurs routinely during pandemics, there will be at least a 10% increase in admissions for influenza-induced myocardial infarctions16 and cerebrovascular accidents,17 with the usual accompanying psychiatric sequelae. Infected alcohol- or opiate-dependent patients with respiratory compromise will require benzodiazepines, methadone, or buprenorphine, which can further depress respiration. Public health policy will dictate whether patients who are mentally ill or have a personality disorder and who refuse treatment and/or quarantine and demand discharge can be legally committed.
Existing hospital staff shortages will be exacerbated by the need for one- on-one observation of infected patients with severe mental retardation or dementia. Increased numbers of translators will be needed for infected deaf and non-English-speaking patients. Security provisions will be inadequate for any significant surge in infected sexual offenders, violent prisoners, and involuntarily committed patients. In addition, a significant number of health care workers will be infected or refuse to treat infected patients, further reducing manpower.18
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.
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 and 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
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.
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