Pregnancy, Influenza & Elevated Psychosis Risks In Adult Offspring

Photo Credit – CDC

 

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It’s been well documented that influenza and pregnancy are a bad combination - one that can endanger both the mother and unborn child’s life – and that women are more susceptible to influenza while (and just after) they are pregnant. It is for this reason that the CDC encourages all pregnant women to get the flu shot (see Pregnant Women & Influenza (Flu)).

 

These risks were well illustrated in an open access research article in the BMJ in 2011 (Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study) that found that pregnant women who were admitted to the hospital with an  H1N1 infection experienced a 3 to 4 times higher rate of preterm birth, 4 to 5 times greater risk of stillbirth, and a 4 to 6 times higher rate of neonatal death.

 

But over the past decade we’ve also seen evidence of a less obvious, and long-delayed, impact of these type of infections.  Namely, an increase in a variety of child, adolescent, and adult development disorders experienced by offspring who were exposed to the flu (or the mother’s immune response) while in the womb.

 

A few examples include:

• In a 2004 study (Serologic evidence of prenatal influenza in the etiology of schizophrenia  Brown et al.) found a 7-fold increase in the risk of developing schizophrenia when exposed to influenza during the first trimester. No increased risk was found for exposure during the second and third trimester.

• Another study from 2008 (Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8  Ellman et al.) suggested that it was prenatal exposure to a type of protein - (proinflammatory cytokines, specifically interleukin-8) – produced by the body during viral infections, that can lead (in rare cases) to brain abnormalities.

• In 2012 research by a team at UC Davis found that fever (from any cause) during pregnancy more than doubled the odds of having a child with autism or developmental delays (see  Is Maternal Influenza or Fever During Pregnancy Associated with Autism or Developmental Delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) Study Zerbo et al.) 
• In November of  2012, in Of Pregnancy, Flu & Autism, we saw a study that found a twofold increase in autism among children with prenatal influenza exposure, and a threefold increase in autism among children with prolonged prenatal fever exposure
• And just last year (May, 2013) we looked at a JAMA Psychiatry report that linked bipolar disorder (BD) to influenza exposure while still in the womb  (see Pregnancy, Influenza, & Bipolar Disorder In Offspring).

 

These studies are admittedly small and less than conclusive, and while they suggest an increase in relative risk over pregnancies without fever or viral infection – in terms of absolute risk – the odds that a mother’s fever or viral infection during pregnancy would result in a developmentally challenged child remains low.

 

We’ve a new study, this time appearing in the American Journal of Psychiatry that adds to, and reinforces some of these earlier studies.  While not finding a statistically significant link between maternal pregnancy and bipolarity in offspring (odds ratio of 1.26), when they refined it to bipolar disorder with psychosis, they determined a nearly fivefold increased risk.

The authors explain:

 

“Since prenatal influenza has been previously associated with schizophrenia, a disorder characterized in large part by psychotic episodes such as hallucinations and delusions, our results support the hypothesis that maternal influenza exposure may preferentially increase the risk for psychosis apart from traditional diagnostic categories.”

 

Although more research is needed to validate these findings, the authors suggest that prevention of maternal influenza infection may decrease the incidence of bipolar disorder with psychotic features in the population.

 

Serological Documentation of Maternal Influenza Exposure and Bipolar Disorder in Adult Offspring

Sarah E. Canetta, Ph.D.; Yuanyuan Bao, M.S.; Mary Dawn T. Co, M.D.; Francis A. Ennis, M.D.; John Cruz, B.S.; Masanori Terajima, M.D., Ph.D.; Ling Shen, Ph.D.; Christoph Kellendonk, Ph.D.; Catherine A. Schaefer, Ph.D.; Alan S. Brown, M.D., M.P.H.

Abstract

Objective The authors examined whether serologically confirmed maternal exposure to influenza was associated with an increased risk of bipolar disorder in the offspring and with subtypes of bipolar disorder, with and without psychotic features.

Method The study used a nested case-control design in the Child Health and Development Study birth cohort. In all, 85 individuals with bipolar disorder were identified following extensive ascertainment and diagnostic assessment and matched to 170 comparison subjects in the analysis. Serological documentation of maternal exposure to influenza was determined using the hemagglutination inhibition assay.

Results No association was observed between serologically documented maternal exposure to influenza and bipolar disorder in offspring. However, maternal serological influenza exposure was related to a significant fivefold greater risk of bipolar disorder with psychotic features.

Conclusions The results suggest that maternal influenza exposure may increase the risk for offspring to develop bipolar disorder with psychotic features. Taken together with earlier associations between prenatal influenza exposure and schizophrenia, these results may suggest that prenatal influenza is a risk factor for psychosis rather than for a specific psychotic disorder diagnosis.

 

 

Obviously this is a major concern for expectant mothers, but we’ve also seen evidence that the influenza virus can be neurotropic - capable of infecting and damaging brain cells – in people of any age, not just those in the womb.

 

• see Revisiting The Influenza-Parkinson’s Link 
• see  Lancet: The Influenza - Guillain Barré Syndrome Connection
• see Stanford Study Finds Influenza – Narcolepsy Connection

 

When you consider the potential long-term health effects of influenza infection – rare or not – it makes sense to do whatever one can reasonably do to avoid infection. 

 

And that means getting the flu shot every year, avoiding people when they are obviously sick, and practicing good flu hygiene (covering coughs, washing hands, avoid touching face) year round.

Acute Flaccid Paralysis Cases In California

 

 

Credit CDC – Non Polio-Enteroviruses

 

 

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Overnight the news media has been filled with numerous reports of an – as yet, unidentified – polio-like paralytic illness that has stricken a small number of children in California over the past two years.  Crof already has a couple of media reports on his blog (see US: A polio-like illness in California children & US: More on the polio-like illness in California), and ProMed Mail released a summary this morning.

 

The basic facts are recounted in the following excerpt from the Los Angeles Times report, after which I’ll have more:

 

Mysterious polio-like illnesses reported in some California children

By Eryn Brown

February 23, 2014

(excerpt)

The afflicted kids suffer severe weakness or paralysis, which strikes rapidly -- sometimes after a mild respiratory illness. Scans of the patients' spinal cords show patterns of damage similar to that found in polio sufferers, Glaser said. Two of the affected children tested positive for enterovirus-68, a virus that is usually associated with respiratory illness but which has been linked to polio-like illnesses as well.

 

Dr. Keith Van Haren, a pediatric neurologist at Stanford University's Lucile Packard Children's Hospital who has worked with Glaser's team, will present the cases of five of the children at the American Academy of Neurology's upcoming annual meeting in Philadelphia.

 

All five patients had paralysis in one or more arms or legs that reached its full severity within two days, he said. None had recovered limb function after six months.

 

"We know definitively that it isn't polio," Van Haren added, noting that all had been vaccinated against that disease.

(Continue . . . )

 

This report, along with others, suggest that 20 to 25 children in California may have developed Acute Flaccid Paralysis (AFP) following a mild respiratory illness over the past couple of years, and investigators expect that once clinicians know to look for it, they may discover it beyond California.

 

Non-polio AFP is a complex and broad clinical syndrome that can be caused by a wide range of pathogens, including West Nile Virus (and other mosquito-borne encephalopathies), echoviruses, adenoviruses, Campylobacter jejuni (leading cause of Guillain-Barre syndrome), a large group of enteroviruses, along with a variety of toxins and poisons.

 

While the exact cause (or causes) of these California cases remains unknown, a viral infection is strongly suspected, and high on the list of suspects are members of the ubiquitous non-polio enterovirus family of viruses or NPEVs  (which includes Coxsackievirus A, Coxsackievirus B, Echoviruses & numerous other Enteroviruses).

 

According to the CDC, NPEVs cause 10 to 15 million – mostly mild and often asymptomatic – infections in the United States each year, primarily among infants, children, and teenagers. Fever, runny nose, sneezing, coughing, a skin rash or mouth blisters, and body and muscle aches are the most commonly reported symptoms. 

 

NPEV infection may also lead to viral conjunctivitis, hand, foot, and mouth disease (HFMD), or viral meningitis and less commonly, a person may develop myocarditis, pericarditis, encephalitis - or in rare cases - even paralysis.

 

The CDC lists the following common Outbreaks of Various Non-Polio Enteroviruses

• Coxsackievirus A16 is the most common cause of hand, foot, and mouth disease (HFMD) in the United States. However, in 2011 and 2012, coxsackievirus A6 was a common cause of HFMD in this country; some of the infected people became severely ill.
• Coxsackievirus A24 and enterovirus 70 have been associated with outbreaks of conjunctivitis.
• Echoviruses 13, 18, and 30 have caused outbreaks of viral meningitis in the United States.
• Enterovirus 71 has caused large outbreaks of HFMD worldwide, especially in children in Asia. Some infections from this virus have been associated with severe neurologic disease, such as brainstem encephalitis.

 

We’ve looked at HFMD outbreaks in the past, most often caused by the Coxsackie A16 virus (and more rarely by Coxsackie A10) here in the United States. In recent years, we’ve also seen the recent emergence of the Coxsackie A6 virus which has been linked to somewhat more severe HFMD cases (see MMWR: Coxsackievirus A6 Notes From The Field).

But it is the Enterovirus 71 that has been most often linked to severe cases of HFMD – particularly across Asia - with serious outbreaks recorded over the past 15 years in places like China, Taiwan, Malaysia, Hong Kong, and two years ago in both Vietnam and Cambodia (see Updating The Cambodian EV71 Story).

 

Last year, in Australia: Acute Flaccid Paralysis & EV71, we looked at a report from the National Enterovirus Reference Laboratory in Australia that described 5 recent cases of acute flaccid paralysis (AFP) in children who tested positive for the EV71 virus.

 

Concerns over the evolution and spread of EV71 have grown in recent years, as detailed in the following 2008 report from The Lancet: Enterovirus 71 infection: a new threat to global public health?  

 

While a potential cause, EV71 is just one of the possible suspects behind these California cases.  Indeed, AFP can be caused by a variety of viral infections, and so there may be more than one etiology involved

 

At least two of the children in California have tested positive for Enterovirus-68, which we looked at in some depth back in 2011 (see MMWR: Clusters Of HEV68 Respiratory Infections 2008-2010).  First detected in California in 1962, but rarely seen since that time, that report summarized six clusters of HEV68 from Asia, Europe, and the United States between 2008-2010.  Those clusters included severe illness, and three fatalities.

 

Although the full spectrum of illness that EV-68 infection can produce has not been well established, it has previously been more commonly associated with respiratory symptoms than with paralysis.

 

So whether EV-68 is actually the cause of these recent California paralysis cases, or simply an incidental finding, is something that will require more research to establish. Despite their outward similarity to NPEV infections, these AFP cases in California may be due to something altogether different.  New viral discoveries are made practically every year.

But most `mystery illnesses’  usually end up being due to previously identified diseases that have either evolved or mutated a bit, or have migrated to a new area.

 

While it is too soon to speculate on the exact cause of these AFP cases, the CDC’s recommendations to prevent NPEV transmission are universally good hygiene suggestions, and are worth following:

 

You can help protect yourself and others from non-polio enterovirus infections by—

• Washing your hands often with soap and water, especially after using the toilet and changing diapers,
• Avoiding close contact, such as touching and shaking hands, with people who are sick, and
• Cleaning and disinfecting frequently touched surfaces.

Referral: Mckenna On The Regulatory Limbo Of Fecal Transplants

C. difficile – Credit CDC PHIL

 

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Roughly 44 years ago Dr. William Nolan wrote a book called `The Making of A Surgeon’, about his internship at Bellevue Hospital in the 1950s that, quite frankly, inspired me to become an EMT, and then a Paramedic.  While dated, it still a good read, and highly recommended. 

 

But I mention it because one of the anecdotes he relates was a hysterically funny account about how he, and two other interns, concocting a `feces laced milkshake’  to try to cure a patient with intractable diarrhea, likely due to a C. Diff infection. 

 

When their resident found out what they’d done, he went ballistic, and for a time all three interns thought their careers were ended.  They waited in fear for days for the patient to die from their ill advised treatment.

 

As it turned out, the `cure’ worked, the patient was none the wiser, and the statute of limitations eventually passed and the story could be told.  Fast forward sixty years and their radical idea – of reintroducing healthy gut bacteria from a stool donor – is now on the cutting edge of medicine.

A little over a year ago, in NEJM: Effectiveness Of Fecal Transplants For C. diff, we looked at the remarkable results being obtained doing this simple procedure – a cure rate of roughly 90%..   All the more important because Clostridium difficile – or C. diff – claims tens of thousands of lives each year, and is – as the name implies – very difficult to treat.

 

More than two years ago Maryn McKenna’s wrote Fecal Transplants: They Work, the Regulations Don’t, which showed how difficult getting this simple, inexpensive and effective treatment can be in the United States due to it falling into a regulatory limbo.  Unfortunately, two years have passed, and little progress has been made in clearing the regulatory minefield. 

 

Today Maryn is back with another report, and a possible solution,  which you can read at:

 

Fecal Transplants: Treat Them Like Tissue, Not Like Drugs

• By Maryn McKenna   02.23.14  8:52 AM  

It’s been a little more than a year since the first-ever clinical trial of fecal transplants — the practice of infusing diluted donor stool into the colon of someone suffering from Clostridium difficile infection — demonstrated that the low-tech process not only works to overcome the disease’s painful, life-disrupting diarrhea, but works better than the standard treatment of antibiotics.

 

That finding confirmed what gastroenterologists had known for a while — not to mention what patients who had sought out the procedure, in the United States or in other countries, could confirm from their own experience of being rapidly and, for the most part, permanently cured.

(Continue . . . .)

OIE: H5N1 Detected In Crows Again – India

Indian House Crow – Photo Credit Wikipedia

 

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While China, Cambodia, Vietnam, and South Korea have garnered most of the avian flu headlines this winter, the H5N1 virus remains endemic in other countries as well, including much of Asia and parts of the Middle East.  In many of these regions, surveillance and reporting is less than optimal, so the true extent of this virus is hard to measure.

 

Although debate over the incidence and importance of wild birds spreading the avian flu virus remains contentious (see India: The H5N1 & Migratory Birds Debate), we have often seen wild and migratory birds test positive for the H5N1 virus.   

 

In addition to having infected more than 20 mammalian species, the H5N1 virus has been detected in more than 150 different types of wild birds (See USGS List of Species Affected by H5N1 (Avian Influenza)).

 

Waterfowl (ducks & geese) and gallinaceous birds (turkeys, grouse, chickens & quail) are most often associated with carriage of the H5N1 virus, but terrestrial birds such as crows, starlings, pigeons, and sparrows are also known to carry, and shed, the virus as well (see 2007’s EID Journal  Role of Terrestrial Wild Birds in Ecology of Influenza A Virus (H5N1).

 

As far back as 2008, we saw reports out of India of crows dying from the H5N1 virus. A little over two years ago India was again plagued with numerous wild bird die offs that were blamed on the avian flu virus (see Media Report: H5N1 Killing Crows In Jharkhand).

 

By mid-December of 2011 the Indian Veterinary Research Institute (IVRI), Bhopal, confirmed that the H5N1 virus was behind at least some of these deaths. (see EpiSouth eweb_195_15_12__11.pdf). Over the next few months, even more reports came in, involving thousands of dead birds (see The Kolkata Crow Mystery & H5N1: A Murder Of Crows) that spread across several northern states.

 

On February  6th, 2012 official notification was made to the OIE of H5N1 virus detections in crows from four states; Jharkhand, Maharashtra, Orissa, and Bihar.

 

While India has reported a number of H5N1 outbreaks in Poultry since then - and at least one die off in pigeons (see Nov. 2012 Pigeon Droppings) - reports of the virus in wild birds have been noticeably absent the past 18 months.

 

At least, until this week, when the OIE was notified of two dead house crows from Keonjhar District, in Orissa state in Eastern India that were found to be infected with the virus.

 

 

Two dead house crows may not seem terribly important, but as the study below indicates, changes in the behavior of the virus in the wild can sometimes be a tip off that something is changing with the virus. This from just last October, in the Archives of Virology:

 

Investigating a crow die-off in January–February 2011 during the introduction of a new clade of highly pathogenic avian influenza virus H5N1 into Bangladesh

Salah Uddin Khan, LaShondra Berman, Najmul Haider, Nancy Gerloff, Md Z. Rahman, Bo Shu, Mustafizur Rahman, Tapan Kumar Dey, Todd C. Davis, Bidhan Chandra Das . . . .

Abstract

We investigated unusual crow mortality in Bangladesh during January-February 2011 at two sites. Crows of two species, Corvus splendens and C. macrorhynchos, were found sick and dead during the outbreaks. In selected crow roosts, morbidity was ~1 % and mortality was ~4 % during the investigation. Highly pathogenic avian influenza virus H5N1 clade 2.3.2.1 was isolated from dead crows.

All isolates were closely related to A/duck/India/02CA10/2011 (H5N1) with 99.8 % and A/crow/Bangladesh/11rs1984-15/2011 (H5N1) virus with 99 % nucleotide sequence identity in their HA genes. The phylogenetic cluster of Bangladesh viruses suggested a common ancestor with viruses found in poultry from India, Myanmar and Nepal. 

<SNIP>

Continuation of surveillance in wild and domestic birds may identify evolution of new avian influenza virus and associated public-health risks.

(Continue . . . )

As the H5N1 virus continues to evolve into new clades or strains, its behavior across various species is likely to change as well. Two years ago, in Differences In Virulence Between Closely Related H5N1 Strains, we looked at a study that found that genetically similar strains can exhibit significantly different pathogenicity in specific hosts.

 

Making any perceived change in how the virus presents or spreads worth noting.

ECDC Epidemiological Update: Chikungunya Spreads In Caribbean And Into South America

Credit CDC

 

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Earlier this week, in COCA Call On Chikungunya –  Feb 18th, I blogged on the CDC’s efforts to inform clinicians of the recent arrival of the Chikungunya virus to the Americas.  Those who missed it can find additional information on that webinar HERE.

 

Until a decade ago, Chikungunya (aka `Chik’) was only found in parts of central Africa, and then only occasionally sparked small outbreaks. 

 

In 2005, however, it jumped to Reunion Island in the Indian Ocean, where it sparked a major epidemic. Since then it has spread rapidly to counties such as India, Thailand, Vietnam, Indonesia, Myanmar, Pakistan, and others in  Asia and  the Western Pacific.

 

Quite famously, Chik was carried by an international traveler from India to Northern Italy in 2007, where it sparked a local outbreak involving roughly 300 people (see It's A Smaller World After All). 

 

While that outbreak was eventually contained, that introduction of the virus to Italy showed that Europe and  the Americas were vulnerable to the importation of the virus, prompting the CDC & PAHO to publish a document  in 2011 called Preparedness and Response for Chikungunya Virus Introduction in the Americas.

 

As predicted, the virus showed up last November (see WHO: Chikungunya In Caribbean – French Part of St. Martins), and since then has spread rapidly between the Leeward and Windward Islands, and has now appeared on the South American continent.

 

Today, the ECDC provides the following Epidemiological update, indicating nearly 6,000 suspected infections have been reported since the fall.

 

 

Epidemiological update: autochthonous cases of chikungunya fever in the Caribbean region and South America

21 Feb 2014

​An outbreak of chikungunya in the Caribbean region was reported from the French part of the island of Saint Martin on 6 December 2013. It is the first time that autochthonous transmission of the virus has been documented in the Americas.

An ECDC risk assessment of the outbreak published on 12 December 2013 concluded that the risk of the disease spreading to other islands in the Caribbean region was high. Since then, autochthonous transmission of chikungunya has been reported from several islands in the Caribbean and recently for the first time in South America (French Guiana).

As of 21 February 2014, more than 5 900 suspected cases have been reported in the following locations:

Caribbean:

• Saint Martin (FR): 1 780 suspect cases
• Sint Maarten (NL): 65 confirmed cases
• Saint Barthélemy: 350 suspect cases
• Martinique: 3 030 suspect cases
• Guadeloupe: 1 380 suspect cases
• British Virgin Islands, Jost Van Dyke islands: 5 confirmed cases;
• Dominica: 45 confirmed cases including one imported case
• Anguilla: 5 confirmed cases including one imported case;
• Island Aruba: one confirmed imported case
• Saint Kitts & Nevis: one confirmed case

South America:

• French Guiana: 7 confirmed/probable cases including 2 autochthonous cases and 5 imported cases.

This overview indicates that the chikungunya outbreak in the Caribbean is still ongoing and reaching now South America.

The chikungunya transmission was detected during a concomitant dengue outbreak in the Caribbean. Both arboviruses are transmitted by the same Aedes aegypti mosquito species. The naïve population, the presence of an effective vector in the region and the movement of people in and between islands and territories are factors that make it likely that the outbreak will continue to spread geographically and increase in numbers.

The conclusions and recommendations of the rapid risk assessment published on 12 December 2013 remain valid.

Clinicians and travel medicine clinics should remain vigilant regarding imported dengue and chikungunya cases from the Caribbean and French Guiana.

 

As with West Nile Virus, Malaria, and Dengue fever – the mosquito vectors for spreading Chikungunya are abundant across much of the United States.

 

Although we’ve seen sporadic cases of viremic CHKV infected travelers to the United States in the past (see 2011 CID Journal report Chikungunya Fever in the United States: A Fifteen Year Review of Cases), those numbers have been small (109 between 1995- 2009), and so far (unlike dengue and WNV), we haven’t seen any evidence of local transmission.

 

But with CHKV now in the Americas, the number of CHKV infected travelers to the United States may well increase,  and any who are viremic (producing large quantities virus in their blood) while visiting regions where suitable mosquito vectors are present, could potentially introduce the virus to the local mosquito population.

Referral: Maryn McKenna On China’s Agricultural Challenges

 

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This morning Maryn McKenna takes a hard look at some of the challenges that China – and the world – face as they gear up their agricultural systems to feed more than 1.3 billion people. As mentioned before in this blog, bird flu is a major threat to one of China’s biggest source of meat-protein – poultry -  and other livestock diseases (PED, PRRS, etc.)  threaten swine, goats, and other domesticated animals.

 

But as Maryn points out in her blog today, China’s growing appetite for meat also raises concerns over water and land usage, agricultural antibiotic use, and food safety. 

 

Follow the link below to read:

 

From Bird Flu to Big Farms: The Rise of China’s Agriculture

• By Maryn McKenna 02.21.14  8:30 AM