The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918-1919 influenza pandemic in the United States

Dr Weeks’ Comment:   Vitamin D  from sunlight can protect against H1V1 influenza  but the CDC and “experts” are not talking about it –  too inexpensive for their consideration.

The possible roles of solar ultraviolet-B radiation and vitamin D in  reducing case-fatality rates from the 1918-1919 influenza pandemic in the United States

 

[Dermato-Endocrinology 1:4, 1-5; July/August 2009];

©2009 Landes Bioscience

 

Report

 

This manuscript has been published online, prior to printing. Once the issue is complete and page numbers have been assigned, the citation will change accordingly.

 

William B. Grant1,* and Edward Giovannucci2

 

1Sunlight, Nutrition and Health Research Center (SUNARC); San Francisco, CA USA; 2Departments of Nutrition and Epidemiology; Harvard School of Public Health; and

Department of Medicine; Brigham and Women’s Hospital; Boston, MA USA

 

 

Deaths during the 1918-1919 influenza pandemic have been

linked to both the influenza virus and secondary bacterial lung

infections. Case fatality rates and percentage of influenza cases

complicated by pneumonia were available from survey data for

twelve United States locations in the 1918-1919 pandemic.

This study analyzes case fatality rates and cases complicated by

pneumonia with respect to estimated summertime and wintertime

solar ultraviolet-B (UVB) doses as indicators of population

mean vitamin D status. Substantial correlations were found for

associations of July UVB dose with case fatality rates (r = -0.72,

p = 0.009) and rates of pneumonia as a complication of influenza

(r = -0.77, p = 0.005). Similar results were found for wintertime

UVB. Vitamin D upregulates production of human cathelicidin,

LL-37, which has both antimicrobial and antiendotoxin activities.

Vitamin D also reduces the production of proinflammatory

cytokines, which could also explain some of the benefit of

vitamin D since H1N1 infection gives rise to a cytokine storm.

The potential role of vitamin D status in reducing secondary

bacterial infections and loss of life in pandemic influence requires

further evaluation.

 

Introduction

 

In the twentieth century, there were three influenza pandemics,

in 1918, 1957 and 1968, caused by H1N1 (Spanish flu), H2N2

(Asian flu) and H3N2 (Hong Kong flu), respectively.1 The

1918-1919 pandemic was different from the subsequent ones as

it was the only one caused by an H1N1 virus, and is the only one

considered in this work.

 

“In 1918, there was one distinct peak of excess death in

young adults aged between 20 and 40 years old; leukopenia and

hemorrhage were prominent features. Acute pulmonary edema and

hemorrhagic pneumonia contributed to rapidly lethal outcome in

young adults. Autopsies disclosed multiple-organ involvement,

including pericarditis, myocarditis, hepatitis and splenomegaly.

These findings are, in part, consistent with clinical manifestations

of human infection with avian influenza A H5N1 virus, in which

reactive hemophagocytic syndrome was a characteristic pathologic

finding that accounted for pancytopenia, abnormal liver function

and multiple organ failure.”1

 

The influenza pandemic of 1918-1919 claimed many lives.

While the influenza virus played an important role, there is

evidence that the primary influenza infection was not necessarily

the proximate cause of death. For example, the median time

to death was 7-10 days, and a substantial proportion of deaths

occurred greater than 2 weeks after onset of the initial symptoms.2

The delay in death has been attributed to the influenza infection

allowing bacteria to colonize the lower respiratory system and

produce lethal pneumonias.2,3 Bacterial pneumonia also was noted

as a serious complication of influenza during 1957-8 influenza

pandemic,4 and antibacterial approaches have previously been

proposed for reduction of the case-fatality rate during influenza

pandemics.5,6

 

Vaccines are the first line of defence against epidemic influenza.

However, successful treatment or prophylaxis of complicating

bacterial pneumonias may be important, since a presently unknown

or poorly characterized virus might cause a pandemic before an

effective vaccine becomes universal.2,5,6 Several months to a year

are typically needed to develop and universally administer an effective

vaccine for a new strain of influenza.7

 

While vaccines are absolutely essential for control of influenza,

they are not always effective in eliminating influenza cases, and the

associated risk of secondary respiratory infections, especially among

older adults. It has been estimated that a recent influenza vaccine

produced only a 27% reduction in hospital admissions for acute

respiratory infections, such as pneumonia.8 Other epidemiological

approaches, such as limiting travel and case containment, could

be part of an overall plan to limit the intensity of an influenza

UVB, vitamin D and pandemic influenza followed by pneumonia

pandemic.9 However such concepts are rarely implemented

successfully. Targeted layered containment has also been proposed

for limiting pandemic influenza cases in the United States.10 Such

epidemiological measures would have serious economic impacts.

 

Since the fatal complications of influenza are due in part to

secondary bacterial infection,2-4 the degree of immunity to the

most common bacterial agents of pneumonia may be important.

Exposure to solar ultraviolet-B (UVB) starts a multi-step process,

starting with biosynthesis of vitamin D and its metabolites, followed

by upregulation of human cathelicidin (LL-37), by 1,25-dihydroxyvitamin

D.11 There are several recent reviews of the effects

of cathelicidin against bacterial infections such as Mycobacterium

tuberculosis.11-16 Cathelicidin appears to be effective in fighting

septicaemia, in part due to its antiendotoxin effects.12

 

The known benefit of cathelicidin is mainly limited to bacterial

or mycoplasmal infections. Cannell et al. hypothesized that

the annual seasonality of influenza was largely due to low solar

UVB irradiation and vitamin D biosynthesis in winter and

early spring.17 A post hoc analysis of self-reported incidence of

acute respiratory illnesses during a randomized controlled trial

of vitamin D for another purpose supported this hypothesis.18

Cannell et al. later extended their hypothesis.19 Regional solar

UVB irradiance is also inversely associated with incidence rates of

respiratory syncytial virus (RSV) infection.20 It is thought that the

higher incidence rates of RSV in darker-skinned infants may be

due to lower vitamin D production in them and their mothers.21

Vitamin D receptor polymorphisms were found correlated with

acute lower respiratory tract infection, primarily bronchiolitis, in

Canada.22 Vitamin D is also thought to reduce the risk of respiratory

infections that may lead to development of asthma.23

 

There are several aspects to incidence and death from influenza

including adaptive and innate immune response, exposure to the

influenza virus, season and development of complications from

other respiratory diseases. We analyzed data from the United

States during the 1918-1919 influenza pandemic to determine

whether solar UVB irradiance and vitamin D status might have

played a role in the development of pneumonia and in influenza-

pneumonia case fatality rates.24

 

Results

 

The rates in each city, latitude and UVB irradiance are shown

in Table 1. The lowest case-fatality rates occurred in the area with

the highest solar UVB irradiance and lowest latitude, San Antonio

TX, while the highest rates were in New London CT, which had

the lowest UVB irradiance and highest latitude. The lowest rates of

pneumonia as a complication of influenza were in Spartanburg SC

and San Antonio, the two areas at the lowest latitudes. The correlation

between case-fatality rates for influenza and cases complicated

by pneumonia was r = 0.78 (p = 0.005).

 

The results for case fatality rates (CFR) with respect to solar

UVB are given in Table 2. Summer UVB irradiance had a slightly

higher correlation coefficient than latitude with CFR. The results

for influenza complicated by pneumonia are also given in Table 2.

The correlation coefficients were slightly higher than those for case

fatality rates. In the regression model, UVB accounted for 46% of

 

 

Table 1

Cities included in the 1918-1919 influenza

pandemic study, case-fatality rates and

percentage of cases who developed

pneumonia24

 

City and No. of No. of Influenza Pneumonia July Latitude

state influenza pneumonia case-complications* UVB (° N)

cases cases fatality (%) dose

rate (kJ/m2)

(deaths

 

per 100

 

cases)

 

New London, 1466 136 3.14 9.3 4.7 40.6

 

CT

Charles 6546 -2.25 -5.3 38.5

County, MD

 

San Francisco, 4021 321 2.24 8.0 6.5 37.6

 

CA

Baltimore, 8199 599 2.10 7.3 5.0 39.3

MD

 

Minor MD 5060 322 1.66 6.4 5.1 39.2

 

towns

Des Moines, 1353 138 1.63 10.2 4.8 41.6

IA

 

Macon, 1681 103 1.49 6.1 7.5 32.8

 

GA

Louisville, 1797 111 1.39 6.2 6.0 38.1

KY

 

Augusta, 1405 63 1.28 4.5 7.3 33.5

 

GA

Little Rock, 3565 159 1.09 4.5 7.1 34.8

AR

 

Spartanburg, 1126 35 0.89 3.1 7.0 35.0

 

SC

San Antonio, 6701 303 0.78 4.5 8.2 31.6

TX

 

Total 42,920 2290

 

*Incidence of pneumonia in influenza cases.

 

Table 2

Association between UVB irradiance and

case-fatality rate of influenza or rate of

pneumonia as a complication of influenza

with respect to UVB indices, linear regressions

(from table 25 in Britten24)

 

Outcome

UVB indicator r, adjusted r2, p

 

Case-fatality rate July UVB -0.72, 0.46, 0.009

 

Latitude 0.68, 0.42, 0.014

Pneumonia as a July UVB -0.77, 0.55, 0.005

complication of influenza

 

Latitude 0.81, 0.62, 0.003

 

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Dermato-Endocrinology

 


 

UVB, vitamin D and pandemic influenza followed by pneumonia

 

the variation in case-fatality rates of pneumonia and 55% of the

variation in rates of pneumonia as a complication of influenza.

 

Discussion

 

There was an inverse association between UVB irradiance

and case-fatality rate of influenza and rate of pneumonia as a

complication of influenza in the US. Both UVB indices gave

similar results. According to data in Britten,24 the 1918 influenza

pandemic reached eastern United States cities in September, and

San Francisco in October. Peak mortality rates extended from late

October to early December. Based on serum 25(OH)D measurements

of 45-year old British adults, levels would be intermediate

between summer and wintertime values.

 

There is other evidence for a role of vitamin D reducing the

risk of pneumonia. For example, pneumonia deaths in England

and Wales in the period 1988-92 had a peak-trough ratio of

 

2.7 with the peak in December and January and trough in JulySeptember.

31 In Ethiopia, there was a 13-fold higher prevalence

of rickets among children with pneumonia than among controls

(odds ratio: 13.37 (95% CI 8.08-24.22), p < 0.001) in Ethiopia.32

Low serum 25(OH)D (<22.5 nmol/L) was associated with higher

risk of lower respiratory tract infection (odds ratio: 0.09; 95% CI

0.03-0.24; p < 0.001) in India.33

From inspection of the incidence and mortality rates from the

1918-1919 influenza pandemic at the total population level, it is

not possible to draw conclusions about vitamin D with respect to

pandemic influenza incidence.

 

As discussed above, the established role of vitamin D in upregulating

production of catheliciden, an endogenous anti-bacterial

peptide, may be a potential explanation of the association we

observed. An additional potential mechanism may be the role

of vitamin D in the reduction of pro-inflammatory cytokines.

One of the important observations of deaths during the 1918-19

influenza pandemic was that the death rate was high for young

adults.34 This is different than for seasonal influenza, during which

mortality rates are higher for the elderly and infants. The reason for

this difference seems to be that those in their 20s and 30s have a

more robust immune system which can mount a stronger attack on

microbial infections. From recent studies, it has been determined

that both H1N1 and H5N1 viruses induce a T-helper 1 (Th1)

type cytokine response to viral infection of macrophages.35 These

 

35

 

cytokines are proinflammatory and include IL-6 and TNFa.

Nuclear factor kappaB (NF.B) is also an important risk factor.36

Influenza A (H5N1) viruses induce production of proinflammatory

cytokines at a greater rate than do H1N1 viruses.37,38

1,25-dihydroxyvitamin D [1,25(OH)2D] reduces the production

of Th1 cells, thus shifting the Th1/Th2 balance towards Th2,

which is less inflammatory.39-41 1,25(OH)D has also been found

to reduce the production of NF.B42 and TNFa.43 Infection of

macrophages also induces a toll like receptor induction of human

cathelicidin, LL-37,44 which is effective in combating bacterial

infections such tuberculosis44 and others.45 Thus, an additional

mechanism whereby vitamin D could reduce the severity and likeliness

of death from H1N1 and H5N1 viral infections is reduced

production of proinflammatory cytokines and NF.B. However,

 

 

suppressing proinflammatory cytokines did not reduce the risk

of death for mice infected with H5N1 viruses.46,47 These results

may not apply to the H1N1 virus in humans because mice have

different immune responses than humans.

 

One strength of this study is that solar UVB was the primary

source of vitamin D since in 1919, vitamin D had not yet been

isolated or identified. The main limitation of this study is that

other confounding factors were not evaluated. For example, differences

in medical treatment or defensive measures48 in the twelve

cities were not considered. Also, differences in ethnic background

and skin pigmentation were not considered. The fraction of

African-Americans varied between locations. This was a study of

aggregates rather than individual subjects. Findings that apply to

aggregates may not apply to individuals. Another limitation is that

data presented in Britten24 were available for only twelve cities.

While the sampling was made under specific instructions and

careful supervision, “in 10 or more districts so situated geographically

as to give, presumably, a fair sample of the general population

of the city.”, the method of selecting the districts would probably

not meet today’s standards for random sampling. A further limitation

is that the fraction of the population surveyed varied from

 

0.039 in San Francisco to 1.00 in Charles County, MD, while

the number of people surveyed in each region varied from 4,123

in Augusta, GA to 18,682 in San Francisco. Also, as the country

was at war then, the total populations of each region had some

additional uncertainty.

Data and Methods

 

The approach taken in this work to investigate the role of

innate immune response is to examine case fatality rates for those

who contracted the H1N1 influenza virus. The body can have

both innate and adaptive immune responses; for respiratory infections,

the adaptive response is based on either prior exposure to the

same or similar virus, while the innate response is based on other

immune parameters such as T cell subsets and immunoglobulin

concentrations25 and LL-37. It is assumed that those who developed

H1N1 influenza had weaknesses in both the adaptive and

innate immune systems but that the strength of the innate immune

system is more important for survival.

 

A study was found that reported data for influenza and pneumonia

case fatality rates for twelve cities in nine U.S. states;24

the proportion of influenza cases complicated by pneumonia was

determined for eleven cities. The data reported (Table 1) are from

special surveys by the United States Public Health Service. These

surveys were conducted in ten cities “varying in population from

22,500 to 680,000 and certain small towns of Maryland and one

rural county of Maryland.” The locations were chosen to be widely

scattered, and generally in “localities in which the Public Health

Service was at the time maintaining established organizations

prepared to collect the requisite data reliably and efficiently.” The

surveys “were made as soon as possible after the subsidence of the

autumn (1918) wave of the epidemic in each locality” and generally,

started around December 2, 1918 and completed by the end

of December. However, second surveys were also conducted in

Baltimore and San Francisco to check for recrudescence which had

 

Dermato-Endocrinology 2009; Vol. 1 Issue 4

 


 

UVB, vitamin D and pandemic influenza followed by pneumonia

 

taken place in the interval. The Louisville canvass was made before

the epidemic had run its full course. “In the case of Spartanburg,

SC some time after the completion of the canvass in the city itself,

an additional survey was made of adjacent mill villages. These

villages had a disproportionately large population of one selected

class-mill workers-and for this reason the Spartanburg data are not

altogether comparable with those collected in other localities.” The

population canvassed ranged from 4,123 in Augusta to 33,316

in Baltimore and represented 3.9% (San Francisco) to more than

30% of the total population. There were 42,920 cases of influenza

and 2,290 cases of pneumonia in Table 1.24

 

“In making inquiry as to the type or nature of illness, the

enumerators were instructed to ask which members of a family

had “influenza,” “flu,” “grippe,” “pneumonia,” or “colds” since

September 1, 1918. Persons who were said to have been only

“feeling badly,” or as having a “cold” were recorded as “doubtful”

cases. If, however, the illness lasted not less than three days and

was of such severity as to confine the patient to bed for the whole

of one day, the case was classed as “influenza,” unless otherwise

diagnosed by the attending physician.”

 

Solar UVB indices. Summertime UVB irradiance for the

United States was estimated using data from the NASA Total

Ozone Mapping Spectrometer.26 This index has been used successfully

in ecologic studies of cancer mortality rates in the United

States.27,28 Winter UVB irradiance was estimated using a cosine

law that estimates solar irradiance based on season and latitude,

which are the determinants of solar zenith angle. Solar zenith angle

is the most important determinant of solar irradiance in winter.

This index has been found correlated with risk of multiple sclerosis,

29 for which the Epstein-Barr virus is a risk factor and vitamin

D a risk reduction factor,30 likely in part through combating the

virus through induction of LL-37.

 

Statistical analysis. Multiple linear regression was used to assess

the independent contributions of UVB irradiance and latitude to

case-fatality rates of pneumonia. All analyses were performed using

SPSS Grad Pack 13.0 (SPSS Inc., Chicago, IL).

 

Summary and Conclusion

 

More research on this topic is needed. There is no question

that vaccine development and distribution is the most important

and reliable strategy for control of influenza epidemics and their

resulting mortality. On a far less well-established level of certainty

it should be determined whether higher serum 25(OH)D levels

might be associated with lower incidence of bacterial pneumonia

complicating influenza, particularly in older adults. Providing

vitamin D supplements or fortifying commonly consumed foods

with higher amounts of vitamin D should be evaluated further as a

possibly useful component of a comprehensive, vaccine-centered,

program to reduce influenza mortality rates, both in pandemics

and seasonal influenza, especially in the elderly.

 

Acknowledgements

 

 

WBG receives funding from the UV Foundation (McLean,

VA), the Vitamin D Society (Canada), and the European Sunlight

Association (Brussels).

 

 

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Dermato-Endocrinology

2009; Vol. 1 Issue 4

 

 

Vitamin D may reduce the risk of incidence and death from the current A/H1N1 “swine flu” pandemic

 

William B. Grant, Ph.D.

Sunlight, Nutrition, and Health Research Center (SUNARC) P.O. Box 641603 San Francisco, CA 94164-1603, USA www.sunarc.org wbgrant@infionline.net 1-415-409-1980

 

Target journal:  The Medical Journal of Australia

 

Sir:

The current worldwide pandemic of A/H1N1 influenza “swine flu” has the potential to cause the infection and death of many people.  This virus appears to have some seasonality, in common with epidemic influenza.  There is good evidence that epidemic influenza is seasonal due to annual variations in solar ultraviolet-B (UVB) irradiance and vitamin D production.1  The beneficial role of vitamin D is thought to be induction of human cathelicidin, LL-37, which has antimicrobial and antiendotoxin effects and, thus, seems to explain the reduced risk of infection of epidemic influenza.  However, vitamin D did not seem to reduce the risk of infection during the 1918-19 pandemic A/H1N1 influenza.  However, there is evidence from an ecological study that solar UVB and vitamin D reduced case-fatality rates after infection by that virus: case-fatality rates were much lower in southern United States cities than in northern cities.2  The mechanisms are thought to be suppression of the cytokine storm and reduced risk of bacterial pneumonia due to LL-37 induction.  There is growing evidence that the current A/H1N1 influenza virus can be considered seasonal, with higher rates in winter.  In addition, it has been reported that Australian Aborigines have much higher rates of respiratory infectious than European-Australians.3  Aborigines also have very low serum 25-hydroxyvitamin D levels,4,5 due to dark skin and indoor lifestyles.  Thus, it would be useful to do a study in Australia of serum 25-hydroxyvitamin D levels of those who become infected with or die from swine flu.  In addition, it would be worthwhile to recommend that people take vitamin D supplements especially in winter at doses of 1000-4000 IU/day in order to reduce the risk of respiratory infections including influenza.  There are many other health benefits of vitamin D and very few risks.

 

Disclosure

I receive funding from the UV Foundation (McLean, VA), the Vitamin D Society (Canada), and the European Sunlight Association (Brussels).

 

References

1. Cannell JJ, Zasloff M, Garland CF, Scragg R, Giovannucci E. On the epidemiology of influenza. Virol J. 2008;5:29.

 

2. Grant WB, Giovannucci E. The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918-1919 influenza pandemic in the United States.  Dermato-Endocrinology. 2009;1(4), epub.

 

3. Gracey M, King M. Indigenous health part 1: determinants and disease patterns. Lancet. 2009;374:65-75.

 

4. Nowson CA, Margerison C. Vitamin D intake and vitamin D status of Australians. Med J Aust. 2002;177:149-52.

 

5. Benson J, Wilson A, Stocks N, Moulding N. Muscle pain as an indicator of vitamin D deficiency in an urban Australian Aboriginal population. Med J Aust. 2006;185:76-7.

 

 

 

 


 

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Dr Weeks’ Comment:   Vitamin D  from sunlight can protect against H1V1 influenza  but the CDC and “experts” are not talking about it –  too inexpensive for their consideration. The possible roles of solar ultraviolet-B radiation and vitamin D in  reducing case-fatality rates from the 1918-1919 influenza pandemic in the United States   [Dermato-Endocrinology 1:4, 1-5;…
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