Increasing Incidence and Severity of Coccidioidomycosis at a Naval Air Station

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Increasing Incidence and Severity of Coccidioidomycosis at a Naval

Air Station

Posted on: Sunday, 14 September 2008,

RedOrbit - Dallas,TX*

By Lee, Crum-Cianflone,

http://www.redorbit.com/news/health/1554472/increasing_incidence_and_

severity_of_coccidioidomycosis_at_a_naval_air/

ABSTRACT Background: Increasing rates of coccidioidomycosis among

the general population are being described. Given the large number

of military personnel stationed and training in endemic areas, data

regarding infection trends among military members would be

informative. Methods: We performed a retrospective epidemiological

study concerning the incidence and severity of clinical cases of

coccidioidomycosis at a naval base located in an endemic area in

California. Results: Eighty-two military beneficiaries at the base

were diagnosed with coccidioidomycosis from January 2002 to December

2006. Among active duty personnel, the rate of coccidioidomycosis

rose 10-fold during the 5-year study period: 29.88 to 313.71 cases

per 100,000 person-years. The incidence of coccidioidal infections

occurring in active duty members was higher than other military

beneficiaries at the base. The median age of patients with a

coccidioidal infection was 28 years, and 73% were male. Sixty-six

had primary pulmonary disease and 14 had disseminated disease; data

were unavailable for two cases. The number of disseminated cases

increased significantly over time; by 2006, 30% of the diagnosed

cases were disseminated disease. Among cases of dissemination, 43%

occurred among Caucasian/non-Hispanics. Disseminated disease was

associated with high complement fixation titers and a more recent

year of diagnosis. Although the sample size was small, we found no

differences in rates of disseminated disease by race, likely due to

the large number of cases among Caucasians. Conclusions:

Coccidioidomycosis incidence rates have significantly increased

during the last 5 years among military beneficiaries. Active duty

members were more likely to develop coccidioidomycosis than

dependents or retirees, perhaps related to the number and intensity

of exposures in this group. INTRODUCTION

Coccidioidomycosis, known as " Valley Fever, " is a common fungal

infection which has gained notoriety over the past decade due to the

increased incidence and severity-oftentimes despite treatment.1-3 It

was first described in 1892, appearing in a soldier in Argentina and

became more apparent as a significant public health concern during

the 1930s and 1940s, particularly in the San Joaquin Valley in

southern California, with the " dust bowl " migrations.4-6 Since then,

coccidioidomycosis has become a well-described endemic mycotic

infection in the lower Sonoran zone.7 It is estimated that 150,000

infections occur annually, and epidemiological studies show that

~40% develop symptomatic disease with protean manifestations ranging

from mild pulmonary disease to more severe forms.6-8 Approximately 1

to 2% will develop disseminated disease, most frequently with

involvement of the skin, bones, joints, and the meninges. The risk

for dissemination appears to be increased in specific racial groups

(especially African Americans and Filipinos), pregnant or postpartum

women, elderly persons, and immunosuppressed individuals, such as

those with AIDS or cancer, or those who are transplant recipients.9-

12

Increasing numbers of infections have been reported in California

and Arizona over the past 15 years,1,5,13,14 and coccidioidomycosis

is now one of the most frequent causes of community-acquired

pneumonia.15 These findings may be partly due to environmental

factors, construction activities, migration of increasing numbers of

people into endemic areas, and the rising number of

immunocompromised hosts in these areas. Trends of coccidioidomycosis

among specific populations, such as the military, have not been

reported.

More than 350,000 military personnel are stationed at bases within

endemic regions of the United States, including in California,

Arizona, Nevada, New Mexico, Utah, and Texas; in addition, thousands

more individuals conduct training exercises on temporary active duty

order to these locations.16 Military exercises often create dusty

conditions which may aerosolize the infectious arthroconidia, which

when inhaled lead to infection. Numerous outbreaks and sporadic

cases among military members have been reported.6,16-23 Active

surveillance and documentation of incidence rates of the disease in

the military setting have not been recently evaluated. Whether

military personnel are experiencing increasing rates of infections,

similar to reports in the general population, is unknown. Hence, we

conducted an epidemiological evaluation to determine the incidence

and predictors of coccidioidomycosis among military members at a

naval base located in the San Joaquin Valley.

METHODS

A retrospective evaluation was conducted for coccidioidomycosis

cases at the Naval Air Station Lemoore (NASL), which is located in

Kings County in the central valley of California (Fig. 1). Cases

were identified between January 1, 2002 and December 31, 2006 by

recording patients presenting to the NASL internal medicine clinic

with infection and by searching the laboratory's computerized

database. A case was defined as a positive immunoglobulin M (IgM)

and immunoglobulin G (IgG) enzyme-linked immunosorbent assay test, a

positive immunodiffusion test, or a positive complement fixation

(CF) of >/= 1:2 in the setting of a clinical illness consistent with

coccidioidomycosis. An isolated positive IgM without IgG

seroconversion, a CF of

Previous laboratory data and medical record information were

reviewed for each patient to ensure that the case was a new

diagnosis of coccidioidomycosis and not recurrent disease or a

follow-up result from a previously diagnosed case; only new

diagnoses of coccidioidomycosis were included in the study. Patient

demographics and clinical information was obtained.

The patient population at NASL consisted of ~17,046 persons,

including 6,694 active duty members, 7,443 dependents, and 2,909

retirees; these numbers were estimated, as continuous turnover was

seen among the military personnel at the base; however, we are not

aware of any substantial changes in the number of personnel over the

study time period. Demographic characteristics of the entire

population served at the NASL hospital were: average age of 26 years

(range, 1 day to 95 years); 47% were male and 53% were female. Of

those with race recorded in the hospital database, 28.4% were

Caucasian/non-Hispanic, 7.9% were Caucasian/ Hispanic, 5.4% were

African American, 5.1% were Asian/ Pacific Islander, 2.0% were

American Indian/Alaskan, and 0.7% were other. Of note, nearly one-

half of enrollees did not report race/ethnicity on the medical

registration form.

A subanalysis was performed on the active duty population; this

group (active duty personnel) represented 39% (6,694 of 17,046) of

the total hospital population; the average age was 26 years, and

85.3% were male. The race distribution was 56.3% (n = 3,769)

Caucasian/non-Hispanic, 18.2% (n = 1,219) Caucasian/Hispanic, 11% (n

= 740) African American, 5.1% (n = 340) Filipino, 4.4% (n = 297)

American Indian/Alaskan Native, 3.8% (n = 253) Asian/Pacific

Islander, and 1.2% (n = 76) other/unknown.

Statistical analyses included descriptive statistics on the cases of

coccidioidomycosis. The number of cases over time used the chi^sup

2^ test for trend. Univariate comparisons used the Fisher's exact

test for categorical variables and the Wilcoxon rank test for

continuous variables. Variables significant in the univariate model

(p < 0.05) were included in a backward stepwise multivariate

logistic regression model (STATA software 9.0; College Station,

Texas).

RESULTS

Incidence Rates

During the evaluation period, 82 patients were newly diagnosed with

coccidioidomycosis. The total number of cases increased 6.8- fold

during the 5-year study period from 4 cases during 2002 to 27 cases

by the year 2006 (chi^sup 2^ = 14.7, p < 0.001) (Fig. 2). The

incidence rate for the overall population at the base was 96 cases

per 100,000 person-years (PY); the rate increased from 23 cases per

100,000 persons in 2002 to 158 cases per 100,000 person-years in

2006. The incidence rate of coccidioidomycosis among active duty

military members overall was 176 cases per 100,000 PY; the rate rose

10-fold during the 5-year study period: 30 to 314 cases per 100,000

PY. Notably, the incidence rate among nonactive duty members treated

at the medical facility did not significantly change over time (p =

0.24). In 2006, the incidence rate of coccidioidal infections

occurring in active duty members was 5.4-fold higher compared to

military beneficiaries not serving on active duty at the base (Fig.

2).

Similar trends have also been noted locally: the Kings County Public

Health Department reported that coccidioidomycosis rates in both the

local civilian and prison populations have increased over time (Fig.

3). The number of cases among civilians in the county increased from

13 to 123 cases during the years 2000 to 2005 (incidence rate from 9

to 88 cases per 100,000 PY). Similar, but higher, rates occurred

among the prison population as the incidence rates rose from 32 to

200 cases per 100,000 PY (Fig. 3).

Seasonal Trends

Coccidioidal cases were most commonly diagnosed during the late fall

and winter months at Lemoore, with the highest number during the

months of December and January. Seasonal trends are shown in Figure

4. Clinical Manifestations

Of the 82 cases of coccidioidomycosis, 80 (98%) had complete medical

records; in two cases, the patient was referred to an outside

medical facility and information was not available. Of patients with

complete information, 66 (82.5%) patients with coccidioidomycosis

had pulmonary disease alone and 14 (17.5%) had disseminated disease

(Table I). At the time of presentation, 11 (13.4%) of the pulmonary

cases had no evidence of dissemination and normal chest radiographs,

but had a history of a respiratory infection. Of those with

pulmonary disease with an infiltrate (n = 55) on chest radiograph at

presentation, 47 (85.5%) of 55 had single- lobe involvement. Two-

thirds of patients had right lung involvement. The lower segments

were involved in 55% of cases, the upper lobes in 33%, and the

middle lobe in 13%. Adenopathy was detected in seven chest

radiographs; an effusion was found in two patients, both of whom

were diagnosed with an empyema. Erythema nodosum accompanied two

(3%) of the cases.

Of the 14 cases of disseminated disease, 5 (36%) had multiple areas

of extrapulmonary involvement. Dissemination involved the skin (n =

10), central nervous system (n = 5), bone (n = 5), and pericardium

(n = 1). Not only did the number of coccidioidomycosis cases

increase over the study period, but the percentage of cases with

dissemination also increased (chi^sup 2^ test 3.9, p = 0.047). In

2002, no cases of disseminated disease were reported; in 2006, 8

(30%) of the 27 were diagnosed with dissemination (Fig. 5).

Demographic and Risk Factor Assessments

Of those with coccidioidomycosis, 59 (72.0%) were active duty

members, 13 (15.8%) were dependents, and 10 (12.2%) were retirees (2

of the retirees were guards at a local county prison). Among all

military beneficiaries at the NASL, the median age of the patients

with coccidioidomycosis was 28 years (range 9-69 years). Two

patients were under the age of 18 years (dependent children) and

seven were over the age of 50 years (retirees/dependents). Sixty

(73.2%) of the patients were male; male gender was associated with a

3.1-fold higher rate of infection compared to females on the base (p

< 0.001). The race distribution of cases was Caucasian/non-Hispanic

in 42.4%, Caucasian/Hispanic in 18.6%, Filipino in 18.6%, African

American in 11.9%, and Asian in 8.5% among those with race recorded

in the medical profile; 22 of the patients did not have a race/

ethnicity listed in their record.

Most (72%) of the coccidioidomycosis cases occurred among the active

duty population. Among the 59 active duty members with

coccidioidomycosis, the median age of active duty members was 26

years and 49 (83.1%) were male. Among active duty members, males and

females had similar risk for infection (odds ratio (OR), 0.84; p =

0.24). Race included 18 (30.5%) Caucasians, 11 (18.6%) Hispanics, 6

(10.2%) African Americans, 5 (8.5%) Asians, and 5 (8.5%) Filipinos.

In 14 (23.7%) cases, race was not recorded in the medical notes or

registration information.

Among active duty members, the highest incidence rates for pulmonary

disease occurred among Asians (237 cases per 100,000 PY) and

Hispanics (164 cases per 100,000 PY). The relative risk for

pulmonary disease was 2.6 for Hispanics (p = 0.02) and 3.8 for

Asians (p = 0.06) compared to Caucasian/non-Hispanic military

personnel. For each race, the number of uncomplicated pulmonary

infections was more common than disseminated cases, except in

Filipinos, in which the incidence was the same; these data are

limited by the small sample size (Table I).

Of those with disseminated disease (n = 14), the median age was 24

years (mean, 27.9, range, 19-59); all cases occurred among active

duty members. The age or sex of patients with disseminated versus

pulmonary disease was not significantly different. The race among

disseminated cases was Caucasian/non-Hispanic, six (42.9%); African

American, two (14.3%); Filipino, two (14.3%); Asian, two (14.3%);

Hispanic, one (7.1%); and unknown one (7.1%). Asians, Filipinos, and

African Americans (in descending order) had the highest incidence

rates of disseminated disease after accounting for the race of the

personnel at the base; of note, Caucasians had a substantial rate of

disseminated disease, with an incidence of 31.8 cases per 100,000

PY. The risk of disseminated disease was not significantly predicted

by race, perhaps due to the high rate among the comparator group of

Caucasian/non-Hispanics.

Coccidioides spp. infections occurred in a relatively healthy

population with only two patients with diabetes mellitus, one with

cancer (multiple myeloma), and one with human immunodeficiency virus

infection who had robust CD4 counts. Two patients were pregnant and/

or postpartum during the time of diagnosis. Of this group of

patients with comorbidities, only two developed disseminated disease

(a diabetic male and a postpartum female). The other diabetic

patient developed severe primary pulmonary disease requiring a

prolonged intensive care unit stay and partial lung resection due to

an empyema. The others had uncomplicated pulmonary disease.

Laboratory Findings

Laboratory data showed complement fixation titers ranging from 0 to

1:256. Those with pulmonary disease had a median titer of 1:8

(range, 0-1:64); 16% (n = 7) had a titer of > 1:16 but no clinical

evidence of dissemination. Patients with proven disseminated disease

had a median titer of 1:32 (range, 1:4-1:256). Interestingly, 50%

had a titer of

Overall, the median white blood count was 10,200 cells/ mm^sup 3^

(range, 3,800-25,000); 46% had an elevated white blood cell count at

the time of diagnosis. The erythrocyte sedimentation rate (ESR) was

a median of 64 per hour (range, 1-122). The ESR was >20 in 81% of

patients, >50 in 62%, and >100 in 16%. The eosinophil percentage

ranged from 0 to 34% (median, 4%), with 41% of patients having >6%.

The absolute eosinophil count was as high at 6,630/mm^sup 3^ and 40%

had a count >500/mm^sup 3^. Comparing patients with pulmonary and

disseminated disease, no statistically significant differences were

found in the white blood count, absolute eosinophil count, or ESR

values. However, the CF titer was higher among disseminated than

pulmonary cases (p = 0.002).

Outcome Data

Sixteen (20.0%) of the 80 cases with complete data were

hospitalized, including 7 (50%) with disseminated disease and 9

(14%) with pulmonary involvement. One active duty member underwent a

pericardial window for coccidioidal pericarditis, but was able to

remain on active duty service. Two patients required surgical

partial resection of their lungs due to empyemas unresponsive to

antifungal therapy alone. There were no deaths, but two persons had

significant morbidity from the disease requiring medical retirement

from the military.

Correlations and Multivariate Analyses

Variables which were correlated included disseminated disease with a

more recent year of diagnosis, higher CF titers, and

hospitalization. In the multivariate analysis, a high CF titer

remained predictive for dissemination (OR, 1.04; p = 0.003); a trend

toward a more recent year of coccidioidomycosis diagnosis and having

disseminated disease (OR, 2.39; p = 0.06) was identified.

DISCUSSION

This is the first surveillance study in several decades to describe

clinical diagnoses of coccidioidomycosis among a defined military

population residing at a naval base. Our evaluation demonstrated

that the incidence of coccidioidomycosis has significantly increased

among military beneficiaries during the years 2002 to 2006. These

trends are consistent with studies showing rising rates in the

general population of Kings County and other locations in California

and Arizona.13,14,24,25

The overall incidence rate of clinical infections in our study was

96 cases per 100,000 PY. This rate is higher than previous rates

reported at Lemoore during the 1970s (~10 cases per 100,000 PY).17

However, our rate is not considerably different from recent rates in

the general U.S. population. Previously reported data using a

similar diagnostic strategy demonstrated a rate of 86 cases per

100,000 PY among the general population in Kern County; these data

were from the late 1990s.12 Higher incidence rates have been

reported recently, including rates of 3,000 cases per 100,000 PY

among prison inmates in California during 2005.25

Among our study cohort, a greater proportion of active duty members

were affected in comparison to the nonactive duty (i.e., dependents

and retirees). This may be due to greater soil exposures during work-

related activities or training exercises. Previous studies have

shown that exposure to dust is a risk factor for disease;

individuals in professions at higher risk of infection include

archeologists, as well as construction and agricultural workers.2

Military personnel may experience dust exposure as part of military

training exercises or other work-related activities; alternatively,

the young military cohort may engage in recreational activities

associated with dust exposure. Another reason that active duty

members may have had more infections than retirees is that persons

who recently moved into an endemic area are known to be at higher

risk due to lack of protective immunity10; active duty personnel

typically change duty stations every few years and may be at higher

risk than retirees who have resided at the base for a longer

duration of time.

As expected, most patients presented with respiratory symptoms and

pulmonary involvement, as coccidioidomycosis is transmitted by

inhalation of spores. However, the large proportion of cases that

were disseminated disease is of interest. Traditionally, only 1% of

cases diagnosed are disseminated, but in our cohort, 17.5% (14 of

80) had extrapulmonary involvement; in 2006, the figure was 30%.

This is likely an indicator that only the " tip of the iceberg " of

cases were clinically recognized and that the number of actual cases

may have been severalfold higher than reported in this article.

Another possible explanation for the high proportion of disseminated

cases is that the fungus, Coccidioides immitis, has increased in

virulence and that more infections are resulting in disseminated

forms of the disease. Although a higher percentage of dissemination

can be seen among immunosuppressed hosts and the elderly,10,12 our

population was comprised of mainly young, healthy individuals who

were immunocompetent. Finally, both clinically recognized cases and

dissemination may be heightened among groups with intense, high-

inoculum exposures.17,19 Further evaluation is warranted to better

understand the epidemiology of coccidioidal infections in this

population. One such strategy would be the use of a coccidioidal

skin test preparation to more accurately identify infections which

may not be clinically recognized. Such evaluations were performed in

the 1970s at a different military base in California, Twenty-nine

Palms, and it was noted that among Marines permanently stationed at

the base, 25.4% converted their skin test to positive over a 6- to 8-

month period.26 This conversion rate was likely related to the fact

that this group was in the tank battalion, which has a high

likelihood of dust inhalation. More recent investigations, using

enzyme-linked immunosorbent assay testing,27 as well as unpublished

data using skin tests, have shown much lower rates of infections

among military personnel.

We observed a seasonal pattern, whereby most cases were identified

during winter months. This is consistent with previous reports

demonstrating that the highest number of exposures to the airborne

arthroconidia occurs during the fall months, corresponding to dry,

windy weather conditions.6,25,28 A recent survey suggested that the

peak exposure to fungal spores occurs in October to November.24

Given the incubation period of 1 to 3 weeks and a possible delay in

the clinical diagnosis of cases, the seasonal trends we noted appear

to be consistent with these data. A second exposure peak, as

recognized by Connie,24 also occurs in the months of June to July

(Fig. 4).

In our study, a higher percentage of male military beneficiaries

were diagnosed with coccidioidomycosis. This trend remained after

accounting for the number of males at the base. Other studies have

also noted a higher rate of coccidioidomycosis among men,

potentially due to occupational or recreational activity differences

between the sexes. Of interest, the male gender association with

coccidioidal infections was mitigated when examining only those on

active duty; this may have been due to the fact that the active duty

females had similar work-related exposures than men, which placed

them at equal risk. Further studies examining gender-specific work

and recreational activities and their corresponding risk for

infection would be useful.

Non-Caucasian ethnic groups, particularly Filipinos and African

Americans, are thought to be more likely to develop disseminated

disease.6,22,29 Caucasian patients appear to be at the lowest risk

of dissemination; in the current study, 43% of patients with

dissemination were Caucasian. This is partially explained by the

large number of Caucasians at the base. However, we were surprised

at the high incident rates among this group. A similar experience

was noted by et al.17 in association with a dust storm at

NASL in the 1970s. The increasing number of mixed racial backgrounds

may make race associations difficult; for instance, although one

patient reported being " Caucasian, " she had a significant Native

American ancestry.

Despite the fact that mostly young healthy persons were affected by

this infection, 20% of the patients required hospitalization; this

may incur significant medical costs estimated as $23,000 to $34,000

per patient.11,30 Even among those not hospitalized, missed workdays

and outpatient medical care results are important expenses. Serious

disease requiring surgical procedures and/or military medical

discharges occurred in a minority of our cases, perhaps due to the

aggressive medical management provided in the cases at a nearby

tertiary naval hospital.

Prevention is paramount among patients at-risk for

coccidioidomycosis. Methods to reduce dust formation are important

considerations. Persons who cannot avoid dusty conditions should

wear a facemask. Outdoor physical training sites should be modified

for dust reduction, and aquatic exercise programs should be used

when dust levels are high. Although prophylaxis using an azole is

being studied to prevent clinical disease among high-risk patients

(transplant recipients and AIDS patients),9 the efficacy and cost-

effectiveness of such a strategy is unclear, especially among large

groups such as the military. A vaccine against Coccidioides spp.

would be the best preventive strategy, but currently is not

available.

Our study had some limitations. Cases included in our investigation

were only those definitively diagnosed as coccidioidomycosis, which

may have underestimated the true number of infections. Furthermore,

some patients may have transferred to another base before the

diagnosis of coccidioidomycosis was made. On the other hand, some

military personnel are present on the base for short training

exercises and are not accounted for in the total population of the

base; however, to our knowledge, the cases in this report were among

persons permanently stationed or residing at the base. Another

limitation was the lack of complete ethnicity data; however, we are

not aware of any specific biases regarding military personnel

reporting ethnicity. Furthermore, to more accurately assess the

racial impact on dissemination, a larger number of cases is needed.

Finally, although we report seasonal trends in the diagnosis of

coccidioidomycosis, many patients were treated with several courses

of antibiotics before evaluation for coccidioidomycosis, which may

have delayed the diagnosis.

In summary, there has been an increase in the number and severity of

coccidioidomycosis cases among our military personnel. Further

epidemiological research studies on the driving forces of these

trends are needed. In the meantime, clinicians should maintain a

high index of suspicion for coccidioidomycosis, and workplaces in

endemic areas should consider implementing both educational programs

and prevention strategies for this disease.

ACKNOWLEDGMENTS

We thank Judy Christensen, graphic Artist, for her work in the

preparation of this article.

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2001. J Infect Dis 2005; 191: 1981-7.

Lee, MD*; Crum-Cianflone, MD MPH1

* Internal Medicine Department, Naval Hospital Lemoore Naval Air

Station, Lemoore, CA.

[dagger] Infectious Disease Division, Naval Medical Center San

Diego, CA 92134; the Infectious Disease Clinical Research Program

(IDCRP), Uniformed Services University of the Health Sciences,

Bethesda, MD.

The data in this article were presented in part at the Sixth

International Symposium on Coccidioidomycosis August 23-27, 2006,

Stanford University, Stanford, CA.

The views expressed in this article are those of the author and do

not necessarily reflect the official policy or position of the

Department of the Navy, Department of Defense, nor the U.S.

Government.

This manuscript was received for review in June 2007. The revised

manuscript was accepted for publication in May 2008.

Copyright Association of Military Surgeons of the United States Aug

2008

© 2008 Military Medicine. Provided by ProQuest LLC. All rights

Reserved.

Source: Military Medicine

[Guest guest]

--- In , " tigerpaw2c " <tigerpaw2c@...>

wrote:

>

> Increasing Incidence and Severity of Coccidioidomycosis at a Naval

> Air Station

> Posted on: Sunday, 14 September 2008,

> RedOrbit - Dallas,TX*

> By Lee, Crum-Cianflone,

>

>

http://www.redorbit.com/news/health/1554472/increasing_incidence_and_

> severity_of_coccidioidomycosis_at_a_naval_air/

>

> ABSTRACT Background: Increasing rates of coccidioidomycosis among

> the general population are being described. Given the large number

> of military personnel stationed and training in endemic areas,

data

> regarding infection trends among military members would be

> informative. Methods: We performed a retrospective epidemiological

> study concerning the incidence and severity of clinical cases of

> coccidioidomycosis at a naval base located in an endemic area in

> California. Results: Eighty-two military beneficiaries at the base

> were diagnosed with coccidioidomycosis from January 2002 to

December

> 2006. Among active duty personnel, the rate of coccidioidomycosis

> rose 10-fold during the 5-year study period: 29.88 to 313.71 cases

> per 100,000 person-years. The incidence of coccidioidal infections

> occurring in active duty members was higher than other military

> beneficiaries at the base. The median age of patients with a

> coccidioidal infection was 28 years, and 73% were male. Sixty-six

> had primary pulmonary disease and 14 had disseminated disease;

data

> were unavailable for two cases. The number of disseminated cases

> increased significantly over time; by 2006, 30% of the diagnosed

> cases were disseminated disease. Among cases of dissemination, 43%

> occurred among Caucasian/non-Hispanics. Disseminated disease was

> associated with high complement fixation titers and a more recent

> year of diagnosis. Although the sample size was small, we found no

> differences in rates of disseminated disease by race, likely due

to

> the large number of cases among Caucasians. Conclusions:

> Coccidioidomycosis incidence rates have significantly increased

> during the last 5 years among military beneficiaries. Active duty

> members were more likely to develop coccidioidomycosis than

> dependents or retirees, perhaps related to the number and

intensity

> of exposures in this group. INTRODUCTION

>

> Coccidioidomycosis, known as " Valley Fever, " is a common fungal

> infection which has gained notoriety over the past decade due to

the

> increased incidence and severity-oftentimes despite treatment.1-3

It

> was first described in 1892, appearing in a soldier in Argentina

and

> became more apparent as a significant public health concern during

> the 1930s and 1940s, particularly in the San Joaquin Valley in

> southern California, with the " dust bowl " migrations.4-6 Since

then,

> coccidioidomycosis has become a well-described endemic mycotic

> infection in the lower Sonoran zone.7 It is estimated that 150,000

> infections occur annually, and epidemiological studies show that

> ~40% develop symptomatic disease with protean manifestations

ranging

> from mild pulmonary disease to more severe forms.6-8 Approximately

1

> to 2% will develop disseminated disease, most frequently with

> involvement of the skin, bones, joints, and the meninges. The risk

> for dissemination appears to be increased in specific racial

groups

> (especially African Americans and Filipinos), pregnant or

postpartum

> women, elderly persons, and immunosuppressed individuals, such as

> those with AIDS or cancer, or those who are transplant

recipients.9-

> 12

>

> Increasing numbers of infections have been reported in California

> and Arizona over the past 15 years,1,5,13,14 and

coccidioidomycosis

> is now one of the most frequent causes of community-acquired

> pneumonia.15 These findings may be partly due to environmental

> factors, construction activities, migration of increasing numbers

of

> people into endemic areas, and the rising number of

> immunocompromised hosts in these areas. Trends of

coccidioidomycosis

> among specific populations, such as the military, have not been

> reported.

>

> More than 350,000 military personnel are stationed at bases within

> endemic regions of the United States, including in California,

> Arizona, Nevada, New Mexico, Utah, and Texas; in addition,

thousands

> more individuals conduct training exercises on temporary active

duty

> order to these locations.16 Military exercises often create dusty

> conditions which may aerosolize the infectious arthroconidia,

which

> when inhaled lead to infection. Numerous outbreaks and sporadic

> cases among military members have been reported.6,16-23 Active

> surveillance and documentation of incidence rates of the disease

in

> the military setting have not been recently evaluated. Whether

> military personnel are experiencing increasing rates of

infections,

> similar to reports in the general population, is unknown. Hence,

we

> conducted an epidemiological evaluation to determine the incidence

> and predictors of coccidioidomycosis among military members at a

> naval base located in the San Joaquin Valley.

>

> METHODS

>

> A retrospective evaluation was conducted for coccidioidomycosis

> cases at the Naval Air Station Lemoore (NASL), which is located in

> Kings County in the central valley of California (Fig. 1). Cases

> were identified between January 1, 2002 and December 31, 2006 by

> recording patients presenting to the NASL internal medicine clinic

> with infection and by searching the laboratory's computerized

> database. A case was defined as a positive immunoglobulin M (IgM)

> and immunoglobulin G (IgG) enzyme-linked immunosorbent assay test,

a

> positive immunodiffusion test, or a positive complement fixation

> (CF) of >/= 1:2 in the setting of a clinical illness consistent

with

> coccidioidomycosis. An isolated positive IgM without IgG

> seroconversion, a CF of

>

> Previous laboratory data and medical record information were

> reviewed for each patient to ensure that the case was a new

> diagnosis of coccidioidomycosis and not recurrent disease or a

> follow-up result from a previously diagnosed case; only new

> diagnoses of coccidioidomycosis were included in the study.

Patient

> demographics and clinical information was obtained.

>

> The patient population at NASL consisted of ~17,046 persons,

> including 6,694 active duty members, 7,443 dependents, and 2,909

> retirees; these numbers were estimated, as continuous turnover was

> seen among the military personnel at the base; however, we are not

> aware of any substantial changes in the number of personnel over

the

> study time period. Demographic characteristics of the entire

> population served at the NASL hospital were: average age of 26

years

> (range, 1 day to 95 years); 47% were male and 53% were female. Of

> those with race recorded in the hospital database, 28.4% were

> Caucasian/non-Hispanic, 7.9% were Caucasian/ Hispanic, 5.4% were

> African American, 5.1% were Asian/ Pacific Islander, 2.0% were

> American Indian/Alaskan, and 0.7% were other. Of note, nearly one-

> half of enrollees did not report race/ethnicity on the medical

> registration form.

>

> A subanalysis was performed on the active duty population; this

> group (active duty personnel) represented 39% (6,694 of 17,046) of

> the total hospital population; the average age was 26 years, and

> 85.3% were male. The race distribution was 56.3% (n = 3,769)

> Caucasian/non-Hispanic, 18.2% (n = 1,219) Caucasian/Hispanic, 11%

(n

> = 740) African American, 5.1% (n = 340) Filipino, 4.4% (n = 297)

> American Indian/Alaskan Native, 3.8% (n = 253) Asian/Pacific

> Islander, and 1.2% (n = 76) other/unknown.

>

> Statistical analyses included descriptive statistics on the cases

of

> coccidioidomycosis. The number of cases over time used the chi^sup

> 2^ test for trend. Univariate comparisons used the Fisher's exact

> test for categorical variables and the Wilcoxon rank test for

> continuous variables. Variables significant in the univariate

model

> (p < 0.05) were included in a backward stepwise multivariate

> logistic regression model (STATA software 9.0; College Station,

> Texas).

>

> RESULTS

>

> Incidence Rates

>

> During the evaluation period, 82 patients were newly diagnosed

with

> coccidioidomycosis. The total number of cases increased 6.8- fold

> during the 5-year study period from 4 cases during 2002 to 27

cases

> by the year 2006 (chi^sup 2^ = 14.7, p < 0.001) (Fig. 2). The

> incidence rate for the overall population at the base was 96 cases

> per 100,000 person-years (PY); the rate increased from 23 cases

per

> 100,000 persons in 2002 to 158 cases per 100,000 person-years in

> 2006. The incidence rate of coccidioidomycosis among active duty

> military members overall was 176 cases per 100,000 PY; the rate

rose

> 10-fold during the 5-year study period: 30 to 314 cases per

100,000

> PY. Notably, the incidence rate among nonactive duty members

treated

> at the medical facility did not significantly change over time (p

=

> 0.24). In 2006, the incidence rate of coccidioidal infections

> occurring in active duty members was 5.4-fold higher compared to

> military beneficiaries not serving on active duty at the base

(Fig.

> 2).

>

> Similar trends have also been noted locally: the Kings County

Public

> Health Department reported that coccidioidomycosis rates in both

the

> local civilian and prison populations have increased over time

(Fig.

> 3). The number of cases among civilians in the county increased

from

> 13 to 123 cases during the years 2000 to 2005 (incidence rate from

9

> to 88 cases per 100,000 PY). Similar, but higher, rates occurred

> among the prison population as the incidence rates rose from 32 to

> 200 cases per 100,000 PY (Fig. 3).

>

> Seasonal Trends

>

> Coccidioidal cases were most commonly diagnosed during the late

fall

> and winter months at Lemoore, with the highest number during the

> months of December and January. Seasonal trends are shown in

Figure

> 4. Clinical Manifestations

>

> Of the 82 cases of coccidioidomycosis, 80 (98%) had complete

medical

> records; in two cases, the patient was referred to an outside

> medical facility and information was not available. Of patients

with

> complete information, 66 (82.5%) patients with coccidioidomycosis

> had pulmonary disease alone and 14 (17.5%) had disseminated

disease

> (Table I). At the time of presentation, 11 (13.4%) of the

pulmonary

> cases had no evidence of dissemination and normal chest

radiographs,

> but had a history of a respiratory infection. Of those with

> pulmonary disease with an infiltrate (n = 55) on chest radiograph

at

> presentation, 47 (85.5%) of 55 had single- lobe involvement. Two-

> thirds of patients had right lung involvement. The lower segments

> were involved in 55% of cases, the upper lobes in 33%, and the

> middle lobe in 13%. Adenopathy was detected in seven chest

> radiographs; an effusion was found in two patients, both of whom

> were diagnosed with an empyema. Erythema nodosum accompanied two

> (3%) of the cases.

>

> Of the 14 cases of disseminated disease, 5 (36%) had multiple

areas

> of extrapulmonary involvement. Dissemination involved the skin (n

=

> 10), central nervous system (n = 5), bone (n = 5), and pericardium

> (n = 1). Not only did the number of coccidioidomycosis cases

> increase over the study period, but the percentage of cases with

> dissemination also increased (chi^sup 2^ test 3.9, p = 0.047). In

> 2002, no cases of disseminated disease were reported; in 2006, 8

> (30%) of the 27 were diagnosed with dissemination (Fig. 5).

>

> Demographic and Risk Factor Assessments

>

> Of those with coccidioidomycosis, 59 (72.0%) were active duty

> members, 13 (15.8%) were dependents, and 10 (12.2%) were retirees

(2

> of the retirees were guards at a local county prison). Among all

> military beneficiaries at the NASL, the median age of the patients

> with coccidioidomycosis was 28 years (range 9-69 years). Two

> patients were under the age of 18 years (dependent children) and

> seven were over the age of 50 years (retirees/dependents). Sixty

> (73.2%) of the patients were male; male gender was associated with

a

> 3.1-fold higher rate of infection compared to females on the base

(p

> < 0.001). The race distribution of cases was Caucasian/non-

Hispanic

> in 42.4%, Caucasian/Hispanic in 18.6%, Filipino in 18.6%, African

> American in 11.9%, and Asian in 8.5% among those with race

recorded

> in the medical profile; 22 of the patients did not have a race/

> ethnicity listed in their record.

>

> Most (72%) of the coccidioidomycosis cases occurred among the

active

> duty population. Among the 59 active duty members with

> coccidioidomycosis, the median age of active duty members was 26

> years and 49 (83.1%) were male. Among active duty members, males

and

> females had similar risk for infection (odds ratio (OR), 0.84; p =

> 0.24). Race included 18 (30.5%) Caucasians, 11 (18.6%) Hispanics,

6

> (10.2%) African Americans, 5 (8.5%) Asians, and 5 (8.5%)

Filipinos.

> In 14 (23.7%) cases, race was not recorded in the medical notes or

> registration information.

>

> Among active duty members, the highest incidence rates for

pulmonary

> disease occurred among Asians (237 cases per 100,000 PY) and

> Hispanics (164 cases per 100,000 PY). The relative risk for

> pulmonary disease was 2.6 for Hispanics (p = 0.02) and 3.8 for

> Asians (p = 0.06) compared to Caucasian/non-Hispanic military

> personnel. For each race, the number of uncomplicated pulmonary

> infections was more common than disseminated cases, except in

> Filipinos, in which the incidence was the same; these data are

> limited by the small sample size (Table I).

>

> Of those with disseminated disease (n = 14), the median age was 24

> years (mean, 27.9, range, 19-59); all cases occurred among active

> duty members. The age or sex of patients with disseminated versus

> pulmonary disease was not significantly different. The race among

> disseminated cases was Caucasian/non-Hispanic, six (42.9%);

African

> American, two (14.3%); Filipino, two (14.3%); Asian, two (14.3%);

> Hispanic, one (7.1%); and unknown one (7.1%). Asians, Filipinos,

and

> African Americans (in descending order) had the highest incidence

> rates of disseminated disease after accounting for the race of the

> personnel at the base; of note, Caucasians had a substantial rate

of

> disseminated disease, with an incidence of 31.8 cases per 100,000

> PY. The risk of disseminated disease was not significantly

predicted

> by race, perhaps due to the high rate among the comparator group

of

> Caucasian/non-Hispanics.

>

> Coccidioides spp. infections occurred in a relatively healthy

> population with only two patients with diabetes mellitus, one with

> cancer (multiple myeloma), and one with human immunodeficiency

virus

> infection who had robust CD4 counts. Two patients were pregnant

and/

> or postpartum during the time of diagnosis. Of this group of

> patients with comorbidities, only two developed disseminated

disease

> (a diabetic male and a postpartum female). The other diabetic

> patient developed severe primary pulmonary disease requiring a

> prolonged intensive care unit stay and partial lung resection due

to

> an empyema. The others had uncomplicated pulmonary disease.

>

> Laboratory Findings

>

> Laboratory data showed complement fixation titers ranging from 0

to

> 1:256. Those with pulmonary disease had a median titer of 1:8

> (range, 0-1:64); 16% (n = 7) had a titer of > 1:16 but no clinical

> evidence of dissemination. Patients with proven disseminated

disease

> had a median titer of 1:32 (range, 1:4-1:256). Interestingly, 50%

> had a titer of

>

> Overall, the median white blood count was 10,200 cells/ mm^sup 3^

> (range, 3,800-25,000); 46% had an elevated white blood cell count

at

> the time of diagnosis. The erythrocyte sedimentation rate (ESR)

was

> a median of 64 per hour (range, 1-122). The ESR was >20 in 81% of

> patients, >50 in 62%, and >100 in 16%. The eosinophil percentage

> ranged from 0 to 34% (median, 4%), with 41% of patients having

>6%.

> The absolute eosinophil count was as high at 6,630/mm^sup 3^ and

40%

> had a count >500/mm^sup 3^. Comparing patients with pulmonary and

> disseminated disease, no statistically significant differences

were

> found in the white blood count, absolute eosinophil count, or ESR

> values. However, the CF titer was higher among disseminated than

> pulmonary cases (p = 0.002).

>

> Outcome Data

>

> Sixteen (20.0%) of the 80 cases with complete data were

> hospitalized, including 7 (50%) with disseminated disease and 9

> (14%) with pulmonary involvement. One active duty member underwent

a

> pericardial window for coccidioidal pericarditis, but was able to

> remain on active duty service. Two patients required surgical

> partial resection of their lungs due to empyemas unresponsive to

> antifungal therapy alone. There were no deaths, but two persons

had

> significant morbidity from the disease requiring medical

retirement

> from the military.

>

> Correlations and Multivariate Analyses

>

> Variables which were correlated included disseminated disease with

a

> more recent year of diagnosis, higher CF titers, and

> hospitalization. In the multivariate analysis, a high CF titer

> remained predictive for dissemination (OR, 1.04; p = 0.003); a

trend

> toward a more recent year of coccidioidomycosis diagnosis and

having

> disseminated disease (OR, 2.39; p = 0.06) was identified.

>

> DISCUSSION

>

> This is the first surveillance study in several decades to

describe

> clinical diagnoses of coccidioidomycosis among a defined military

> population residing at a naval base. Our evaluation demonstrated

> that the incidence of coccidioidomycosis has significantly

increased

> among military beneficiaries during the years 2002 to 2006. These

> trends are consistent with studies showing rising rates in the

> general population of Kings County and other locations in

California

> and Arizona.13,14,24,25

>

> The overall incidence rate of clinical infections in our study was

> 96 cases per 100,000 PY. This rate is higher than previous rates

> reported at Lemoore during the 1970s (~10 cases per 100,000 PY).17

> However, our rate is not considerably different from recent rates

in

> the general U.S. population. Previously reported data using a

> similar diagnostic strategy demonstrated a rate of 86 cases per

> 100,000 PY among the general population in Kern County; these data

> were from the late 1990s.12 Higher incidence rates have been

> reported recently, including rates of 3,000 cases per 100,000 PY

> among prison inmates in California during 2005.25

>

> Among our study cohort, a greater proportion of active duty

members

> were affected in comparison to the nonactive duty (i.e.,

dependents

> and retirees). This may be due to greater soil exposures during

work-

> related activities or training exercises. Previous studies have

> shown that exposure to dust is a risk factor for disease;

> individuals in professions at higher risk of infection include

> archeologists, as well as construction and agricultural workers.2

> Military personnel may experience dust exposure as part of

military

> training exercises or other work-related activities;

alternatively,

> the young military cohort may engage in recreational activities

> associated with dust exposure. Another reason that active duty

> members may have had more infections than retirees is that persons

> who recently moved into an endemic area are known to be at higher

> risk due to lack of protective immunity10; active duty personnel

> typically change duty stations every few years and may be at

higher

> risk than retirees who have resided at the base for a longer

> duration of time.

>

> As expected, most patients presented with respiratory symptoms and

> pulmonary involvement, as coccidioidomycosis is transmitted by

> inhalation of spores. However, the large proportion of cases that

> were disseminated disease is of interest. Traditionally, only 1%

of

> cases diagnosed are disseminated, but in our cohort, 17.5% (14 of

> 80) had extrapulmonary involvement; in 2006, the figure was 30%.

> This is likely an indicator that only the " tip of the iceberg " of

> cases were clinically recognized and that the number of actual

cases

> may have been severalfold higher than reported in this article.

> Another possible explanation for the high proportion of

disseminated

> cases is that the fungus, Coccidioides immitis, has increased in

> virulence and that more infections are resulting in disseminated

> forms of the disease. Although a higher percentage of

dissemination

> can be seen among immunosuppressed hosts and the elderly,10,12 our

> population was comprised of mainly young, healthy individuals who

> were immunocompetent. Finally, both clinically recognized cases

and

> dissemination may be heightened among groups with intense, high-

> inoculum exposures.17,19 Further evaluation is warranted to better

> understand the epidemiology of coccidioidal infections in this

> population. One such strategy would be the use of a coccidioidal

> skin test preparation to more accurately identify infections which

> may not be clinically recognized. Such evaluations were performed

in

> the 1970s at a different military base in California, Twenty-nine

> Palms, and it was noted that among Marines permanently stationed

at

> the base, 25.4% converted their skin test to positive over a 6- to

8-

> month period.26 This conversion rate was likely related to the

fact

> that this group was in the tank battalion, which has a high

> likelihood of dust inhalation. More recent investigations, using

> enzyme-linked immunosorbent assay testing,27 as well as

unpublished

> data using skin tests, have shown much lower rates of infections

> among military personnel.

>

> We observed a seasonal pattern, whereby most cases were identified

> during winter months. This is consistent with previous reports

> demonstrating that the highest number of exposures to the airborne

> arthroconidia occurs during the fall months, corresponding to dry,

> windy weather conditions.6,25,28 A recent survey suggested that

the

> peak exposure to fungal spores occurs in October to November.24

> Given the incubation period of 1 to 3 weeks and a possible delay

in

> the clinical diagnosis of cases, the seasonal trends we noted

appear

> to be consistent with these data. A second exposure peak, as

> recognized by Connie,24 also occurs in the months of June to July

> (Fig. 4).

>

> In our study, a higher percentage of male military beneficiaries

> were diagnosed with coccidioidomycosis. This trend remained after

> accounting for the number of males at the base. Other studies have

> also noted a higher rate of coccidioidomycosis among men,

> potentially due to occupational or recreational activity

differences

> between the sexes. Of interest, the male gender association with

> coccidioidal infections was mitigated when examining only those on

> active duty; this may have been due to the fact that the active

duty

> females had similar work-related exposures than men, which placed

> them at equal risk. Further studies examining gender-specific work

> and recreational activities and their corresponding risk for

> infection would be useful.

>

> Non-Caucasian ethnic groups, particularly Filipinos and African

> Americans, are thought to be more likely to develop disseminated

> disease.6,22,29 Caucasian patients appear to be at the lowest risk

> of dissemination; in the current study, 43% of patients with

> dissemination were Caucasian. This is partially explained by the

> large number of Caucasians at the base. However, we were surprised

> at the high incident rates among this group. A similar experience

> was noted by et al.17 in association with a dust storm at

> NASL in the 1970s. The increasing number of mixed racial

backgrounds

> may make race associations difficult; for instance, although one

> patient reported being " Caucasian, " she had a significant Native

> American ancestry.

>

> Despite the fact that mostly young healthy persons were affected

by

> this infection, 20% of the patients required hospitalization; this

> may incur significant medical costs estimated as $23,000 to

$34,000

> per patient.11,30 Even among those not hospitalized, missed

workdays

> and outpatient medical care results are important expenses.

Serious

> disease requiring surgical procedures and/or military medical

> discharges occurred in a minority of our cases, perhaps due to the

> aggressive medical management provided in the cases at a nearby

> tertiary naval hospital.

>

> Prevention is paramount among patients at-risk for

> coccidioidomycosis. Methods to reduce dust formation are important

> considerations. Persons who cannot avoid dusty conditions should

> wear a facemask. Outdoor physical training sites should be

modified

> for dust reduction, and aquatic exercise programs should be used

> when dust levels are high. Although prophylaxis using an azole is

> being studied to prevent clinical disease among high-risk patients

> (transplant recipients and AIDS patients),9 the efficacy and cost-

> effectiveness of such a strategy is unclear, especially among

large

> groups such as the military. A vaccine against Coccidioides spp.

> would be the best preventive strategy, but currently is not

> available.

>

> Our study had some limitations. Cases included in our

investigation

> were only those definitively diagnosed as coccidioidomycosis,

which

> may have underestimated the true number of infections.

Furthermore,

> some patients may have transferred to another base before the

> diagnosis of coccidioidomycosis was made. On the other hand, some

> military personnel are present on the base for short training

> exercises and are not accounted for in the total population of the

> base; however, to our knowledge, the cases in this report were

among

> persons permanently stationed or residing at the base. Another

> limitation was the lack of complete ethnicity data; however, we

are

> not aware of any specific biases regarding military personnel

> reporting ethnicity. Furthermore, to more accurately assess the

> racial impact on dissemination, a larger number of cases is

needed.

> Finally, although we report seasonal trends in the diagnosis of

> coccidioidomycosis, many patients were treated with several

courses

> of antibiotics before evaluation for coccidioidomycosis, which may

> have delayed the diagnosis.

>

> In summary, there has been an increase in the number and severity

of

> coccidioidomycosis cases among our military personnel. Further

> epidemiological research studies on the driving forces of these

> trends are needed. In the meantime, clinicians should maintain a

> high index of suspicion for coccidioidomycosis, and workplaces in

> endemic areas should consider implementing both educational

programs

> and prevention strategies for this disease.

>

> ACKNOWLEDGMENTS

>

> We thank Judy Christensen, graphic Artist, for her work in the

> preparation of this article.

>

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> Lee, MD*; Crum-Cianflone, MD MPH1

>

> * Internal Medicine Department, Naval Hospital Lemoore Naval Air

> Station, Lemoore, CA.

>

> [dagger] Infectious Disease Division, Naval Medical Center San

> Diego, CA 92134; the Infectious Disease Clinical Research Program

> (IDCRP), Uniformed Services University of the Health Sciences,

> Bethesda, MD.

>

> The data in this article were presented in part at the Sixth

> International Symposium on Coccidioidomycosis August 23-27, 2006,

> Stanford University, Stanford, CA.

>

> The views expressed in this article are those of the author and do

> not necessarily reflect the official policy or position of the

> Department of the Navy, Department of Defense, nor the U.S.

> Government.

>

> This manuscript was received for review in June 2007. The revised

> manuscript was accepted for publication in May 2008.

>

> Copyright Association of Military Surgeons of the United States

Aug

> 2008

>

> © 2008 Military Medicine. Provided by ProQuest LLC. All rights

> Reserved.

>

>

>

> Source: Military Medicine

>