acute histoplasmosis: clinical, epidemiologic and serologic findings of an outbreak associated with...

Acute Histoplasmosis: Clinical, Epidemiologic and Serologic Findings of an Outbreak Associated with Exposure to a Fallen Tree

]OEL I. WARD, M.D.

Atlantu, Georgia

MARK WEEKS, M.P.H.

DAVID ALLEN, M.D., M.P.H.

ROBERT H. HUTCHESON, jr.. M.D., M.P.H. Nashville, l’ennessee

RICHARD ANDERSON, M.D.

l,‘runklin, ‘J’ennessee

DAVID W. FRASER, M.D.

LEO KAUFMAN, Ph.D.

LIBERO AJELLO, Ph.D.

/1tluntcl. Gsorgiu

ANDERSON SPICKARD. M.D.

Nashville. Tennessee

From the Bacterial Diseases Division. BUIXXU or Epitlcmiology, Center for Disease Control,

Atlanta. C;corgia. the State Dcpartmcnt of Public

Health. Nashville, Tennessee. the Williamson

County Hospital, Franklin, Tennessee, the My-

cology Division, Bureau of Laboratories, Center

for Discasc Control. Atlanta. Qorgia; and the

Division of Internal Medicine, V;~ntlcrl~ilt Uni-

vwsity, Nashville. Requests for reprints should

1~: atltlrcsscd to Dr. jocl 1. Ward. Center for Dis-

~IISC Control, Bacterial Diseases Division, Bureau

of Epitlt:miology, Atlanta. Ct?orgiit 30333. Man-

rwxipt accepted October 26. 1978.

An outbreak of acute histoplasmosis occurred among 42 people who gathered for two days in May 1977 to cut and clear a fallen oak tree near Nashville (Williamson County), Tennessee. Thirty-two (76 per cent) of the participants had serologic evidence of infection; 20 (46 per cent) had acute pulmonary disease and of these, three required hospitalization. Frequent symptoms of acute pulmonary disease included fever, malaise, chest pain, headache, cough, myalgia, weight loss (16 pounds) and stomach cramps. Chest roentgenograms re- vealed abnormalities in 67 per cent of the ill participants. The disease developed in two dogs that were also present at the activities.

Illness began an average of 14 days after exposure. Risk of illness was associated with sawing the tree, and loading wood and bark into a truck, as well as the length of the time spent near the tree.

Tests for fungal antibodies in serum obtained from the participants and community controls, (those who lived in the county but did not have symptoms of respiratory illness) were used to establish criteria for serologic ‘diagnosis. Immunodiffusion tests with initial serum samples were most useful for diagnosis; the presence of an M precipitin band was 76 per cent sensitive and was 97 $er cent specific as judged by data from community controls. Similarly, the mycelial form antigen Histoplasma capsulatum complement fixation test at a titer 11:6 was 55 per cent sensitive and 97 per cent specific, and the yeast-form antigen complement fixation test at a titer of 2 1:16 was 75 per cent sensitive and 77 per cent specific. When serum obtained four weeks afteb exposure (one to two weeks after onset of symptoms) was compared with serum obtained eight weeks after exposure, a fourfold increase in complement ‘fixation antibodies was detected in 26 per’cent of those infected.

Over a two day period in May 1977, 42 persons and five dogs were exposed to Histoplasma capsulatum during the cutting and clearing of a fallen tree in an area long known to be endemic for histoplasmosis [l]. During the outbreak, we collected detailed information about exposure and clinical follow-up of all participants which permitted better definition of the clinical responses to H. capsulatum infection. We also obtained serum from the participants during the acute and convalescent phases which allowed a better definition of the immune responses useful in diagnosing acute histoplasmosis.

Many outbreaks of acute histoplasmosis have been reported [I?.-121 and reviewed [X+-E], and the spectrum of clinical illness has been characterized [16]. Nevertheless, the diagnosis of acute histoplasmosis can be difficult. Symptoms of acute illness are similar to pneumonia from other causes and, frequently, H. capsulatum cannot be isolated

April 1979 The American Journal of Medicine Volume 66 567

ACLJTE HISTOPLASMOSIS-WARD ET AL.

Figure idence 1977.

1. Phc dograph of tr .ee and re !S-

before the storm on May 6.

Figure 2. Photograph taken during the tree cutting activities, May 7, 1977.

from clinical specimens. Diagnosis often depends on the BACKGROUND

development of specific antibody responses, but anti- In the evening of May 6,1977. a violent thunderstorm body tests can be difficult to interpret, particularly in struck Williamson County, Tennessee, south of Nash- endemic areas, because of cross reactions with other ville. This storm toppled an old partially rotten white oak fungal antigens and the persistence of low levels of tree in the front yard of a residence, which was the antibody for years after exposure [17-201. Such was the largest tree in the area and was a neighborhood land- case in this outbreak. mark (Figure 1). On May 7 and 8,42 people gathered to

588 April 1676 The American Journal of Medicine Volume 66

cut and clear the fallen tree, including the resident family, friends, relatives and neighbors. The activity became a weekend event which, in addition to the clearing work, involved drinking, eating, playing and socializing in the yard. The working participants brought rakes, saws, axes and chain saws for the work [Figure 2) while others prepared food and children played in the yard. Five dogs were ato present.

METHODS

All 42 participants at the weekend activities were interviewed between June 1 and June 12, 1977. Information collected on a standardized questionnaire included age, sex, occupation, history of previous residence, smoking history and a detailed history of activities in the previous month, particularly those on May 7 and 8. Details of any illness or hospitalization subsequent to the activities were also obtained.

A clinical definition of acute histoplasmosis was established for the purpose of epidemiologic and serologic analysis. The case definition included participants who had fever (>lOl”F) and malaise in addition to cough, chest pain or weight loss (25 pounds) which occurred in the month after the activities.

Saline-induced sputum for culture was obtained from 15 of the ill participants, and tracheal aspirates were obtained from the two ill dogs. Most of these specimens were obtained one to two weeks after the onset of illness. Sputum was streaked on Sabouraud medium, with and’without antibiotics, and observed for at least two weeks. Smears of these sputum specimens were also examined with fluorescent antibody conjugates for H. capsulatum [19].

Chest roentgcnograms were obtained of 15 ill participants one day to two weeks following the onset of symptoms.

Serum specimens were obtained from all 42 participants between May 24 and June 9, 1977, and from 33 participants again two weeks later. Complement fixation tests with the yeast-form and mycelial antigens of H. capsulatum, the yeast-form antigens of Blastomyces dermatitidis and Cocci- dioides immitis were performed [17]. All titers are reported as reciprocals. Immunodiffusion tests with antigens of H. caps&turn, B. dermatitidis and C. immitis were also performed [17]. Control serum specimens were obtained from 31 persons who were not exposed at the tree cutting activities but who lived in Williamson County. These persons included persons hospitalized at the local hospital for nonrespiratory illness or local couples who applied for marriage certificates. Control serum specimens were also obtained from five dogs in Williamson County.

Thirty soil specimens and tree debris were collected at the site and processed in an attempt to demonstrate H. capsulatum in the area. The procedure used involved the preparation of aqueous suspensions of the specimens. intraperitoneal inoc- ulation of mice with the supernatant from the suspensions, and subsequent culturing of the livers and spleens of the mice (211.

RESULTS

Clinical. All participants had been well during and immediately after the activities. On May 16, however, a two and a half year old girl who had been playing in

ACUTE HISTOPLASMOSIS-WARD ET AL.

the area of the activities had a temperature of 103’F, malaise, myalgia, rash and stomach cramps which lasted for two days. On the 11th day after the end of the activities, a 12 year old boy who had participated in the activities, had a temperature of 102”F, cough, chest pains, dyspnea, headache and malaise which lasted four days. On the 12th day, four participants had symptoms of acute pneumonia with high fever; three of these participants required hospitalization. Among those hospitalized was the 44 year old owner of the residence who was present at the activities for the greatest duration of time and had the most contact with the tree. His clinical history follows:

The owner is a white male business executive who became ill on the 12th day after the tree cutting activities. He had been exposed for 9 hours in the yard on the first day and for 11 hours on the second day actively participating in the sawing, hauling, and raking of the branches, leaves and debris. Symptoms included chills, temperature of 105OF, myalgia, nonproductive cough, chest pain, malaise and headache. After two days of progressive symptoms, he was admitted to the hospital and, although his initial physical examination was unremarkable, a chest roentgenogram showed hilar adenopathy and scattered faint nodular densities in both lungs (Figure 3). Two days later, bilateral rales were heard and repeat chest roentgenogram showed multiple nodular infiltrates in both lung fields and

hilar adenopathy (Figure 4). Sputum and blood cultures were negative for fungi and bacteria. His white blood cell count was 7,300/mm3; polymorphonuclear leukocytes 43 per cent, band forms 22 per cent. lymphocytes 24 per cent, monocytes 8 per cent, eosinophils 2 per cent and atypical lymphocytes 1 per cent. A tuberculin skin test was negative.

Although all fungal serology was negative on admission, by the sixth hospital day his reciprocal titers were as follows: Yeast-form H. capsulatum complement fixation 32, mycelial-form H. capsulatum complement fixation 16 and B. dermatitidis complement fixation 32. lmmunodiffusion tests remained negative. By the 17th hospital day his reciprocal titers were yeast-form complement fixation 128, mycelial-form complement fixation 32 and B. dermatitidis complement fixation 128; an M immunodiffusion precipitin band was present.

Soon after admission, his respiratory rate increased, he became cyanotic (oxygen tension (PO,) 45 torr, carbon dioxide tension (PCO~) 24.7, pH 7.52) and delirious. His liver function, which was normal on admission, became progressively abnormal during the first week. A diffuse erythematous rash also developed over the chest and abdomen, which may have been related to histoplasmosis or caused by a brief course of sul- fonamide therapy he received.

Although amphotericin B is generally not recommended for the treatment of acute histoplasmosis, he was given the drug (in gradually increasing doses to 30 mg/day) because of hyp- oxia, delerium. high fevers and abnormal liver function tests. His condition gradually improved although improvement may have been coincidental with therapy. Pulmonary function studies confirmed normal pulmonary function one month after symptoms began. A chest roentgenogram nine months later showed calcification in some of the ill-defined nodular dcn-



Figure 3. Chest roentgenogram of patient taken 14 days after the tree cutting shows hilar adenopathy and faint nodular densities in the right lower lung field.

TABLE I Symptoms and Chest Roentgenographic Findfngs of Exposed Persons

Olher Participants Cases Seroposilive’ Seronegative

Data No. % No. % No.---- %

Symptoms Fever 20 100 1 8 0 0

Temperature 2101’F 18 90 1 8 0 0 Duration >7 days 7 35 0 0 0 0

Malaise 18 90 0 0 0 0 Chest pain 15 75 0 0 2 20 Headache 8+ 73 0 0 1 10 Cough 14 70 0 0 0 0 Myalgia 14 70 0 0 0 0 Chills 12 60 0 0 0 0 Weight loss (X lb) 10 50 0 0 0 0 Stomach cramps 8 40 3 25 0 0 Nausea 7 35 0 0 0 0 Rash 7+ 35 0 0 0 0

Roentgenographic findings Pulmonary infiltrates 10 67 ND* ND Enlarged hilar nodes 13 07 ND ND

l Serologic criteria: H. capsulatum, yeast form antigen complement fixation test, titer 16 or fourfold rise or mycelial form antigen complement fixation test, titer 8 or fourfold rise or M or H immunodiffusion precipitin band. + Information only available for eleven patients. + Four patients were receiving medication. 5 Not done.



HISTOPLASMA

YEAST-FORM CF MYCELIAL-FORM CF

. . . . I . . . . . .

. . . . . . i . . . . . . . :::t i A?:::

: :: . . . . . I I tt

CASES OTHER CONTROL PARTICIP*NTS

STANDARD DEVIATION GEOMETRIC MEAN TITER

.

. . . . .

. . . . . . . .

. . . . . l i .

__ ___... __ __~____ BLASTOMYCES

YEAST-FORM CF

. -

::::*: . . . . :: . . . . . ttt;. . . . . i. ::::.:

CASES OTHER CONTROL PARTlClPANTS

. . . .

. . .

. . . . . T . . . . I . . . . . . . . . I

. ..” :::1:: MP# CASES OTHER CONTROL

PARTICIPANTS

_. 1 Figure 5. Results of initial Histoplasma and Blastomyces complement fixation tests.

sities, and the hilar shadows remain enlarged. The patient is asymptomatic and liver function returned to normal.

The symptoms reported by all the participants are summarized in Table I. Twenty participants met the clinical case definition; six of the remaining participants reported symptoms which did not meet the case definition. Of these, one had only a temperature of 162°F which lasted for 2 hours, another had a headache and chest pain lasting 12 hours, another had only chest pain for one day, and the remaining three reported only stomach cramps. The incubation period, from the last day of activities to the onset of symptoms of cases, av- eraged 14.4 days (range eight to 24 days).

Chest roentgenograms were obtained for 15 of the participants fulfilling the case definition, and 87 per cent (13 of 15) had abnormalities [Table I). Ten had diffuse patchy and irregular pulmonary infiltrates bilaterally and enlarged hilar lymph nodes. Three had only enlarged perihilar nodes. The three sickest persons had sequential chest roentgenograms which demonstrated a progression of pulmonary infiltrates and enlarging hilar nodes, None had calcified or cavitary lesions in the two months after exposure.

Of the five dogs present at the activities, only two were present for more than 2 hours. Two weeks after the activities, both of these dogs had acute illness characterized by malaise, anorexia, ruffled fur, cough and pho- tophobia; one dog had superficial ulcers of the tongue and oral mucus membranes. In both dogs chest roentgenograms were obtained late in their illness; one was

normal and the other had diffuse pulmonary infiltrates. Both dogs recovered.

Induced sputum specimens from participants meeting the case definition and bronchial washings from two ill dogs were negative for H. capsulatum. Serology. The results of complement fixation titers of the initial serum specimens (obtained one to two weeks after the onset of symptoms] are summarized in Figure 5. More of the participants fulfilling the case definition had high yeast-form H. capsulatum complement fixation antibody titers (75 per cent with titers 216) than did the other participants (41 per cent) or the community controls (32 per cent). Initial serum samples in many cases also had elevated complement fixation titers to mycelial H. capsulatum antigens (histoplasmin] (55 per cent with titers L8), but other participants (41 per cent) had a similar prevalence of high antibody titers. Four of the participants who fulfilled the case definition had negative results on the initial complement fixation listed in Figure 5. In two of these cases both complement fixation antibody titers (>32) and M precipitin bands later developed in immunodiffusion tests. Follow-up serum specimens were not obtained in the two other cases with negative serology, but in both acute febrile illness [temperatures 2163’F), chills, muscle aches, rash and cough were present following the activities. Comple- ment fixation tests for C. immitis were negative in all specimens tested.

The results of initial immunodiffusion tests are summarized in Table II. H precipitin bands were found in


ACUTE HISTOPLASMOSIS-WARD ET AL

TABLE II H. capsulatum lmmunodlffuslon Tests in Exposed Persons and Controls

Precipitin Band Present Initial Sample Convalescent sample

Data No. % No. %

M precipitin

Cases 15120’ 75 10115 677 Other participants 10122 45 4117 24z Controls l/37 3 -

H precipitin

Cases 4120 20 0115 0 Other participants Of22 0 0117 0 Controls 0131 0 -

NOTE: Initial sample obtained four weeks after exposure; convalescent sample obtained eight weeks after exposure. l Patients whose serum had M or H precipitins/no. of patients tested. t One person acquired and two persons lost M precipitin. x Five persons lost M precipitin.

20 per cent of the cases but in none of the other participants or controls. M precipitin bands were found in 75 per cent of the cases, in 45 per cent of the other participants and in 3 per cent of the controls. The presence of an M or H precipitin band was associated with 216

complement fixation titer to the yeast-form antigen of H. capsulatum in all cases and in all but two other participants. All immunodiffusion tests to B. dermatitidis and C. immitis antigens were negative;

The changes in complement fixation titers seen in specimens obtained during the convalescent phase are summarized in Table III. Many of the participants who

fulfilled the case definition had a rtwofold rise in complement fixation antibody titer to yeast-form H. capsulatum antigen (54 per cent) or mycelial-form antigen (36 per cent). Fewer participants who did not fulfill the case definition had twofold rises in complement fixation titer in yeast-form antigens (32 per cent), but 50 per cent had a ltwofold rise to mycelial-form antigen. Only the participants who fulfilled the case definition had M or H precipitins in serum obtained during the convalescent phase that were not present in serum obtained during the acute phase.

To assess the validity of each serologic test to identify persons with symptomatic acute histoplasmosis, we compared the serologic results in persons meeting the clinical case definition with those in community controls. We determined the sensitivity and specificity for each test at each titer to determine the optimum cutoff values. The sensitivity was determined by dividing the number of cases with “positive” tests by the number of cases tested. The specificity was determined by dividing the number of controls’with “negative” tests by the number of controls tested [22]. An optimum titer was selected as the lowest titer with the greatest sensitivity and specificity. The optimum titer for H. capsulatum yeast-form antigen complement fixation tests was 216;

at this titer the sensitivity was 75 per cent and the specificity was 77 per cent. The optimum titer for mycelial- form complement fixation tests was 18; at this titer the sensitivity was 55 per cent and the specificity was 97 per cent. Similarly, the optimum titer for B. dermatitidis yeast-form antigen complement fixation test in diagnosing acute histoplasmosis was 18; at this titer the sensitivity was 60 per cent and the specificity was 100

TABLE III Changes in Histoplasma and Blastomyces Complement Flxatlon Test Titers from Acute-Phase to Convalescent-Phase Serum Specimens

l/8- Decreased

114. ll2- Un- two- Increased

lour- eight- 16- Total

H. capsulatum Yeast-form titers

Cases

Other participants

Histoplasmin titers Cases

lold lold

. .

.

I . .

changed

8

(47)

(596,

(487,

fold

4

(24)

A

(122,

fold told fold

3 1 1

(16) (6) (6)

& “. .‘.

(241) “’ “’

Tested

17

16

17

Other participants

B. dermatitidis Yeast-form titers

Cases

. . & (368,

7

(44) .’ “. A 16

t:2, (244, f:2) A t:, f& (5 . 17

Other 16

participants GB, & &I A ... ” “.

NOTE: Initial titers obtained four weeks after exposure: convalescent titers obtained eight weeks after exposure. Figures in parentheses indicate per cents.



TABLE IV Risk ol Hlstopiasmosis by Exposure

Time in

Yard

NJ

Ill

@.I

All Participants’ Well

(no.1

Ill (no.1

SaWill#

Well (M).)

PWSOISWhOEllgag8dh LOawnof

Ill b.1

<l 1 7 13 0 1 0 0 2-5 3 6 33 1 1 50 2 6-9 4 4 50 2 1 67 4 310 12 5 71 11 3 79 12

Total 20 22 48 14 6 70 18

l p <0.02, X2 for linear trend. t Relative risk associated with sawing adjusted for time in yard = 3.4, p = 0.29. Mantel-Haenszel test. t Relative risk associated with loading, adjusted for time in yard = 12.6, p = 0.057, Mantel-Haenszel test.

0 2 so 3 57 3 80

8 69

5 Attack rate.

per cent. The presence of a M precipitin band in initial immunodiffusion tests was 75 per cent sensitive and 97 per cent specific. The presence of an H precipitin band was 20 per cent sensitive and 100 per cent specific.

To determine who had asymptomatic infections, we reevaluated participants who did not fulfill the case definition, using the aforementioned serologic criteria. Among the other participants 1.2 (54.5 per cent) had the following positive serologic findings: 10 persons had an M precipitin, 10 persons had 28 titer in H. capsulatum mycelial-form antigen complement fixation tests, nine persons had ?16 titer in yeast-form antigen complement fixation tests, eight persons had 28 titer in yeast-form B. dermatitidis complement fixation tests and in three persons a fourfold rise in titer developed in complement fixation tests, two to yeast-form antigens and one to mycelial-form antigen. Ten of these 12 participants met two or more of the serologic criteria. Although these participants had serologic evidence of acute histoplasmosis, they did not have symptoms which fulfilled the case definition. However, four did have symptoms. Three had only stomach cramps which began 10 days to two weeks after the activities and lasted four days. One other participant had a temperature of 10PF which began 13 days after the activities and lasted only 2 hours; he had no other symptoms.

Serologic tests performed on serum obtained from the two ill dogs confirmed the diagnosis of histoplasmosis. The initial serum samples from both dogs had titers 2128 in yeast-form H. capsulatum complement fixation tests, 264 in myceljal-form complement fixation tests, 264 in yeast-form B. dermatitidis complement fixation tests, and in both dogs precipitins developed in serum obtained during the convalescent phase two weeks after illness. Serum obtained from five control dogs that lived in the community but were not exposed to the tree had no detectable complement fixation or precipitin antibodies to H. capsulatum, B. dermatitidis or C. immitis. Epidemiologic Analysis. To determine which factors may have contributed to the risk of illness or the risk of

infection (seropositivity] we compared both the group of cases and the group of seropositive well participants to the seronegative well participants. There were no significant differences in age, sex composition or smoking history. Although the duration of residence in Tennessee tended to be shorter (mean 4.95 years, range one to 25 yearsj in the cases and in the seropositive well participants (mean 4.5 years, range two to 11 years) when compared to that in the seronegative well participants (mean 15.3 years, range 2 to 52 years), the difference was not statistically significant (p = 0.1 Mann-Whitney U test). Infected participants (cases plus seropositive well participants) spent significantly more time at the activities (mean 17.2 hours/person) than did the seronegative participants (mean 5.1 hours/person) (p = 0.04, Chi square for linear trend].

To determine the possible source of infection, we assessed the relative risk of illness for participants who spent time in the house and yard at the residence and for those who did different tasks during the activities. There was no increased risk (or protection) for participants who spent more time in the house: however, the infected participants spent significantly more time in the yard (mean 10.0 hours/person) than did seronegative well participants (mean 3.2 hours/person) (p = 0.02, Chi square for linear trend] (Table IV). Activities in the yard included raking, sawing, loading wood and debris into a truck, playing or observing. Each activity was analyzed for association with illness after compensating for the time spent in the yard, a confounding variable, using the Mantel-Haenszel test 1231. The only activities associated with appreciable risk of illness over and above being in the yard were sawing (relative risk = 3.4, p = 0.29) and loading debris onto the truck (relative risk = 12.6, p = 0.057) (Table IV). Environmental Smdies. Although the area around the yard and tree was once a farm, it was not known to be a roosting site for birds or chickens. Bird nests or bird droppings were not observed in or around the tree.

After the recognition of illness in several participants, the remains of the tree were soaked in gasoline and



burned. Subsequently, a total of 30 environmental specimens from the area were processed for pathogenic fungi. These specimens included grass and soil from the area of the activities and what remained of unburned pieces of tree bark and decayed trunk. All specimens were negative for H. capsulatum.

COMMENTS

This is the first large outbreak reported of histoplasmosis associated with tree cutting and it occurred in an area prominent in the medical history of histoplasmosis [I]. It was in Williamson County that Dodd, Thompkins and Demonbreum [24,25] first described histoplasmosis in this country. it is also where Christie and Peterson [26] demonstrated reactivity to histoplasmin, and Zeidberg and Ajello [2l] recovered H. capsulatum from soil specimens. In this outbreak, 31 of 42 exposed persons (74 per cent) had evidence of infection: 29 (48 per cent] were acutely ill. Most previously reported outbreaks of histoplasmosis have been associated with exposure to bird or bat excreta (56 per cent of outbreaks) or with visits to farm cellars, barns or caves (32 per cent) within endemic areas [l5]. Although H. capsulatum could not be isolated from remains of the tree, epidemiologic evidence implicated the tree as the source of infection. Risk of illness was associated with time spent near the tree and, particularly, with having direct contact with tree parts [i.e., sawing or loading]. Two previous reports have described cases of acute illness in which the source of infection was rotted wood [27,28], but in this outbreak the part of the tree that was contaminated could not be determined. Although the tree was not a prominent bird roost, some parts of it may have been covered with bird droppings.

The diagnosis of histoplasmosis in this outbreak, as in most, was established first by clinical and epidemiologic features and subsequently by serologic findings. H. capsulatum was not isolated from saline-induced sputum specimens, and it was not identified with fluorescent antibody conjugates applied to sputum smears. Although several of these specimens were taken two weeks after the onset of illness, the fungus is frequently difficult to culture even with selective media. Almost all of the ill persons had chest roentgenograms charac- teristic of acute histoplasmosis. The diagnosis for many who became ill was not apparent until the epidemiologic evidence suggested a common-source outbreak with an incubation period of two weeks and until sub- Sequent serologic information was obtained. The two dogs who became ill in association with the other participants were early indications that the etiologic agent was a fungus. H. capsulatum is well known to affect dogs [29-311, as is B. dermatitidis.

The features of illness observed in this outbreak were similar to those in previously described outbreaks [14,15]. We observed a generalized erythematous rash in seven patients, but we did not observe erythema nodosum or erythema multiforme which have previ-

ously been described in association with histoplasmosis outbreaks [32,33]. In four of the patients the rash may have been related to medication received rather than to histoplasmosis. In addition to the 20 participants who had acute illness, 12 of the other participants who had either no symptoms or mild symptoms had serologic evidence of acute histoplasmosis. Notably, of the four who had mild symptoms, three had only stomach cramps; this symptom was also reported in eight of the cases.

The diagnosis of histoplasmosis often depends upon the results of serologic tests, but diagnostic titers must be prudently interpreted especially for those within endemic areas. A complement fixation titer of 8 or greater with either the mycelial-form or the yeast-form antigens is generally considered presumptive evidence of histoplasmosis. In this outbreak the immunodiffusion test on initial serum specimens was most useful in diagnosing infection, particularly for those with asymptomatic infections. The presence of an H precipitin was 100 per cent specific but only 20 per cent sensitive, whereas the presence of M precipitin was 97 per cent specific and 75 per cent sensitive. Early in acute histoplasmosis complement fixation antibodies to B. dermatitidis are detected and the titers are often higher than those detected by H. capsulatum complement fixation tests [17], This immunologic cross reaction tends not to persist in later serum specimens. If infection by B. dermatitidis can be ruled out by clinical or epidemiologic evidence, negative cultures or immunodiffusion tests, then the presence of complement fixation antibodies to yeast-form B. dermatitidis antigens can be an early indicator of H. capsulatum infection. In this outbreak the test was 60 per cent sensitive and 100 per cent specific for this purpose, thus-it may be useful in histoplasmosis endemic regions in detecting early infections in persons with preexisting low levels of H. capsulatum antibodies. A relatively low proportion of infected subjects (28 per cent) had a significant (Ifourfold) rise in complement fixation antibody titers. This was prob- ably because antibody titers were already elevated in many of the initial serum specimens, which were obtained four weeks after exposure and one to two weeks after the onset of illness. It should be emphasized that qur estimates for sensitivity and specificity for serologic diagnosis are based primarily on specimens obtained one to two weeks after the onset of illness, which com- monly is the time a specimen is obtained in clinical practice.

The control measures instituted in this outbreak included burning the remains of the tree and covering the area around the tree with 2 inches of topsoil, which was then reseeded with grass. Spraying a 3 per cent formalin solution on soil contaminated with H. capsulatum spores has been a control measure used in previous large outbreaks [34]. In this outbreak, H. capsulatum spores were not identified in the soil. Since the tree had been de- stroyed, further control measures did not seem war- ranted.



ACKNOWLEDGMENT

We wish to acknowledge the assistance of Lynn West- erman, W. E. Daniels, Tennessee Department of Public Health and Maxine Clark, Mycology Immunology

Branch, Mycology Division, CDC. We are also indebted to Brian Plikaytis, Bureau of Epidemiology, CDC, for statistical assistance and to William Schaffner, M.D., Vanderbilt University for his advice and critical ap- praisal of this manuscript.

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acute histoplasmosis: clinical, epidemiologic and serologic findings of an outbreak associated with...

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