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Acute pulmonary coccidioidomycosis in children
376
March, 1967 T h e ]ournal of P E D I A T R I C S
Acute pulmonary coccidioidomycosisin children Observations of the clinical [eatures of acute pulmonary coccidioidomycosis in 73 children have indicated the importance of erythema multiforme and chest pain at the onset. The variability of the clinical course and roentgenographic manifestations is described.
Henry Burtt Richardson, Jr., Captain, USAF (MC), ~" John A. Anderson, Captain, USAF (MC), and Buchanan M. McKay, M.D. ~~ TUCSON~
ARIZ.
A C U T E C O C C I D I O I D O M Y C O S I S was first described as a benign, self-limited infection in 1936,1 and two series of children with this illness and associated erythema nodosum were reported in 1939. 2,a The present report outlines the clinical features of 37 children with acute pulmonary coccidioidomycosis observed in the highly endemic area of Tucson, Arizona. Emphasis is placed particularly on the erythematous rash present so frequently at the onset of symptoms in our patients, and rarely stressed in previous reports in the literature. Within the past several years coccidioidomycosis has been recognized with increasing frequency outside endemic areas of the desert Southwest. 4-6 This has resulted from rapid transportation and the development of tourist attractions, winter resorts, and military bases in endemic areas. The incubation pcThe views expressed herein are those of the authors and do not necessarily reflect the views o[ the United States Air Force or the Department of Defense. This paper was presented, in part, at the Pediatric Tri-Service Seminar, Walter Reed Army Medical Center, Washington, D.C., o n March 4, 1965. ~Present address, Project HOPE, CasiUa 629, Trajillo, Peru. eeAddress for reprints, Chief, Pediatrics Service, Davls-Monthan AFB Hospital, Tucson, Ariz. (Zol. 70, No. 3, part 1, pp. 376-382
riod of 7 to 28 days, usually 10 to 16 days, makes it reasonable to expect the onset of acute manifestations of illness in areas quite remote from those in which the infection was acquired. ETIOLOGY The etiologic agent of coccidioidomycosis is the biphasic fungus, Coccidioides immitis. The natural growth distribution of this organism is sharply limited to desert areas with long, hot summers, relatively warm winters, rainfall limited to 5 to 20 inches per year, and an elevation below 5,000 feet. The vegetative or saprophytic phase of the fungus life cycle produce~ specialized mycelial segments of two types, arthrospores and chlamydospores. Either form when inhaled into the lungs undergoes changes to produce the characteristic coccidioidal spherule. Mature spherules contain many endospores, each capable of producing a new spherule or, under proper conditions, of reverting to the saprophytic phase. The spherule and endospore cycle comprises the parasitic phase. Spherules and endospores are present in sputum during active disease, but coccidioidomycosis is not transmitted directly from one human host to another since
Volume 70 Number 3, part 1
only arthrospores and chlamydospores are infectious for man. EPIDEMIOLOGY
The potential for acquiring the acute pulmonary disease is apparently independent of such factors as age, sex, and race, except as these relate to the possibility of exposure to the fungus in dust. Considerable seasonable variation occurs, an increased incidence generally being associated with hot, dry, windy periods following the rainy season. In the Tucson area rains occur during January and February, and again during late July and August. The highest seasonal incidence of acute coccidioidomycosis is during the late spring and early fall. Surveys utilizing skin tests have shown that infection with Coccidioides immitis increases directly with the duration of time spent in an endemic area. 7 The disease in a stable population is primarily one of childhood. It was shown by Gifford s that in Kern County, California, a highly endemic area, over half of the 2,718 preschool and school children had positive skin reactions to coccidioidin. Seventeen per cent of the children resident in the area less than one year had positive skin tests, whereas 77 per cent of those whose residence exceeded ten years had positive reactions. During World W a r II, Smith 7 found that 10 to 25 per cent of susceptible military recruits stationed in highly endemic areas acquired dermal sensitivity to coccidioidin each year. In a study of 1,000 children in a private pediatric clinic in Tucson, 9 unselected by duration of residence in the endemic area, 7 per cent of the children under 5 and 38 per cent of children from 13 to 18 years of age had positive skin tests. CLINICAL
FEATURES
The clinical features of acute pulmonary coccidioidomycosis are variable. In approximately 60 per cent of instances the patient is asymptomatic, and in about 40 per cent the symptoms may be described as "flulike." Anorexia, fever, cough, and chest pain are frequently noted. Two types of rash are
Acute pulmonary coccidloidomycosis
377
associated with the illness. A "toxic" erythema may occur at the onset of symptoms, or a delayed hypersensitivity rash, usually erythema nodosum, may occur one to three weeks later. The most common roentgenographic finding is a pneumonic infiltration with associated pleural reaction, at times with hilar adenopathy. The infiltrative lesion often develops into a granuloma which later may cavitate or calcify, but usually disappears spontaneously. CLINICAL MATERIAL The present report summarizes the clinical findings of 36 children with acute, symptomatic, pulmonary coccidioidomycosis, and of one patient with an insidious onset and asymptomatic course. All 37 patients were seen in the Outpatient Clinic at DavisMonthan Air Force Base Hospital near Tucson, Arizona, between May, 1963, and November, 1964. The diagnosis of acute pulmonary coccidioidomycosis was established in all but one instance by a combination of the signs and symptoms of acute illness, changes in the chest seen radiographically, and a positive coccidioidin skin test when first seen, or, in the majority of instances, by subsequent conversion. The single exception was asymptomatic, but met the other criteria. Extensive prior experience has demonstrated the correlation between the clinical features of the acute illness described in the present series and positive serum precipitin reactions? ~ This diagnostic study was performed only occasionally among these patients. The precipitins generally are present within the first 3 weeks of disease and disappear in 3 or 4 months. Complement fixation tests were also infrequently obtained, their main usefulness being not in diagnosis but as an indication of impending dissemination, a rare occurrence in children. Only one pediatric patient in our clinic has had disseminated disease within the past 5 years. The ages of the patients ranged from 3 to 16 years. There were 23 boys and 14 girls. All were Caucasian. Twenty-nine cases diagnosed between Oct.
378
Richardson, Anderson, and McKay
The Journal o[ Pediatrics March 1967
1, 1963, and Sept. 30, 1964, were divided according to month of onset. There were two peaks, one with 10 cases in OctoberNovember, 1963, and the other with 8 cases in June-July, 1964. There were 1 or 2 cases in each of the other 8 months of the 12 month period. T h e characteristic symptoms and signs were fever, cough, chest pain, and rash. Thirty-two of the children had fever, which was above t02 ~ F. in 13 instances. Twenty patients had congh. T h e findings that were most helpful in suggesting the diagnosis of pulmonary coccidioidomycosis were chest pain and the rather typical rash, neither of which is commonly noted in children with other acute febrile illnesses, particularly in combination. Both chest pain and rash were present in 18 patients. T h e rash appeared alone in 13, and the chest pain alone in 3. I n only 3 patients of the present series was neither manifestation present. T h e rash noted in 31 of the 37 patients
ranged from a diffuse, maculopapular eruption primarily on the trunk and proximal extremities, to erythema multiforme, sometimes over the entire body but most frequently on the anterior and inner thighs and lower trunk. I n several instances lesions of the erythema multiforme type were present on the palms and soles. T h e rash usually foIlowed the first evidence of acute illness within 48 hours, and it was frequently present within 24 hours. I n 7 of the children the presence of a rash in the mouth was noted; in 4 this appeared to be of the erythema multiforme type, and in the other 3 consisted of a diffuse, hemorrhagic eruption of the buccal mucosa and the mucous membrane of the lips. T h e appearance of the initial rash in 2 patients who developed erythema multiforme within several hours of examination revealed tiny white papules surrounded by an erythematous areola approximately 1 era. in diameter, closely resembling the rash of erythema toxicum in newborn infants. I n only one patient of the 37, an
Table I. Diagnostic features in patients without unequivocal skin test conversion
Case
Rash
Fever
Cough
Chest ~ain
Eosinophils (%)
1
++
+
+
+
2 3 4
0 ++ ++
++ + ++
0 + +
0 0 +
5
++
+
+
0
6
6 7
++ + ++
0 0
0 +
7 13
8 9 10
++ 0 ++ ++ ++
+ +
0 + +
+ 0 +
0 6 5
11 12
++, E.N.w ++
+ ++
0 0
+ 0
4 16
13 14 15
++ 0 ++
+ + 0
+ 0 0
+ 0 +
0 4 4
16 !7 I8
0 ++ 0
0 + 0
0 + 0
+ 0 0
~'HN, Hilar nodes. tSeg., Segmental. ~NR, Not recorded. ~E.N., E~Tthema nodosum.
5
8 1 NR
3 NR NR
Coccidioidinskin test (days) ++,
4
NR,:~ 4; +% 35 NR, I; +% 60 +% 9 +,
2
+% 6 ++, 6 -,+ 1; ++, +-, 1; N R , ++, 12
21 24
++, 18 NR, 1; ++, 42 +, +% +,
1 6 4
-,+ 5, ++, 16 NR, 5; +% 108 ++, ?30
Volume 7,0 Number 3, part 1
A c u t e p u l m o n a r y coccidioidomycosis
l 1-year-old boy, was erythema nodosum noted. T h e late hypersensitivity rash described in the literature as erythema multiforme with a face a n d "collar" distribution a n d associated with a strongly positive skin test reaction was not seen in our patients. T w e n t y of the 30 patients with a "toxic" erythema had negative or equivocal skin tests at the time of the rash, 5 h a d no skin test applied, or its result was not recorded, d u r i n g the week of the rash, a n d 5 had weakly or moderately positive skin tests d u r i n g the initial clinical phase. T h e rash of these last 5 was not different from that of the others. T h e chest pain present in 21 of the patients was most frequently pleuritic in type, a n d generally was in the area of the roentgenographically demonstrated infiltration. A n o t h e r c o m m o n form of pain was a dull, substernal ache, frequently attributed to enlarged mediastinal lymph nodes. A b n o r m a l physical signs were rarely noted o n e x a m i n a t i o n of the chest. These con-
379
sisted of rales in 2 patients, dullness to percussion in 2 others, a n d tenderness of the chest wall in one. T h e acute symptoms lasted from 1 or 2 days to a b o u t 10 days. Several children with rash h a d no other symptoms despite roentgenographic evidence of p u l m o n a r y infection. All of the children were asymptomatic within 1 m o n t h after onset. White blood cell counts were obtained in 32 patients d u r i n g the acute phase of their illness. T h e counts ranged from 6,000 to 26,000 per cubic millimeter. Of these, 14 were u n d e r 10,000 per cubic millimeter a n d contained from 3 to 13 per cent of eosinophils, the average being 6 per cent. Fifteen of the counts ranged from 10,000 to 20,000 per cubic millimeter; eosinophilia was 0 to 13 per cent with a n average of 4 per cent. T h e 3 counts over 20,000 per cubic millimeter had a similar p a t t e r n of eosinophilia. T h e eosinophilia was often of assistance in supporting the diagnosis of coccidioidomycosis, especially in patients without a rash
Radiographic findings Initial
Follow-up
PPD
Pneumonitis
Pleural reaction
Granuloma
Cavitation
HN +~
Other
Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg.
Seg.'~ Seg. Seg. Seg. Seg. Seg. Seg. Seg. Seg. Seg. 0 Seg. Seg. Seg. Seg. Seg. Seg. NR
0 0 0 + + 0 + 0 + 0 + 0 0 0 0 0 0 NR
0 + 0 + + 0 + + NR + 0 + + + + + + +
0 0 0 0 0 0 0 0 NR + 0 0 + 0 0 0 + +
0 + 0 "2-_ + + + 0 NR 0 + + 0 + + + 0 0
Precipitins +, 7 days Precipitins -, 15 days Complement fixation positive ++++ 1:4, 5 months
380
Richardson, Anderson, and McKay
whose presenting complaints of fever, cough, and chest pain, associated with roentgenographic evidence of pulmonary infiltration, could easily have led to the mistaken diagnosis of bacterial pneumonia. The coccidioidin skin test was suggestively or definitely positive when the child was first seen in 10 instances, each within a week of the onset of symptoms. In several of these patients a positive result was obtained when the child was tested within 48 hours of frank symptoms. Eight children had no skin test during the first week or, if one was performed, its result was not recorded. Subsequently each patient had a positive reaction. Nineteen patients had negative skin tests during the acute phase of illness and then converted to a positive reaction. One child had a negative skin test 24 days after onset, but it was positive 7 days later. The clinical features in patients failing to show unequivocal conversions from negative to positive dermal reactions are outlined in Table I. Radiographic changes in acute coccidioidomycosis, although not necessarily characteristic of the disease, are of assistance in diagnosis. In our patients the important roentgen features were: (1) pneumonitis, (2) hilar lymphadenopathy, (3) pleural reaction, (4) granuloma formation, and (5) cavitation. In 34 patients the onset of symptoms was accompanied by an acute pneumonic infiltration. In 26 this was localized to one bronchopulmonary segment. The infiltration was most often described as "smudgy" or "ground glass-like," rather than "granular" or "streaky." In 9 patients, pleural reaction accompanied the pneumonitis and was usually Iimited to a fissure or other pleural surface adjoining the pneumonic process. In 18 instances hilar adenopathy was associated with the acute parenchymal infiltration and always appeared on the same side. Resolution of this adenopathy did not parallel that of the accompanying infiltration, 8 resolving before, 2 after, and 8 with the parenchymal focus. In one patient there was
The ]ournal o[ Pediatrics March 1967
radiographic evidence of hilar adenopathy and pleural reaction without any evidence of pulmonary infiltration. In 26 patients the pneumonic process cleared, leaving a rounded density, the gran~ uloma or coccidioidoma. The duration of the granulomatous lesion was variable. Uniform follow-up was not obtained, but complete resolution of the granuloma was noted in 10 of 16 patients observed more than 4 months. Five of the 26 patients with granuloma developed cavitation. These cavities usually appeared thin walled, with smooth, regular outlines, and most were small and centrally located in the nodule, becoming progressively smaller as the nodule underwent resolution. Two of the 5 disappeared within 6 months. Amphotericin B is rarely indicated in the therapy of children with the acute pulmonary form of coccidioidomycosis. Management is primarily symptomatic, and complete recovery can be expected in almost every patient. In our series, bed rest was recommended during the febrile course and thereafter activity was restricted only in the event of fatigue. There were no ill effects of activity within the child's tolerance, and, from our experience, more harm may be done by overrestriction than by excessive activity. It is also essential to emphasize to the family that even with extensive pulmonary cavitation cross infection is not known to occur. One patient with asymptomatic pulmonary coccidioidomycosis is included to demonstrate the striking radiographic changes that may be present unaccompanied by signs or symptoms. The patient is a 10-year-old girl who had lived in Arizona for 2 years, having been in excellent health with no history of acute illnesses. In June, 1964, a roentgenogram of the chest was obtained as part of a general health survey and revealed a granuloma in the right perihilar area (Fig. 1, A). Physical examination at that time and subsequently has been normal. An intermediate PPD test was negative, and a coccidioidin skin test (1:100) was positive, in early July, 1964. Subsequent chest roentgenograms revealed an increase in the right perihilar reaction and the development of cavitation
Volume 7,0 Number 3, part 1
Acute pulmonary coccidioidomycosis
381
DISCUSSION
Fig. 1. A, Granuloma and pleural reaction present on routine chest roentgenogram of an asymptomatic patient on June 23, 1964. B, Cavitation of lesion in superior segment of right lower tobe on Oct. 21, 1964. C, Spontaneous resolution of cavity by Nov. 13, 1964. of the granuloma, followed by spontaneous resolution of the cavity (Fig. 1, B and C). Throughout the entire course of the pulmonary lesion the patient remained asymptomatic.
There is divergence in the descriptions of the predominant cutaneous manifestations of acute coccidioidal disease between our patients and those described in the early reports3, 3 In our experience, more than 50 per cent of children with acute symptomatic coccidioidomycosis had erythema multiforme within the first few days after onset of other symptoms. It was generally differentiated readily from the rash of other exanthems. The experience of the pediatric group at the Tucson Clinic xl supports our observations; 24 per cent of their series of 200 cases diagnosed by positive skin tests revealed a history of erythema multiforme during the acute stage. Half of the 10 children reported by Winn and co-workers1~ had a rash earlY in the course of their illness, and Huxtable 13 reported a single instance of such a rash. Erythema nodosum is an uncommon lesion in primary coccidioidal disease of children in the Tucson area. It occurred only once in this series. Two other children with this lesion have been seen in our Pediatric Clinic during the past 5 years, reflecting an incidence of approximately 1 per cent. Erythema nodosum appears to be more common in the San Joaquin Valley. The two pediatric series of acute coccidioidomycosis published in 19392, 3 described this manifestation in 29 of 31 patients. A marked hypersensitivity to the coccidioidin skin test coincides with erythema nodosum as with late-occurring erythema multiforme associated with coccidioidomycosis. Dennis and Hansen 14 in a review article state that "from one to 3 weeks after the onset, 5 to 20 per cent of subjects with the clinical disease develop erythema nodosum, erythema multiforme, toxic macular eruption, or arthralgia." In our experience a toxic eruption, usually erythema multiforme, occurred in a large percentage of children at the onset of the clinical disease and erythema nodosum and arthralgia were infrequent. Fiese, 1~ in his excellent monograph on coccidioidomycosis, stated that "the earliest skin lesion is a generalized fine erythematous macular rash which occurs in roughly 10 per
3 8 2 Richardson, Anderson, and McKay
cent of the cases," and further points out t h a t it "usually appears within a day or 2 after the first symptoms and subsides within a week." H e described it as often similar to the rash of measles, a n d occasionally to that of urticaria. W e have noted the toxic eruption to be more frequent in children t h a n in adults. Despite different methods of patient selection a n d control of age between our series a n d others reported in the literature, there is evidence that a real difference exists in the skin manifestations of children with coccidioidomycosis in Tucson c o m p a r e d with those in the San J o a q u i n Valley. I n Tucson, the early rash is more frequently e r y t h e m a m u h i f o r m e t h a n morbiliform a n d the late hypersensitivity rashes are m u c h less frequent. No microbiologic difference in the etiologic agent has been noted. F u r t h e r investigation is necessary both to, define a n d to explain the variation in the clinical findings. T h e diagnosis of acute p u l m o n a r y coccidioidomycosis should be suspected in nonendemic areas in any child with the combination of a n erythematous rash a n d a pulm o n a r y infiltrate. A recent history of residence in an endemic a r e a or exposure to fomites from such an area would be expected, a n d further support is lent by the characteristic chest p a i n a n d eosinophilia. Skin test conversion or positive serologic reactions would be necessary to confirm the diagnosis. T r e a t m e n t should be limited to symptomatic measures. A m p h o t e r i c i n is a potentially dangerous agent a n d should be prescribed for children only with firm evidence of i m p e n d i n g dissemination. Surgery for the almost always benign g r a n u l o m a or cavity is not indicated. SUMMARY
I n 37 children with acute p u l m o n a r y coccidioidomycosis, the p r e d o m i n a n t features were fever, cough, chest pain, e r y t h e m a multiforme early in the course, a n d roentgenographic p u l m o n a r y changes. T h e n a t u r e of the skin rash during the acute phase of illness in the children ob-
The Journal o[ Pediatrics March 1967
served in this series is contrasted with other series in the recorded liteiature. The authors wish to thank Lieutenant Colonel Jerrold L. Wheaton, USAF (MC), for his support and assistance in the preparation of this report and Peter R. Meis, M.D., for review of the manuscript. REFERENCES
1. Dickson, Ernest C., and Cifford, Myrnie A.: Coccidioides infection (coccidioidomyeosis). II. The primary type of infection, Arch. Int. Med. 62: 853, 1938. 2. Faber, H. K., Smith, C. E., and Dickson, E. C.: Acute coccidioidomycosis with erythema nodosum in children, J. PBmAT. 15: 163, 1939. 3. Thorner, J. E.: Erythema nodosum in childhood associated with infection by the Oidium coccidioides; report of seven cases, Arch. Pedlar. 56: 628, 1939. 4. Kunstadter, R. N., and Milzer, A.: Incidence of mycotic infections in children with acute respiratory disease, Am. J. Dis. Child. 81: 306, 1951. 5. Izenstark, Jos. L.: Modern travel and coccidioidomycosis, South. M. J. 56: 745, 1963. 6. Klein, Edward W., and Griffin, John P.: Coccidioidomyeosis (diagnosis outside the Sonoran zone). The roentgen features of acute muttiple pulmonary cavities, Am. J. Roentgenol. 94: 553, 1965. 7. Smith, Charles E.: Abstract of comments following Mead, C. I.: Coceidioidomycosis in Children, J. A. M. A. 146: 85, 1951. 8. Gifford, M. A.: Coccidioidomycosis in Kern County, Calif., Proc. Sixth Pacific Science Congress 5: 791, 1939. 9. Seagle, Jos. B.: Clinical aspects of primary pulmonary coccidioidomycosis in children. Unpublished data. 10. McKay, Buchanan M.: Unpublished data. 11. Thompson, Hugh C., Cochran, Hiram D., Kemberling, Sidney R., and Laidlaw, Elizabeth H.: Coccidioidomycosis--incidence in school children; characteristics as seen in private pediatric practice. Unpublished data. 12. Winn, W. A., Levine, H. B., Broderick, J. E., and Crane, R. W.: A localized epidemic of coccidioidal infection; primary coccidioidomycosis occurring in a group of ten children infected in a backyard playground in the San Joaquin Valley of California, New England J. Med. 268: 867, 1963. 13. ttuxtable, R.: Coccidioidomycosls; clinical conference at the Los Angeles Childrens Hospital, J. PEDIAT. 42: 739, 1953. i~. Dennis, J. L., and Itansen, A. E.: Coccidioidomycosis in children, Pediatrics l l : 481, 1954. 15. Fiese, M. J.: Coccidioidomycosis, Springfield, Ill., 1958, Charles C Thomas, Publisher, p. 133.
March, 1967 T h e ]ournal of P E D I A T R I C S
Acute pulmonary coccidioidomycosisin children Observations of the clinical [eatures of acute pulmonary coccidioidomycosis in 73 children have indicated the importance of erythema multiforme and chest pain at the onset. The variability of the clinical course and roentgenographic manifestations is described.
Henry Burtt Richardson, Jr., Captain, USAF (MC), ~" John A. Anderson, Captain, USAF (MC), and Buchanan M. McKay, M.D. ~~ TUCSON~
ARIZ.
A C U T E C O C C I D I O I D O M Y C O S I S was first described as a benign, self-limited infection in 1936,1 and two series of children with this illness and associated erythema nodosum were reported in 1939. 2,a The present report outlines the clinical features of 37 children with acute pulmonary coccidioidomycosis observed in the highly endemic area of Tucson, Arizona. Emphasis is placed particularly on the erythematous rash present so frequently at the onset of symptoms in our patients, and rarely stressed in previous reports in the literature. Within the past several years coccidioidomycosis has been recognized with increasing frequency outside endemic areas of the desert Southwest. 4-6 This has resulted from rapid transportation and the development of tourist attractions, winter resorts, and military bases in endemic areas. The incubation pcThe views expressed herein are those of the authors and do not necessarily reflect the views o[ the United States Air Force or the Department of Defense. This paper was presented, in part, at the Pediatric Tri-Service Seminar, Walter Reed Army Medical Center, Washington, D.C., o n March 4, 1965. ~Present address, Project HOPE, CasiUa 629, Trajillo, Peru. eeAddress for reprints, Chief, Pediatrics Service, Davls-Monthan AFB Hospital, Tucson, Ariz. (Zol. 70, No. 3, part 1, pp. 376-382
riod of 7 to 28 days, usually 10 to 16 days, makes it reasonable to expect the onset of acute manifestations of illness in areas quite remote from those in which the infection was acquired. ETIOLOGY The etiologic agent of coccidioidomycosis is the biphasic fungus, Coccidioides immitis. The natural growth distribution of this organism is sharply limited to desert areas with long, hot summers, relatively warm winters, rainfall limited to 5 to 20 inches per year, and an elevation below 5,000 feet. The vegetative or saprophytic phase of the fungus life cycle produce~ specialized mycelial segments of two types, arthrospores and chlamydospores. Either form when inhaled into the lungs undergoes changes to produce the characteristic coccidioidal spherule. Mature spherules contain many endospores, each capable of producing a new spherule or, under proper conditions, of reverting to the saprophytic phase. The spherule and endospore cycle comprises the parasitic phase. Spherules and endospores are present in sputum during active disease, but coccidioidomycosis is not transmitted directly from one human host to another since
Volume 70 Number 3, part 1
only arthrospores and chlamydospores are infectious for man. EPIDEMIOLOGY
The potential for acquiring the acute pulmonary disease is apparently independent of such factors as age, sex, and race, except as these relate to the possibility of exposure to the fungus in dust. Considerable seasonable variation occurs, an increased incidence generally being associated with hot, dry, windy periods following the rainy season. In the Tucson area rains occur during January and February, and again during late July and August. The highest seasonal incidence of acute coccidioidomycosis is during the late spring and early fall. Surveys utilizing skin tests have shown that infection with Coccidioides immitis increases directly with the duration of time spent in an endemic area. 7 The disease in a stable population is primarily one of childhood. It was shown by Gifford s that in Kern County, California, a highly endemic area, over half of the 2,718 preschool and school children had positive skin reactions to coccidioidin. Seventeen per cent of the children resident in the area less than one year had positive skin tests, whereas 77 per cent of those whose residence exceeded ten years had positive reactions. During World W a r II, Smith 7 found that 10 to 25 per cent of susceptible military recruits stationed in highly endemic areas acquired dermal sensitivity to coccidioidin each year. In a study of 1,000 children in a private pediatric clinic in Tucson, 9 unselected by duration of residence in the endemic area, 7 per cent of the children under 5 and 38 per cent of children from 13 to 18 years of age had positive skin tests. CLINICAL
FEATURES
The clinical features of acute pulmonary coccidioidomycosis are variable. In approximately 60 per cent of instances the patient is asymptomatic, and in about 40 per cent the symptoms may be described as "flulike." Anorexia, fever, cough, and chest pain are frequently noted. Two types of rash are
Acute pulmonary coccidloidomycosis
377
associated with the illness. A "toxic" erythema may occur at the onset of symptoms, or a delayed hypersensitivity rash, usually erythema nodosum, may occur one to three weeks later. The most common roentgenographic finding is a pneumonic infiltration with associated pleural reaction, at times with hilar adenopathy. The infiltrative lesion often develops into a granuloma which later may cavitate or calcify, but usually disappears spontaneously. CLINICAL MATERIAL The present report summarizes the clinical findings of 36 children with acute, symptomatic, pulmonary coccidioidomycosis, and of one patient with an insidious onset and asymptomatic course. All 37 patients were seen in the Outpatient Clinic at DavisMonthan Air Force Base Hospital near Tucson, Arizona, between May, 1963, and November, 1964. The diagnosis of acute pulmonary coccidioidomycosis was established in all but one instance by a combination of the signs and symptoms of acute illness, changes in the chest seen radiographically, and a positive coccidioidin skin test when first seen, or, in the majority of instances, by subsequent conversion. The single exception was asymptomatic, but met the other criteria. Extensive prior experience has demonstrated the correlation between the clinical features of the acute illness described in the present series and positive serum precipitin reactions? ~ This diagnostic study was performed only occasionally among these patients. The precipitins generally are present within the first 3 weeks of disease and disappear in 3 or 4 months. Complement fixation tests were also infrequently obtained, their main usefulness being not in diagnosis but as an indication of impending dissemination, a rare occurrence in children. Only one pediatric patient in our clinic has had disseminated disease within the past 5 years. The ages of the patients ranged from 3 to 16 years. There were 23 boys and 14 girls. All were Caucasian. Twenty-nine cases diagnosed between Oct.
378
Richardson, Anderson, and McKay
The Journal o[ Pediatrics March 1967
1, 1963, and Sept. 30, 1964, were divided according to month of onset. There were two peaks, one with 10 cases in OctoberNovember, 1963, and the other with 8 cases in June-July, 1964. There were 1 or 2 cases in each of the other 8 months of the 12 month period. T h e characteristic symptoms and signs were fever, cough, chest pain, and rash. Thirty-two of the children had fever, which was above t02 ~ F. in 13 instances. Twenty patients had congh. T h e findings that were most helpful in suggesting the diagnosis of pulmonary coccidioidomycosis were chest pain and the rather typical rash, neither of which is commonly noted in children with other acute febrile illnesses, particularly in combination. Both chest pain and rash were present in 18 patients. T h e rash appeared alone in 13, and the chest pain alone in 3. I n only 3 patients of the present series was neither manifestation present. T h e rash noted in 31 of the 37 patients
ranged from a diffuse, maculopapular eruption primarily on the trunk and proximal extremities, to erythema multiforme, sometimes over the entire body but most frequently on the anterior and inner thighs and lower trunk. I n several instances lesions of the erythema multiforme type were present on the palms and soles. T h e rash usually foIlowed the first evidence of acute illness within 48 hours, and it was frequently present within 24 hours. I n 7 of the children the presence of a rash in the mouth was noted; in 4 this appeared to be of the erythema multiforme type, and in the other 3 consisted of a diffuse, hemorrhagic eruption of the buccal mucosa and the mucous membrane of the lips. T h e appearance of the initial rash in 2 patients who developed erythema multiforme within several hours of examination revealed tiny white papules surrounded by an erythematous areola approximately 1 era. in diameter, closely resembling the rash of erythema toxicum in newborn infants. I n only one patient of the 37, an
Table I. Diagnostic features in patients without unequivocal skin test conversion
Case
Rash
Fever
Cough
Chest ~ain
Eosinophils (%)
1
++
+
+
+
2 3 4
0 ++ ++
++ + ++
0 + +
0 0 +
5
++
+
+
0
6
6 7
++ + ++
0 0
0 +
7 13
8 9 10
++ 0 ++ ++ ++
+ +
0 + +
+ 0 +
0 6 5
11 12
++, E.N.w ++
+ ++
0 0
+ 0
4 16
13 14 15
++ 0 ++
+ + 0
+ 0 0
+ 0 +
0 4 4
16 !7 I8
0 ++ 0
0 + 0
0 + 0
+ 0 0
~'HN, Hilar nodes. tSeg., Segmental. ~NR, Not recorded. ~E.N., E~Tthema nodosum.
5
8 1 NR
3 NR NR
Coccidioidinskin test (days) ++,
4
NR,:~ 4; +% 35 NR, I; +% 60 +% 9 +,
2
+% 6 ++, 6 -,+ 1; ++, +-, 1; N R , ++, 12
21 24
++, 18 NR, 1; ++, 42 +, +% +,
1 6 4
-,+ 5, ++, 16 NR, 5; +% 108 ++, ?30
Volume 7,0 Number 3, part 1
A c u t e p u l m o n a r y coccidioidomycosis
l 1-year-old boy, was erythema nodosum noted. T h e late hypersensitivity rash described in the literature as erythema multiforme with a face a n d "collar" distribution a n d associated with a strongly positive skin test reaction was not seen in our patients. T w e n t y of the 30 patients with a "toxic" erythema had negative or equivocal skin tests at the time of the rash, 5 h a d no skin test applied, or its result was not recorded, d u r i n g the week of the rash, a n d 5 had weakly or moderately positive skin tests d u r i n g the initial clinical phase. T h e rash of these last 5 was not different from that of the others. T h e chest pain present in 21 of the patients was most frequently pleuritic in type, a n d generally was in the area of the roentgenographically demonstrated infiltration. A n o t h e r c o m m o n form of pain was a dull, substernal ache, frequently attributed to enlarged mediastinal lymph nodes. A b n o r m a l physical signs were rarely noted o n e x a m i n a t i o n of the chest. These con-
379
sisted of rales in 2 patients, dullness to percussion in 2 others, a n d tenderness of the chest wall in one. T h e acute symptoms lasted from 1 or 2 days to a b o u t 10 days. Several children with rash h a d no other symptoms despite roentgenographic evidence of p u l m o n a r y infection. All of the children were asymptomatic within 1 m o n t h after onset. White blood cell counts were obtained in 32 patients d u r i n g the acute phase of their illness. T h e counts ranged from 6,000 to 26,000 per cubic millimeter. Of these, 14 were u n d e r 10,000 per cubic millimeter a n d contained from 3 to 13 per cent of eosinophils, the average being 6 per cent. Fifteen of the counts ranged from 10,000 to 20,000 per cubic millimeter; eosinophilia was 0 to 13 per cent with a n average of 4 per cent. T h e 3 counts over 20,000 per cubic millimeter had a similar p a t t e r n of eosinophilia. T h e eosinophilia was often of assistance in supporting the diagnosis of coccidioidomycosis, especially in patients without a rash
Radiographic findings Initial
Follow-up
PPD
Pneumonitis
Pleural reaction
Granuloma
Cavitation
HN +~
Other
Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg.
Seg.'~ Seg. Seg. Seg. Seg. Seg. Seg. Seg. Seg. Seg. 0 Seg. Seg. Seg. Seg. Seg. Seg. NR
0 0 0 + + 0 + 0 + 0 + 0 0 0 0 0 0 NR
0 + 0 + + 0 + + NR + 0 + + + + + + +
0 0 0 0 0 0 0 0 NR + 0 0 + 0 0 0 + +
0 + 0 "2-_ + + + 0 NR 0 + + 0 + + + 0 0
Precipitins +, 7 days Precipitins -, 15 days Complement fixation positive ++++ 1:4, 5 months
380
Richardson, Anderson, and McKay
whose presenting complaints of fever, cough, and chest pain, associated with roentgenographic evidence of pulmonary infiltration, could easily have led to the mistaken diagnosis of bacterial pneumonia. The coccidioidin skin test was suggestively or definitely positive when the child was first seen in 10 instances, each within a week of the onset of symptoms. In several of these patients a positive result was obtained when the child was tested within 48 hours of frank symptoms. Eight children had no skin test during the first week or, if one was performed, its result was not recorded. Subsequently each patient had a positive reaction. Nineteen patients had negative skin tests during the acute phase of illness and then converted to a positive reaction. One child had a negative skin test 24 days after onset, but it was positive 7 days later. The clinical features in patients failing to show unequivocal conversions from negative to positive dermal reactions are outlined in Table I. Radiographic changes in acute coccidioidomycosis, although not necessarily characteristic of the disease, are of assistance in diagnosis. In our patients the important roentgen features were: (1) pneumonitis, (2) hilar lymphadenopathy, (3) pleural reaction, (4) granuloma formation, and (5) cavitation. In 34 patients the onset of symptoms was accompanied by an acute pneumonic infiltration. In 26 this was localized to one bronchopulmonary segment. The infiltration was most often described as "smudgy" or "ground glass-like," rather than "granular" or "streaky." In 9 patients, pleural reaction accompanied the pneumonitis and was usually Iimited to a fissure or other pleural surface adjoining the pneumonic process. In 18 instances hilar adenopathy was associated with the acute parenchymal infiltration and always appeared on the same side. Resolution of this adenopathy did not parallel that of the accompanying infiltration, 8 resolving before, 2 after, and 8 with the parenchymal focus. In one patient there was
The ]ournal o[ Pediatrics March 1967
radiographic evidence of hilar adenopathy and pleural reaction without any evidence of pulmonary infiltration. In 26 patients the pneumonic process cleared, leaving a rounded density, the gran~ uloma or coccidioidoma. The duration of the granulomatous lesion was variable. Uniform follow-up was not obtained, but complete resolution of the granuloma was noted in 10 of 16 patients observed more than 4 months. Five of the 26 patients with granuloma developed cavitation. These cavities usually appeared thin walled, with smooth, regular outlines, and most were small and centrally located in the nodule, becoming progressively smaller as the nodule underwent resolution. Two of the 5 disappeared within 6 months. Amphotericin B is rarely indicated in the therapy of children with the acute pulmonary form of coccidioidomycosis. Management is primarily symptomatic, and complete recovery can be expected in almost every patient. In our series, bed rest was recommended during the febrile course and thereafter activity was restricted only in the event of fatigue. There were no ill effects of activity within the child's tolerance, and, from our experience, more harm may be done by overrestriction than by excessive activity. It is also essential to emphasize to the family that even with extensive pulmonary cavitation cross infection is not known to occur. One patient with asymptomatic pulmonary coccidioidomycosis is included to demonstrate the striking radiographic changes that may be present unaccompanied by signs or symptoms. The patient is a 10-year-old girl who had lived in Arizona for 2 years, having been in excellent health with no history of acute illnesses. In June, 1964, a roentgenogram of the chest was obtained as part of a general health survey and revealed a granuloma in the right perihilar area (Fig. 1, A). Physical examination at that time and subsequently has been normal. An intermediate PPD test was negative, and a coccidioidin skin test (1:100) was positive, in early July, 1964. Subsequent chest roentgenograms revealed an increase in the right perihilar reaction and the development of cavitation
Volume 7,0 Number 3, part 1
Acute pulmonary coccidioidomycosis
381
DISCUSSION
Fig. 1. A, Granuloma and pleural reaction present on routine chest roentgenogram of an asymptomatic patient on June 23, 1964. B, Cavitation of lesion in superior segment of right lower tobe on Oct. 21, 1964. C, Spontaneous resolution of cavity by Nov. 13, 1964. of the granuloma, followed by spontaneous resolution of the cavity (Fig. 1, B and C). Throughout the entire course of the pulmonary lesion the patient remained asymptomatic.
There is divergence in the descriptions of the predominant cutaneous manifestations of acute coccidioidal disease between our patients and those described in the early reports3, 3 In our experience, more than 50 per cent of children with acute symptomatic coccidioidomycosis had erythema multiforme within the first few days after onset of other symptoms. It was generally differentiated readily from the rash of other exanthems. The experience of the pediatric group at the Tucson Clinic xl supports our observations; 24 per cent of their series of 200 cases diagnosed by positive skin tests revealed a history of erythema multiforme during the acute stage. Half of the 10 children reported by Winn and co-workers1~ had a rash earlY in the course of their illness, and Huxtable 13 reported a single instance of such a rash. Erythema nodosum is an uncommon lesion in primary coccidioidal disease of children in the Tucson area. It occurred only once in this series. Two other children with this lesion have been seen in our Pediatric Clinic during the past 5 years, reflecting an incidence of approximately 1 per cent. Erythema nodosum appears to be more common in the San Joaquin Valley. The two pediatric series of acute coccidioidomycosis published in 19392, 3 described this manifestation in 29 of 31 patients. A marked hypersensitivity to the coccidioidin skin test coincides with erythema nodosum as with late-occurring erythema multiforme associated with coccidioidomycosis. Dennis and Hansen 14 in a review article state that "from one to 3 weeks after the onset, 5 to 20 per cent of subjects with the clinical disease develop erythema nodosum, erythema multiforme, toxic macular eruption, or arthralgia." In our experience a toxic eruption, usually erythema multiforme, occurred in a large percentage of children at the onset of the clinical disease and erythema nodosum and arthralgia were infrequent. Fiese, 1~ in his excellent monograph on coccidioidomycosis, stated that "the earliest skin lesion is a generalized fine erythematous macular rash which occurs in roughly 10 per
3 8 2 Richardson, Anderson, and McKay
cent of the cases," and further points out t h a t it "usually appears within a day or 2 after the first symptoms and subsides within a week." H e described it as often similar to the rash of measles, a n d occasionally to that of urticaria. W e have noted the toxic eruption to be more frequent in children t h a n in adults. Despite different methods of patient selection a n d control of age between our series a n d others reported in the literature, there is evidence that a real difference exists in the skin manifestations of children with coccidioidomycosis in Tucson c o m p a r e d with those in the San J o a q u i n Valley. I n Tucson, the early rash is more frequently e r y t h e m a m u h i f o r m e t h a n morbiliform a n d the late hypersensitivity rashes are m u c h less frequent. No microbiologic difference in the etiologic agent has been noted. F u r t h e r investigation is necessary both to, define a n d to explain the variation in the clinical findings. T h e diagnosis of acute p u l m o n a r y coccidioidomycosis should be suspected in nonendemic areas in any child with the combination of a n erythematous rash a n d a pulm o n a r y infiltrate. A recent history of residence in an endemic a r e a or exposure to fomites from such an area would be expected, a n d further support is lent by the characteristic chest p a i n a n d eosinophilia. Skin test conversion or positive serologic reactions would be necessary to confirm the diagnosis. T r e a t m e n t should be limited to symptomatic measures. A m p h o t e r i c i n is a potentially dangerous agent a n d should be prescribed for children only with firm evidence of i m p e n d i n g dissemination. Surgery for the almost always benign g r a n u l o m a or cavity is not indicated. SUMMARY
I n 37 children with acute p u l m o n a r y coccidioidomycosis, the p r e d o m i n a n t features were fever, cough, chest pain, e r y t h e m a multiforme early in the course, a n d roentgenographic p u l m o n a r y changes. T h e n a t u r e of the skin rash during the acute phase of illness in the children ob-
The Journal o[ Pediatrics March 1967
served in this series is contrasted with other series in the recorded liteiature. The authors wish to thank Lieutenant Colonel Jerrold L. Wheaton, USAF (MC), for his support and assistance in the preparation of this report and Peter R. Meis, M.D., for review of the manuscript. REFERENCES
1. Dickson, Ernest C., and Cifford, Myrnie A.: Coccidioides infection (coccidioidomyeosis). II. The primary type of infection, Arch. Int. Med. 62: 853, 1938. 2. Faber, H. K., Smith, C. E., and Dickson, E. C.: Acute coccidioidomycosis with erythema nodosum in children, J. PBmAT. 15: 163, 1939. 3. Thorner, J. E.: Erythema nodosum in childhood associated with infection by the Oidium coccidioides; report of seven cases, Arch. Pedlar. 56: 628, 1939. 4. Kunstadter, R. N., and Milzer, A.: Incidence of mycotic infections in children with acute respiratory disease, Am. J. Dis. Child. 81: 306, 1951. 5. Izenstark, Jos. L.: Modern travel and coccidioidomycosis, South. M. J. 56: 745, 1963. 6. Klein, Edward W., and Griffin, John P.: Coccidioidomyeosis (diagnosis outside the Sonoran zone). The roentgen features of acute muttiple pulmonary cavities, Am. J. Roentgenol. 94: 553, 1965. 7. Smith, Charles E.: Abstract of comments following Mead, C. I.: Coceidioidomycosis in Children, J. A. M. A. 146: 85, 1951. 8. Gifford, M. A.: Coccidioidomycosis in Kern County, Calif., Proc. Sixth Pacific Science Congress 5: 791, 1939. 9. Seagle, Jos. B.: Clinical aspects of primary pulmonary coccidioidomycosis in children. Unpublished data. 10. McKay, Buchanan M.: Unpublished data. 11. Thompson, Hugh C., Cochran, Hiram D., Kemberling, Sidney R., and Laidlaw, Elizabeth H.: Coccidioidomycosis--incidence in school children; characteristics as seen in private pediatric practice. Unpublished data. 12. Winn, W. A., Levine, H. B., Broderick, J. E., and Crane, R. W.: A localized epidemic of coccidioidal infection; primary coccidioidomycosis occurring in a group of ten children infected in a backyard playground in the San Joaquin Valley of California, New England J. Med. 268: 867, 1963. 13. ttuxtable, R.: Coccidioidomycosls; clinical conference at the Los Angeles Childrens Hospital, J. PEDIAT. 42: 739, 1953. i~. Dennis, J. L., and Itansen, A. E.: Coccidioidomycosis in children, Pediatrics l l : 481, 1954. 15. Fiese, M. J.: Coccidioidomycosis, Springfield, Ill., 1958, Charles C Thomas, Publisher, p. 133.