17 Surawicz B: Role of electrolytes in etiology and management of cardiac arrhythmias. Prog Cardiovasc Dis 8:364386, 1966 18 Manchester J, Shelburne J, Oslci F, et al: Relationship of antianginal agents to hemoglobin-oxygen affinity. Circulation 45 ( suppl2): 109, 1972 (abstract) 19 Schrumpf JD, Sheps OS, et al: Effects oE propranolol on hemoglobin oxygen affinity in the anginal syndrome. Am J Cardiol33:170, 1974 (abstract)
Disseminated Histoplasmosis Followed by Disseminated Coccidioidomycosis• Peter Kapltm, M.D., F.C.C.P.; John R. Gravblll, M.D.; and Dtmlel Thor, M.D.
A case of dJIIemlnatecl hlltoplaanosll foDowecl later by c:occldfoldomyCOids Is described. 11ae cJin. lc:al IIIDess amd lmmllllOiolk lhldles ........ IIIIJde defecta that may bave alsted aatec:edent to IDfec:tioa 8DCI, thus, provided 1111 opportualty for widespread cU.sendnadoa by these IIOI'IIIally DODOpportualltk . . . Dl&ma. Poor c:orrelatloa ,... DOted betweea tbe c:llaiall c:oane amd in vitro teses of cell-mediated lmmDDity. dlllemfnatecl
A
lthough most patients exposed to fungi handle their infection without serious illness, some develop progressive and, at times, life-threatening disease. Recently, attention has been focused on the immunosuppressed host in whom mycotic and mycobacterial infections frequently occur. 1 · ' Occasionally, mixed fungal and mycobacterial infections occur in the same individual in whom no underlying neoplastic or immunosuppressed condition is apparent.M We report herein an unusual patient in whom disseminated coccicidioidomycosis occurred one year after he was treated for disseminated histoplasmosis. Immunologic evaluation suggested a subtle primary immune deficit that may have predisposed him to both infections.
CASE REPoRT A 35-year-old Caucasian man was previously hOIPitalized
in August 1971, with a three-week history of nonproductive
cough, fever, mya)gias, and headache. Physical enminatioo upon admission revealed a chronically ill man with inspiratory rales over the right anterior' portion of the chest and splenomegaly. On admission the chest ll:-ray 6lm showed a diffuse miliary pattern. Pertinent laboratory data included a white blood cell OOUDt oE 3,700/cu mm, with a normal •From the Department of Pulmonary Disease, United States Air Force Medical Center Scott, Scott Air Force Base, Dlinois; the Departments of Medicine, Nashville Veterans Administration Hospital and Vanderbilt University Hospital, Nashville, Tenn; and the Departments of Microbiology and Pathology, University of Texas Health Science Center, San Antonio. The views expressed herein are those of the authors and do not necessarily reflect the views of the United StateS Air Force or the Department of Defense. Reprint reqfA68ts: Dr. Kapltm, 320 Etue North Aoeooe, PitAburgh 15212
238 KAPLAN, GRAYBIU, THOR
differential count Hepatic function, renal function, the serum glucose level, the results of serum protein electrophoresis, and the findings from examinations of the cerebrospinal fluid were all normal Histoplasma capsulatum was cultured from blood, urine, sputum, bone marrow, and pulmonary aspirate. Therapy with amphotericin B was begun on the fourth day of hospitalization. The patient's condition rapidly improved, and within two weeks, he became asymptomatic and afebrile. Splenomegaly and anemia resolved, and his chest ll:-ray 61m cleared. Tbe patient received a total dose- of 1.5 gm of amphotericin B, with therapy finishing in November 1971. Subsequent fungal cultures were negative. The results of serial fungal serologic studies are summarized in Table 1. After leaving the hospital in March 1972, the patient was transferred to Arizona. In October 1972, he develaped transient cough, fever, mya)gias, and swelling of the left anlcle. The coccidioidin complement-fixation titer increased from 1:2 to 1:64. During November 1972, three cutaneous nodules appeared. The patient was hospitalized in December 1972 and, other than the cutaneous lesions, was totally asymptomatic. Physical examination revealed a healthy appearing man, With the only significant findings being three oval erythematous infiltrative lesions on the right side of his neck, his right uilla, and his badt. These varied from 1 to 2 em in diameter. Biopsy of the axillary lesion revealed granulomas, with Coccidioidu immUV seen on staining with methenamine silver. Cultures were also positive. At that time the patient had a 22-mm reaction to a skin test with a 1: 100 dilution of coccidioidin, as shown in Table 2. The skin test for mumps was positive on multiple occasions; however, the patient had negative results on tests with histoplasmin and Candida. The leukocyte count, results of serum electrophoresis, levels oE immunoglobulins and serum complement, chest ll:ray 61m, findings from a bone survey, and cerebrospinal fluid were all normal. Following a single injection of typhoid vaccine, the serum agglutination titer for Salmonella twho.a 0 antigen rose from less than 1:40 to more than 1:640. In December 1972, therapy with amphotericin B was reinstituted and was continued through June 1973, for a total dose of 3.2 gm. During therapy, gradual healing of the cutaneous lesions occurred, and the patient remained asymptomatic. Concurrent with the therapy with amphotericin B, the migration inhibiting factor converted from the previously negative response to an equivocally positive response one month larer, at a time when transformation response was clearly positive for coccidioidin (Table 2). During this period the patient's clinically mild cutaneous disease regressed. He remained free of clinically active lesions through January 1974. Interestingly, the complement-fixation titer (Table 1) fell to 1 :2 by May 1973, but later began to increase. In July and September 1973, a disturbing depression in transformation to coccidioidin was noted, and two months later, the patient lost his cutaneous reactivity to a 1 :100 dilution of
coocidioidbL
In January 1974, the patient returned, complaining of
diffuse low bade pain. A left paravertebral mass at the level
of Tl0-11 had become apparent radiographically. The cere- . brospinal fluid was normal. Lymphocyte transformation was normal, but response to a skin test with coccidioidin was positive only at the high concentration of 1:10. The complement-hation titer had risen to 1:64 by February. Lymphocyte transformation was selectively depressed to coccidioidin. A presumptive diagnosis of recurrent disseminated coccidioidomycosis was made, and therapy with amphorericin B was reinstituted. In March 1974, after 600 mg of amphotericin B
CHEST, 72: 2, AUGUST, 1977
Table
1--Serolo~
Data
Histoplasmosis
Date
Coccidioidomycosis
Histoplasmin Antigen Complement Fixation•
Yeast Antigen Complement Fixation•
Precipitin Bands*
1:16 1:8 1:8 1:8 1:8 1:8 1:8 1:8 1:8 1:8 1:8
1:1024 1:128 1:64 1:32 1:8 1:8 1:8 1:8 1:8 1:8 1:8
Histoplasmosis Histoplasmosis Histoplasmosis Negative Negative Negative Negative Negative Negative Negative Negative
1:8 1:8 1:8
1:8 1:8 1:8
Negative Negative Negative
8/16/71 9/'JJ.)/71 11/19/71 3/8/72 8/6/72 12/18/72 2/12/72 5/21/73 8/7/73 11/5/73 1/7/74 2/25/74 5/8/74 6/3/74 8/12/74
Coccidioidin ComplementFixation Titers
Precipitin Test
Negative Negative Negative Negative Negative 1:32** 1:8** 1 :2** 1:4** 1:8** 1:32** 1:64** 1:32** 1:32** 1 :16**
Negative Negative Negative Negative Negative Negative•• Negative•• Negative•• Negative•• Negative•• Negative•• Negative•• Negative•• Negative•• Negative••
*Standardized method from Center for Disease Control. • **Kindly performed by D. Pappagianis, M.D., Davis, Calif. was administered without radiographic evidence of improvement, the patient underwent surgical exploration of the left paravertebral space, but no lesion was found. Following surgery the patient develOPed a left pleural effusion which persisted for six weeks. No fungal organisms could be seen or grown in multiple specimens of pleural fluid or from pleural biopsy. Therapy with amphotericin B was continued until June 1974, for a total dose of 2 gm. Otherwise, the patient's postoperative course was uneventful. The paravertebral mass disappeared on follow-up x-ray fihns. Immunologic reevaluation in May 1974 indicated persistent hyporeactivity on skin tests with coccidioidin, normal transformation, and negative results on assay for migration-inhibition factor. Despite continuing immunologic impairment and strong serologic suggestion of Table
2-Srudi~
12/18/72 1/4/73 2/6/73 5/24/73 7/24/73 9/4/73 11/4/73 1/7/74 1/29/74 2/8/74 2/27/74 5/8/74 5/15/74 8/12/74 8/19/74
Coccidiodin 1:100 1:10
Histoplasmin Candida 0
22
20
0 15
of CeU-Medialed Immunity
Lymphocyte Transformation, CPM X 10-u
Induration on Skin Test, mm Date
active coccidioidomycosis, the patient remained clinically well. In August 1974 the complement-fi.xation titer decreased to 1:16. For the first time, skin tests with Candida albicana extract were positive on two occasions, suggesting continued varying immunologic competence. Transient depression of coccidioidin-induced lymphocyte transformation on three occasions suggested that serum blodcing factors, similar to those described in tuberculosis or leprosy, might be operative.7,8 Therefore, a number of studies of transformation of the patient's lymphocytes were concurrently performed with autologous serum and heatinactivated pooled human serum from normal donors. No differences were found between the two, suggesting that humoral factors did not play a role in suppressing lymphocyte transformation.
Unstimulated
Coccidiodin
Histoplasmin Candida
1.4 1.2 12.0 3.3 4.0
12.0 35.0 24.0 3.6 1.7
18.0
56.0
13.0
1.6 21.0
2.1 2.2
14.0 16.0
14.0 21.0
0.3
0.2
8.1
3.2
14.5
19.3
Migration Inhibiting Factor (Migration Index) • • Coccidioidin
Histoplasmin Candida
0 0
0 0
30
0 0
0 0
0
30
0
0
0
30
0
0
0
30
0
50
24.0
101 75
110
86
80
30
*Ratio of stimulated to unstimulated greater than 3 is positive. • ••Index greater than 80 is negative; 70 to 79 is equivocal ; and below 70 is positive.•
CHEST, 72: 2, AUGUST, 1977
giSSEMINATED HISTOPLASMOSIS FOLLOWED BY COCCIDIOIDOMYCOSIS 239
DISCUSSION
Cell-mediated immunity has been increasingly appreciated as a critical element in host defense against certain fungi. 6 • 7 •9 Gross alteration of cellular immunity, either by lymphoreticular malignant diseases or by immunosuppressive agents, markedly heightens susceptibility to certain fungi, which have been accordingly characterized as "opportunists." Other fungi which are similarly contained by cell-mediated immunity generally affect the normal host. These include both Histoplasma capsulatum and C immitis. 10 Underlying depression of cell-mediated immunity has been infrequently investigated in these mycoses and is not considered a major factor; however, clinical evidence suggests that depressed cell-mediated immunity may be a factor in permitting these organisms to flourish in man. Occasionally, dual infections occur in the same patient. The coexistence of tuberculosis with blastomycosis, histoplasmosis, or coccidioidomycosis is a well-recognized phenomenon.s Simultaneous pulmonary coccidioidomycosis and histoplasmosis have been reported;• however, in dual pulmonary infection, the relative pathogenetic importance of immunologic and mechanical factors, such as breakdown of old inactive foci, is unknown. Finally, the occurrence of coccidioidomycosis in immunosuppressed patients may not be rare as previously suspected.U In our patient, the results of tests for humoral immune function, including levels of immunoglobulins and complement and the response to typhoid vaccination, were normal. The patient was able to generate high titer complement-fixing coccidioidin antibody; however, such antibody has not been proven beneficial in coccidioidomycosis and, indeed, is associated with progression of disease. 12 On the other hand. the results of tests for cell-mediated immune response were abnormal. The patient had recovered from disseminated histoplasmosis and yet had a persistently negative skin test to this antigen. The major fault did not appear to be recognition, because his lymphocytes transformed well to histoplasmin. With intact recognition the negative skin test (and migration inhibiting factor) place the defect in the effector arm of the immune response, like that observed in cryptococcosis.18 Similarly, our patient had a defective effector response to coccidioidin. Unlike his reaction to histoplasmin. this defect was initially limited to migration inhibiting factor. The combination of a positive skin test with coccidioidin and negative migration inhibiting factor bas been p~ viously seen in patients with coccidioidomycosis, usually in patients with clinically mild disease. 6 This pattern of more limited immune defect seems to correlate with clinically mild disease.14 Our patient's failure to maintain a strong skin test or to develop a positive migration inhibiting factor while receiving therapy with amphotericin B may further support an underlying defect in immune responsiveness. The ability to develop cutaneous responsiveness to one antigen (coccidioidin) but not to another (histoplasmin) remains unexplained, but similar phenomena have been observed in other patients
240 KAPLAN, GRAYBILL, THOR
with coccidioidomycosis. The later weakening reactivity on the skin test and negative migration inhibiting factor correlate with suspected clinical relapse. Although organisms were not recovered from the paraspinous area, this may have reflected antecedent therapy with amphotericin B. Two of three episodes of depressed lymphocyte transformation occurred at times when the patient was feeling well, was receiving no therapy with amphotericin B, and had a relatively low serologic titer. If this represents true immunologic failure, it certainly does not correlate well with the clinical status of the patient and is unlikely to be secondary to worsening infection. The clinical and immunologic course of this patient offers several observations. First, our understanding of cell-mediated immunity is very incomplete and not simply assessed by a skin test. More subtle deficiencies exist and, as suggested by our patient, may enable normally "nonopportunistic" fungi to disseminate throughout the body. Second, in vitro measurements of cell-mediated immunity may fluctuate independently of the skin test and may not closely correlate with the clinical status of the patient. One must therefore be cautious in placing great prognostic weight upon such assays. Third, serum blocking factors associated with neoplastic and certain mycobacterial and mycotic diseases could not be demonstrated in this patient; their role in coccidioidomycosis remains to be defined.
fu:FERENCES I Kaplan MH, Annstrong D, Rosen P: Tuberculosis Ciomplicating neoplastic disease. Cancer 33:850, 1974 2 Hill RB, Rowlands DT, Rifkind D : Infectious pulmonary disease in patients receiving immunosuppressive therapy for organ transplantation. N Engl J Med 271:1021-1027, 1964 3 Cotton BH, Penido JRF, Birsner ]W, et al : Co-existing pulmonary coccidioidomycosis and tuberculosis: A review of 24 cases. Am Rev Tuberc 70:109, 1954 4 Perry LV, Jenkins DE, Whitcomb FC: Simultaneously occurring pulmonary coccidioidomycosis and histoplasmosis. Am Rev Respir Dis 92:952-957, 1965 5 A Guide to the Perfonnanoe of the Standardized Diagnostic Complement Fixing Method and Adaptation to Micro Test. Atlanta, Center for Diseaee Control, 1969 6 Graybill JR, Silva], Alford RH, et al: Immunologic and clinical improvement ot1 progressive coccidioidomycosis following administration of transfer factor. Cell Immunol 8:120-135, 1973 7 Bullock WE, Fasal P: Studies of immune mechanisms in leprosy. J Immunoll06:888-889, 1971 8 Heilman DH, ·McFarland W: Inhibition of tuberculininduced mitogenesis in cultures of lymphocytes from tuberculous donors. Int Arch Allergy Appl Immunol 30: 58-66, 1966 9 Biggar WD, Meuwissen HJ, Good RA : Successful defense against Histoplasma capsulatum in hypogammaglobulinemia. Arch Intern Med 128:585-590, 1971 10 Hart PD, Russell E, Remington JS: The compromised host and infection: 2. Deep fungal infection. ] Infect Dis 120:169-191, 1969 11 Deresinski SC, Stevens DA : Coccidioidomycosis in compromised hosts. Medicine 54:377-395, 1974
CHEST, 72: 2, AUGUST, 1977
12 Smith CE, Saito MT, Simons SA: Pattern of 39,500 serologic tests in coccidioidomycosis. JAMA 160:546-552, 1956 13 Graybill JR, Alford RH: 'Cell-mediated immunity in cryptococcosis. Cell Immunol14:12-21, 1974 14 Thor DE, Graybill JR, Levine BB, Et al: Immunologic deficits in coccidioidomycosis: Results of transfer factor therapy. Clin Exp Immunol, to be published
Removal of Foreign Bodies (Two Teeth) by Fiberoptic. Bronchoscopy* John F. Fieselmann, M.D.; 00 Dooold C. Zavala, M.D., F.C.C.P.;t and Lon W. Keirn, M.D., F.C.C.P.t
In special situations the flexible fiberoptlc bronchoscope, with its increased visual nmge and extended capabilities fO.. e:Draction, may be utilized to augment rigid bronchoscopy. Recently developed tools for e:Dractlon (claw,
basket, forceps, and · baBoon catheter) may be inserted through the channel of the fiberoptic bronchoscope to captnre llll8ll, peripheral foreign objects. We present the case of a 76-year-old man in whom two aspirated teeth were removed from the right lower lobe (RB.. and RB"') using the fiberoptic bronchoscope, a wire basket, and a Fogarty baBoon catheter. Rigid tnbe bronchoscopy was contraindicated because the patient had just snstalned a frac:tnred skull and jaw in an automobile accident.
can be used in special situations, eg, on patients being mechanically ventilated and on those with fractures of the jaw, cervical spine, or skull. The following case is presented to illustrate a unique application of the fiberoptic bronchoscope in removing two foreign bodies (teeth) frpm a traumatized elderly man in whom use of the rigid bronchoscope was contraindicated.
A 76-year-old man was admitted to the Iowa City Veterans Administration Hospital in May 1976, following an automobile accident. On examination, he was obtunded and had mild tachycardia (pulse rate, 112 beats per minute), tachypnea (respiration rate, 25/min), and multiple facial lacerations. Three of his front teeth ·had ·undergone traumatic avulsion, and many of the remaining teeth were loose. Decreased breath sounds and coarse rales were audible over the upper anterior portion of the left side of the chest. A right hemiparesis and a right Babinski's response were present. Chest x-ray films showed an infiltrate of the left upper lobe. Roentgenograms of the skull and jaws showed a linear fracture of the temporal-parietal area and a fracture of the left mandible. Oral intubation was performed, and the patient was given oxygen therapy with warm humidification. With a fractional concentration of oxygen in the inspired gas, of 40 percent, the arterial oxygen pressure was 149 mm Hg,
T
rad.itionally, the open-tube rigid bronchoscope is used to remove aspirated foreign bodies from the tracheobronchial tree. With the aid of grasping forceps and special tools, approximately 90 to 95 percent-of all foreign bodies can be extracted by this standard technique. Failure to promptly recover the foreign object
For additional comment, see pages 264, 265 commonly results in pneumonia, formation of an abscess, empyema, and even death. Until recently, if conventional methOds were not successful, the only other option was early thoracotomy and transpleural bronchotomy. Currently, the flexible fiberoptic bronchoscope, with its increased visual range and extended capabilities for extraction, may be utilized to augment rigid bronchoscopy in removal of foreign bodies. Recently developed tools for extraction (claw, basket, forceps, and balloon catheter) have been used experimentally to capture small foreign objects in the peripheral · airways of dogs. 1 • 2 In addition, the flexible fiberoptic bronchoscope From the University of Iowa Haspitals and Clinics, and the College of Medicine, University of Iowa, Iowa City. .. Pulmonary Fellow, Department of Internal Medicine. tDirector, Pulmonary Diagnostic Laboratory, Department of Internal Medicine and Career Research Awardee, American Lung Association of Iowa tpulnionary Division, Department of Medicine, University of Nebraska Medical Center, and Assistant Director, Respiratory Therapy Department, Bishop Clarlcson Memorial Hospitals, Omaha, Nebraska. Reprint requests: Dr. Fieselmann, Umoemty of Iowa Hospltals, Iowa City 52240 . 0
CHEST, 72: 2, AUGUST, 1977
1. Chest x-ray film of 76-year-old man, showing two aspirated teeth ( aN'Ows) in right lower lobe.
FIGURE
REMOVAL OF FOREI8N BODIES BY FOB 241
Disseminated Histoplasmosis Followed by Disseminated Coccidioidomycosis• Peter Kapltm, M.D., F.C.C.P.; John R. Gravblll, M.D.; and Dtmlel Thor, M.D.
A case of dJIIemlnatecl hlltoplaanosll foDowecl later by c:occldfoldomyCOids Is described. 11ae cJin. lc:al IIIDess amd lmmllllOiolk lhldles ........ IIIIJde defecta that may bave alsted aatec:edent to IDfec:tioa 8DCI, thus, provided 1111 opportualty for widespread cU.sendnadoa by these IIOI'IIIally DODOpportualltk . . . Dl&ma. Poor c:orrelatloa ,... DOted betweea tbe c:llaiall c:oane amd in vitro teses of cell-mediated lmmDDity. dlllemfnatecl
A
lthough most patients exposed to fungi handle their infection without serious illness, some develop progressive and, at times, life-threatening disease. Recently, attention has been focused on the immunosuppressed host in whom mycotic and mycobacterial infections frequently occur. 1 · ' Occasionally, mixed fungal and mycobacterial infections occur in the same individual in whom no underlying neoplastic or immunosuppressed condition is apparent.M We report herein an unusual patient in whom disseminated coccicidioidomycosis occurred one year after he was treated for disseminated histoplasmosis. Immunologic evaluation suggested a subtle primary immune deficit that may have predisposed him to both infections.
CASE REPoRT A 35-year-old Caucasian man was previously hOIPitalized
in August 1971, with a three-week history of nonproductive
cough, fever, mya)gias, and headache. Physical enminatioo upon admission revealed a chronically ill man with inspiratory rales over the right anterior' portion of the chest and splenomegaly. On admission the chest ll:-ray 6lm showed a diffuse miliary pattern. Pertinent laboratory data included a white blood cell OOUDt oE 3,700/cu mm, with a normal •From the Department of Pulmonary Disease, United States Air Force Medical Center Scott, Scott Air Force Base, Dlinois; the Departments of Medicine, Nashville Veterans Administration Hospital and Vanderbilt University Hospital, Nashville, Tenn; and the Departments of Microbiology and Pathology, University of Texas Health Science Center, San Antonio. The views expressed herein are those of the authors and do not necessarily reflect the views of the United StateS Air Force or the Department of Defense. Reprint reqfA68ts: Dr. Kapltm, 320 Etue North Aoeooe, PitAburgh 15212
238 KAPLAN, GRAYBIU, THOR
differential count Hepatic function, renal function, the serum glucose level, the results of serum protein electrophoresis, and the findings from examinations of the cerebrospinal fluid were all normal Histoplasma capsulatum was cultured from blood, urine, sputum, bone marrow, and pulmonary aspirate. Therapy with amphotericin B was begun on the fourth day of hospitalization. The patient's condition rapidly improved, and within two weeks, he became asymptomatic and afebrile. Splenomegaly and anemia resolved, and his chest ll:-ray 61m cleared. Tbe patient received a total dose- of 1.5 gm of amphotericin B, with therapy finishing in November 1971. Subsequent fungal cultures were negative. The results of serial fungal serologic studies are summarized in Table 1. After leaving the hospital in March 1972, the patient was transferred to Arizona. In October 1972, he develaped transient cough, fever, mya)gias, and swelling of the left anlcle. The coccidioidin complement-fixation titer increased from 1:2 to 1:64. During November 1972, three cutaneous nodules appeared. The patient was hospitalized in December 1972 and, other than the cutaneous lesions, was totally asymptomatic. Physical examination revealed a healthy appearing man, With the only significant findings being three oval erythematous infiltrative lesions on the right side of his neck, his right uilla, and his badt. These varied from 1 to 2 em in diameter. Biopsy of the axillary lesion revealed granulomas, with Coccidioidu immUV seen on staining with methenamine silver. Cultures were also positive. At that time the patient had a 22-mm reaction to a skin test with a 1: 100 dilution of coccidioidin, as shown in Table 2. The skin test for mumps was positive on multiple occasions; however, the patient had negative results on tests with histoplasmin and Candida. The leukocyte count, results of serum electrophoresis, levels oE immunoglobulins and serum complement, chest ll:ray 61m, findings from a bone survey, and cerebrospinal fluid were all normal. Following a single injection of typhoid vaccine, the serum agglutination titer for Salmonella twho.a 0 antigen rose from less than 1:40 to more than 1:640. In December 1972, therapy with amphotericin B was reinstituted and was continued through June 1973, for a total dose of 3.2 gm. During therapy, gradual healing of the cutaneous lesions occurred, and the patient remained asymptomatic. Concurrent with the therapy with amphotericin B, the migration inhibiting factor converted from the previously negative response to an equivocally positive response one month larer, at a time when transformation response was clearly positive for coccidioidin (Table 2). During this period the patient's clinically mild cutaneous disease regressed. He remained free of clinically active lesions through January 1974. Interestingly, the complement-fixation titer (Table 1) fell to 1 :2 by May 1973, but later began to increase. In July and September 1973, a disturbing depression in transformation to coccidioidin was noted, and two months later, the patient lost his cutaneous reactivity to a 1 :100 dilution of
coocidioidbL
In January 1974, the patient returned, complaining of
diffuse low bade pain. A left paravertebral mass at the level
of Tl0-11 had become apparent radiographically. The cere- . brospinal fluid was normal. Lymphocyte transformation was normal, but response to a skin test with coccidioidin was positive only at the high concentration of 1:10. The complement-hation titer had risen to 1:64 by February. Lymphocyte transformation was selectively depressed to coccidioidin. A presumptive diagnosis of recurrent disseminated coccidioidomycosis was made, and therapy with amphorericin B was reinstituted. In March 1974, after 600 mg of amphotericin B
CHEST, 72: 2, AUGUST, 1977
Table
1--Serolo~
Data
Histoplasmosis
Date
Coccidioidomycosis
Histoplasmin Antigen Complement Fixation•
Yeast Antigen Complement Fixation•
Precipitin Bands*
1:16 1:8 1:8 1:8 1:8 1:8 1:8 1:8 1:8 1:8 1:8
1:1024 1:128 1:64 1:32 1:8 1:8 1:8 1:8 1:8 1:8 1:8
Histoplasmosis Histoplasmosis Histoplasmosis Negative Negative Negative Negative Negative Negative Negative Negative
1:8 1:8 1:8
1:8 1:8 1:8
Negative Negative Negative
8/16/71 9/'JJ.)/71 11/19/71 3/8/72 8/6/72 12/18/72 2/12/72 5/21/73 8/7/73 11/5/73 1/7/74 2/25/74 5/8/74 6/3/74 8/12/74
Coccidioidin ComplementFixation Titers
Precipitin Test
Negative Negative Negative Negative Negative 1:32** 1:8** 1 :2** 1:4** 1:8** 1:32** 1:64** 1:32** 1:32** 1 :16**
Negative Negative Negative Negative Negative Negative•• Negative•• Negative•• Negative•• Negative•• Negative•• Negative•• Negative•• Negative•• Negative••
*Standardized method from Center for Disease Control. • **Kindly performed by D. Pappagianis, M.D., Davis, Calif. was administered without radiographic evidence of improvement, the patient underwent surgical exploration of the left paravertebral space, but no lesion was found. Following surgery the patient develOPed a left pleural effusion which persisted for six weeks. No fungal organisms could be seen or grown in multiple specimens of pleural fluid or from pleural biopsy. Therapy with amphotericin B was continued until June 1974, for a total dose of 2 gm. Otherwise, the patient's postoperative course was uneventful. The paravertebral mass disappeared on follow-up x-ray fihns. Immunologic reevaluation in May 1974 indicated persistent hyporeactivity on skin tests with coccidioidin, normal transformation, and negative results on assay for migration-inhibition factor. Despite continuing immunologic impairment and strong serologic suggestion of Table
2-Srudi~
12/18/72 1/4/73 2/6/73 5/24/73 7/24/73 9/4/73 11/4/73 1/7/74 1/29/74 2/8/74 2/27/74 5/8/74 5/15/74 8/12/74 8/19/74
Coccidiodin 1:100 1:10
Histoplasmin Candida 0
22
20
0 15
of CeU-Medialed Immunity
Lymphocyte Transformation, CPM X 10-u
Induration on Skin Test, mm Date
active coccidioidomycosis, the patient remained clinically well. In August 1974 the complement-fi.xation titer decreased to 1:16. For the first time, skin tests with Candida albicana extract were positive on two occasions, suggesting continued varying immunologic competence. Transient depression of coccidioidin-induced lymphocyte transformation on three occasions suggested that serum blodcing factors, similar to those described in tuberculosis or leprosy, might be operative.7,8 Therefore, a number of studies of transformation of the patient's lymphocytes were concurrently performed with autologous serum and heatinactivated pooled human serum from normal donors. No differences were found between the two, suggesting that humoral factors did not play a role in suppressing lymphocyte transformation.
Unstimulated
Coccidiodin
Histoplasmin Candida
1.4 1.2 12.0 3.3 4.0
12.0 35.0 24.0 3.6 1.7
18.0
56.0
13.0
1.6 21.0
2.1 2.2
14.0 16.0
14.0 21.0
0.3
0.2
8.1
3.2
14.5
19.3
Migration Inhibiting Factor (Migration Index) • • Coccidioidin
Histoplasmin Candida
0 0
0 0
30
0 0
0 0
0
30
0
0
0
30
0
0
0
30
0
50
24.0
101 75
110
86
80
30
*Ratio of stimulated to unstimulated greater than 3 is positive. • ••Index greater than 80 is negative; 70 to 79 is equivocal ; and below 70 is positive.•
CHEST, 72: 2, AUGUST, 1977
giSSEMINATED HISTOPLASMOSIS FOLLOWED BY COCCIDIOIDOMYCOSIS 239
DISCUSSION
Cell-mediated immunity has been increasingly appreciated as a critical element in host defense against certain fungi. 6 • 7 •9 Gross alteration of cellular immunity, either by lymphoreticular malignant diseases or by immunosuppressive agents, markedly heightens susceptibility to certain fungi, which have been accordingly characterized as "opportunists." Other fungi which are similarly contained by cell-mediated immunity generally affect the normal host. These include both Histoplasma capsulatum and C immitis. 10 Underlying depression of cell-mediated immunity has been infrequently investigated in these mycoses and is not considered a major factor; however, clinical evidence suggests that depressed cell-mediated immunity may be a factor in permitting these organisms to flourish in man. Occasionally, dual infections occur in the same patient. The coexistence of tuberculosis with blastomycosis, histoplasmosis, or coccidioidomycosis is a well-recognized phenomenon.s Simultaneous pulmonary coccidioidomycosis and histoplasmosis have been reported;• however, in dual pulmonary infection, the relative pathogenetic importance of immunologic and mechanical factors, such as breakdown of old inactive foci, is unknown. Finally, the occurrence of coccidioidomycosis in immunosuppressed patients may not be rare as previously suspected.U In our patient, the results of tests for humoral immune function, including levels of immunoglobulins and complement and the response to typhoid vaccination, were normal. The patient was able to generate high titer complement-fixing coccidioidin antibody; however, such antibody has not been proven beneficial in coccidioidomycosis and, indeed, is associated with progression of disease. 12 On the other hand. the results of tests for cell-mediated immune response were abnormal. The patient had recovered from disseminated histoplasmosis and yet had a persistently negative skin test to this antigen. The major fault did not appear to be recognition, because his lymphocytes transformed well to histoplasmin. With intact recognition the negative skin test (and migration inhibiting factor) place the defect in the effector arm of the immune response, like that observed in cryptococcosis.18 Similarly, our patient had a defective effector response to coccidioidin. Unlike his reaction to histoplasmin. this defect was initially limited to migration inhibiting factor. The combination of a positive skin test with coccidioidin and negative migration inhibiting factor bas been p~ viously seen in patients with coccidioidomycosis, usually in patients with clinically mild disease. 6 This pattern of more limited immune defect seems to correlate with clinically mild disease.14 Our patient's failure to maintain a strong skin test or to develop a positive migration inhibiting factor while receiving therapy with amphotericin B may further support an underlying defect in immune responsiveness. The ability to develop cutaneous responsiveness to one antigen (coccidioidin) but not to another (histoplasmin) remains unexplained, but similar phenomena have been observed in other patients
240 KAPLAN, GRAYBILL, THOR
with coccidioidomycosis. The later weakening reactivity on the skin test and negative migration inhibiting factor correlate with suspected clinical relapse. Although organisms were not recovered from the paraspinous area, this may have reflected antecedent therapy with amphotericin B. Two of three episodes of depressed lymphocyte transformation occurred at times when the patient was feeling well, was receiving no therapy with amphotericin B, and had a relatively low serologic titer. If this represents true immunologic failure, it certainly does not correlate well with the clinical status of the patient and is unlikely to be secondary to worsening infection. The clinical and immunologic course of this patient offers several observations. First, our understanding of cell-mediated immunity is very incomplete and not simply assessed by a skin test. More subtle deficiencies exist and, as suggested by our patient, may enable normally "nonopportunistic" fungi to disseminate throughout the body. Second, in vitro measurements of cell-mediated immunity may fluctuate independently of the skin test and may not closely correlate with the clinical status of the patient. One must therefore be cautious in placing great prognostic weight upon such assays. Third, serum blocking factors associated with neoplastic and certain mycobacterial and mycotic diseases could not be demonstrated in this patient; their role in coccidioidomycosis remains to be defined.
fu:FERENCES I Kaplan MH, Annstrong D, Rosen P: Tuberculosis Ciomplicating neoplastic disease. Cancer 33:850, 1974 2 Hill RB, Rowlands DT, Rifkind D : Infectious pulmonary disease in patients receiving immunosuppressive therapy for organ transplantation. N Engl J Med 271:1021-1027, 1964 3 Cotton BH, Penido JRF, Birsner ]W, et al : Co-existing pulmonary coccidioidomycosis and tuberculosis: A review of 24 cases. Am Rev Tuberc 70:109, 1954 4 Perry LV, Jenkins DE, Whitcomb FC: Simultaneously occurring pulmonary coccidioidomycosis and histoplasmosis. Am Rev Respir Dis 92:952-957, 1965 5 A Guide to the Perfonnanoe of the Standardized Diagnostic Complement Fixing Method and Adaptation to Micro Test. Atlanta, Center for Diseaee Control, 1969 6 Graybill JR, Silva], Alford RH, et al: Immunologic and clinical improvement ot1 progressive coccidioidomycosis following administration of transfer factor. Cell Immunol 8:120-135, 1973 7 Bullock WE, Fasal P: Studies of immune mechanisms in leprosy. J Immunoll06:888-889, 1971 8 Heilman DH, ·McFarland W: Inhibition of tuberculininduced mitogenesis in cultures of lymphocytes from tuberculous donors. Int Arch Allergy Appl Immunol 30: 58-66, 1966 9 Biggar WD, Meuwissen HJ, Good RA : Successful defense against Histoplasma capsulatum in hypogammaglobulinemia. Arch Intern Med 128:585-590, 1971 10 Hart PD, Russell E, Remington JS: The compromised host and infection: 2. Deep fungal infection. ] Infect Dis 120:169-191, 1969 11 Deresinski SC, Stevens DA : Coccidioidomycosis in compromised hosts. Medicine 54:377-395, 1974
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12 Smith CE, Saito MT, Simons SA: Pattern of 39,500 serologic tests in coccidioidomycosis. JAMA 160:546-552, 1956 13 Graybill JR, Alford RH: 'Cell-mediated immunity in cryptococcosis. Cell Immunol14:12-21, 1974 14 Thor DE, Graybill JR, Levine BB, Et al: Immunologic deficits in coccidioidomycosis: Results of transfer factor therapy. Clin Exp Immunol, to be published
Removal of Foreign Bodies (Two Teeth) by Fiberoptic. Bronchoscopy* John F. Fieselmann, M.D.; 00 Dooold C. Zavala, M.D., F.C.C.P.;t and Lon W. Keirn, M.D., F.C.C.P.t
In special situations the flexible fiberoptlc bronchoscope, with its increased visual nmge and extended capabilities fO.. e:Draction, may be utilized to augment rigid bronchoscopy. Recently developed tools for e:Dractlon (claw,
basket, forceps, and · baBoon catheter) may be inserted through the channel of the fiberoptic bronchoscope to captnre llll8ll, peripheral foreign objects. We present the case of a 76-year-old man in whom two aspirated teeth were removed from the right lower lobe (RB.. and RB"') using the fiberoptic bronchoscope, a wire basket, and a Fogarty baBoon catheter. Rigid tnbe bronchoscopy was contraindicated because the patient had just snstalned a frac:tnred skull and jaw in an automobile accident.
can be used in special situations, eg, on patients being mechanically ventilated and on those with fractures of the jaw, cervical spine, or skull. The following case is presented to illustrate a unique application of the fiberoptic bronchoscope in removing two foreign bodies (teeth) frpm a traumatized elderly man in whom use of the rigid bronchoscope was contraindicated.
A 76-year-old man was admitted to the Iowa City Veterans Administration Hospital in May 1976, following an automobile accident. On examination, he was obtunded and had mild tachycardia (pulse rate, 112 beats per minute), tachypnea (respiration rate, 25/min), and multiple facial lacerations. Three of his front teeth ·had ·undergone traumatic avulsion, and many of the remaining teeth were loose. Decreased breath sounds and coarse rales were audible over the upper anterior portion of the left side of the chest. A right hemiparesis and a right Babinski's response were present. Chest x-ray films showed an infiltrate of the left upper lobe. Roentgenograms of the skull and jaws showed a linear fracture of the temporal-parietal area and a fracture of the left mandible. Oral intubation was performed, and the patient was given oxygen therapy with warm humidification. With a fractional concentration of oxygen in the inspired gas, of 40 percent, the arterial oxygen pressure was 149 mm Hg,
T
rad.itionally, the open-tube rigid bronchoscope is used to remove aspirated foreign bodies from the tracheobronchial tree. With the aid of grasping forceps and special tools, approximately 90 to 95 percent-of all foreign bodies can be extracted by this standard technique. Failure to promptly recover the foreign object
For additional comment, see pages 264, 265 commonly results in pneumonia, formation of an abscess, empyema, and even death. Until recently, if conventional methOds were not successful, the only other option was early thoracotomy and transpleural bronchotomy. Currently, the flexible fiberoptic bronchoscope, with its increased visual range and extended capabilities for extraction, may be utilized to augment rigid bronchoscopy in removal of foreign bodies. Recently developed tools for extraction (claw, basket, forceps, and balloon catheter) have been used experimentally to capture small foreign objects in the peripheral · airways of dogs. 1 • 2 In addition, the flexible fiberoptic bronchoscope From the University of Iowa Haspitals and Clinics, and the College of Medicine, University of Iowa, Iowa City. .. Pulmonary Fellow, Department of Internal Medicine. tDirector, Pulmonary Diagnostic Laboratory, Department of Internal Medicine and Career Research Awardee, American Lung Association of Iowa tpulnionary Division, Department of Medicine, University of Nebraska Medical Center, and Assistant Director, Respiratory Therapy Department, Bishop Clarlcson Memorial Hospitals, Omaha, Nebraska. Reprint requests: Dr. Fieselmann, Umoemty of Iowa Hospltals, Iowa City 52240 . 0
CHEST, 72: 2, AUGUST, 1977
1. Chest x-ray film of 76-year-old man, showing two aspirated teeth ( aN'Ows) in right lower lobe.
FIGURE
REMOVAL OF FOREI8N BODIES BY FOB 241
