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Blastomycosis and pregnancy
Blastomycosis and Pregnancy Luciano B. Lemos, MD, Mahdia Soofi, MD, and Emran Amir, MD Blastomycosis is an exceedingly uncommon complication of pregnancy, rarely encountered by the practicing obstetrician. However, recognizing its presence during pregnancy and expeditiously initiating appropriate therapy is of critical importance to the mother and fetus. Mississippi has the highest prevalence of blastomycosis in North America. Nevertheless, there have been only three pregnancies complicated by this fungal disease at the University of Mississippi Medical Center (Jackson, MS) during two decades. During the same time frame there were another 120 blastomycotic patients treated at the University of Mississippi Medical Center. As a condition of partial immunodepression, a nonobligatory opportunistic fungal disease like blastomycosis can complicate pregnancy. From data on our three patients and 16 other published cases, it seems that fetal risk exceeds maternal risk. There were a total of 20 babies born from mothers with blastomycosis. Only two babies (10%) had transplacental infection and both succumbed to blastomycosis. None of the 18 affected mothers for whom data was available died of the disease. Furthermore, there was never progression in the mothers, with 14 complete cures and considerable postpartum regressions of lesions in the other four women. Even the three women who received no treatment had either noticeable improvement or total regression of the disease after delivery. One of the two stillborns with blastomycosis was born to an untreated mother. Ann Diagn Pathol 6: 211-215, 2002. Copyright 2002, Elsevier Science (USA). All rights reserved. Index Words: Blastomycosis, transplacental infection, pregnancy, immunodepression
P
ULMONARY mycoses are infrequently reported in pregnancy, and the association between pregnancy and blastomycosis has been reported only occasionally.1-3 Blastomycosis in pregnancy requires decisive antifungal therapy because it can put the mother and the conceptus at risk.4 Mississippi has the highest incidence of blastomycosis in the country.5 According to the literature, blastomycosis is less common in women than men. The reported male:female ratios from three large patient series relevant to epidemiology of blastomycosis are 1.6:1,1.8:1, and 7.9:1, respectively.6-8 In Mississippi, this ratio is reportedly 1.7:1.5 We report
From the Department of Pathology, University of Mississippi Medical Center, Jackson, MS; and the Department of Pathology, University of Texas at Houston. Address reprint requests to Luciano B. Lemos, MD, Department of Pathology, LBJ Hospital, Third Floor, 5656 Kelley, Houston, TX 77026. Copyright 2002, Elsevier Science (USA). All rights reserved. 1092-9134/02/0604-0002$35.00/0 doi:10.1053/adpa.2002.34729
our experience with blastomycosis in pregnant women among a group of 123 patients with the disease. The literature on the subject was reviewed up to April 2002. Material and Methods The computerized medical record files of the University of Mississippi Medical Center (UMMC, Jackson, MS) were searched for patients with blastomycosis for the period from January 1980 through May 2000 (20 years and 5 months). All the charts and or microfilms from the patients were reviewed. The medical literature on blastomycosis and pregnancy was thoroughly reviewed from the time of the initial publications by Gilchrist in 1894 and 18969-11 through the large series of cases reported in the 1930s, 1940s, and 1950s, until the present time.5,12-16 Results Our search at UMMC yielded a total of 123 patients with the diagnosis of blastomycosis.
Annals of Diagnostic Pathology, Vol 6, No 4 (August), 2002: pp 211-215
211
212
Lemos, Soofi, and Amir Table 1. Blastomycosis and Pregnancy: Presentation of Data From 19 patients
Age/Race
Prg Week
195127
21/AA
24
Lung, skin
195831 197317
33/CC 23/AA
20 32
Skin Lung, skin
197728 198120 198224
19/AA 23/AA 27/C
24 36 28
198335
23/AA
34
Lung Lung Skin, SubC, mediastinum Skin, bone
198421
31/unk
36
198719
34/unk
22
Lung-miliary, skin, bone Lung
198719 198823 199026
39/unk 30/unk 23/unk
26 18 33
Lung, ARDS Lung, skin, bone Lung
199225
30/AA
6
Skin, bone
199329
unk/unk
24
Lung, skin
199518
29/C
29
199832 Unpub Unpub Unpub
unk/unk 17/AA 36/AA 21/AA
32 31 24 28
YearREF
Organs Involved
Treatment
Iodides, Xray, Vaccines, prepartum None Amphoter B, postpartum Amphoter B, prepartum None Amphoter B prepartum
Status of Mother
Status of Baby/Placenta
Diagnosis
Cured
Free/free
Biopsy/skin
Cured “Good effect” Cured “Recover” Cured
Free/unk Unk/unk
Culture/skin Biopsy/lung
Free/unk Unk/unk Free/free
Wet prep/aspiration Biopsy/lung Wet prep/pus subcut Autopsy/baby
Ketoconazole postpartum Amphoter B postpartum
Cured Cured
Amphoter B prepartum
Cured
Amphoter B prepartum Amphoter B prepartum Amphoter B prepartum: 3 days None, refused
Cured Cured Cured
Cured
Lung, skin
Amphoter B,* ketoconazole Amphoter B prepartum
unk Lung, skin Lung Lung
unk Amphoter B prepartum Amphoter B prepartum Amphoter B prepartum
“Healing”
Death blasto/ unk Free/free Free/unk (twins) Free/unk Free/free Free/blasto Death blasto/ unk Unk/unk
“Good Free/free response” unk Unk/unk Cured Free/free Cured Free/unk Cured Free/unk
Biopsy/skin Wet prep/sputum Wet prep/sputum Biopsy/skin Biopsy/lung Biopsy/baby’s lung Unk Wet prep/bronch brush Unk Wet prep/skin Cytology/pulmonary Cytology/pulmonary
Abbreviations: Unpub, unpublished; REF, reference; Prg week, stage of pregnancy in weeks; B, black; W, white; unk, unknown data; Subcut, subcutaneous; X-ray, radiotherapy; Amphoter; amphotericin; Prep, preparation; blasto, blastomycosis; bronch brush, bronchial brushing *Pre- and postpartum.
Among these patients, 44 were females and three were pregnant (6.8%). The literature search yielded another 16 cases of pregnancy-associated blastomycosis.17-32 Demographic and clinical data including diagnosis, treatment, and survival of the mother and conceptus were reviewed and results are depicted in Table 1. Discussion Although extensive, our bibliographic search might have missed some cases from the literature because little attention was drawn to the association between blastomycosis and pregnancy in several reports. The literature on this subject is primarily restricted to isolated case reports, with the exception of one article reporting on two patients.19 In
several reports about blastomycosis, single cases of pregnancy were presented briefly as illustrations or mentioned lightly among large series of patients.20,29,32-34 There are also cases reported twice, such as the case by Ismail and Lerner24 from 1982, which is also shown as an isolated illustration in Rippon’s book, Medical Mycology: The Pathogenic Fungi and the Pathogenic Actinomycetes.34 All the evidence indicates that a case report of a baby and mother with blastomycosis from 1983 is the same one presented later in 1986.30,35 An additional case that would be the seventeenth from the literature was not included in this report because the etiologic diagnosis of blastomycosis was never confirmed.33 During an outbreak of blastomycosis this 29-year-old pregnant patient in her third trimester
Blastomycosis and Pregnancy
presented with pneumonia, allegedly caused by Blastomyces dermatitidis. Although she never received treatment.33 Age, Race, and Stage of Pregnancy The ages of 17 patients of the 19 depicted in Table1 varied from 17 to 39 years, with a mean of 27 years. Ages were not disclosed in two patients. According to Chapman et al,5 the mean age of women with blastomycosis in Mississippi is 46 ⫾ 18.9 years. The race of seven patients was not mentioned, while of the remaining 12 patients, nine were black and three were white. The ratio between black and white patients with blastomycosis in Mississippi is 1.8 to 1.5 The stage of pregnancy at the time of diagnosis of blastomycosis varied from 6 weeks to 36 weeks (average, 26.7 weeks). Organ Involvement Organ involvement is not mentioned in only one case32 (Table1). Lungs alone (localized blastomycosis) were involved in seven patients (39%). Disseminated disease was encountered in 11 cases (63%). Pulmonary involvement, either alone or as multiorgan involvement, occurred in the majority of patients (14 out of 18, 78%). Treatment and Outcome Three patients received no treatment. One woman in 1992 had refused treatment and was considered “better with lesions healing well” 3 months after delivery. Her baby boy was born with blastomycosis, subsequently died and only at the baby’s autopsy was the diagnosis definitely established.25 Another untreated pregnant patient reported on before the advent of modern antifungal therapy (1958) was considered cured with a follow-up of 2.5 years.31 The third untreated patient was reported in 1981 and she had a “complete recovery” according to the report.20 The patient from 1958 had one skin lesion on the face and negative chest X-rays.31 The 1992 patient had skin and bone lesions.25 Data regarding treatment was available for 15 other patients. The patient from 195127 was treated with iodides, radiotherapy, and vaccines, which would be recognized today as empiric and ineffective forms of treatment.4 However, this patient was considered cured from her disseminated disease with one year of follow-up. The other 14 women were treated according to modern pro-
213
tocols.4 Amphotericin B is the drug of choice for blastomycosis in pregnancy because the azoles are potentially teratogenic and embryotoxic.4 Amphotericin B was given to 13 patients (11 prepartum and two postpartum). Ketoconazole was administered to two patients after delivery.29,35 One of these patients had taken both drugs, namely amphotericin prepartum and ketoconazole postpartum.29 All of the 14 patients treated with antifungal drugs were considered either cured (12 patients) or had “good response” (two patients) according to the reports. It seems from the available data that blastomycosis runs a favorable course in most treated pregnant women. None of the women died, even the patients who had the acute respiratory distress syndrome responded to treatment with amphotericin B with recovery.26 Acute respiratory distress syndrome in patients with blastomycosis carries a very bad prognosis, with mortality reported up to 89% in nonpregnant patients.36,37 Pregnancy is considered a condition that leads to partial immunodepression, not only at the placental level because of high hormonal concentrations, but also at the level of T-cell response and consequently at the cell-mediated arm of global immunity.1,3,22,23,29 Blastomycosis, like many other fungal diseases, elicits a cell-mediated response which depends totally on T-cell function.38 Therefore, the partial immunodepression of pregnancy3,22,39 probably facilitates the appearance of blastomycosis, either de novo or as reactivation. When the pregnancy is over, the disease seems to be brought under control even without antifungal treatment (Table 1). Blastomycosis is not recognized as an obligatory opportunistic fungal infection, but it is known to affect immunodepressed patients in considerable numbers.5,29 Among 123 blastomycotic patients from UMMC, including the three patients in this report, 25% had associated disorders that led to immunodeppression.40,41 Perinatal Outcome and Placental Involvement Perinatal outcome and placental positivity for blastomycosis is shown in Table 1. Among the three fetuses reported from UMMC, one was female and two were males. Infant sex was mentioned in another nine reports from the literature.19,21,2326,28,30,31 The overall numbers are eight males and four females. Both stillborns that died with blastomycosis were males.25,30,35 Apparently none of the
214
Lemos, Soofi, and Amir
12 babies exposed to amphotericin B in utero suffered any adverse effects from the drug. Furthermore, the two babies that died never received the drug.25,30,35 The placentas were not examined in these two patients. There is one case in which the placenta exhibited blastomycosis histologically but the male baby was born in good health. The mother had had acute respiratory distress syndrome and received amphotericin starting only 3 days before delivery.26 Overall, the status of the placenta was mentioned in only seven cases, one from UMMC and six from the literature.18,21,23,24,26,27 The placentas were free of fungus in six cases and positive in one. As mentioned previously, the baby from whom the corresponding placenta was positive was born free of disease.26 Methods of Diagnosis and Specimens The methods of diagnosis of blastomycosis were reported in all but two cases29,32 (Table1). Histology was the first method to identify the organism in eight out of 18 women (44%), wet preparation in seven out of 18 (39%), and cytology from pulmonary fluids in three out of 18 (17%). Two from the latter were from UMMC. At UMMC, cytology has proven to be able to diagnose blastomycosis in up to 97% of patients.40 Culture was the first method to detect the fungus in one out of 18 (5%) of the mothers. The organs examined by histology per number of cases were: lung, 3; skin, 3; and babies’ tissues, 2 (1 lung biopsy, 1 autopsy). The fact that in two cases the final diagnosis could only be established after examination of babies’ tissues confirms the knowledge that blastomycosis can mimic other conditions and even be treated as other diseases for a long time.41,42 In the six cases diagnosed by wet preparation with KOH, the material examined was: pulmonary fluids (four cases) and pus from skin or subcutaneous lesions (two cases). Culture was the first method to identify the etiologic agent in only one patient from whom pus out of a skin lesion was submitted.31 Results from cultures are known in 18 out of 19 patients. In 14 out of 18 cases (78%), the cultures eventually became positive; in three out of 18 cases (17%), they were negative; and in one out of 18 cases (6%), culture was not performed. In the three UMMC cases, cultures were negative in two and positive in one.
Underlying Diseases Among the 19 pregnant patients with blastomycosis in Table1, other underlying diseases were present in three instances: sarcoidosis in two cases (one receiving corticosteroids)19 and diabetes mellitus plus rheumatoid arthritis in the third patient.18 The patients with sarcoidosis could be considered at further risk of immunodepression. Although diabetes mellitus is associated with blastomycosis in a considerable number of patients,5,41 it is not clear if diabetes is a predisposing factor for blastomycosis. In mucormycosis, diabetes mellitus is clearly a facilitating factor for the fungal disease.43 References 1. Catanzaro A: Pulmonary mycosis in pregnant women. Chest 1984;86:14S-18S 2. Purtilo DT: Opportunistic mycotic infections in pregnant women. Am J Obstet Gynecol 1975;122:607-610 3. Blotta MHSL, Altemani AM, Amaral E, et al: Placental involvement in paracoccidioidomycosis. J Med Vet Mycol 1993; 31:249-257 4. Chapman SW, Bradsher RW Jr, Campbell GD Jr, et al: Practice guidelines for the management of patients with blastomycosis. Clin Infect Dis 2000;30:679-683 5. Chapman SW, Lin AC, Hendricks KA, et al: Endemic blastomycosis in Mississippi: Epidemiological and clinical studies. Semin Respir Infect 1997;12:219-228 6. Furcolow ML, Chick EW, Busey JF, et al: Prevalence and incidence studies of human and canine blastomycosis. I. Cases in the United States, 1885-1968. Am Rev Respir Dis 1970;102: 60-67 7. Baumgardner DJ, Buggy BP, Mattson BJ, et al: Epidemiology of blastomycosis in a region of high endemicity in north central Wisconsin. Clin Infect Dis 1992;15:629-635 8. Davies SF, Sarosi GA: Epidemiological and clinical features of pulmonary blastomycosis. Semin Respir Infect 1997;12:206218 9. Gilchrist TC: A case of blastomycetic dermatitis in man. Johns Hopkins Hosp Rep 1896;1:269-283 10. Gilchrist TC: Protozoan dermatitis. J Cutan Gen-Urin Dis 1894;12:496-499 11. Gilchrist TC, Stokes WR: The presence of an oidium in the tissues of a case of pseudo-lupus vulgaris. Bull Johns Hopkins Hosp 1896;7:129-133 12. Stober AM: Systemic blastomycosis: A report of its pathological, bacteriological and clinical features. Arch Intern Med 1914;13:509-556 13. Martin DS, Smith DT: Blastomycosis (American blastomycosis, Gilchrist’s disease). I. A review of the literature. Am Rev Tuberc 1939;39:275-304 14. Bonoff CP: Acute primary pulmonary blastomycosis. Radiology 1950;54:157-164 15. Kunkel WM Jr, Weed LA, McDonald JR, et al: North American blastomycosis – Gilchrist’s disease: A clinicopathologic study of ninety cases. Surg Gynecol Obstet 1954;99:1-26
Blastomycosis and Pregnancy 16. Cherniss EI, Waisbren BA: North American blastomycosis: A clinical study of 40 cases. Ann Intern Med 1956;44:105-123 17. Baum GL, Schwarz J, Barlow PB: Sarcoidosis and specific etiologic agents: A continuing enigma. Chest 1973;63:488-494 18. Chakravarty A, Salgia R, Mason E, et al: Pneumonia and infraorbital abscess in a 29-year-old diabetic pregnant woman. Chest 1995;107:1752-1754 19. Cohen I: Absence of congenital infection and teratogenesis in three children born to mothers with blastomycosis and treated with amphotericin B during pregnancy. Pediatr Infect Dis 1987;6:76-77 20. Cope JR: Blastomycosis: Diagnostic difficulties. South Med J 1981;74:284-287 21. Daniel L, Salit IE: Blastomycosis during pregnancy. Can Med Assoc J 1984;131:759-761 22. Gall SA: Maternal adjustments in the immune system in normal pregnancy. Clin Obstet Gynecol 1983;26:521-536 23. Hager H, Welt SI, Cardasis JP, et al: Disseminated blastomycosis in a pregnant woman successfully treated with amphotericin-B. A case report. J Reprod Med 1988;33:485-488 24. Ismail MA, Lerner SA: Disseminated blastomycosis in a pregnant woman: Review of amphotericin B usage during pregnancy. Am Rev Respir Dis 1982;126:350-353 25. Maxson S, Miller SF, Tryka AF, et al: Perinatal blastomycosis: A review. Pediatr Infect Dis J 1992;11:760-763 26. MacDonald D, Alguire PC: Adult respiratory distress syndrome due to blastomycosis during pregnancy. Chest 1990;98: 1527-1528 27. Noojin RO, Praytor HB: Systemic blastomycosis complicated with pregnancy. Report of a case with clinical course and immunologic reactions. JAMA 1951;147:749-751 28. Neiberg AD, Mavromatis F, Dyke J, et al: Blastomyces dermatitidis treated during pregnancy: Report of a case. Am J Obstet Gynecol 1977;128:911-912 29. Pappas PG, Threlkeld MG, Bedsole GD, et al: Blastomycosis in immunocompromised patients. Medicine 1993;72:311325
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30. Tuthill SW: Disseminated blastomycosis treated with ketoconazole. South Med J 1986;79:1188-1189 31. Wheeler CE, Cawley EP: An unusual case of blastomycosis occurring during pregnancy. Arch Dermatol 1958;77:120-122 32. Vasquez JE, Mehta JB, Agrawal R, et al: Blastomycosis in northeast Tennessee. Chest 1998;114:436-443 33. Baumgardner DJ, Burdick JS: An outbreak of human and canine blastomycosis. Rev Infect Dis 1991;13:898-905 34. Rippon JW: Blastomycosis, in Rippon JW (ed): Medical Mycology: The Pathogenic Fungi and the Pathogenic Actinomycetes (ed 3). Philadelphia, PA, Saunders, 1988, pp 474-605 35. Watts EA, Gard PD Jr, Tuthill SW: First reported case of intrauterine transmission of blastomycosis. Pediatr Infect Dis 1983;2:308-310 36. Meyer KC, McManus EJ, Maki DG: Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome. N Engl J Med 1993;329:1231-1236 37. Lemos L, Baliga M, Guo M: Acute respiratory distress syndrome and blastomycosis: Presentation of nine cases and review of the literature. Ann Diagn Pathol 2001;5:1-9 38. Brummer E, Morozumi PA, Vo PT, et al: Protection against pulmonary blastomycosis: Adoptive transfer with T lymphocytes, but not serum, from resistant mice. Cell Immunol 1982;73:349-359 39. Weinberg ED: Pregnancy-associated depression of cellmediated immunity. Rev Infect Dis 1984;6:814-831 40. Lemos LB, Guo M, Baliga M: Blastomycosis: Organ involvement and etiologic diagnosis. A review of 123 patients from Mississippi. Ann Diagn Pathol 2000;4:391-406 41. Lemos LB, Baliga M, Guo M: Blastomycosis: The great pretender can also be an opportunist. Initial clinical diagnosis and associated diseases in 123 patients. Ann Diagn Pathol 2002; 6:194-203 42. Wallace J: Pulmonary blastomycosis: A great masquerader. Chest 2002;121:677-679 43. Anand VK, Alemar G, Griswold JA Jr: Intracranial complications of mucormycosis: An experimental model and clinical review. Laryngoscope 1992;102:656-662
P
ULMONARY mycoses are infrequently reported in pregnancy, and the association between pregnancy and blastomycosis has been reported only occasionally.1-3 Blastomycosis in pregnancy requires decisive antifungal therapy because it can put the mother and the conceptus at risk.4 Mississippi has the highest incidence of blastomycosis in the country.5 According to the literature, blastomycosis is less common in women than men. The reported male:female ratios from three large patient series relevant to epidemiology of blastomycosis are 1.6:1,1.8:1, and 7.9:1, respectively.6-8 In Mississippi, this ratio is reportedly 1.7:1.5 We report
From the Department of Pathology, University of Mississippi Medical Center, Jackson, MS; and the Department of Pathology, University of Texas at Houston. Address reprint requests to Luciano B. Lemos, MD, Department of Pathology, LBJ Hospital, Third Floor, 5656 Kelley, Houston, TX 77026. Copyright 2002, Elsevier Science (USA). All rights reserved. 1092-9134/02/0604-0002$35.00/0 doi:10.1053/adpa.2002.34729
our experience with blastomycosis in pregnant women among a group of 123 patients with the disease. The literature on the subject was reviewed up to April 2002. Material and Methods The computerized medical record files of the University of Mississippi Medical Center (UMMC, Jackson, MS) were searched for patients with blastomycosis for the period from January 1980 through May 2000 (20 years and 5 months). All the charts and or microfilms from the patients were reviewed. The medical literature on blastomycosis and pregnancy was thoroughly reviewed from the time of the initial publications by Gilchrist in 1894 and 18969-11 through the large series of cases reported in the 1930s, 1940s, and 1950s, until the present time.5,12-16 Results Our search at UMMC yielded a total of 123 patients with the diagnosis of blastomycosis.
Annals of Diagnostic Pathology, Vol 6, No 4 (August), 2002: pp 211-215
211
212
Lemos, Soofi, and Amir Table 1. Blastomycosis and Pregnancy: Presentation of Data From 19 patients
Age/Race
Prg Week
195127
21/AA
24
Lung, skin
195831 197317
33/CC 23/AA
20 32
Skin Lung, skin
197728 198120 198224
19/AA 23/AA 27/C
24 36 28
198335
23/AA
34
Lung Lung Skin, SubC, mediastinum Skin, bone
198421
31/unk
36
198719
34/unk
22
Lung-miliary, skin, bone Lung
198719 198823 199026
39/unk 30/unk 23/unk
26 18 33
Lung, ARDS Lung, skin, bone Lung
199225
30/AA
6
Skin, bone
199329
unk/unk
24
Lung, skin
199518
29/C
29
199832 Unpub Unpub Unpub
unk/unk 17/AA 36/AA 21/AA
32 31 24 28
YearREF
Organs Involved
Treatment
Iodides, Xray, Vaccines, prepartum None Amphoter B, postpartum Amphoter B, prepartum None Amphoter B prepartum
Status of Mother
Status of Baby/Placenta
Diagnosis
Cured
Free/free
Biopsy/skin
Cured “Good effect” Cured “Recover” Cured
Free/unk Unk/unk
Culture/skin Biopsy/lung
Free/unk Unk/unk Free/free
Wet prep/aspiration Biopsy/lung Wet prep/pus subcut Autopsy/baby
Ketoconazole postpartum Amphoter B postpartum
Cured Cured
Amphoter B prepartum
Cured
Amphoter B prepartum Amphoter B prepartum Amphoter B prepartum: 3 days None, refused
Cured Cured Cured
Cured
Lung, skin
Amphoter B,* ketoconazole Amphoter B prepartum
unk Lung, skin Lung Lung
unk Amphoter B prepartum Amphoter B prepartum Amphoter B prepartum
“Healing”
Death blasto/ unk Free/free Free/unk (twins) Free/unk Free/free Free/blasto Death blasto/ unk Unk/unk
“Good Free/free response” unk Unk/unk Cured Free/free Cured Free/unk Cured Free/unk
Biopsy/skin Wet prep/sputum Wet prep/sputum Biopsy/skin Biopsy/lung Biopsy/baby’s lung Unk Wet prep/bronch brush Unk Wet prep/skin Cytology/pulmonary Cytology/pulmonary
Abbreviations: Unpub, unpublished; REF, reference; Prg week, stage of pregnancy in weeks; B, black; W, white; unk, unknown data; Subcut, subcutaneous; X-ray, radiotherapy; Amphoter; amphotericin; Prep, preparation; blasto, blastomycosis; bronch brush, bronchial brushing *Pre- and postpartum.
Among these patients, 44 were females and three were pregnant (6.8%). The literature search yielded another 16 cases of pregnancy-associated blastomycosis.17-32 Demographic and clinical data including diagnosis, treatment, and survival of the mother and conceptus were reviewed and results are depicted in Table 1. Discussion Although extensive, our bibliographic search might have missed some cases from the literature because little attention was drawn to the association between blastomycosis and pregnancy in several reports. The literature on this subject is primarily restricted to isolated case reports, with the exception of one article reporting on two patients.19 In
several reports about blastomycosis, single cases of pregnancy were presented briefly as illustrations or mentioned lightly among large series of patients.20,29,32-34 There are also cases reported twice, such as the case by Ismail and Lerner24 from 1982, which is also shown as an isolated illustration in Rippon’s book, Medical Mycology: The Pathogenic Fungi and the Pathogenic Actinomycetes.34 All the evidence indicates that a case report of a baby and mother with blastomycosis from 1983 is the same one presented later in 1986.30,35 An additional case that would be the seventeenth from the literature was not included in this report because the etiologic diagnosis of blastomycosis was never confirmed.33 During an outbreak of blastomycosis this 29-year-old pregnant patient in her third trimester
Blastomycosis and Pregnancy
presented with pneumonia, allegedly caused by Blastomyces dermatitidis. Although she never received treatment.33 Age, Race, and Stage of Pregnancy The ages of 17 patients of the 19 depicted in Table1 varied from 17 to 39 years, with a mean of 27 years. Ages were not disclosed in two patients. According to Chapman et al,5 the mean age of women with blastomycosis in Mississippi is 46 ⫾ 18.9 years. The race of seven patients was not mentioned, while of the remaining 12 patients, nine were black and three were white. The ratio between black and white patients with blastomycosis in Mississippi is 1.8 to 1.5 The stage of pregnancy at the time of diagnosis of blastomycosis varied from 6 weeks to 36 weeks (average, 26.7 weeks). Organ Involvement Organ involvement is not mentioned in only one case32 (Table1). Lungs alone (localized blastomycosis) were involved in seven patients (39%). Disseminated disease was encountered in 11 cases (63%). Pulmonary involvement, either alone or as multiorgan involvement, occurred in the majority of patients (14 out of 18, 78%). Treatment and Outcome Three patients received no treatment. One woman in 1992 had refused treatment and was considered “better with lesions healing well” 3 months after delivery. Her baby boy was born with blastomycosis, subsequently died and only at the baby’s autopsy was the diagnosis definitely established.25 Another untreated pregnant patient reported on before the advent of modern antifungal therapy (1958) was considered cured with a follow-up of 2.5 years.31 The third untreated patient was reported in 1981 and she had a “complete recovery” according to the report.20 The patient from 1958 had one skin lesion on the face and negative chest X-rays.31 The 1992 patient had skin and bone lesions.25 Data regarding treatment was available for 15 other patients. The patient from 195127 was treated with iodides, radiotherapy, and vaccines, which would be recognized today as empiric and ineffective forms of treatment.4 However, this patient was considered cured from her disseminated disease with one year of follow-up. The other 14 women were treated according to modern pro-
213
tocols.4 Amphotericin B is the drug of choice for blastomycosis in pregnancy because the azoles are potentially teratogenic and embryotoxic.4 Amphotericin B was given to 13 patients (11 prepartum and two postpartum). Ketoconazole was administered to two patients after delivery.29,35 One of these patients had taken both drugs, namely amphotericin prepartum and ketoconazole postpartum.29 All of the 14 patients treated with antifungal drugs were considered either cured (12 patients) or had “good response” (two patients) according to the reports. It seems from the available data that blastomycosis runs a favorable course in most treated pregnant women. None of the women died, even the patients who had the acute respiratory distress syndrome responded to treatment with amphotericin B with recovery.26 Acute respiratory distress syndrome in patients with blastomycosis carries a very bad prognosis, with mortality reported up to 89% in nonpregnant patients.36,37 Pregnancy is considered a condition that leads to partial immunodepression, not only at the placental level because of high hormonal concentrations, but also at the level of T-cell response and consequently at the cell-mediated arm of global immunity.1,3,22,23,29 Blastomycosis, like many other fungal diseases, elicits a cell-mediated response which depends totally on T-cell function.38 Therefore, the partial immunodepression of pregnancy3,22,39 probably facilitates the appearance of blastomycosis, either de novo or as reactivation. When the pregnancy is over, the disease seems to be brought under control even without antifungal treatment (Table 1). Blastomycosis is not recognized as an obligatory opportunistic fungal infection, but it is known to affect immunodepressed patients in considerable numbers.5,29 Among 123 blastomycotic patients from UMMC, including the three patients in this report, 25% had associated disorders that led to immunodeppression.40,41 Perinatal Outcome and Placental Involvement Perinatal outcome and placental positivity for blastomycosis is shown in Table 1. Among the three fetuses reported from UMMC, one was female and two were males. Infant sex was mentioned in another nine reports from the literature.19,21,2326,28,30,31 The overall numbers are eight males and four females. Both stillborns that died with blastomycosis were males.25,30,35 Apparently none of the
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12 babies exposed to amphotericin B in utero suffered any adverse effects from the drug. Furthermore, the two babies that died never received the drug.25,30,35 The placentas were not examined in these two patients. There is one case in which the placenta exhibited blastomycosis histologically but the male baby was born in good health. The mother had had acute respiratory distress syndrome and received amphotericin starting only 3 days before delivery.26 Overall, the status of the placenta was mentioned in only seven cases, one from UMMC and six from the literature.18,21,23,24,26,27 The placentas were free of fungus in six cases and positive in one. As mentioned previously, the baby from whom the corresponding placenta was positive was born free of disease.26 Methods of Diagnosis and Specimens The methods of diagnosis of blastomycosis were reported in all but two cases29,32 (Table1). Histology was the first method to identify the organism in eight out of 18 women (44%), wet preparation in seven out of 18 (39%), and cytology from pulmonary fluids in three out of 18 (17%). Two from the latter were from UMMC. At UMMC, cytology has proven to be able to diagnose blastomycosis in up to 97% of patients.40 Culture was the first method to detect the fungus in one out of 18 (5%) of the mothers. The organs examined by histology per number of cases were: lung, 3; skin, 3; and babies’ tissues, 2 (1 lung biopsy, 1 autopsy). The fact that in two cases the final diagnosis could only be established after examination of babies’ tissues confirms the knowledge that blastomycosis can mimic other conditions and even be treated as other diseases for a long time.41,42 In the six cases diagnosed by wet preparation with KOH, the material examined was: pulmonary fluids (four cases) and pus from skin or subcutaneous lesions (two cases). Culture was the first method to identify the etiologic agent in only one patient from whom pus out of a skin lesion was submitted.31 Results from cultures are known in 18 out of 19 patients. In 14 out of 18 cases (78%), the cultures eventually became positive; in three out of 18 cases (17%), they were negative; and in one out of 18 cases (6%), culture was not performed. In the three UMMC cases, cultures were negative in two and positive in one.
Underlying Diseases Among the 19 pregnant patients with blastomycosis in Table1, other underlying diseases were present in three instances: sarcoidosis in two cases (one receiving corticosteroids)19 and diabetes mellitus plus rheumatoid arthritis in the third patient.18 The patients with sarcoidosis could be considered at further risk of immunodepression. Although diabetes mellitus is associated with blastomycosis in a considerable number of patients,5,41 it is not clear if diabetes is a predisposing factor for blastomycosis. In mucormycosis, diabetes mellitus is clearly a facilitating factor for the fungal disease.43 References 1. Catanzaro A: Pulmonary mycosis in pregnant women. Chest 1984;86:14S-18S 2. Purtilo DT: Opportunistic mycotic infections in pregnant women. Am J Obstet Gynecol 1975;122:607-610 3. Blotta MHSL, Altemani AM, Amaral E, et al: Placental involvement in paracoccidioidomycosis. J Med Vet Mycol 1993; 31:249-257 4. Chapman SW, Bradsher RW Jr, Campbell GD Jr, et al: Practice guidelines for the management of patients with blastomycosis. Clin Infect Dis 2000;30:679-683 5. Chapman SW, Lin AC, Hendricks KA, et al: Endemic blastomycosis in Mississippi: Epidemiological and clinical studies. Semin Respir Infect 1997;12:219-228 6. Furcolow ML, Chick EW, Busey JF, et al: Prevalence and incidence studies of human and canine blastomycosis. I. Cases in the United States, 1885-1968. Am Rev Respir Dis 1970;102: 60-67 7. Baumgardner DJ, Buggy BP, Mattson BJ, et al: Epidemiology of blastomycosis in a region of high endemicity in north central Wisconsin. Clin Infect Dis 1992;15:629-635 8. Davies SF, Sarosi GA: Epidemiological and clinical features of pulmonary blastomycosis. Semin Respir Infect 1997;12:206218 9. Gilchrist TC: A case of blastomycetic dermatitis in man. Johns Hopkins Hosp Rep 1896;1:269-283 10. Gilchrist TC: Protozoan dermatitis. J Cutan Gen-Urin Dis 1894;12:496-499 11. Gilchrist TC, Stokes WR: The presence of an oidium in the tissues of a case of pseudo-lupus vulgaris. Bull Johns Hopkins Hosp 1896;7:129-133 12. Stober AM: Systemic blastomycosis: A report of its pathological, bacteriological and clinical features. Arch Intern Med 1914;13:509-556 13. Martin DS, Smith DT: Blastomycosis (American blastomycosis, Gilchrist’s disease). I. A review of the literature. Am Rev Tuberc 1939;39:275-304 14. Bonoff CP: Acute primary pulmonary blastomycosis. Radiology 1950;54:157-164 15. Kunkel WM Jr, Weed LA, McDonald JR, et al: North American blastomycosis – Gilchrist’s disease: A clinicopathologic study of ninety cases. Surg Gynecol Obstet 1954;99:1-26
Blastomycosis and Pregnancy 16. Cherniss EI, Waisbren BA: North American blastomycosis: A clinical study of 40 cases. Ann Intern Med 1956;44:105-123 17. Baum GL, Schwarz J, Barlow PB: Sarcoidosis and specific etiologic agents: A continuing enigma. Chest 1973;63:488-494 18. Chakravarty A, Salgia R, Mason E, et al: Pneumonia and infraorbital abscess in a 29-year-old diabetic pregnant woman. Chest 1995;107:1752-1754 19. Cohen I: Absence of congenital infection and teratogenesis in three children born to mothers with blastomycosis and treated with amphotericin B during pregnancy. Pediatr Infect Dis 1987;6:76-77 20. Cope JR: Blastomycosis: Diagnostic difficulties. South Med J 1981;74:284-287 21. Daniel L, Salit IE: Blastomycosis during pregnancy. Can Med Assoc J 1984;131:759-761 22. Gall SA: Maternal adjustments in the immune system in normal pregnancy. Clin Obstet Gynecol 1983;26:521-536 23. Hager H, Welt SI, Cardasis JP, et al: Disseminated blastomycosis in a pregnant woman successfully treated with amphotericin-B. A case report. J Reprod Med 1988;33:485-488 24. Ismail MA, Lerner SA: Disseminated blastomycosis in a pregnant woman: Review of amphotericin B usage during pregnancy. Am Rev Respir Dis 1982;126:350-353 25. Maxson S, Miller SF, Tryka AF, et al: Perinatal blastomycosis: A review. Pediatr Infect Dis J 1992;11:760-763 26. MacDonald D, Alguire PC: Adult respiratory distress syndrome due to blastomycosis during pregnancy. Chest 1990;98: 1527-1528 27. Noojin RO, Praytor HB: Systemic blastomycosis complicated with pregnancy. Report of a case with clinical course and immunologic reactions. JAMA 1951;147:749-751 28. Neiberg AD, Mavromatis F, Dyke J, et al: Blastomyces dermatitidis treated during pregnancy: Report of a case. Am J Obstet Gynecol 1977;128:911-912 29. Pappas PG, Threlkeld MG, Bedsole GD, et al: Blastomycosis in immunocompromised patients. Medicine 1993;72:311325
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30. Tuthill SW: Disseminated blastomycosis treated with ketoconazole. South Med J 1986;79:1188-1189 31. Wheeler CE, Cawley EP: An unusual case of blastomycosis occurring during pregnancy. Arch Dermatol 1958;77:120-122 32. Vasquez JE, Mehta JB, Agrawal R, et al: Blastomycosis in northeast Tennessee. Chest 1998;114:436-443 33. Baumgardner DJ, Burdick JS: An outbreak of human and canine blastomycosis. Rev Infect Dis 1991;13:898-905 34. Rippon JW: Blastomycosis, in Rippon JW (ed): Medical Mycology: The Pathogenic Fungi and the Pathogenic Actinomycetes (ed 3). Philadelphia, PA, Saunders, 1988, pp 474-605 35. Watts EA, Gard PD Jr, Tuthill SW: First reported case of intrauterine transmission of blastomycosis. Pediatr Infect Dis 1983;2:308-310 36. Meyer KC, McManus EJ, Maki DG: Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome. N Engl J Med 1993;329:1231-1236 37. Lemos L, Baliga M, Guo M: Acute respiratory distress syndrome and blastomycosis: Presentation of nine cases and review of the literature. Ann Diagn Pathol 2001;5:1-9 38. Brummer E, Morozumi PA, Vo PT, et al: Protection against pulmonary blastomycosis: Adoptive transfer with T lymphocytes, but not serum, from resistant mice. Cell Immunol 1982;73:349-359 39. Weinberg ED: Pregnancy-associated depression of cellmediated immunity. Rev Infect Dis 1984;6:814-831 40. Lemos LB, Guo M, Baliga M: Blastomycosis: Organ involvement and etiologic diagnosis. A review of 123 patients from Mississippi. Ann Diagn Pathol 2000;4:391-406 41. Lemos LB, Baliga M, Guo M: Blastomycosis: The great pretender can also be an opportunist. Initial clinical diagnosis and associated diseases in 123 patients. Ann Diagn Pathol 2002; 6:194-203 42. Wallace J: Pulmonary blastomycosis: A great masquerader. Chest 2002;121:677-679 43. Anand VK, Alemar G, Griswold JA Jr: Intracranial complications of mucormycosis: An experimental model and clinical review. Laryngoscope 1992;102:656-662