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Blastomycosis during pregnancy: a case report and review of the literature
Diagnostic Microbiology and Infectious Disease xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Diagnostic Microbiology and Infectious Disease journal homepage: www.elsevier.com/locate/diagmicrobio
Blastomycosis during pregnancy: a case report and review of the literature Thomas Baker a,⁎, Ami Patel a, Pierre Halteh b, Sima S. Toussi c, Patricia DeLaMora c, Shari Lipner b, Audrey N. Schuetz d, Barry Hartman a a
NewYork-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, 525 E 68th St, New York, NY 10065 NewYork-Presbyterian Hospital, Weill Cornell Medicine, Department of Dermatology, 1305 York Avenue, 9th Floor, New York, NY 10021 NewYork-Presbyterian Hospital, Weill Cornell Medicine, Department of Pediatrics, 525 E 68th St, New York, NY 10065 d Mayo Clinic, Rochester, MN, Department of Laboratory Medicine and Pathology, 200 1st St SW, Rochester, MN 55905 b c
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 7 February 2017 Accepted 21 February 2017 Available online xxxx
The diagnosis of blastomycosis during pregnancy is rare, but can carry significant clinical questions for both the infected mother and developing fetus. Furthermore, given its rarity, providers have little available data to help manage and counsel patients in this uncommon, yet serious, scenario. We present a case of blastomycosis in a woman at 38 weeks' gestation and review all published cases of blastomycosis during pregnancy. It is our hope to provide a multidisciplinary understanding of the current knowledge surrounding the presentation, diagnosis, management, and outcome of this unusual infection. © 2017 Elsevier Inc. All rights reserved.
Keywords: Blastomycosis pregnancy
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . Case description . . . . . . . . . Case series . . . . . . . . . . . . Clinical presentation . . . . . . . Diagnosis and microbiology . . . . Multidisciplinary management . . . 6.1. Obstetrics . . . . . . . . . 6.2. Pulmonary . . . . . . . . 6.3. Infectious diseases . . . . . 6.4. Pediatric infectious diseases . 7. Outcomes . . . . . . . . . . . . 8. Conclusions . . . . . . . . . . . References . . . . . . . . . . . . . .
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1. Introduction Blastomycosis is caused by Blastomyces dermatitidis, a thermally dimorphic fungus endemic to the southeastern, south central, and Midwestern United States (particularly the Great Lakes Basin and St. Lawrence River Valley) in addition to the Canadian provinces of Manitoba and Ontario. Infection with B. dermatitidis can involve a diverse range of organ systems, leading to a broad spectrum of clinical presentations. Primary disease can involve the lung through inhalation of fungal ⁎ Corresponding author. Tel.: +1-610-888-7154; fax: +1-212-737-5783. E-mail address: [email protected] (T. Baker).
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conidia (with pneumonia being the most common presenting diagnosis) and the skin through direct cutaneous inoculation (Saccente and Woods, 2010). The infection can subsequently disseminate to seemingly any part of the body, including the skin, genitourinary system, bones, central nervous system (CNS), spleen, liver, and thyroid (Witorsch and Utz, 1968). Disseminated disease is more commonly encountered in immunocompromised hosts (Saccente and Woods, 2010). Pregnancy itself appears to predispose mothers to partial immunosuppression, potentially increasing the likelihood of initial infection and subsequent dissemination (Mor and Cardenas, 2010). Perinatal blastomycosis remains a rare entity and descriptions are limited to case reports. The optimal management of both the mother
http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015 0732-8893/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Baker T, et al, Blastomycosis during pregnancy: a case report and review of the literature, Diagn Microbiol Infect Dis (2017), http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015
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T. Baker et al. / Diagnostic Microbiology and Infectious Disease xxx (2017) xxx–xxx
and infant is unclear. We present a case of disseminated blastomycosis in a pregnant woman at 38 weeks' gestation along with a review of the current literature surrounding presentation, diagnosis, management, and outcomes of blastomycosis in pregnancy. 2. Case description The patient was a previously healthy 35-year-old woman who developed a dry cough during her 30th week of gestation. She was living in New York City, but had visited Ontario, Canada one month prior to cough onset. Her cough persisted for 2 weeks and she was prescribed a 7 day course of azithromycin, with no improvement. At 35 weeks' gestation she developed acute onset epigastric and right upper quadrant pain and was admitted to the hospital with concern for acute appendicitis. Her initial workup, including abdominal MRI and abdominal CT imaging, was negative for appendicitis. CT imaging revealed an edematous pancreas with peripancreatic inflammatory changes consistent with pancreatitis. Amylase and lipase levels were found to be 894 U/L (28–100 U/L) and 1190 U/L (22–51 U/L), respectively. The CT imaging also captured her lower lung fields, revealing a multifocal pneumonia primarily within the left lower lobe. She was placed on bowel rest with improvement in abdominal pain and pancreatic enzymes, given a 7 day course of piperacillin-tazobactam for presumed bacterial pneumonia, and then discharged home. At home her cough continued with the development of daily night sweats and a 12 lb. weight loss. She denied any fevers during this time period. At 36 weeks' gestation she developed skin lesions on her forehead, right upper arm, and buttocks (Fig. 1) as well as several tender subcutaneous nodules on her extremities. She presented to her dermatologist at 38 weeks' gestation and underwent skin biopsy of her right arm lesion. Dermatopathology showed superficial coalescing nodular foci of neutrophilic and granulomatous inflammation, within which were thick-walled, broad-based yeast forms, consistent with cutaneous blastomycosis (Figs. 2 and 3). Upon notification of these biopsy results, still at 38 weeks' gestation, she was admitted to the hospital. A chest X-ray revealed a right upper
Fig. 1. Forehead (top) and arm (bottom) skin lesions at presentation.
Fig. 2. Skin biopsy (H&E, 100× magnification). The dermis shows a rich neutrophilic inflammatory infiltrate with lymphocytes and multi-nucleated giant cells. Spherical Blastomyces yeast forms (arrows), some demonstrating broad-based budding, are seen.
lobe dense consolidation with air bronchograms and bilateral lung base patchy airspace opacities. She was started on 5 mg/kg liposomal amphotericin B (L-AmB) for suspected disseminated blastomycosis. The decision was made against early induction of labor and she underwent spontaneous vaginal delivery on day 4 of admission. CSF sampling during epidural placement was unremarkable. Maternal Histoplasma and Blastomyces quantitative urinary antigen assays were 4.6 ng/mL (0–0.4 ng/mL) and 5.8 ng/mL (0–0.2 ng/mL) respectively. Her initial skin biopsy grew B. dermatitidis confirmed by DNA probe nucleic acid hybridization of the isolate. After 2 weeks of intravenous L-AmB, treatment was converted to oral itraconazole 300 mg every 12 hours. Serial serum levels of itraconazole were monitored and the patient continued to breastfeed throughout treatment. After 6 months of therapy, a CT of the chest showed no residual disease and treatment was stopped. The baby was born full term by normal spontaneous vaginal delivery. He was well appearing with a normal exam. Placental pathology showed no evidence of blastomycosis and cord blood fungal cultures were negative. At 2 days of age a peripheral white blood cell count, Creactive protein, erythrocyte sedimentation rate, and plain film of the chest were normal. At 3 days of age serum and urine Blastomyces dermatitidis antigen was sent. The urine was negative, but the serum could not be processed due to an insufficient sample. At 5 weeks of age he continued to do well and repeat urine antigen testing was negative. He remains healthy at 1 year.
Fig. 3. Skin biopsy (Gomori's methenamine silver stain [GMS], 400× magnification). Broad-based budding yeast forms are highlighted with GMS.
Please cite this article as: Baker T, et al, Blastomycosis during pregnancy: a case report and review of the literature, Diagn Microbiol Infect Dis (2017), http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015
T. Baker et al. / Diagnostic Microbiology and Infectious Disease xxx (2017) xxx–xxx
3. Case series Review of the current literature revealed an additional 22 published cases of maternal blastomycosis during pregnancy (Table 1). The vast majority of patients presented during their 2nd and 3rd trimesters (21/23 [91%]). Multisystem organ involvement was present in 11/23 (48%) of cases and the pulmonary system was most frequently involved (17/23 [74%]). When reported, most mothers had spontaneous vaginal deliveries (17/19 [89%]). There were no maternal deaths reported and all mothers were cured or had favorable outcomes. Outcomes are available for 21 out of 24 reported infants born to women diagnosed with blastomycosis. Two infants (10%) died in the newborn period; both were full term. One presented at 3 weeks of life in cardiac arrest, and the other presented at 18 days of life with fever and respiratory distress. At autopsy both infants had evidence of pulmonary blastomycosis, and the 18 day old infant also had dissemination to the kidney. Both of the mothers of these two infants were diagnosed with disseminated blastomycosis, after the infant's cause of death was determined; and did not receive antepartum treatment. There were an additional 3 infants born to women who were diagnosed with blastomycosis, but not treated antepartum, who did well. The clinical evaluation of infants born to mothers with pregnancies complicated by blastomycosis in this series was limited. Ten case reports included placental pathology, only one of which showed evidence of fungal infection. Five infants had additional evaluations performed at birth, including chest radiographs, kidney function, and therapeutic drug monitoring (Table 1). Where extended follow ups were reported, all infants had favorable outcomes.
4. Clinical presentation The clinical presentation of blastomycosis is variable and can involve multiple organ systems. The most common presentation in the general population involves the lungs and is as high as 91% of patients in one study (Chapman et al., 1997). Cough, shortness of breath, and hemoptysis can accompany general symptoms of fever, night sweats, and weight loss. Patients may receive multiple rounds of antibiotics for a presumed bacterial pneumonia and experience significant delays in accurate diagnosis. Indeed, of these pregnant cases, many experienced similar presenting symptoms and failed treatment with systemic antibiotics prior to providers establishing the correct diagnosis (Chakravarty et al., 1995; Daniel and Salit, 1984; MacDonald and Alguire, 1990). Skin involvement is the second most common presentation of blastomycosis (Bradsher, 2014; Chapman et al., 1997; Lemos et al., 2000). Skin findings vary, but generally appear clinically as irregularly bordered verrucous lesions. In patients with disseminated disease, subcutaneous nodules or abscesses can also be seen (Body, 1996; Smith and Gauthier, 2015). Skin involvement was commonly seen among these pregnant women, many sharing similarly described lesions or nodules. Cutaneous involvement in these cases, however, more commonly occurred as part of multiorgan disease, rather than primary infection alone. This supports an understanding that skin involvement is frequently due to lymphohematogenous spread of the organisms rather than direct inoculation (Saccente and Woods, 2010). Thus, clinicians should have a high degree of suspicion for underlying systemic disease in pregnant patients with isolated cutaneous infection. Compared to pulmonary and skin disease, multiorgan involvement is less frequent in the general population, occurring in approximately 15% of cases (Baumgardner et al., 1992; Chapman et al., 1997). Of the reported cases in pregnancy, multiorgan involvement was the most frequently encountered presentation (with the lung remaining the most commonly involved organ). Although these cases are limited, multiorgan disease may be more likely in pregnant patients. As mentioned previously, this observation is potentially due to the depressed cellular immunity seen in pregnancy (Mor and Cardenas, 2010).
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Interestingly, the patient in this case report was diagnosed with pancreatitis both radiographically and through laboratory testing. Although pancreatic masses due to B. dermatitidis and mycoses resembling periampullary tumors have been reported, to our knowledge blastomycosis has not been previously reported in association with acute pancreatitis (Deutsch et al., 2007; Paganini et al., 2010). Additionally, no laboratory testing or imaging findings suggested biliary obstruction or potential masses in this patient. It remains unclear if the pancreatitis was related to the blastomycosis, but, if so, would be the first documented occurrence. 5. Diagnosis and microbiology Clinical and radiographic manifestations in patients with blastomycosis can be nonspecific. Therefore, visualization of yeast forms in tissue and/or growth of the fungus in culture is necessary for a definitive diagnosis and are considered gold standards for diagnosis (Saccente and Woods, 2010). B. dermatitidis grows within 5–10 days on culture media as white to off-white or waxy colonies that become gray to brown as aerial hyphae develop. Microscopically the mold form of B. dermatitidis demonstrates septate hyphae with conidiophores ending in single terminal conidia resembling lollipops. The yeast form grows at 37 °C and demonstrates buttery, soft tan colonies which grow in 7–10 days (Bennett et al., 2015). Although culture is a sensitive method, confirmatory testing is often necessary with the DNA probe to rule out morphologically similar species. The confirmatory test for suspected colonies of Blastomyces spp. is the chemiluminescent DNA nucleic acid hybridization probe [AccuProbe, Gen-Probe, Inc., San Diego, CA], which is performed on the isolated colonies. This test cross-reacts with Paracoccidioides spp. and Emmonsia parva (formerly Chrysosporium parvum) (Accuprobe product insert, GenProbe, Inc.; Padhye et al., 1994). Although Emmonsia parva (agent of adiaspiromycosis) can rarely cause pulmonary disease in humans, the histopathologic appearance and clinical presentation differ from Blastomyces. Given the difference in the geographic distribution and microscopic morphology of B. dermatitidis and Paracoccidioides (South and Central America), such cross-reactions may not be problematic (Saccente and Woods, 2010; Smith and Gauthier, 2015). Histopathologic diagnosis of B. dermatitidis can be made on biopsy or by cytologic examination of material obtained on fine needle aspiration or from formalin-fixed paraffin-embedded tissue. In human tissue, the host response is often pyogranulomatous (e.g. mixture of neutrophils and granulomatous inflammation), and thickening of the epidermis is characteristically seen on skin biopsies (Fig. 2) (Bennett et al., 2015). Blastomyces are spherical yeasts 8–15 microns in size with thick double-contour cell walls and broad-based budding. Periodic acidSchiff (PAS) and Grocott methenamine silver (GMS) stains highlight the organisms (Fig. 3). Detection of antibodies to Blastomyces aids in the diagnosis of blastomycosis when used alongside other laboratory tests and the clinical presentation. Available antibody tests include qualitative enzyme immunoassays (EIAs), immunodiffusion assays, and complement fixation assays. The Blastomyces antibody EIA detects yeast phase antigens in serum, with a sensitivity of approximately 85% in patients with culture-positive blastomycosis; therefore, a negative result cannot rule out infection. However, specificity of the Blastomyces antibody EIA is high, and specimens positive by EIA do not require further testing. Immunodiffusion assays are also useful due to their relatively high specificity (N90%), but false negatives are found in approximately 10% of disseminated cases and 60% of cases with localized disease (Klein et al., 1987). Complement fixation assays are less sensitive than the immunodiffusion technique (Richer et al., 2014). Antigen EIA assays performed on urine or other sources also demonstrate limited sensitivity (Frost and Novicki, 2015). Although some studies have shown high sensitivity of urine antigen detection assay of N90% (i.e., sensitivity 92.9% and specificity 79.3% when tested in 42 patients
Please cite this article as: Baker T, et al, Blastomycosis during pregnancy: a case report and review of the literature, Diagn Microbiol Infect Dis (2017), http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015
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T. Baker et al. / Diagnostic Microbiology and Infectious Disease xxx (2017) xxx–xxx
Table 1 Perinatal blastomycosis in 23 pregnant patients.
Citation
Organ Mother's EGA at Presentation Systems Methods of Diagnosis Age Involved (weeks) (years)
Mode of Treatment Delivery
Baker, 2016
35
38
Lung, skin
Suprenant, 2015
31
37
Skin
Skin biopsy: pathology/culture/PCR
SV
Tyler, 2013
20
18
Lung
BAL: cytology/culture
SV
Youssef, 2013
32
34
Lung
Lung biopsy: pathology
CS
Pipitone, 2005
24
6
Skin
Skin biopsy: culture/PCR
SV
Lemos, 2002
17
31
Lung, skin
Skin: wet prep
NR
Lemos, 2002
36
24
Lung
Pulmonary fluid: cytology
NR
Lemos, 2002
21
28
Lung
Pulmonary fluid: cytology
NR
Chakravarty, 29 1995
29
Lung, skin
BAL: cytology/culture Abscess: culture
SV
Pappas,1993 NR
24
Lung, skin
Skin biopsy: culture
NR
Maxson, 1992
30
6
Skin biopsy: SV pathology/culture/PCR/serology
Skin, bone
Infant: lung biopsy pathology/culture
Maternal Outcomes
• FT • Healthy
CXR normal, placenta normal, urine antigen negative at day 2 and 38
Cured
• FT • Healthy
NR
Favorable at 5 months
• FT • Healthy
Placenta normal
Favorable
• FT • Healthy
Placenta normal
Favorable at 4 months
• FT • Healthy
NR
Favorable
• Unknown if FT • Healthy
Placenta normal
Cured
• Unknown if FT • Heatlhy
NR
Cured
• Unknown if FT • Healthy
NR
Cured
• FT • Healthy
Placenta normal
Favorable
NR
NR
Cured
• FT • Presented at 18 days with fever and cough; found to have disseminated disease (lung, renal) • Death
None, delivered at home
Favorable
None
CS
Ante/postpartum • Birth at 33 weeks AmB for 4 weeks • Healthy
Antepartum AmB
23
33
Lung
Lung biopsy: pathology/culture
Hager, 1988
18
30
Lung, skin, bone
Skin biopsy
SV
Cohen, 1987
39
26
Lung
Sputum: wet prep/culture
SV
Cohen, 1987
34
22
Lung, GU
Sputum: wet prep/culture Urine: culture
SV
Daniel, 1984
31
36
Lung, skin, bone, joint
Skin biopsy: pathology/culture Synovial fluid: pathology/culture
SV
34
Skin, bone, GU
Infant: lung pathology/culture Mother: Urine/sputum/skin SV culture
23
Infant Evaluation at Birth
SV
MacDonald, 1990
Watts, 1983
Ante/postpartum L-AmB for 2 weeks, then 6 months of itraconazole Deferred until 6 weeks postpartum, then itraconazole for at least 5 months Anaphylaxis to L-AmB, then ante/postpartum itraconazole for 12 months Antepartum L-AmB, then postpartum oral itraconazole for at least 4 months Antepartum L-AmB (duration NR) Antepartum AmB (duration NR) Antepartum AmB (duration NR) Antepartum AmB (duration NR) Antepartum AmB (duration NR) Antepartum ketoconazole for 4 weeks, then AmB (duration NR)
Infant Outcomes
Placenta with dimorphic fungal spores on maternal and fetal side; all infant Cured cultures negative (not specified further)
• FT • Healthy
Placenta normal
Cured
• FT • Healthy
Serum creatinine 1.1 mgl/dL, urinalysis normal
Cured
• Birth at 35 weeks • Healthy (twins)
NR
Cured
Postpartum AmB for 6 weeks
• Birth at 36 weeks • Healthy
CXR normal, placenta normal
Favorable at 3 months
Postpartum ketoconazole for 10 months
• FT • Presented at 3 weeks with cardiac arrest; found to have lung involvement
NR
Cured
Antepartum AmB for 13 weeks Antepartum AmB for 10 weeks
Please cite this article as: Baker T, et al, Blastomycosis during pregnancy: a case report and review of the literature, Diagn Microbiol Infect Dis (2017), http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015
T. Baker et al. / Diagnostic Microbiology and Infectious Disease xxx (2017) xxx–xxx
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Table 1 (continued)
Citation
Organ Mother's EGA at Presentation Systems Methods of Diagnosis Age Involved (weeks) (years)
Mode of Treatment Delivery
Infant Outcomes
Infant Evaluation at Birth
Maternal Outcomes
• Death Ismail, 1982
27
28
Skin
Skin specimen: pathology/culture
Cope, 1981
23
36
Lung
Lung biopsy: culture
SV SV
NR
NR
Favorable
SV
None
• FT • Healthy
NR
Cured
SV
B. dermatitidis vaccine Local excision and radiation Potassium iodide
• FT • Healthy
CXR normal, placenta normal
Cured
Tracheal aspirate: wet prep
SV
Baum,1973
23
32
Lung, skin
Lung biopsy: pathology/culture Skin biopsy: pathology/culture
SV
Wheeler, 1958
33
24
Skin
Skin specimen: culture
Skin biopsy: pathology Sputum: wet prep
Favorable
Postpartum AmB (duration NR)
Lung
Lung, skin
Cured
Cured
24
24
NR
Cord AmB level 0.12μg/ml, placenta normal NR NR
19
21
• Unknown in FT • Healthy
• FT • Healthy
Neiberg, 1977
Noojin, 1951
Ante/postpartum AmB for 4 months None Antepartum AmB for 1 month
Abbreviations: EGA = estimated gestational age; FT = full term; NR = not reported; BAL = bronchoalveolar lavage; SV = spontaneous vaginal; CS = cesarean section; GU = genitourinary.
with culture- or histopathology-confirmed blastomycosis, most of whom had disseminated disease), other studies have failed to show such high sensitivity (Durkin et al., 2004). Authors of a recent study in a blastomycosis-endemic region reported that only 76% of patients with culture- or histology-proven blastomycosis were positive by urine antigen testing (Frost and Novicki, 2015). Urine EIA is most sensitive for isolated pulmonary disease and less so for disseminated disease. Serial urine antigenuria can be used to follow resolution of symptoms during and after treatment. Pediatric data on the utility of urine antigen testing is very limited. A recent retrospective review of 14 pediatric cases of blastomycosis found urine antigen tests to be more reliable than serology. Urine antigen testing was positive in all 3 patients tested by this method (Anderson et al., 2013). Another case series of 4 pediatric patients all tested positive for blastomycosis by urinary antigen testing (Mongkolrattanothai et al., 2006). Although the antigen detection test by MiraVista Diagnostics (Indianapolis, IN) has been FDA-cleared for urine, bronchoalveolar lavage (BAL) fluid and CSF, other antigen detection assays may not be validated for use with non-urine sources. One limitation of the antigen detection method is cross reactivity between B. dermatitidis and other fungi, particularly Histoplasma, Paracoccidioides, and Penicillium marneffei (Durkin et al., 2004; Saccente and Woods, 2010; Smith and Gauthier, 2015). While cross reactivity with H. capsulatum has been attributed to shared glycoprotein antigens, the reason for cross reactivity with other fungal organisms has not been established. Nevertheless, a positive urine antigen test may aid in initiation of appropriate therapy (Smith and Gauthier, 2015). 6. Multidisciplinary management 6.1. Obstetrics Although environmental exposure may account for infant infection, it is possible that this organism can be transmitted from mother to infant (Maxson et al., 1992; Watts et al., 1983). Thus, optimal treatment of blastomycosis in pregnant patients both cures the infected mother and limits transmission risk to the fetus. The underlying route of maternal transmission, however, remains unclear; intrauterine transmission, an ascending vaginal infection, and aspiration of vaginal secretions at delivery have been theorized (Maxson et al., 1992; Watts et al., 1983). Therefore, both timing and mode of delivery may be considerations for providers and patients.
At this time, however, there are no studies comparing induced vs. spontaneous or vaginal vs. cesarean deliveries surrounding maternal or neonatal outcomes in perinatal blastomycosis. While the two infant deaths were reported following vaginal deliveries, the mothers did not yet have a diagnosis of blastomycosis, nor received antifungal therapy prior to delivery. Additionally, the majority of vaginal deliveries have favorable outcomes for both neonate and mother. Data remain too limited for any recommendations regarding time and mode of delivery. For the time being, decisions surrounding this aspect of care should be made on a case by case basis including input from clinicians across multiple disciplines and the patient. 6.2. Pulmonary Pulmonary involvement is the most common presentation of blastomycosis in the general population as well as in this case series. Bronchoscopy with bronchoalveolar lavage (BAL) is frequently utilized to obtain specimens, especially in cases in which patients may go months without an accurate diagnosis. The use of bronchoscopy in the pregnant population raises unique questions, however, given the procedural risks to mother and fetus. These risks include induction of premature labor, medication-related toxicities, maternal cardiac arrhythmias, hypoxemia, aspiration, pneumothorax, pulmonary hemorrhage, and hypotension (Bahhady and Ernst, 2004). Before proceeding with bronchoscopy, clinicians should approach more accessible skin or soft tissue lesions for biopsy and culture. If these are not available, sputum culture is also a viable alternative. In a study of 63 adult patients from an area endemic for blastomycosis who were diagnosed with pulmonary blastomycosis by positive culture or serology, the diagnostic yield of noninvasive respiratory specimens (e.g., culture of sputum, tracheal aspirate or gastric washings) was 75% when one specimen was collected for culture but increased to 86% when multiple specimens (average of 2.6 samples per patient) were submitted (Martynowicz and Prakash, 2002). As discussed previously, urine antigen tests are helpful for diagnosis, but they are limited clinically in both their cross reactivity and potential time delay in receiving results. If bronchoscopy is ultimately felt to be necessary, important precautions should be taken. These include performing the bronchoscopy in a well-equipped hospital with ready access to obstetric and neonatology services, consulting a pharmacologist regarding the teratogenicity of any medications to be used and an anesthesiologist about options for
Please cite this article as: Baker T, et al, Blastomycosis during pregnancy: a case report and review of the literature, Diagn Microbiol Infect Dis (2017), http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015
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conscious sedation, fetal monitoring, continuous cardiac monitoring, pulse oximetry, and intermittent sphygmomanometry during the procedure, and positioning the patient in the left lateral decubitus position if possible (Bahhady and Ernst, 2004). 6.3. Infectious diseases Once the diagnosis is made, pregnant patients with blastomycosis should be started on lipid formulation AmB, 3–5 mg/kg per day. Based on Infectious Diseases Society of America (IDSA) guidelines, treatment with L-AmB should continue for 1–2 weeks or until improvement is noted. Following L-AmB, patients can be switched to oral itraconazole, 200 mg 3 times per day for 3 days and then 200 mg twice per day for 6–12 months for mild to moderate disease, and 12 months for moderately severe disease. Azole antifungals should be avoided during pregnancy due to their potential teratogenicity, which may extend the duration of L-AmB therapy until delivery. After 2 weeks of itraconazole therapy, serum levels should be checked to ensure adequate drug exposure (Chapman et al., 2008). For those with pulmonary disease, some clinicians may also elect to follow serial chest XR imaging during therapy. In the general population, CNS disease is present in 5–10% of cases of disseminated blastomycosis; meningitis, leptomeningeal disease, and mass-like lesions have been reported (Brown et al., 2015; Bush et al., 2013). Of these 23 cases, none had reported CNS disease. Given the potential for CNS involvement clinicians should remain vigilant in the pregnant population. Brain magnetic resonance imaging (MRI) and lumbar puncture should be considered in pregnant patients diagnosed with blastomycosis who have severe headache, meningismus, or focal neurologic deficit. The diagnosis of CNS disease remains challenging. Cerebrospinal fluid (CSF) analysis may reveal a lymphocytic pleocytosis, but CSF cultures are frequently negative. Brain MRI may show enhancing lesions or leptomeningeal disease (Bush et al., 2013). Isolation of the organism from the CNS can require invasive biopsy of these lesions. Given these diagnostic difficulties, clinicians may make a presumptive diagnosis of CNS blastomycosis combining abnormal CSF or MRI findings with confirmation of B. dermatitidis infection outside of the CNS. Patients with CNS disease should receive 4–6 weeks of L-AmB followed by oral fluconazole 800 mg per day, itraconazole 200 mg 2 or 3 times per day, or voriconazole 200–400 mg twice per day. IDSA guidelines suggest this therapy continues for 12 months and until resolution of CSF abnormalities (Chapman et al., 2008). Serial brain MRI may also be reasonable in patients with enhancing lesions or other abnormalities. 6.4. Pediatric infectious diseases Blastomycosis in infants less than one year of age is exceedingly rare. In a retrospective review of 114 pediatric cases of blastomycosis the mean age was 12 years; the youngest was 5 months old, but no further details are provided (Frost et al., 2015). The most common presentation was isolated pulmonary disease (79%), followed by multi-organ involvement (12%) and extra-pulmonary disease (8.8%). The 2 cases illustrated here are the 2 youngest cases and both had severe pulmonary disease. A recent case series described 3 previously healthy infants between the ages of 4–6 months who acquired blastomycosis infection post-natally (Pelly et al., 2014). All 3 similarly developed severe pulmonary disease requiring intubation and ventilation, and prolonged hospital stays. As mentioned previously, the evaluation and management of neonates exposed to blastomycosis during the perinatal period has not been established. The evaluation of the infant in this case at birth and follow up was reassuring. Urine antigen testing was repeated at 5 week follow up, but it is unknown if monitoring antigenuria is useful in predicting risk of disease in asymptomatic infants, and was subsequently not repeated. Parents were counseled on possible symptoms
warranting emergent evaluation of the infant. The most common symptoms in the infant series described included fever, cough, and increased work of breathing. Neonates with evidence of blastomycosis and children with severe disease should be treated with L-AmB, as recommended by the IDSA guidelines. Itraconazole is a therapeutic option for children with mild to moderate infection, or as step down therapy. Pediatric pharmacokinetic data is limited, but available literature regarding itraconazole administration in the pediatric population suggests it is safe, with little adverse effects (Binder et al., 2009; Chen et al., 2016). 7. Outcomes Mortality due to blastomycosis in the general population has been reported to be between 6 and 12% (Azar et al., 2015; Crampton et al., 2002). Outcome data for blastomycosis during pregnancy are very limited, but in this case series all mothers recovered favorably without any reported deaths. There were 2 infant deaths, but importantly neither of these mothers received any form of antepartum therapy and both mothers had evidence of disseminated disease. No other infants in these case reports had any reported disease burden and none had teratogenic effects. 8. Conclusions Blastomycosis during pregnancy remains a rare occurrence. Clinicians should be suspicious of this diagnosis in pregnant patients who live in or have traveled to endemic areas and are presenting in their 2nd or 3rd trimesters with complaints of cough, fever, shortness of breath, night sweats, or weight loss with or without skin lesions. The diagnosis is generally obtained through biopsy and culture, and other diagnostic modalities such as urine antigen testing or serologic testing should not be used alone to exclude disease. Treatment of pregnant women consists of intravenous L-AmB transitioning to oral itraconazole after delivery. Overall, mothers have done well on therapy with favorable outcomes. There have been no reported infant deaths to mothers receiving either antepartum diagnosis or treatment. In this case series, infant mortality is 10% overall and 40% in infants born to mothers not receiving antepartum treatment. Diagnosis and treatment modalities for pregnant women with blastomycosis will likely continue to evolve as our understanding of this disease improves. References Anderson EJ, Ahn PB, Yogev R, Jaggi P, Shippee DB, Shulman ST. Blastomycosis in Children: A Study of 14 Cases. J Pediatric Infect Dis Soc 2013;2(4):386–90. Azar MM, Assi R, Relich RF, Schmitt BH, Norris S, Wheat LJ, et al. Blastomycosis in Indiana: Clinical and Epidemiologic Patterns of Disease Gleaned from a Multicenter Retrospective Study. Chest 2015;148(5):1276–84. Bahhady IJ, Ernst A. Risks of and recommendations for flexible bronchoscopy in pregnancy: a review. Chest 2004;126(6):1974–81. Baumgardner DJ, Buggy BP, Mattson BJ, Burdick JS, Ludwig D. Epidemiology of blastomycosis in a region of high endemicity in north central Wisconsin. Clin Infect Dis 1992; 15(4):629–35. Bennett J, Dolin R, Blaser M. Blastomycosis, Bradsher, W. Principles and Practice of Infectious Disease, (2963–2973). Philadelphia, PA: Saunders; 2015. Binder B, Richtig E, Weger W, Ginter-Hanselmayer G. Tinea capitis in early infancy treated with itraconazole: a pilot study. J Eur Acad Dermatol Venereol 2009;23(10):1161–3. Body BA. Cutaneous manifestations of systemic mycoses. Dermatol Clin 1996;14(1): 125–35. Bradsher RW. The endemic mimic: blastomycosis an illness often misdiagnosed. Trans Am Clin Climatol Assoc 2014;125:188–202. [discussion 202]. Brown DA, Whealy MA, Van Gompel JJ, Williams LN, Klaas JP. Diagnostic Dilemma in Primary Blastomyces dermatitidis Meningitis: Role of Neurosurgical Biopsy. Case Rep Neurol 2015;7(1):63–70. Bush JW, Wuerz T, Embil JM, Del Bigio MR, McDonald PJ, Krawitz S. Outcomes of persons with blastomycosis involving the central nervous system. Diagn Microbiol Infect Dis 2013;76(2):175–81. Chakravarty A, Salgia R, Mason E, Rajendran R, Muthuswamy P. Pneumonia and infraorbital abscess in a 29-year-old diabetic pregnant woman. Chest 1995;107(6):1752–4. Chapman SW, Lin AC, Hendricks KA, Nolan RL, Currier MM, Morris KR, et al. Endemic blastomycosis in Mississippi: epidemiological and clinical studies. Semin Respir Infect 1997;12(3):219–28.
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T. Baker et al. / Diagnostic Microbiology and Infectious Disease xxx (2017) xxx–xxx Chapman SW, Dismukes WE, Proia LA, Bradsher RW, Pappas PG, Threlkeld MG, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis 2008;46(12):1801–12. Chen S, Sun K-Y, Feng XW, Ran X, Lama J, Ran YP. Efficacy and safety of itraconazole use in infants. World J Pediatr 2016;12(4):399–407. Crampton TL, Light RB, Berg GM, Meyers MP, Schroeder GC, Hershfield ES, et al. Epidemiology and clinical spectrum of blastomycosis diagnosed at Manitoba hospitals. Clin Infect Dis 2002;34(10):1310–6. Daniel L, Salit IE. Blastomycosis during pregnancy. Can Med Assoc J 1984;131(7):759–61. Deutsch JC, Burke TL, Nelson TC. Pancreatic and splenic blastomycosis in an immunecompetent woman diagnosed by endoscopic ultrasonography-guided fine-needle aspiration. Endoscopy 2007;39(Suppl. 1):E272–3. Durkin M, Witt J, Lemonte A, Wheat B, Connolly P. Antigen assay with the potential to aid in diagnosis of blastomycosis. J Clin Microbiol 2004;42(10):4873–5. Frost HM, Novicki TJ. Blastomyces Antigen Detection for Diagnosis and Management of Blastomycosis. J Clin Microbiol 2015;53(11):3660–2. Frost HM, Anderson J, Ivacic L, Meece J. Blastomycosis in Children: An Analysis of Clinical, Epidemiologic, and Genetic Features. J Pediatr Infect Dis Soc 2015. Klein BS, Vergeront JM, Kaufman L, et al. Serological tests for blastomycosis: assessments during a large point-source outbreak in Wisconsin. J Infect Dis 1987;155(2):262–8. Lemos LB, Guo M, Baliga M. Blastomycosis: organ involvement and etiologic diagnosis. A review of 123 patients from Mississippi. Ann Diagn Pathol 2000;4(6):391–406. MacDonald D, Alguire PC. Adult respiratory distress syndrome due to blastomycosis during pregnancy. Chest 1990;98(6):1527–8. Martynowicz MA, Prakash UBS. Pulmonary blastomycosis: an appraisal of diagnostic techniques. Chest 2002;121(3):768–73.
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Maxson S, Miller SF, Tryka AF, Schutze GE. Perinatal blastomycosis: a review. Pediatr Infect Dis J 1992;11(9):760–3. Mongkolrattanothai K, Peev M, Wheat LJ, Marcinak J. Urine antigen detection of blastomycosis in pediatric patients. Pediatr Infect Dis J 2006;25(11):1076–8. Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol 2010;63(6):425–33. Padhye AA, Smith G, Standard PG, McLaughlin D, Kaufman L. Comparative evaluation of chemiluminescent DNA probe assays and exoantigen tests for rapid identification of Blastomyces dermatitidis and Coccidioides immitis. J Clin Microbiol 1994;32(4): 867–70. Paganini CBL, Ferreira AB, Minanni CA, Lopes de Pontes FE, Ribeiro C, Silva RA, et al. Blastomycosis: a differential diagnosis of periampullary tumors. Pancreas 2010;39(7):1120–2. Pelly L, Al Juaid A, Fanella S. Severe blastomycosis in infants. Pediatr Infect Dis J 2014; 33(11):1189–91. Richer SM, Smedema ML, Durkin MM, Brandhorst TT, Hage CA, Connolly PA, et al. Development of a highly sensitive and specific blastomycosis antibody enzyme immunoassay using Blastomyces dermatitidis surface protein BAD-1. Clin Vaccine Immunol 2014;21(2):143–6. Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev 2010;23(2):367–81. Smith JA, Gauthier G. New Developments in Blastomycosis. Semin Respir Crit Care Med 2015;36(5):715–28. Watts EA, Gard PD, Tuthill SW. First reported case of intrauterine transmission of blastomycosis. Pediatr Infect Dis 1983;2(4):308–10. Witorsch P, Utz JP. North American blastomycosis: a study of 40 patients. Medicine (Baltimore) 1968;47(3):169–200.
Please cite this article as: Baker T, et al, Blastomycosis during pregnancy: a case report and review of the literature, Diagn Microbiol Infect Dis (2017), http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015
Contents lists available at ScienceDirect
Diagnostic Microbiology and Infectious Disease journal homepage: www.elsevier.com/locate/diagmicrobio
Blastomycosis during pregnancy: a case report and review of the literature Thomas Baker a,⁎, Ami Patel a, Pierre Halteh b, Sima S. Toussi c, Patricia DeLaMora c, Shari Lipner b, Audrey N. Schuetz d, Barry Hartman a a
NewYork-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, 525 E 68th St, New York, NY 10065 NewYork-Presbyterian Hospital, Weill Cornell Medicine, Department of Dermatology, 1305 York Avenue, 9th Floor, New York, NY 10021 NewYork-Presbyterian Hospital, Weill Cornell Medicine, Department of Pediatrics, 525 E 68th St, New York, NY 10065 d Mayo Clinic, Rochester, MN, Department of Laboratory Medicine and Pathology, 200 1st St SW, Rochester, MN 55905 b c
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 7 February 2017 Accepted 21 February 2017 Available online xxxx
The diagnosis of blastomycosis during pregnancy is rare, but can carry significant clinical questions for both the infected mother and developing fetus. Furthermore, given its rarity, providers have little available data to help manage and counsel patients in this uncommon, yet serious, scenario. We present a case of blastomycosis in a woman at 38 weeks' gestation and review all published cases of blastomycosis during pregnancy. It is our hope to provide a multidisciplinary understanding of the current knowledge surrounding the presentation, diagnosis, management, and outcome of this unusual infection. © 2017 Elsevier Inc. All rights reserved.
Keywords: Blastomycosis pregnancy
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . Case description . . . . . . . . . Case series . . . . . . . . . . . . Clinical presentation . . . . . . . Diagnosis and microbiology . . . . Multidisciplinary management . . . 6.1. Obstetrics . . . . . . . . . 6.2. Pulmonary . . . . . . . . 6.3. Infectious diseases . . . . . 6.4. Pediatric infectious diseases . 7. Outcomes . . . . . . . . . . . . 8. Conclusions . . . . . . . . . . . References . . . . . . . . . . . . . .
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1. Introduction Blastomycosis is caused by Blastomyces dermatitidis, a thermally dimorphic fungus endemic to the southeastern, south central, and Midwestern United States (particularly the Great Lakes Basin and St. Lawrence River Valley) in addition to the Canadian provinces of Manitoba and Ontario. Infection with B. dermatitidis can involve a diverse range of organ systems, leading to a broad spectrum of clinical presentations. Primary disease can involve the lung through inhalation of fungal ⁎ Corresponding author. Tel.: +1-610-888-7154; fax: +1-212-737-5783. E-mail address: [email protected] (T. Baker).
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conidia (with pneumonia being the most common presenting diagnosis) and the skin through direct cutaneous inoculation (Saccente and Woods, 2010). The infection can subsequently disseminate to seemingly any part of the body, including the skin, genitourinary system, bones, central nervous system (CNS), spleen, liver, and thyroid (Witorsch and Utz, 1968). Disseminated disease is more commonly encountered in immunocompromised hosts (Saccente and Woods, 2010). Pregnancy itself appears to predispose mothers to partial immunosuppression, potentially increasing the likelihood of initial infection and subsequent dissemination (Mor and Cardenas, 2010). Perinatal blastomycosis remains a rare entity and descriptions are limited to case reports. The optimal management of both the mother
http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015 0732-8893/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Baker T, et al, Blastomycosis during pregnancy: a case report and review of the literature, Diagn Microbiol Infect Dis (2017), http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015
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T. Baker et al. / Diagnostic Microbiology and Infectious Disease xxx (2017) xxx–xxx
and infant is unclear. We present a case of disseminated blastomycosis in a pregnant woman at 38 weeks' gestation along with a review of the current literature surrounding presentation, diagnosis, management, and outcomes of blastomycosis in pregnancy. 2. Case description The patient was a previously healthy 35-year-old woman who developed a dry cough during her 30th week of gestation. She was living in New York City, but had visited Ontario, Canada one month prior to cough onset. Her cough persisted for 2 weeks and she was prescribed a 7 day course of azithromycin, with no improvement. At 35 weeks' gestation she developed acute onset epigastric and right upper quadrant pain and was admitted to the hospital with concern for acute appendicitis. Her initial workup, including abdominal MRI and abdominal CT imaging, was negative for appendicitis. CT imaging revealed an edematous pancreas with peripancreatic inflammatory changes consistent with pancreatitis. Amylase and lipase levels were found to be 894 U/L (28–100 U/L) and 1190 U/L (22–51 U/L), respectively. The CT imaging also captured her lower lung fields, revealing a multifocal pneumonia primarily within the left lower lobe. She was placed on bowel rest with improvement in abdominal pain and pancreatic enzymes, given a 7 day course of piperacillin-tazobactam for presumed bacterial pneumonia, and then discharged home. At home her cough continued with the development of daily night sweats and a 12 lb. weight loss. She denied any fevers during this time period. At 36 weeks' gestation she developed skin lesions on her forehead, right upper arm, and buttocks (Fig. 1) as well as several tender subcutaneous nodules on her extremities. She presented to her dermatologist at 38 weeks' gestation and underwent skin biopsy of her right arm lesion. Dermatopathology showed superficial coalescing nodular foci of neutrophilic and granulomatous inflammation, within which were thick-walled, broad-based yeast forms, consistent with cutaneous blastomycosis (Figs. 2 and 3). Upon notification of these biopsy results, still at 38 weeks' gestation, she was admitted to the hospital. A chest X-ray revealed a right upper
Fig. 1. Forehead (top) and arm (bottom) skin lesions at presentation.
Fig. 2. Skin biopsy (H&E, 100× magnification). The dermis shows a rich neutrophilic inflammatory infiltrate with lymphocytes and multi-nucleated giant cells. Spherical Blastomyces yeast forms (arrows), some demonstrating broad-based budding, are seen.
lobe dense consolidation with air bronchograms and bilateral lung base patchy airspace opacities. She was started on 5 mg/kg liposomal amphotericin B (L-AmB) for suspected disseminated blastomycosis. The decision was made against early induction of labor and she underwent spontaneous vaginal delivery on day 4 of admission. CSF sampling during epidural placement was unremarkable. Maternal Histoplasma and Blastomyces quantitative urinary antigen assays were 4.6 ng/mL (0–0.4 ng/mL) and 5.8 ng/mL (0–0.2 ng/mL) respectively. Her initial skin biopsy grew B. dermatitidis confirmed by DNA probe nucleic acid hybridization of the isolate. After 2 weeks of intravenous L-AmB, treatment was converted to oral itraconazole 300 mg every 12 hours. Serial serum levels of itraconazole were monitored and the patient continued to breastfeed throughout treatment. After 6 months of therapy, a CT of the chest showed no residual disease and treatment was stopped. The baby was born full term by normal spontaneous vaginal delivery. He was well appearing with a normal exam. Placental pathology showed no evidence of blastomycosis and cord blood fungal cultures were negative. At 2 days of age a peripheral white blood cell count, Creactive protein, erythrocyte sedimentation rate, and plain film of the chest were normal. At 3 days of age serum and urine Blastomyces dermatitidis antigen was sent. The urine was negative, but the serum could not be processed due to an insufficient sample. At 5 weeks of age he continued to do well and repeat urine antigen testing was negative. He remains healthy at 1 year.
Fig. 3. Skin biopsy (Gomori's methenamine silver stain [GMS], 400× magnification). Broad-based budding yeast forms are highlighted with GMS.
Please cite this article as: Baker T, et al, Blastomycosis during pregnancy: a case report and review of the literature, Diagn Microbiol Infect Dis (2017), http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015
T. Baker et al. / Diagnostic Microbiology and Infectious Disease xxx (2017) xxx–xxx
3. Case series Review of the current literature revealed an additional 22 published cases of maternal blastomycosis during pregnancy (Table 1). The vast majority of patients presented during their 2nd and 3rd trimesters (21/23 [91%]). Multisystem organ involvement was present in 11/23 (48%) of cases and the pulmonary system was most frequently involved (17/23 [74%]). When reported, most mothers had spontaneous vaginal deliveries (17/19 [89%]). There were no maternal deaths reported and all mothers were cured or had favorable outcomes. Outcomes are available for 21 out of 24 reported infants born to women diagnosed with blastomycosis. Two infants (10%) died in the newborn period; both were full term. One presented at 3 weeks of life in cardiac arrest, and the other presented at 18 days of life with fever and respiratory distress. At autopsy both infants had evidence of pulmonary blastomycosis, and the 18 day old infant also had dissemination to the kidney. Both of the mothers of these two infants were diagnosed with disseminated blastomycosis, after the infant's cause of death was determined; and did not receive antepartum treatment. There were an additional 3 infants born to women who were diagnosed with blastomycosis, but not treated antepartum, who did well. The clinical evaluation of infants born to mothers with pregnancies complicated by blastomycosis in this series was limited. Ten case reports included placental pathology, only one of which showed evidence of fungal infection. Five infants had additional evaluations performed at birth, including chest radiographs, kidney function, and therapeutic drug monitoring (Table 1). Where extended follow ups were reported, all infants had favorable outcomes.
4. Clinical presentation The clinical presentation of blastomycosis is variable and can involve multiple organ systems. The most common presentation in the general population involves the lungs and is as high as 91% of patients in one study (Chapman et al., 1997). Cough, shortness of breath, and hemoptysis can accompany general symptoms of fever, night sweats, and weight loss. Patients may receive multiple rounds of antibiotics for a presumed bacterial pneumonia and experience significant delays in accurate diagnosis. Indeed, of these pregnant cases, many experienced similar presenting symptoms and failed treatment with systemic antibiotics prior to providers establishing the correct diagnosis (Chakravarty et al., 1995; Daniel and Salit, 1984; MacDonald and Alguire, 1990). Skin involvement is the second most common presentation of blastomycosis (Bradsher, 2014; Chapman et al., 1997; Lemos et al., 2000). Skin findings vary, but generally appear clinically as irregularly bordered verrucous lesions. In patients with disseminated disease, subcutaneous nodules or abscesses can also be seen (Body, 1996; Smith and Gauthier, 2015). Skin involvement was commonly seen among these pregnant women, many sharing similarly described lesions or nodules. Cutaneous involvement in these cases, however, more commonly occurred as part of multiorgan disease, rather than primary infection alone. This supports an understanding that skin involvement is frequently due to lymphohematogenous spread of the organisms rather than direct inoculation (Saccente and Woods, 2010). Thus, clinicians should have a high degree of suspicion for underlying systemic disease in pregnant patients with isolated cutaneous infection. Compared to pulmonary and skin disease, multiorgan involvement is less frequent in the general population, occurring in approximately 15% of cases (Baumgardner et al., 1992; Chapman et al., 1997). Of the reported cases in pregnancy, multiorgan involvement was the most frequently encountered presentation (with the lung remaining the most commonly involved organ). Although these cases are limited, multiorgan disease may be more likely in pregnant patients. As mentioned previously, this observation is potentially due to the depressed cellular immunity seen in pregnancy (Mor and Cardenas, 2010).
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Interestingly, the patient in this case report was diagnosed with pancreatitis both radiographically and through laboratory testing. Although pancreatic masses due to B. dermatitidis and mycoses resembling periampullary tumors have been reported, to our knowledge blastomycosis has not been previously reported in association with acute pancreatitis (Deutsch et al., 2007; Paganini et al., 2010). Additionally, no laboratory testing or imaging findings suggested biliary obstruction or potential masses in this patient. It remains unclear if the pancreatitis was related to the blastomycosis, but, if so, would be the first documented occurrence. 5. Diagnosis and microbiology Clinical and radiographic manifestations in patients with blastomycosis can be nonspecific. Therefore, visualization of yeast forms in tissue and/or growth of the fungus in culture is necessary for a definitive diagnosis and are considered gold standards for diagnosis (Saccente and Woods, 2010). B. dermatitidis grows within 5–10 days on culture media as white to off-white or waxy colonies that become gray to brown as aerial hyphae develop. Microscopically the mold form of B. dermatitidis demonstrates septate hyphae with conidiophores ending in single terminal conidia resembling lollipops. The yeast form grows at 37 °C and demonstrates buttery, soft tan colonies which grow in 7–10 days (Bennett et al., 2015). Although culture is a sensitive method, confirmatory testing is often necessary with the DNA probe to rule out morphologically similar species. The confirmatory test for suspected colonies of Blastomyces spp. is the chemiluminescent DNA nucleic acid hybridization probe [AccuProbe, Gen-Probe, Inc., San Diego, CA], which is performed on the isolated colonies. This test cross-reacts with Paracoccidioides spp. and Emmonsia parva (formerly Chrysosporium parvum) (Accuprobe product insert, GenProbe, Inc.; Padhye et al., 1994). Although Emmonsia parva (agent of adiaspiromycosis) can rarely cause pulmonary disease in humans, the histopathologic appearance and clinical presentation differ from Blastomyces. Given the difference in the geographic distribution and microscopic morphology of B. dermatitidis and Paracoccidioides (South and Central America), such cross-reactions may not be problematic (Saccente and Woods, 2010; Smith and Gauthier, 2015). Histopathologic diagnosis of B. dermatitidis can be made on biopsy or by cytologic examination of material obtained on fine needle aspiration or from formalin-fixed paraffin-embedded tissue. In human tissue, the host response is often pyogranulomatous (e.g. mixture of neutrophils and granulomatous inflammation), and thickening of the epidermis is characteristically seen on skin biopsies (Fig. 2) (Bennett et al., 2015). Blastomyces are spherical yeasts 8–15 microns in size with thick double-contour cell walls and broad-based budding. Periodic acidSchiff (PAS) and Grocott methenamine silver (GMS) stains highlight the organisms (Fig. 3). Detection of antibodies to Blastomyces aids in the diagnosis of blastomycosis when used alongside other laboratory tests and the clinical presentation. Available antibody tests include qualitative enzyme immunoassays (EIAs), immunodiffusion assays, and complement fixation assays. The Blastomyces antibody EIA detects yeast phase antigens in serum, with a sensitivity of approximately 85% in patients with culture-positive blastomycosis; therefore, a negative result cannot rule out infection. However, specificity of the Blastomyces antibody EIA is high, and specimens positive by EIA do not require further testing. Immunodiffusion assays are also useful due to their relatively high specificity (N90%), but false negatives are found in approximately 10% of disseminated cases and 60% of cases with localized disease (Klein et al., 1987). Complement fixation assays are less sensitive than the immunodiffusion technique (Richer et al., 2014). Antigen EIA assays performed on urine or other sources also demonstrate limited sensitivity (Frost and Novicki, 2015). Although some studies have shown high sensitivity of urine antigen detection assay of N90% (i.e., sensitivity 92.9% and specificity 79.3% when tested in 42 patients
Please cite this article as: Baker T, et al, Blastomycosis during pregnancy: a case report and review of the literature, Diagn Microbiol Infect Dis (2017), http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015
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Table 1 Perinatal blastomycosis in 23 pregnant patients.
Citation
Organ Mother's EGA at Presentation Systems Methods of Diagnosis Age Involved (weeks) (years)
Mode of Treatment Delivery
Baker, 2016
35
38
Lung, skin
Suprenant, 2015
31
37
Skin
Skin biopsy: pathology/culture/PCR
SV
Tyler, 2013
20
18
Lung
BAL: cytology/culture
SV
Youssef, 2013
32
34
Lung
Lung biopsy: pathology
CS
Pipitone, 2005
24
6
Skin
Skin biopsy: culture/PCR
SV
Lemos, 2002
17
31
Lung, skin
Skin: wet prep
NR
Lemos, 2002
36
24
Lung
Pulmonary fluid: cytology
NR
Lemos, 2002
21
28
Lung
Pulmonary fluid: cytology
NR
Chakravarty, 29 1995
29
Lung, skin
BAL: cytology/culture Abscess: culture
SV
Pappas,1993 NR
24
Lung, skin
Skin biopsy: culture
NR
Maxson, 1992
30
6
Skin biopsy: SV pathology/culture/PCR/serology
Skin, bone
Infant: lung biopsy pathology/culture
Maternal Outcomes
• FT • Healthy
CXR normal, placenta normal, urine antigen negative at day 2 and 38
Cured
• FT • Healthy
NR
Favorable at 5 months
• FT • Healthy
Placenta normal
Favorable
• FT • Healthy
Placenta normal
Favorable at 4 months
• FT • Healthy
NR
Favorable
• Unknown if FT • Healthy
Placenta normal
Cured
• Unknown if FT • Heatlhy
NR
Cured
• Unknown if FT • Healthy
NR
Cured
• FT • Healthy
Placenta normal
Favorable
NR
NR
Cured
• FT • Presented at 18 days with fever and cough; found to have disseminated disease (lung, renal) • Death
None, delivered at home
Favorable
None
CS
Ante/postpartum • Birth at 33 weeks AmB for 4 weeks • Healthy
Antepartum AmB
23
33
Lung
Lung biopsy: pathology/culture
Hager, 1988
18
30
Lung, skin, bone
Skin biopsy
SV
Cohen, 1987
39
26
Lung
Sputum: wet prep/culture
SV
Cohen, 1987
34
22
Lung, GU
Sputum: wet prep/culture Urine: culture
SV
Daniel, 1984
31
36
Lung, skin, bone, joint
Skin biopsy: pathology/culture Synovial fluid: pathology/culture
SV
34
Skin, bone, GU
Infant: lung pathology/culture Mother: Urine/sputum/skin SV culture
23
Infant Evaluation at Birth
SV
MacDonald, 1990
Watts, 1983
Ante/postpartum L-AmB for 2 weeks, then 6 months of itraconazole Deferred until 6 weeks postpartum, then itraconazole for at least 5 months Anaphylaxis to L-AmB, then ante/postpartum itraconazole for 12 months Antepartum L-AmB, then postpartum oral itraconazole for at least 4 months Antepartum L-AmB (duration NR) Antepartum AmB (duration NR) Antepartum AmB (duration NR) Antepartum AmB (duration NR) Antepartum AmB (duration NR) Antepartum ketoconazole for 4 weeks, then AmB (duration NR)
Infant Outcomes
Placenta with dimorphic fungal spores on maternal and fetal side; all infant Cured cultures negative (not specified further)
• FT • Healthy
Placenta normal
Cured
• FT • Healthy
Serum creatinine 1.1 mgl/dL, urinalysis normal
Cured
• Birth at 35 weeks • Healthy (twins)
NR
Cured
Postpartum AmB for 6 weeks
• Birth at 36 weeks • Healthy
CXR normal, placenta normal
Favorable at 3 months
Postpartum ketoconazole for 10 months
• FT • Presented at 3 weeks with cardiac arrest; found to have lung involvement
NR
Cured
Antepartum AmB for 13 weeks Antepartum AmB for 10 weeks
Please cite this article as: Baker T, et al, Blastomycosis during pregnancy: a case report and review of the literature, Diagn Microbiol Infect Dis (2017), http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015
T. Baker et al. / Diagnostic Microbiology and Infectious Disease xxx (2017) xxx–xxx
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Table 1 (continued)
Citation
Organ Mother's EGA at Presentation Systems Methods of Diagnosis Age Involved (weeks) (years)
Mode of Treatment Delivery
Infant Outcomes
Infant Evaluation at Birth
Maternal Outcomes
• Death Ismail, 1982
27
28
Skin
Skin specimen: pathology/culture
Cope, 1981
23
36
Lung
Lung biopsy: culture
SV SV
NR
NR
Favorable
SV
None
• FT • Healthy
NR
Cured
SV
B. dermatitidis vaccine Local excision and radiation Potassium iodide
• FT • Healthy
CXR normal, placenta normal
Cured
Tracheal aspirate: wet prep
SV
Baum,1973
23
32
Lung, skin
Lung biopsy: pathology/culture Skin biopsy: pathology/culture
SV
Wheeler, 1958
33
24
Skin
Skin specimen: culture
Skin biopsy: pathology Sputum: wet prep
Favorable
Postpartum AmB (duration NR)
Lung
Lung, skin
Cured
Cured
24
24
NR
Cord AmB level 0.12μg/ml, placenta normal NR NR
19
21
• Unknown in FT • Healthy
• FT • Healthy
Neiberg, 1977
Noojin, 1951
Ante/postpartum AmB for 4 months None Antepartum AmB for 1 month
Abbreviations: EGA = estimated gestational age; FT = full term; NR = not reported; BAL = bronchoalveolar lavage; SV = spontaneous vaginal; CS = cesarean section; GU = genitourinary.
with culture- or histopathology-confirmed blastomycosis, most of whom had disseminated disease), other studies have failed to show such high sensitivity (Durkin et al., 2004). Authors of a recent study in a blastomycosis-endemic region reported that only 76% of patients with culture- or histology-proven blastomycosis were positive by urine antigen testing (Frost and Novicki, 2015). Urine EIA is most sensitive for isolated pulmonary disease and less so for disseminated disease. Serial urine antigenuria can be used to follow resolution of symptoms during and after treatment. Pediatric data on the utility of urine antigen testing is very limited. A recent retrospective review of 14 pediatric cases of blastomycosis found urine antigen tests to be more reliable than serology. Urine antigen testing was positive in all 3 patients tested by this method (Anderson et al., 2013). Another case series of 4 pediatric patients all tested positive for blastomycosis by urinary antigen testing (Mongkolrattanothai et al., 2006). Although the antigen detection test by MiraVista Diagnostics (Indianapolis, IN) has been FDA-cleared for urine, bronchoalveolar lavage (BAL) fluid and CSF, other antigen detection assays may not be validated for use with non-urine sources. One limitation of the antigen detection method is cross reactivity between B. dermatitidis and other fungi, particularly Histoplasma, Paracoccidioides, and Penicillium marneffei (Durkin et al., 2004; Saccente and Woods, 2010; Smith and Gauthier, 2015). While cross reactivity with H. capsulatum has been attributed to shared glycoprotein antigens, the reason for cross reactivity with other fungal organisms has not been established. Nevertheless, a positive urine antigen test may aid in initiation of appropriate therapy (Smith and Gauthier, 2015). 6. Multidisciplinary management 6.1. Obstetrics Although environmental exposure may account for infant infection, it is possible that this organism can be transmitted from mother to infant (Maxson et al., 1992; Watts et al., 1983). Thus, optimal treatment of blastomycosis in pregnant patients both cures the infected mother and limits transmission risk to the fetus. The underlying route of maternal transmission, however, remains unclear; intrauterine transmission, an ascending vaginal infection, and aspiration of vaginal secretions at delivery have been theorized (Maxson et al., 1992; Watts et al., 1983). Therefore, both timing and mode of delivery may be considerations for providers and patients.
At this time, however, there are no studies comparing induced vs. spontaneous or vaginal vs. cesarean deliveries surrounding maternal or neonatal outcomes in perinatal blastomycosis. While the two infant deaths were reported following vaginal deliveries, the mothers did not yet have a diagnosis of blastomycosis, nor received antifungal therapy prior to delivery. Additionally, the majority of vaginal deliveries have favorable outcomes for both neonate and mother. Data remain too limited for any recommendations regarding time and mode of delivery. For the time being, decisions surrounding this aspect of care should be made on a case by case basis including input from clinicians across multiple disciplines and the patient. 6.2. Pulmonary Pulmonary involvement is the most common presentation of blastomycosis in the general population as well as in this case series. Bronchoscopy with bronchoalveolar lavage (BAL) is frequently utilized to obtain specimens, especially in cases in which patients may go months without an accurate diagnosis. The use of bronchoscopy in the pregnant population raises unique questions, however, given the procedural risks to mother and fetus. These risks include induction of premature labor, medication-related toxicities, maternal cardiac arrhythmias, hypoxemia, aspiration, pneumothorax, pulmonary hemorrhage, and hypotension (Bahhady and Ernst, 2004). Before proceeding with bronchoscopy, clinicians should approach more accessible skin or soft tissue lesions for biopsy and culture. If these are not available, sputum culture is also a viable alternative. In a study of 63 adult patients from an area endemic for blastomycosis who were diagnosed with pulmonary blastomycosis by positive culture or serology, the diagnostic yield of noninvasive respiratory specimens (e.g., culture of sputum, tracheal aspirate or gastric washings) was 75% when one specimen was collected for culture but increased to 86% when multiple specimens (average of 2.6 samples per patient) were submitted (Martynowicz and Prakash, 2002). As discussed previously, urine antigen tests are helpful for diagnosis, but they are limited clinically in both their cross reactivity and potential time delay in receiving results. If bronchoscopy is ultimately felt to be necessary, important precautions should be taken. These include performing the bronchoscopy in a well-equipped hospital with ready access to obstetric and neonatology services, consulting a pharmacologist regarding the teratogenicity of any medications to be used and an anesthesiologist about options for
Please cite this article as: Baker T, et al, Blastomycosis during pregnancy: a case report and review of the literature, Diagn Microbiol Infect Dis (2017), http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.015
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T. Baker et al. / Diagnostic Microbiology and Infectious Disease xxx (2017) xxx–xxx
conscious sedation, fetal monitoring, continuous cardiac monitoring, pulse oximetry, and intermittent sphygmomanometry during the procedure, and positioning the patient in the left lateral decubitus position if possible (Bahhady and Ernst, 2004). 6.3. Infectious diseases Once the diagnosis is made, pregnant patients with blastomycosis should be started on lipid formulation AmB, 3–5 mg/kg per day. Based on Infectious Diseases Society of America (IDSA) guidelines, treatment with L-AmB should continue for 1–2 weeks or until improvement is noted. Following L-AmB, patients can be switched to oral itraconazole, 200 mg 3 times per day for 3 days and then 200 mg twice per day for 6–12 months for mild to moderate disease, and 12 months for moderately severe disease. Azole antifungals should be avoided during pregnancy due to their potential teratogenicity, which may extend the duration of L-AmB therapy until delivery. After 2 weeks of itraconazole therapy, serum levels should be checked to ensure adequate drug exposure (Chapman et al., 2008). For those with pulmonary disease, some clinicians may also elect to follow serial chest XR imaging during therapy. In the general population, CNS disease is present in 5–10% of cases of disseminated blastomycosis; meningitis, leptomeningeal disease, and mass-like lesions have been reported (Brown et al., 2015; Bush et al., 2013). Of these 23 cases, none had reported CNS disease. Given the potential for CNS involvement clinicians should remain vigilant in the pregnant population. Brain magnetic resonance imaging (MRI) and lumbar puncture should be considered in pregnant patients diagnosed with blastomycosis who have severe headache, meningismus, or focal neurologic deficit. The diagnosis of CNS disease remains challenging. Cerebrospinal fluid (CSF) analysis may reveal a lymphocytic pleocytosis, but CSF cultures are frequently negative. Brain MRI may show enhancing lesions or leptomeningeal disease (Bush et al., 2013). Isolation of the organism from the CNS can require invasive biopsy of these lesions. Given these diagnostic difficulties, clinicians may make a presumptive diagnosis of CNS blastomycosis combining abnormal CSF or MRI findings with confirmation of B. dermatitidis infection outside of the CNS. Patients with CNS disease should receive 4–6 weeks of L-AmB followed by oral fluconazole 800 mg per day, itraconazole 200 mg 2 or 3 times per day, or voriconazole 200–400 mg twice per day. IDSA guidelines suggest this therapy continues for 12 months and until resolution of CSF abnormalities (Chapman et al., 2008). Serial brain MRI may also be reasonable in patients with enhancing lesions or other abnormalities. 6.4. Pediatric infectious diseases Blastomycosis in infants less than one year of age is exceedingly rare. In a retrospective review of 114 pediatric cases of blastomycosis the mean age was 12 years; the youngest was 5 months old, but no further details are provided (Frost et al., 2015). The most common presentation was isolated pulmonary disease (79%), followed by multi-organ involvement (12%) and extra-pulmonary disease (8.8%). The 2 cases illustrated here are the 2 youngest cases and both had severe pulmonary disease. A recent case series described 3 previously healthy infants between the ages of 4–6 months who acquired blastomycosis infection post-natally (Pelly et al., 2014). All 3 similarly developed severe pulmonary disease requiring intubation and ventilation, and prolonged hospital stays. As mentioned previously, the evaluation and management of neonates exposed to blastomycosis during the perinatal period has not been established. The evaluation of the infant in this case at birth and follow up was reassuring. Urine antigen testing was repeated at 5 week follow up, but it is unknown if monitoring antigenuria is useful in predicting risk of disease in asymptomatic infants, and was subsequently not repeated. Parents were counseled on possible symptoms
warranting emergent evaluation of the infant. The most common symptoms in the infant series described included fever, cough, and increased work of breathing. Neonates with evidence of blastomycosis and children with severe disease should be treated with L-AmB, as recommended by the IDSA guidelines. Itraconazole is a therapeutic option for children with mild to moderate infection, or as step down therapy. Pediatric pharmacokinetic data is limited, but available literature regarding itraconazole administration in the pediatric population suggests it is safe, with little adverse effects (Binder et al., 2009; Chen et al., 2016). 7. Outcomes Mortality due to blastomycosis in the general population has been reported to be between 6 and 12% (Azar et al., 2015; Crampton et al., 2002). Outcome data for blastomycosis during pregnancy are very limited, but in this case series all mothers recovered favorably without any reported deaths. There were 2 infant deaths, but importantly neither of these mothers received any form of antepartum therapy and both mothers had evidence of disseminated disease. No other infants in these case reports had any reported disease burden and none had teratogenic effects. 8. Conclusions Blastomycosis during pregnancy remains a rare occurrence. Clinicians should be suspicious of this diagnosis in pregnant patients who live in or have traveled to endemic areas and are presenting in their 2nd or 3rd trimesters with complaints of cough, fever, shortness of breath, night sweats, or weight loss with or without skin lesions. The diagnosis is generally obtained through biopsy and culture, and other diagnostic modalities such as urine antigen testing or serologic testing should not be used alone to exclude disease. Treatment of pregnant women consists of intravenous L-AmB transitioning to oral itraconazole after delivery. Overall, mothers have done well on therapy with favorable outcomes. There have been no reported infant deaths to mothers receiving either antepartum diagnosis or treatment. In this case series, infant mortality is 10% overall and 40% in infants born to mothers not receiving antepartum treatment. Diagnosis and treatment modalities for pregnant women with blastomycosis will likely continue to evolve as our understanding of this disease improves. References Anderson EJ, Ahn PB, Yogev R, Jaggi P, Shippee DB, Shulman ST. Blastomycosis in Children: A Study of 14 Cases. J Pediatric Infect Dis Soc 2013;2(4):386–90. Azar MM, Assi R, Relich RF, Schmitt BH, Norris S, Wheat LJ, et al. Blastomycosis in Indiana: Clinical and Epidemiologic Patterns of Disease Gleaned from a Multicenter Retrospective Study. Chest 2015;148(5):1276–84. Bahhady IJ, Ernst A. Risks of and recommendations for flexible bronchoscopy in pregnancy: a review. Chest 2004;126(6):1974–81. Baumgardner DJ, Buggy BP, Mattson BJ, Burdick JS, Ludwig D. Epidemiology of blastomycosis in a region of high endemicity in north central Wisconsin. Clin Infect Dis 1992; 15(4):629–35. Bennett J, Dolin R, Blaser M. Blastomycosis, Bradsher, W. Principles and Practice of Infectious Disease, (2963–2973). Philadelphia, PA: Saunders; 2015. Binder B, Richtig E, Weger W, Ginter-Hanselmayer G. Tinea capitis in early infancy treated with itraconazole: a pilot study. J Eur Acad Dermatol Venereol 2009;23(10):1161–3. Body BA. Cutaneous manifestations of systemic mycoses. Dermatol Clin 1996;14(1): 125–35. Bradsher RW. The endemic mimic: blastomycosis an illness often misdiagnosed. Trans Am Clin Climatol Assoc 2014;125:188–202. [discussion 202]. Brown DA, Whealy MA, Van Gompel JJ, Williams LN, Klaas JP. Diagnostic Dilemma in Primary Blastomyces dermatitidis Meningitis: Role of Neurosurgical Biopsy. Case Rep Neurol 2015;7(1):63–70. Bush JW, Wuerz T, Embil JM, Del Bigio MR, McDonald PJ, Krawitz S. Outcomes of persons with blastomycosis involving the central nervous system. Diagn Microbiol Infect Dis 2013;76(2):175–81. Chakravarty A, Salgia R, Mason E, Rajendran R, Muthuswamy P. Pneumonia and infraorbital abscess in a 29-year-old diabetic pregnant woman. Chest 1995;107(6):1752–4. Chapman SW, Lin AC, Hendricks KA, Nolan RL, Currier MM, Morris KR, et al. Endemic blastomycosis in Mississippi: epidemiological and clinical studies. Semin Respir Infect 1997;12(3):219–28.
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