Vertical Transmission of Histoplasmosis Associated With Anti-Tumor Necrosis Factor Therapy

Abstract

Therapeutics blocking the activity of tumor necrosis factor (anti-TNF) are a risk factor for invasive fungal infections; however, infectious risks to infants born to mothers receiving anti-TNF therapy are not well defined. We report a case of vertical transmission of disseminated histoplasmosis in a mother-infant pair exposed to anti-TNF therapy.

Histoplasma capsulatum is a dimorphic fungus endemic to the Ohio, Mississippi, and Missouri River valleys of the United States. Infection typically results from inhalation of aerosolized spores, and clinical manifestations range from self-limited pulmonary histoplasmosis to life-threatening disseminated disease [ 1 ]. Severe disease is more likely in infants and immunocompromised hosts [ 2–4 ].

Biological agents blocking the activity of tumor necrosis factor (anti-TNF) are a risk factor for invasive fungal infections, including histoplasmosis [ 4 ]. Anti-TNF agents are (1) approved for various inflammatory conditions, (2) the standard of care for treating severe inflammatory bowel disease (IBD), and (3) designated pregnancy category B [ 5 ]. Expert consensus is that anti-TNF agents do not increase risk of birth defects or adverse pregnancy outcomes [ 5 , 6 ]; however, infectious risks to infants born to mothers receiving anti-TNF therapy are not well defined. We report a case of vertical transmission of disseminated histoplasmosis in a mother-infant pair exposed to anti-TNF therapy.

CASE REPORT

The Mother

A woman living in Tennessee was diagnosed with IBD at age 33 and required high-dose infliximab (anti-TNF monoclonal antibody; 10 mg/kg every 6 weeks) to control her disease. She also experienced recurrent miscarriages but maintained a pregnancy at age 41. She enrolled in a multicenter IBD study (the Pregnancy in IBD and Neonatal Outcomes [PIANO] registry) [ 6 ] during the second trimester. Her final dose of infliximab was administered at 32 weeks gestation.

At 35 weeks gestation, she developed dyspnea initially attributed to decreased lung capacity in the setting of third trimester pregnancy. She experienced premature labor and delivered a female infant at 36 weeks gestation. Her dyspnea persisted, and 10 days postpartum she developed fever. Chest radiograph revealed a new left lung opacity. She was treated for pneumonia, but her symptoms worsened. A computed tomography scan of the chest demonstrated miliary nodularity and a left upper lobe infiltrate. Laboratory tests were notable for elevated transaminases (aspartate aminotransferase [AST] 81 and alanine aminotransferase [ALT] 77 [normal range, 4–40] units/L) and anemia (hemoglobin, 9.2 g/dL [normal range, 11.8–16]). Urine Histoplasma antigen (MiraVista Diagnostics, Indianapolis, Indiana) was above the limit of quantification (>19 ng/mL). Histoplasma antigen and antibodies from the cerebrospinal fluid (CSF) were not detected. Fungal cultures from the blood (BACTEC, Franklin Lakes, New Jersey) and CSF (Brain-Heart Infusion, Sabouraud, and Mycosel agar) were negative.

She was diagnosed with disseminated histoplasmosis, treated with 2 weeks of intravenous liposomal amphotericin B (5 mg/kg once daily), and then transitioned to oral itraconazole capsules (200 mg 3 times per day for 3 days, then 200 mg twice daily) to complete 12 months of treatment. Her symptoms resolved, and her IBD has remained in remission without additional infliximab. Plasma infliximab level at the time of delivery was high at 59.7 µg/mL.

Of note, before starting infliximab, a screening chest radiograph was normal except for sequela of granulomatous disease, a common finding in H capsulatum endemic areas. She also reported that before and during her pregnancy she worked near a construction site and 5 months earlier a coworker was reportedly diagnosed with pulmonary histoplasmosis.

The Infant

A 2.8 kg female infant was born at 36 weeks gestation via vaginal delivery. The immediate newborn period was uncomplicated, and she was discharged from the hospital on the third day of life. At 3 weeks of life, shortly after the mother was diagnosed with disseminated histoplasmosis, the infant was referred to an infectious diseases specialist.

At the time of evaluation, the infant was asymptomatic, had a normal physical exam, and was appropriately gaining weight. However, laboratory tests were notable for elevated transaminases (AST 170 and ALT 118 [normal range 20–65] units/L) and leukocytosis (WBC 22.4 × 10 ³ /µL [normal range 4.3–18.3]). Other blood cell counts were normal. Histoplasma antibodies were detectable in serum by immunodiffusion but not by complement fixation. Histoplasma antigen levels were >19 ng/mL in urine and serum (Figure 1 ). Lumbar puncture revealed CSF with 24 nucleated cells, zero red blood cells, and detectable Histoplasma antigen (below the limit of quantification [<0.4 ng/mL]; Figure 1 ). Fungal cultures from blood, urine, and CSF were negative. Magnetic resonance imaging of the brain revealed cortical and periventricular punctate lesions predominantly involving the right temporal and parieto-occipital regions. These lesions were thought to represent areas of bland parenchymal hemorrhages, which could have been due to birth trauma or infection. Chest radiograph, abdominal ultrasound, echocardiogram, and ophthalmologic examinations were unremarkable.

Figure 1.

Histoplasma antigen levels in the infant's umbilical cord blood, serum, urine, and cerebrospinal fluid (CSF) over time and with respect to antifungal therapy.

Maternal serum and infant umbilical cord blood, collected on the day of birth as part of the PIANO study, were analyzed to evaluate for vertical transmission. Histoplasma antigen was >19 ng/mL from maternal serum, confirming disseminated histoplasmosis at the time of delivery. Cord blood also had detectable levels of Histoplasma antigen (<4 ng/mL; Figure 1 ), demonstrating that H capsulatum crossed the placenta into fetal circulation. Histopathology of the placenta was also reviewed, but was without signs of granulomatous inflammation, and no fungal forms were seen with Grocott-Gomori methenamine silver stain of the placental membranes, chorionic villi, and umbilical cord. Infliximab level measured from cord blood was 110.1 µg/mL, consistent with active transport across the placenta.

The infant was diagnosed with transplacentally acquired disseminated histoplasmosis with probable involvement of the central nervous system. She was initially treated with intravenous liposomal amphotericin B (5 mg/kg once daily). After 6 weeks of amphotericin, she was also started on oral itraconazole suspension (15 mg/kg per day in 3 divided doses for 3 days, then 10 mg/kg per day divided twice daily). After 8 weeks of antifungal therapy, with serum itraconazole level of 2.5 µg/mL (therapeutic range, 1–10 µg/mL), Histoplasma antigen levels declining, and Histoplasma antibody titers rising, amphotericin B was discontinued. After 18 weeks of antifungal therapy, infliximab was no longer detectable, but Histoplasma antigenemia persisted at low levels (1.89 ng/mL; Figure 1 ). The infant continues to thrive and will remain on itraconazole at least until Histoplasma antigen levels are no longer quantifiable.

DISCUSSION

This is the first description of umbilical cord blood-confirmed vertical transmission of disseminated histoplasmosis in a mother-infant pair exposed to anti-TNF therapy. Only 2 other cases of transplacental infection with H capsulatum in humans have been reported, both in the setting of maternal human immunodeficiency virus (HIV)/acquired immune deficiency syndrome [ 8 , 9 ].

Infants with disseminated histoplasmosis usually present with fever, pancytopenia, and elevated transaminases [ 2 , 3 ]. Our infant was well appearing; however, she had elevated transaminases, leukocytosis, and Histoplasma antigen detectable in high levels, consistent with the diagnosis of disseminated histoplasmosis. Circulating infliximab was an additional risk factor, and we speculate that if diagnosis and treatment had been delayed, this infant might have developed severe disease due to H capsulatum. Therefore, we propose thorough evaluation for possible histoplasmosis in all infants born to immunocompromised mothers with confirmed histoplasmosis (Figure 2 ).

Figure 2.

Approach to recognition and management of histoplasmosis acquired through vertical transmission. Abbreviations: CBC, complete blood count; CSF, cerebrospinal fluid; MRI, magnetic resonance image.

There are guidelines for management of children and adults with histoplasmosis [ 1 ], but no such guidelines exist for management of newborns diagnosed with histoplasmosis acquired through vertical transmission. In 1 previously reported case, in which there was concomitant vertical transmission of histoplasmosis and HIV, treatment consisted of amphotericin B and itraconazole for 14 weeks followed by long-term suppressive itraconazole [ 8 ]. In the other reported case, the infant did not acquire HIV and was successfully treated with amphotericin B for 15 weeks [ 9 ]. Based on these reports, the existing guidelines, and our experience, we propose that histoplasmosis acquired through vertical transmission can be effectively treated with either amphotericin B alone or with amphotericin B followed by itraconazole. We recommend continuing amphotericin at least until clinical improvement is demonstrated, Histoplasma antigen levels decline, and therapeutic levels of itraconazole are achieved. Antifungal therapy should be continued for a minimum duration of 12 weeks; however, prolonged therapy (6–12 months) should be considered, especially in the setting of severe disease, immunodeficiency, or ongoing immunosuppression (Figure 2 ).

Active IBD during pregnancy is associated with increased risk of complications; therefore, achieving remission is ideal and may require anti-TNF therapy [ 5 ]. Of the anti-TNF agents, infliximab and adalimumab are immunoglobulin isotype G1 antibodies, which are actively transported across the placenta during the third trimester. Certolizumab is a pegylated antibody fragment that is only passively transported across the placenta. Data from the PIANO study has revealed that the mean neonatal serum and cord blood levels of infliximab and adalimumab can be more than 160% of maternal serum levels at the time of birth, whereas infant certolizumab levels are usually less the 4% that of maternal levels. Infliximab and adalimumab can be detected in exposed infants for as long as 6 months [ 10 ]. Thus, it was not surprising that our infant had higher levels of infliximab compared with her mother. However, despite concerns that in utero exposure to and placental transfer of anti-TNF agents might have untoward effects on the developing infant immune system, few cases of significant infant infections (eg, varicella disease) [ 11 ] or adverse events related to the administration of live vaccines (eg, disseminated mycobacterial infection after administration of Bacillus Calmette-Guérin [BCG] vaccine) have been reported in the literature [12]. That said, for this population experts recommend avoiding live vaccines for the first 6 months of life (eg, rotavirus vaccine in the United States; BCG and oral polio vaccines internationally), whereas other inactivated vaccines should be given according to schedule.

CONCLUSIONS

The PIANO registry has reported the results of 384 women on anti-TNF therapy during pregnancy and 107 women on combination therapy including an anti-TNF agent through 2014 [ 6 ]. Our case is the first report of umbilical cord blood-confirmed vertically transmitted H capsulatum from a mother who developed disseminated histoplasmosis during the third trimester of pregnancy while receiving anti-TNF therapy for IBD. This case highlights the need for close monitoring of infants with prenatal exposure to anti-TNF agents, and it provides an approach to the management of histoplasmosis when it develops in neonates in this situation. Additional research is needed to identify the short- and long-term consequences of anti-TNF use during pregnancy in both mothers and infants to determine the true risk of severe infections in this population.