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Keywords:

  • pediatric;
  • histoplasma;
  • inflammatory bowel disease;
  • antitumor necrosis factor alpha therapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Background:

Antitumor necrosis factor alpha (aTNF) therapies are commonly used in the treatment of pediatric inflammatory bowel disease (IBD). However, inhibition of the TNF-alpha pathway predisposes to serious infections, including histoplasmosis, which is the most common invasive fungal infection in individuals on aTNF therapy and carries a high mortality rate when associated with delayed diagnosis. Few data exist on the frequency, presentation, and appropriate treatment of pediatric patients with histoplasmosis on aTNF therapy.

Methods:

Following Institutional Review Board approval, cases were identified then reviewed with their primary gastroenterologist and infectious disease specialists.

Results:

Herein we describe histoplasmosis in five pediatric patients receiving aTNF therapy for IBD in an endemic area.

Conclusions:

Histoplasmosis is an important complication of treatment with TNF-alpha neutralizing agents. Children with IBD treated with aTNF therapy who develop the infection may present with minimal pulmonary symptoms. While discontinuation of aTNF therapy is important initially, few data exist to determine when and how aTNF therapy can be reinstituted. Recognition of Histoplasma capsulatum is often delayed due to the overlap of symptoms with some of the extraintestinal manifestations of IBD and other more prevalent infectious complications. (Inflamm Bowel Dis 2011;)

Antitumor necrosis factor alpha (aTNF) therapies are commonly used in the treatment of pediatric inflammatory bowel disease (IBD). However, inhibition of the TNF-alpha pathway predisposes to serious infections. Histoplasmosis is the most common invasive fungal infection in individuals on aTNF therapy and carries a mortality rate up to 20%.1 In fact, the Food and Drug Administration has recently warned clinicians to carefully monitor for histoplasmosis in patients on aTNF therapy due to the high mortality associated with delayed diagnosis.2, 3 Few data exist on the frequency, presentation, and appropriate treatment of pediatric patients with histoplasmosis on aTNF therapy. Herein we describe histoplasmosis in five pediatric patients receiving aTNF therapy for IBD in an endemic area.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Following Institutional Review Board (IRB) approval, cases were identified at Nationwide Children's Hospital and other regional children's hospitals. All cases were reviewed with their primary gastroenterologist and infectious disease specialists.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Case 1

A 16-year-old female with ileocolonic, nonstricturing, nonpenetrating Crohn's disease (CD) diagnosed 10 months earlier presented with 2 weeks of abdominal pain, fatigue, poor appetite, nausea, headaches, muscle aches, dysuria, and mild shortness of breath (Table 1). Her medications included 6-mercaptopurine (6-MP) and adalimumab. Due to increasing abdominal pain, she had an abdominal and pelvic computed tomography (CT) scan that incidentally noted basal pulmonary nodules. Thoracic imaging demonstrated hilar and mediastinal lymphadenopathy with multiple bilateral centrilobar nodules (Fig. 1). She was found to have positive serum and urine histoplasma antigens. A comprehensive evaluation for other infectious etiologies was negative. Bronchoscopy revealed globally inflamed, friable mucosa with negative cultures.

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Figure 1. Chest CT image at diagnosis from Case 1. Enlarged right paratracheal lymphadenopathy (white arrow).

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Table 1. Summary of Five Cases of Histoplasmosis in Pediatric Inflammatory Bowel Disease Patients Treated with Antitumor Necrosis Factor Alpha Therapy
 Case 1Case 2Case 3Case 4Case 5
  1. 6MP, 6-mercaptopurine; Ag, antigen.

Age at diagnosis of histoplasmosis16 years14 years13 years14 years21 years
GI disease duration10 months7 years3 years10 months10 years
Disease locationIleocolonic; InflammatoryIleocolonic; FistulizingIleocolonic; InflammatoryIleocolonic; FistulizingIleocolonic; Inflammatory
Biologic dose and frequencyAdalimumab; 40 mg q 2 weeks. 5 doses prior to presentationInfliximab 5 mg/kg, q 8 weeks. 2 doses prior to presentationInfliximab 10mg/kg q 6 weeks. 7 doses prior to presentationInfliximab 5 mg/kg q 6 weeks. 5 doses prior to presentationInfliximab 5mg/kg q 8 weeks. 13 doses prior to presentation
Concomitant Immunomodulator6MPMethotrexate6MP6MP6MP
Concomitant steroidSteroid free for 3 monthsSteroid free for 9 monthsSteroid free for over a yearSteroid free for 2 monthsSteroid free for 2 months
Histoplasma antigen (ng/mL), <0.6 negative9.21 urine0.6 urine4.73 urine12.79 serum/ 6.45 urine4.4 serum
Histoplasma complement fixationPositive at a titer of 1:8Positive at titer of 1:16Positive for a titer of 1:64Positive at 1:128; peak of 1:2048Positive titer of 1:16
Bronchoscopy CultureNegativeNANANAPositive
TreatmentItraconazole for 8 monthsAmphoteracin followed by Intraconazole for 26 monthsItraconazole for 6 months.Amphotericin followed by itraconazole (ongoing)Itraconazole for 24 month
Follow-up of histoplasmosis, recurrent antigen detectionAt 2 months urine Histo Ag was 5. At 7 months Histo Ag was <0.6At 3 months Histo Ag was negative at <0.6NAAt ∼5 months: serum Ag 2.33, urine Ag <0.6Negative urine Histo Ag at 18 months
Current age18 years19 years17years15 years27 years

She was diagnosed with systemic histoplasmosis and started on itraconazole therapy. Adalimumab and 6-MP were held. Two months after diagnosis, chest CT demonstrated resolution of the mediastinal lymphadenopathy and pulmonary nodules (Fig. 2). She was treated with itraconazole for 6 months, and then continued on daily prophylaxis for 12 months. Urine histoplasma antigen became undetectable at 7 months.

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Figure 2. Chest CT image from Case 1, 2 months after treatment. Interval resolution of mediastinal adenopathy, specifically the previously noted enlarged right paratracheal node in Figure 1 is no longer identified (white arrow).

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She experienced an exacerbation of her CD 2 years later and was restarted on prednisone and 6-MP. Infliximab was initiated a few months later due to refractory disease. Repeat urine and plasma histoplasma antigens remain negative.

Case 2

A 14-year-old female with ileocolonic and penetrating CD diagnosed at 7 years of age, treated with tapering prednisone, methotrexate, and infliximab, presented with fevers, headaches, myalgias, dizziness, arthralgias, and an intermittent mild cough, followed by anorexia and weight loss. Evaluation included a normal chest x-ray and stable abdominal and pelvic CT scan, and a positive nasopharyngeal swab for parainfluenza. She was subsequently hospitalized with fever, worsening abdominal pain, and fatigue. A chest x-ray obtained 6 weeks later demonstrated multiple pulmonary nodules (Fig. 3). A chest CT confirmed multiple asymmetric small rounded nodules in the right middle and lower lobes bilaterally (Fig. 4). Histoplasma serology was positive. Methotrexate, infliximab and steroids were held. Antifungal therapy was initiated with amphotericin until she defervesced, then followed by itraconazole.

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Figure 3. Chest x-ray (anterior/posterior view) from Case 2. Multiple pulmonary nodules, particularly in the right lung.

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Figure 4. Chest CT image from Case 2. Multiple asymmetric small rounded nodules, predominately in the right middle and lower lobes bilaterally.

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One month later a chest CT demonstrated resolving nodules (Fig. 5); however, her fatigue, abdominal pain, and diarrhea persisted. Methotrexate was restarted while she remained on itraconazole. She completed a treatment course of itraconazole for 3 months. She developed a rectovaginal fistula and was restarted on infliximab every 8 weeks. The urine histoplasma antigen and antibody titers remained negative. Fifteen months post-diagnosis she had a repeat chest CT that demonstrated significant improvement of the nodules. Twenty-two months later, infliximab infusions were increased to 10 mg/kg/dose in addition to weekly methotrexate and itraconazole was discontinued. Over 5 years after the initial infection she continues to have negative urine histoplasma antigen levels and remains in remission on infliximab infusions 10 mg/kg/dose every 8 weeks without fungal prophylaxis.

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Figure 5. Chest CT image from Case 2, 1 month after treatment. There is near complete resolution of the multiple pulmonary nodules.

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Case 3

A 13-year-old male was diagnosed with ileocolonic, nonstricturing, nonpenetrating Crohn's colitis 3 years prior to presenting with intermittent fever, chills, malaise, and worsening fatigue. The fever and fatigue had worsened about 5 days after his last infusion of infliximab. His medications also included 6-MP. A chest x-ray demonstrated diffuse prominent reticulonodular opacities consistent with interstitial pneumonia. A chest CT demonstrated a diffuse reticular nodular pattern in the lung bases. Serum and urine fungal serology were positive for histoplasmosis. He was diagnosed with pulmonary histoplasmosis and started on amphotericin for a week and then switched to intraconazole, with a recommended treatment course of 6 months. Follow-up was completed at another hospital when the family relocated.

Case 4

A 15-year-old female was diagnosed with ileocolonic fistulizing CD 10 months prior to presenting with abdominal pain, fever, mild productive cough, and fatigue. She had been receiving infliximab and 6-MP. An abdominal CT revealed nodularity at the lung bases and a follow-up chest x-ray demonstrated a diffuse interstitial process with a nodular prominence in the right paratracheal region suggesting adenopathy (Fig. 6). A chest CT confirmed mediastinal and hilar nodes with a prominent interstitial process in the lower lobes (Fig. 7). Histoplasma serology was positive, as well as urine and serum antigen. Infliximab therapy was held. She was started on amphotericin and subsequently changed to oral itraconazole secondary to acute renal insufficiency. Two and a half months later a repeat chest x-ray was normal. Her histoplasma levels have been serially monitored and are declining. Due to active CD, she was restarted on oral steroids and 6-MP while remaining on itraconazole. Her steroids were tapered off and at 7 months she remains on 6-MP and itraconazole, with a low positive urine histoplasma antigen and negative serum antigen.

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Figure 6. Chest x-ray (anterior/posterior view) from Case 4. Note the diffuse small-nodule interstitial process with a prominence for the lower lobes, as well as prominence of the right paratracheal region suggesting adenopathy.

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Figure 7. Chest CT image from Case 4. Bilateral diffuse micro nodules in the lungs.

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Case 5

A 21-year-old male diagnosed with Crohn's colitis at age 11 years had been treated with 6-MP and 2 months of infliximab when he developed fever, malaise, night sweats, and cough, for which he received a 5-day course of antibiotics. His respiratory symptoms worsened and he was hospitalized for treatment. His symptoms continued for another 2 weeks despite antibiotics. He underwent a bronchoscopy that grew Histoplasma capsulatum on culture. His urine histoplasma antigen and serology were also positive. He was treated with itraconazole for 12 months, at which time his urine histoplasma antigen was negative. The infliximab was discontinued and he remained in remission on 6-MP.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Histoplasma capsulatum (HC) is a thermally dimorphic ascomycete that causes significant respiratory illness in endemic areas such as the Ohio, Mississippi, and the Missouri River valleys. It is found in warm, moist soils contaminated by bat or bird droppings. Infection occurs by breathing in airborne microconidia (spores) when the soil is disturbed during activities like construction, gardening, cave exploration, and earth-moving projects. Histoplasmosis is the most prevalent endemic mycosis in the United States with an observed incidence rate of 1–2 cases per 10,000 people and a common opportunistic infection, affecting about a quarter million Americans.4–6 Less than 5% of infected immunocompetent people will develop symptoms.7 Infections are typically self-limited or subclinical, and primarily affect the lungs. Disseminated histoplasmosis, which can be fatal if untreated, involves other sites including the bone marrow (Fig. 8), liver, spleen, adrenal glands, mucosal surfaces, and meninges. Symptoms of pulmonary histoplasmosis can include fever, malaise, weight loss, diaphoresis, headache, cough, dyspnea, and chest pain, but with disseminated disease symptoms can be those of widespread systemic illness. Progressive disease occurs in patients with cellular immune dysfunction, primary immune deficiency disorders, HIV infections, and patients on immunosuppressive therapy.

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Figure 8. Histoplasmosis inside a macrophage from bone marrow. Wright-Giemsa stain (image provided by pathologist Samir Kahwash, MD, Nationwide Children's Hospital). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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All of our patients had fatigue, with four out of the five demonstrating intermittent fevers and decreased appetite. Two patients presented with myalgias and arthralgias. All patients required hospitalization. It is unclear whether our cases represent reactivation of latent histoplasmosis or exogenous infection while being immunosuppressed, since only one patient had a previously known negative antibody screen. All patients responded to therapy. The majority of patients in this series did not have prominent respiratory symptoms at presentation, although a cough or mild shortness of breath was present in four of them.

In children with CD on aTNF therapy and presenting with respiratory findings, diagnostic considerations should include atypical pneumonia, Pneumocystis jirovecii, tuberculosis, viral syndromes related to cytomegalovirus, Epstein–Barr virus, adenovirus and fungal infections like blastomycosis, or histoplasmosis depending on the geographic region. Other systemic diseases that could manifest similarly include sarcoidosis, systemic lupus erythematous, rheumatoid arthritis, and malignancy.

Clinical classification of histoplasmosis is based on location (pulmonary or disseminated), duration (acute or chronic), and pattern (primary or reactivated). Most symptomatic patients with acute pulmonary histoplasmosis present with a self-limiting flu-like illness. The infection typically lasts up to 2 weeks then resolves spontaneously. However, a few patients can have severe respiratory symptoms, with prolonged fever, fatigue, weight loss, and diffuse pulmonary infiltrates. It is also hypothesized that immune suppression and immune modulating therapies can alter a typical presentation.

Diagnosis

A definitive diagnosis of histoplasmosis requires a positive culture for HC from blood, sputum, or tissue specimens. Unfortunately, cultures can take 1–6 weeks to grow. HC polysaccharide antigen can be detected using radioimmunoassay or a quantitative enzyme immunoassay testing on serum, urine, or bronchoalveolar lavage fluid. Antigen detection is the most sensitive and rapid test in the first few weeks of infection in acute pulmonary and disseminated infections but a negative result does not rule out an infection. The sensitivity of antigen testing is higher in immunodeficient patients with disseminated disease.8 Serial antigen testing following initial positivity can be used to monitor treatment response and identify relapse in patients.

Complement-fixation antibodies are considered presumptive evidence of active or recent infection if there is a 4-fold increase in titer or a single titer of 1:32 or greater. False-positive testing results from crossreactivity with other fungal species but can usually be differentiated based on clinical and epidemiological circumstances. All of the patients in this series were diagnosed by complement-fixation antibodies.

Treatment

Immunocompetent children with uncomplicated primary pulmonary histoplasmosis rarely require therapy. Treatment is suggested for acute infections in immunocompromised patients and in those with disseminated infections. The majority of patients in this series were treated with itraconazole for periods ranging from 8 to 26 months; two required amphotericin for greater symptom severity. Children with mild to moderate acute pulmonary infections can be treated with itraconazole for a duration ranging from 2–12 weeks. Children with moderate to severe acute pulmonary histoplasmosis should be treated with amphotericin B for 1–2 weeks followed by itraconazole. Children with disseminated histoplasmosis should be treated with amphotericin B for 2–6 weeks, followed by itraconazole. Treatment should continue for ≥12 months and until clinical findings have resolved and antigenemia has cleared.2, 9

Empiric therapy is suggested while awaiting diagnostic results in patients from endemic areas with appropriate clinical features to prevent morbidity and mortality associated with delayed treatment.1, 10 Prophylaxis with itraconazole may be needed in case of continued immunosuppression to prevent relapse. While there is no position statement, current recommendations suggest discontinuing aTNF therapy in patients being treated for histoplasmosis.9 Response to therapy should be monitored by measuring urine antigen levels throughout treatment and for 12 months following treatment.9, 11

Reinstituting aTNF Therapy

In an adult series, aTNF therapies were restarted in seven patients who had previously completed a 10-month antifungal course, three of whom were continued on itraconazole, with no relapse during follow-up ranging from 1–8 years.2 Another approach is to screen for urine histoplasma antigen every 3 months in previously treated patients and closely monitor for rising levels. Long-term antifungal prophylaxis may be needed if aTNF therapy is reinstituted. Two of our patients were successfully reintroduced to aTNF therapy.

Screening

Routine screening for exposure to HC before initiating therapy has not been shown to be beneficial. Specifically, numerous studies have shown that even in endemic areas, exogenous exposure is more common than reactivation in an immunocompromised host. Importantly, screening for histoplasmosis using the skin test or serology has been unable to predict which patients will develop active or disseminated infection.12 Based on these studies screening for antibodies to HC or histoplasma antigen is not recommended.12 Histoplasmosis is an important complication of treatment with TNF-alpha neutralizing agents. Children with IBD treated with aTNF therapy who develop HC infection may present with minimal pulmonary symptoms. While discontinuation of aTNF therapy is important initially, few data exist to determine when and how aTNF therapy can be reinstituted. Recognition of HC is often delayed due to the overlap of symptoms with some of the extraintestinal manifestations of IBD and other more prevalent infectious complications. Early recognition of HC is critical to prevent fatal outcomes.3 Presently, no position statements or screening guidelines are available for this patient population, and further studies are imperative to prevent the morbidity and mortality associated with this disease.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES