Fever and Diffuse Pulmonary Nodules in a Teenager with Leukemia

CASE A 17-year-old male with standard risk B-precursor acute lymphoblastic leukemia, on week 95 of continuation chemotherapy per St. Jude Hospital TOT17 protocol [6 mercaptopurine, dexamethasone and vincristine], presented with fever (102.8 oF), cough, fatigue and decreased appetite for 3 days. There was no history of headache, nasal congestion, runny nose, sore throat, vomiting, diarrhea, abdominal pain or skin rash. His current medications include dexamethasone and 6 mercaptopurine which were stopped on admission. He is also receiving Pneumocystis jiroveci pneumonia (PJP) prophylaxis with intravenous (IV) pentamidine every 4 weeks; he was not compliant with oral trimethoprim/sulfamethoxazole (TMP/SMX) due to anxiety-related emesis. The last dose of IV pentamidine was given 5 weeks earlier. He is also receiving subcutaneous immunoglobulins every 4 weeks; the last dose was given 1 week earlier. He has no recent upper respiratory tract symptoms and no recent travel history. He lives in a rural area with nearby farms, but there was no plowing at that time and no nearby construction sites. The family owns 1 dog and has chickens outside the house. Upon admission, he had a temperature of 38.3 °C, pulse of 110 beats/minute, respiratory rate of 22 breaths/minute and blood pressure of 124/68 mm Hg. He appeared fatigued but not in acute distress. Lung auscultation revealed mild decreased air entry in the right side with no rales or wheezing. The rest of the physical examination was normal. Chest radiograph was normal. His white blood cell count was 1.6 × 103/mm3: absolute neutrophil count was 100/mm3 and absolute lymphocyte count was 100/mm3, hemoglobin was 10.9 g/dL, hematocrit was 33.4% and platelet count was 236 × 103/mm3. During the maintenance phase of chemotherapy, his neutrophil count was mostly within the normal range and his absolute neutrophil count has not dropped below 500 recently, but his absolute lymphocyte count has been chronically low at around 500/mm3. His serum sodium was low at 129 mEq/L, potassium was 3.4 mEq/L, chloride was 93 mEq/L, and blood urea nitrogen and serum creatinine were within normal limits. Liver enzymes were mildly elevated with aspartate aminotransferase of 70 µ/L (10–40), alanine aminotransferase 99 µ/L (7–52), albumin low at 3.2 g/dL. Total bilirubin was 0.53 mg/dL. Serum lactate dehydrogenase was elevated at 686 µ/L (140–280). Nasopharyngeal respiratory viral PCR panel (BioFire FilmArray respiratory panel, bioMérieux, France) was positive for rhinovirus/enterovirus and SARS CoV-2 PCR was negative. Blood cultures from the central line and peripheral vein were obtained and treatment with IV cefepime was started. In view of worsening cough and requirement of supplemental oxygen (2 liters per minute through a nasal cannula) a chest computed tomography (CT) scan was obtained on the second day of admission and showed innumerable bilateral pulmonary nodules measuring up to 7 mm. CT scan of the sinuses showed minimal scattered sinus mucosal thickening without fluid collections, osseous erosion or enhancing lesions. CT scan of the neck showed focal calcification within a nonenlarged right submandibular lymph node, possibly related to sequela of prior infection with no other abnormality. Due to these findings, IV liposomal amphotericin B and azithromycin were added for fungal and atypical pneumonia coverage and bronchoalveolar lavage (BAL) was planned. The serum galactomannan assay was negative. Serum beta D-glucan assay was mildly elevated at 120 pg/mL (0–59). He remained febrile, and on the third day of admission, he became hypotensive, more tachypneic and hypoxemic requiring transfer to the pediatric intensive care unit. No growth was detected in blood cultures. Upon admission to the pediatric intensive care unit, he had a temperature of 39.6 °C, pulse of 120 beats/minute, respiratory rate of 55–65 breaths/minute and blood pressure of 98/34 mm Hg. His respiratory status subsequently worsened but stabilized with supplemental oxygen and bilevel-positive airway pressure. He was alert and oriented. Physical examination was normal except for increased work of breathing, and diminished breath sounds in both lungs with intermittent, nonproductive cough. The eye examination by the ophthalmologist was normal with no signs of vitritis or retinitis. A repeat chest radiograph showed new infiltrates with consolidation of the left lung base and bilateral nodular opacities concerning for atypical bacterial or fungal pneumonia. Cefepime was changed to IV meropenem, and IV vancomycin was added. Azithromycin and liposomal amphotericin B were continued. In addition, treatment for presumptive Pneumocystis jiroveci pneumonia was started with IV TMP/SMX. The patient has also received a single dose of 10 mg IV furosemide with mild improvement in his breathing. The echocardiogram was normal with no cardiac vegetation or thrombus. BAL studies including respiratory viral PCR panel, Gram stain, fungal stain, acid-fast stain, bacterial, mycobacterial and fungal cultures were all negative. BAL cytopathology evaluation did not reveal any fungal organism or Pneumocystis jiroveci by special stains. Pneumocystis PCR from BAL was negative. Legionella culture was negative, and urine legionella antigen was negative for serogroup 1. Blood PCR studies for cytomegalovirus, Epstein-Barr virus, herpes viruses 1 and 2 and Enterovirus were all negative. Serum antigens for Histoplasma, Blastomyces and Cryptococcus were negative. An additional laboratory test was subsequently performed that revealed the diagnosis. DENOUEMENT Fungal PCR (University of Washington Clinical Microbiology Laboratory, Seattle, WA) from BAL fluid incidentally detected Toxoplasma gondii. The Toxoplasma IgG was also elevated at >400 IU/mL (reactive ≥10.5). The patient was clinically improving after starting TMP/SMX treatment. The fungal PCR uses both fungal 28S and internal transcribed spacer sequence DNA as targets. Sequences of amplified DNA are analyzed to identify the fungal pathogen. The internal transcribed spacer region has also been used as a target for species identification and investigation of intraspecific strain variation of protozoa and parasites. Thus, the fungal PCR assay may incidentally detect Acanthamoeba and Balamuthia, Leishmania and Toxoplasma.1 The patient was diagnosed with Toxoplasma pneumonia in the setting of acute lymphoblastic leukemia and chemotherapy. This is likely due to the reactivation of Toxoplasma infection that was acquired earlier in life. Further history revealed that he had exposure to stray cats several years earlier. Treatment of T. gondii with TMP/SMX was continued until the preferred regimen became available. All other antibiotic and antifungal treatments were discontinued. He received sulfadiazine, pyrimethamine and leucovorin daily for the duration of the pyrimethamine. A repeat ophthalmologic examination before discharge remained normal. A follow-up CT scan of the chest 3 weeks after treatment revealed near resolution of the bilateral pulmonary nodules with a few small residual strandy to nodular densities in the lower lungs. Magnetic resonance imaging of the brain was normal. He completed 6 weeks of treatment and a repeat CT of the chest at that point showed complete resolution of pulmonary nodules. Toxoplasma blood PCR tests done during the second week of treatment and at the end of therapy were negative. The treatment course was followed by prophylaxis of both PJP and Toxoplasma with oral TMP/SMX 160–800 mg tablet once daily. Humans acquire T. gondii infection via ingestion of oocysts in soil and water, or cysts from infected animals’ meat and less frequently via transplacental vertical transmission from the mother to the fetus. Transmission via blood transfusion or organ transplantation is rare.2 The incubation period of postnatally acquired infection is around 7 days (range of 4–21 days). Approximately 20%–30% of the world’s population is infected with T. gondii.3 According to the National Health and Nutrition Examination Survey 2011–2014, the seroprevalence of T gondii in people older than 6 years in the United States was 11.1%.4 The clinical manifestations of toxoplasmosis in immunocompetent individuals include asymptomatic or flu-like illness, lymphadenopathy or chorioretinitis. However, immunocompromised patients are at risk of severe illness and dissemination with multiple organ involvement most commonly the lungs.5 The highest risk of T. gondii disease is noted in hematopoietic stem cell transplantation (HSCT) due to reactivation of latent infection in seropositive patients and graft transmission in donor positive (D+) and recipient negative (R−) heart transplant patients.6 The incidence is lower for other solid organ transplant recipients and much lower for oncology and autologous HSCT patients.7 The severity of T. gondii disease is related to the level of immune suppression. Delayed diagnosis is a contributing factor in fatal cases.7 The clinical findings in both primary and reactivated T. gondii disease in the immunocompromised population are similar.7 Fever is a common finding and should prompt the inclusion of toxoplasmosis in the differential diagnosis.8 Reactivation of latent infection in immunocompromised patients can cause encephalitis, brain abscesses, seizures, pneumonia, myocarditis, hepatitis and skin lesions. Ocular manifestations include posterior uveitis or panuveitis with chorioretinitis.7 Reactivation may also be associated with fever of unknown origin, disseminated disease and death.7,9Toxoplasma encephalitis is the most common cause of space-occupying brain lesions in patients with AIDS.10 Our patient did not have any neurological manifestations and magnetic resonance imaging of the brain, though done after 3 weeks of treatment, was normal. The clinical manifestations of T. gondii pneumonia are nonspecific and similar to PJP as noted in our patient. However, the onset tends to be more rapid than PJP.11 Most patients present with fever, nonproductive cough, dyspnea and occasionally hemoptysis. A chest radiograph typically shows bilateral interstitial infiltrates. Multiple nodular infiltrates, single nodules, isolated cavitary disease, lobar infiltrates, pleural effusions and hilar adenopathy can occur.12 Pneumothorax has been reported in AIDS patients.13 Chest CT scan can show ground glass opacities, interstitial infiltrates, crazy-paving pattern, ground glass opacities, septal thickening, interlobular linear opacities, lobar pneumonia, pleural effusions and mediastinal adenopathy.11,12 Given nonspecific clinical and radiological findings, the diagnosis relies on a high index of suspicion in T gondii seropositive patients. Imaging studies are performed as clinically indicated. Ophthalmologic evaluation should be performed on all patients. Definitive diagnosis of T. gondii disease (T. gondii infection and organ involvement) is based on detecting tachyzoites in body fluids or tissues.8 PCR assay can be performed on peripheral blood, bone marrow, BAL, CSF, tissue biopsies, aqueous humor and vitreous fluid and is more sensitive than histopathology.8 In immunocompetent individuals, serologic tests are the primary means of diagnosis. However, in immunocompromised patients, the diagnosis should rely primarily on molecular methods. Toxoplasma blood PCR should be obtained in immunocompromised patients when there is a concern for toxoplasmosis; consecutive testing may be needed if clinical suspicion is high.9T. gondii pneumonia is diagnosed by demonstration of tachyzoites from BAL fluid and/or biopsy specimens. The sensitivity of Giemsa stain and eosin/methylene blue fast staining for visualization of tachyzoites in BAL fluid is low. PCR on BAL fluid or tissue is highly sensitive and specific.14 Metagenomics cell-free DNA sequencing assay in blood can be utilized in special circumstances.15 Screening with Toxoplasma IgG and IgM antibodies should be done in every patient anticipated to become severely immunocompromised.7,8 However, this has not been a standard practice in all oncology patients and Toxoplasma antibodies were not previously checked in our patient. TMP/SMX is the agent of choice in primary prophylaxis used for primary prophylaxis of Toxoplasma in HSCT and solid organ transplant recipients. Prophylaxis with TMP/SMX can also prevent PJP in HSCT patients. Pentamidine, which is used for PJP prophylaxis, has no activity against T. gondii.7 TMP/SMX prophylaxis should be continued for 6 months or until resolution of immunosuppression, whichever is longer.9 For severe toxoplasmosis in immunocompetent or immunocompromised children, the preferred first-line therapy is pyrimethamine with sulfadiazine as a synergistic combination, inhibiting tachyzoite proliferation. Folinic acid or leucovorin is administered simultaneously to prevent the hematologic toxicity of pyrimethamine.8 If preferred therapy is not available or there is a concern with enteric therapy, IV TMP/SMX (10–15 mg/kg/day) should be started as soon as possible until preferred therapy is available.10 Response to therapy is anticipated within 7–10 days as was also noted in our patient. Close monitoring for drug toxicity during therapy is essential. CBC with differential twice weekly for the first 2 weeks then weekly if stable as well as weekly liver and kidney function tests are recommended.9 Urinary sulfa crystals are common during sulfadiazine treatment. Adequate hydration and maintenance of alkaline urine pH are indicated to prevent obstructive uropathy.9 For patients with sulfadiazine allergy, clindamycin, or azithromycin in combination with pyrimethamine can be used. Other potential alternatives include atovaquone, dapsone and doxycycline.8 Because the prognosis of T. gondii disease is dependent on the level of immunosuppression, reduction of immune suppression can be helpful. The duration of therapy is at least 4–6 weeks. After completion of therapy and resolution of parasitemia, secondary prophylaxis is continued for at least 6 months post HSCT, or until the patient is no longer receiving immunosuppressive therapy or immune reconstitution has been accomplished, whichever is longer.9 Mortality of T. gondii disease is highest in allogenic HSCT (60%–90%) but can be significantly decreased with early diagnosis and treatment.6