INFECTIONS AND TREATMENT JOURNAL (ISSN:2634-0925)

We report the 67 years old man of Graves’ disease with invasive pulmonary aspergillosis after prolonged stay in the intensive care unit due to sequential development of pneumonia caused by Streptococcus pneumoniae, thyroid storm and Cytomegalovirus colitis. Antifungal therapy was not given in time before death. The glucocorticoid therapy could facilitate the Cytomegalovirus infection, which might also be associated with the subsequent development of aspergillosis. 

Aspergillosis; Cytomegalovirus; Colitis; Graves’ disease; Thyroid storm

Invasive pulmonary aspergillosis (IPA) could occur after prolonged hospitalization in the intensive care unit (ICU). We report a delayed recognition of infection caused by Aspergillus in a patient with pneumococcal sepsis-induced thyroid storm on prolonged course of glucocorticoid therapy, which then predisposed to Cytomegalovirus (CMV) colitis. Prolonged ICU stay, glucocorticoid therapy and CMV infection all are risk factors for the further development of IPA.  

A 67 years old man of Graves’ disease without regular follow-up presented with progressive dyspnea for 2 weeks. Productive cough and bilateral leg edema were noted in recent 3 days. There was no fever, diarrhea, or skin rash. The patient visited the hospital on October 19, 2015. Laboratory data showed a white blood cell (WBC) count of 5,500/ μL; C-reactive protein (CRP), 8.1 mg/L (normal, <6); procalcitonin (PCT), 12.8 ng/mL (normal, < 0.05); lactate, 6.2 mmole/L (normal, 0.4-2.0); aspartate aminotransferase, 360 U/L (normal, 5-34 ); alanine aminotransferase, 183 U/L (normal, 2-40); total bilirubin, 3.09 mg/dL (normal, 0.2-1.2); direct bilirubin, 2.18 mg/dL (0.1-0.5); creatinine, 2.21 mg/dL; HbA1C, 6.5% and albumin, 3.9%. 

The initial chest x-ray (CXR) film showed cardiomegaly, lung congestion and bilateral pleural effusions (Figure 1A). Influenza A and B rapid antigen screen and polymerase chain reaction (PCR) for influenza A (H1N1) virus in nasopharyngeal swab samples all showed negative results. Urine Pneumococcus rapid screen test was positive, whereas urine Legionella antigen test was negative. An N-terminal pro-brain natriuretic peptide (NTproBNP) of 5943 pg/mL (normal, <125) was noticed. Together with electrocardiogram showing atrial fibrillation with rapid ventricular response, pneumococcal sepsis-induced thyroid storm with congestive heart failure was suspected. An initial blood culture did not reveal any growth, while sputum culture yielded few cefazolin-susceptible Klebsiella pneumoniae.

Thyroid function tests included a free tetraiodothyronine of 2.32 ng/dL (normal, 0.70-1.48); anti-thyroglobulin, 6.6 IU/mL (normal, <5); anti-thyroid peroxidase, 10.0 IU/mL (normal, <5); a thyroid-stimulating hormone (TSH) level of 0.03 μIU/mL (normal, 0.25-4.0); and TSH receptor-Ab, 60.6% (normal, <14). Echocardiography revealed global hypokinesia and poor left ventricular (LV) systolic function with a LV ejection fraction ranging from 19% to 28%. Treatment consisted of propylthiouracil, Lugol’s iodine (2%) solution, hydrocortisone, dopamine, propranolol, digoxin, furosemide and an antibiotic of piperacillin-tazobactam. His lung condition became markedly improved (Figure 1B). A follow-up WBC count of 8,600/μL and a PCT of 1.59 ng/mL were noted on Oct. 29, 2015.

However, fever and bloody stool occurred 2 weeks later. The colorectal examination by colonoscopy revealed a huge recto-sigmoid colon ulcer on November 4 (Figure 2). The histopathology of tissue biopsy confirmed CMV colitis. Meanwhile, CMV antigenemia was 5 positive cells per 200,000 macrophages and CMV viral load was 6,530 IU/mL. A PCR assay for CMV DNA in the stool sample was positive. Meanwhile, the blood screening for Aspergillus antigen of galactomannan index was 0.24 (normal, <0.5). Ganciclovir was added for CMV colitis since November 11, 2015.

In addition, a sputum culture obtained on November 9 yielded Pseudomonas aeruginosa and antibiotic was shifted to ciprofloxacin with good therapeutic results. During the 4th week of hospital stay; however, Aspergillus species was isolated from sputum culture obtained on November 16, 2015. Meanwhile, shock occurred and a CXR film showed nodular patches over left lung field (Figure 1C). A PCT level increased to 8.69 ng/mL and CRP became 35.7 mg/L. A blood culture obtained on November 16 yielded ciprofloxacinresistant Escherichia coli. A blood sample for Aspergillus antigen obtained on November 17 became an index of >5.16. As severe and refractory septic shock and worsening pneumonia (Figure 1D), the patient died on November 19, 2015. Appropriate antibiotics and antifungal therapy were not given in time before death.

Throughout the whole course of hospitalization, the patient had been on hydrocortisone therapy (300 mg/day for 5 days, followed by 150 mg/day for 5 days, 100 mg/day for 8 days, 50 mg/ day for 8 days, then at last 100 mg/day for 6 days). Lymphopenia (<1,000/μL) had persisted for most of time during hospital stay (Figure 3).

Diagnosis of thyroid storm in our reported patient was mainly based on thyrotoxicosis combined with congestive heart failure, arrhythmia, and hepatic disturbances [1]. Infection is one of several risk factors predisposing to thyroid storm [2,3]. The high levels of PCT and lactate as well as positive urine pneumococcal screen test suggested the presence of sepsis in our patient. Prompt initiation of anti-thyroid and antibiotic therapy resulted in rapid improvement.

Management of thyroid storm includes a multimodality treatment, such as propylthiouracil, glucocorticoids, beta-blockers, and monitoring in an ICU [4]. Nonetheless, reactivation of latent CMV infection may occur in previously immunocompetent critically ill individuals [5]. In addition, glucocorticoids are transcription factors that facilitate the transcription of CMV to reactivation [6]. Therefore, prolonged steroid use and stay in the ICU are the most commonly associated risk factors for CMV disease in our patient.

However, worsening pneumonia occurred during 4^th week after admission, as the occurrence of Aspergillus in the sputum culture and positive Aspergillus antigen assay in the blood, which rapidly progressed to fatal pneumonia. Even though an earlier screening for blood Aspergillus antigen assay after 2 weeks of hospitalization was negative during CMV reactivation, it highlights that CMV itself is also a precipitating factor for late-onset IPA. CMV reactivation has been reported to be an independent risk factor for invasive fungal disease among transplant recipients undergoing solid organ and allogeneic hematopoietic stem cell transplantation [7,8]. Host genetic Toll-like receptor polymorphisms and low CD3 lymphopenia are likely to be contributory factors for invasive aspergillosis [7,9]. Therefore, persistent lymphopenia in our patient with CMV disease may hint the need to continuously consider the development of IPA even in the late stage of the course. 

In conclusion, our case highlights invasive Aspergillus infection following CMV colitis, which might be reactivated by prolonged hydrocortisone use for thyroid storm. Our patient reminds physicians that potential co-infections of CMV and aspergillosis cannot be overemphasized. 

The study and waiver from the inform consent process were approved by the Institutional Review Board (IRB) of the Chi Mei Medical Center, Tainan city, Taiwan (IRB Serial number 10801-002).

The authors declare that they have no financial support and competing interests.

1. Akamizu T, Satoh T, Isozaki O, Suzuki A, Wakino S, et al. Diagnosticcriteria, clinical features, and incidence of thyroid storm based onnationwide surveys. Thyroid. 2012 Jul;22(7):661-679.
2. Presti CF, Hart RG. Thyrotoxicosis, atrial fibrillation, andembolism, revisited. Am Heart J. 1989 Apr;117(4):976-977.
3. Yeh CY, Yu WL. A case report of thyroid storm induced by acutesepsis. J Acute Dis. 2016 Mar;5(2):160–161.
4. Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K,et al. 2018 European Thyroid Association Guideline for theManagement of Graves’ Hyperthyroidism. Eur Thyroid J. 2018Aug;7(4):167-186.
5. Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, BulgerEM, et al. Cytomegalovirus reactivation in critically-illimmunocompetent patients. JAMA. 2008 Jul;300(4):413–422. 
6. Inoue-Toyoda M, Kato K, Nagata K, Yoshikawa H. Glucocorticoidsfacilitate the transcription from the human cytomegalovirusmajor immediate early promoter in glucocorticoid receptorand nuclear factor-I-like protein-dependent manner. BiochemBiophys Res Commun. 2015 Feb;458(1):180-185. 
7. Yong MK, Slavin MA, Kontoyiannis DP. Invasive fungal diseaseand cytomegalovirus infection: is there an association? Curr OpinInfect Dis. 2018 Dec;31(6):481-489.
8. Yong MK, Ananda-Rajah M, Cameron PU, Morrissey CO, SpencerA, et al. Cytomegalovirus reactivation is associated withincreased risk of late-onset ivasive fungal disease after allogeneichematopoietic stem cell transplantation: A multicenter studyin the current era of viral load monitoring. Biol Blood MarrowTransplant. 2017 Nov;23(11):1961-1967.
9. Bongomin F, Harris C, Foden P, Kosmidis C, Denning DW. Innateand adaptive immune defects in chronic pulmonary aspergillosis.J Fungi. 2017 May;3(2):E26.