A fatal case of cytomegalovirus pneumonia with Aspergillus infection in a non-transplanted patient : A case report

Abstract

Introduction: Cytomegalovirus (CMV) is a common disease in transplant patients who are also susceptible to secondary bacterial or fungal infections. However, co-infection in non-transplant patients is rare and often complicates diagnosis and treatment.

Patient concerns: The patient was an older adult woman with poor immune function but was not a transplant patient.

Diagnosis: The patient visited the doctor because of fever and shortness of breath for 1 day and was diagnosed with CMV combined with fungal pneumonia.

Interventions: Treatment with ceftriaxone + human immunoglobulin + voriconazole

Outcomes: The patient’s condition continued to deteriorate, and she eventually died of myocardial infarction.

Conclusion: In immunocompromised patients, combination therapy may be a key factor in improving prognosis, in addition to early detection of coinfection.

Introduction

Cytomegalovirus (CMV) infection is ubiquitous, and most people develop a primary infection at some point in their lives ¹. After initial infection, the virus is latent and usually lies dormant in the normal host for life. Although it does not cause disease, it persists in host leukocytes (possibly monocytes) and can be transmitted to an uninfected individual ². When the host is immunocompromised, the latent virus can be activated and cause severe CMV disease and secondary infections ³. During CMV pneumonia, it is easy to infect other pathogens simultaneously because the virus can cause significant cellular immunosuppression that favors coinfection with bacteria and fungi ⁴. Although both CMV and Aspergillus pneumonia exist in transplant recipients ⁵, few cases have been reported in non-transplant patients. The combined infection is difficult to diagnose and treat, and thus may result in a poor prognosis.

Case Report

A 93-year-old Chinese woman presented to the clinic with fever and shortness of breath for 1 day and was admitted for treatment of pneumonia to the outpatient chest X-ray (Fig. 1), with no previous history. 

Diagnostic assessment

At baseline, the results of her diagnostic tests were: white blood cell count (WBC), 6.95×10^9/L; monocyte count (MONO), 0.22×10^9/L; neutrophil count (NEUT %), 82.1%; monocyte count (MONO), 2.8%; platelet count (PLT), 230×10^9/L; the levels of hemoglobin (Hb), 99 g/L; high-sensitivity C-reactive protein (hs-CRP), 78.35 mg/L; procalcitonin (PCT), 0.05 ng/ml; interleukin 6 (IL6), 122.66 pg/mL; myoglobin (myo), 149.0 ng/ml; D-dimer (fluorescence), 726 ng/mL; erythrocyte sedimentation rate (ESR), 86 mm/h; blood CMV IgG, 87.20 U/ml; urine CMV DNA detection < 10^3 IU/ml; HIV antibody/P24 antigen (luminescence method), 0.10 S/ CO, Treponema pallidum antibody (TP-AP), 0.08 S/ CO; normal liver and kidney functions; negative (bronchoalveolar lavage fluid) Xpert MTB/RIF (Xpert) results; (blood) negative T-spot results; CD4 cell count, 128 cells/mul; CD8 cell count, 52 cells/mul; CD3 cell count, 192 cells/mul. The sinus rhythm and T-wave abnormalities on electrocardiography were checked and chest computed tomography (CT) (Fig. 2) revealed bilateral lung infection, with slightly dilated bronchi in the middle lobe of the right lung and in the upper lobe of the left lung. 

Therapeutic intervention

We empirically gave ceftriaxone for the infection. On the 5th day of admission, metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF) revealed 5 CMV sequences, and a relative abundance of 100%. The patients were treated antivirally with ganciclovir and received human immunoglobulin 2.5g/d. The patient continued to have recurrent fever, and the symptoms of shortness of breath worsened from the 10th day of hospitalization. We rechecked some indicators of the patient, PCT < 0.04 ng/ml; blood CMV IgM 0.29 AU/ml; blood CMV IgG 103.00 U/ml; B-type natriuretic peptide (BNP) 79.2 pg/ml; WBC 5.71×10^9/L, NEUT % 80.0%, Hb 87 g/L, PLT 346×10 ^ 9/L, hs-CRP:43.91 mg/L. During this period, we adjusted ceftriaxone to moxifloxacin for antibacterial treatment of urinary tract infection. On day 13, the chest CT (Fig. 3) was reexamined, and the results showed that the pneumonia had progressed; therefore, diagnostic bronchoalveolar lavage under tracheoscopy was performed again. The BALF was sent for mNGS and pathogen cultures, and a lung biopsy was performed simultaneously. The mNGS test results for BALF showed Aspergillus flavus (number of sequences: 336863, confidence level: 99%), Aspergillus fumigatus (number of sequences: 126752, confidence level: 99%), CMV (number of sequences: 81, confidence level: 99%), and TTV-22 (number of sequences: 4, confidence level: 99%). At the same time, Aspergillus was cultured in the BALF. Histopathological examination of the lung (puncture tissue of the right upper lung) showed reactive hyperplasia of the alveolar epithelium with multiple histiocytes and some chronic inflammatory cells infiltrating the alveolar space, morphologically considered as chronic inflammatory changes (Fig. 4). Based on these results, we immediately changed the antifungal treatment to voriconazole. No drug-related adverse effects were observed during treatment.

Follow-up and outcomes

We initiated appropriate treatment measures in a timely manner (Table 1). Unfortunately, the patient suffered a sudden myocardial infarction seven days later and died the following day.

Discussion

The most common manifestations of CMV disease are fever (58%), pneumonia (26.3%), and enterocolitis (15.8%) ⁶. The virus can affect the production of various cytokines and chemokines, inhibit natural killer and T-cell responses, and humoral immune responses; it may be these immunomodulatory properties that lead to the serious indirect consequences of CMV infection. Patients with CMV pneumonia are susceptible to fungal pneumonia, particularly Aspergillus infections. Because invasive pulmonary Aspergillosis progresses rapidly and is associated with high mortality, it is important to exclude fungal infections in patients with CMV disease. Diagnosis of invasive pulmonary Aspergillosis is quite difficult and requires a race against time. Early bronchoscopy and histology, culture, and immunohistochemistry of transbronchial biopsy are essential for the diagnosis of pulmonary coinfection in immunocompromised patients ⁵. mNGS technology may have important prospects in the diagnosis of such patients ⁷. 

Studies have shown that patients with invasive pulmonary Aspergillosis develop thrombosis problems ⁸; an autopsy study of patients with invasive pulmonary Aspergillosis showed vascular damage ⁹, and Aspergillosis may contribute to thrombosis. Our patient had myocardial infarction with no risk factors other than his age. In our case, cytomegalovirus infection was diagnosed early and treated with ganciclovir + human immunoglobulin. During the initial secondary Aspergillus infection, antifungal treatment with voriconazole was also given in time; however, the effect was not satisfactory, and cardiovascular events occurred in a short time, and the final treatment failed. We hypothesize that the patient’s CMV infection was longstanding and slowly progressed, resulting in a life-threatening factor for secondary aspergillin infection that was insensitive to initial therapy. In such immunocompromised populations, early combined anti-Aspergillus infection therapy (triazole combined with echinocandin or polyene combined with echinocandin ¹⁰) may improve prognosis. In addition, it is equally important to assess patients’ risk of thrombosis and initiate anticoagulation over time.Informed consent statement: The patient's family agreed to the publication of this case.

The diagnosis and treatment of this case is achieved by collecting the current and past medical history, physical examination, laboratory examination, imaging examination, and pathological examination.

The advantage of the method in this case is that the BALF was tested twice by mNGS; the limitation is that the pathology does not reveal typical features of fungal infection.

Declarations

Ethics approval and consent to participate: Obtained ethical approval from the hospital and consent from the patient's family.
 Consent for publication: : N/A
 Availability of data and material: : N/A
 Competing interests: N/A
 Funding: FSPY145014
 Authors' contributions: Kunlun Huang completed the collection and organization of cases and the writing of articles.
 Acknowledgements: This case report was supported by the Foshan Medical Cultivation Specialist Project (FSPY145014).

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Table

Table 1   Patient’s summarized timeline.