Death due to human cytomegalovirus infection in a girl with congenital thymic dysplasia | Virology Journal

Death due to human cytomegalovirus infection in a girl with congenital thymic dysplasia |  Virology Journal

Human cytomegalovirus (CMV) or human herpes virus-5 is a member of the family Herpesviridae [1]. It is a prevalent viral pathogen that causes primary infection, usually during childhood. CMV infection cannot be eliminated from the host and produces a wide spectrum of illnesses, ranging from asymptomatic infections to severe multi-organ systemic illnesses. [2, 3]. Congenital cytomegalovirus (cCMV) infection is a common congenital infection that can result in impaired fetal development, stillbirth, severe congenital malformations, and long-term neurodevelopmental sequelae, including mental retardation and sensorineural hearing loss (SNHL); however, most newborns are asymptomatic. [1]. CMV can also cause life-threatening illness in immunocompromised patients, whether the infection is reactivated or acquired through primary CMV infection. In particular, primary CMV infections or reactivation cause severe disease in early-onset children with primary T-cell lymphopenia, natural killer (NK) cell lymphopenia, and many combinations of immunologic defects due to immune dysregulation and persistence of infection. CMV infection related to T-cell depletion [4, 5]. Refractory or resistant CMV infection is also a challenge due to the long-term use of limited antiviral drugs and the increasing number of vulnerable patients. [6]. Whereas refractory CMV infection is defined as viremia that increases after at least two weeks of adequate antiviral therapy, antiviral drug resistance refers to a viral genetic alteration that decreases susceptibility to one or more antiviral drugs. [7].

Children with severe combined immunodeficiency (SCID) with resultant severe T-cell lymphopenia are at risk of severe CMV infection [3]. As a select group of patients, congenital thymic dysplasia represents the archetype of thymic changes in cellular immunodeficiency, leading to reduced or absent cellular immune reactivity with normal immunoglobulin levels. [8]. However, there are few reports of congenital thymic dysplasia exacerbated by CMV infection in primary immunodeficiency with T-cell lymphopenia. We present the case of a 10-month-old girl with congenital thymic dysplasia who presented with refractory disseminated CMV infection after failure of therapy. antiviral.

case presentation

The girl was born to nonconsanguineous parents at 39 weeks’ gestation, with a birth weight of 3400 g and a normal head circumference of 34 cm. She had a brother who died of pneumonia at the age of five months. She had pneumonia and neonatal jaundice, but her condition improved and she was discharged five days later after treatment with piperacillin/tazobactam.

The patient presented dyspnea and tachypnea, and was admitted to the intensive care unit (ICU) at three months of age. The patient weighed 5 kg and appeared to be malnourished. During physical examination, a BCG vaccine scar sinus of approximately 0.5 × 0.3 cm was identified on the left upper arm, and the discharge was Xpert/MTB (mycobacterial tuberculosis) positive. She presented hepatomegaly (liver 4 cm below the costal margin), and laboratory tests revealed liver dysfunction, anemia, hypoproteinemia, and thrombocytopenia (Table 1). A computed tomography (CT) scan of the chest revealed swollen lymph nodes in the left axilla and patchy shadows in both lungs (Fig. 1). She was diagnosed with CMV infection and immunodeficiency due to T-cell lymphopenia with the following clinical history: a) persistent respiratory infection; (b) presence of tuberculosis in a left axillary lymph node; (c) panel of lymphocyte subsets demonstrated T-cell lymphopenia (Table 2); and (d) severe malnutrition. However, the etiology of her persistent immunodeficiency was unknown. Serologic markers for human immunodeficiency virus (HIV) were negative. A virological test showed a negative result. CMV immunoglobulin M (CMV– IgM) and positive CMV immunoglobulin G (CMV– IgG). The CV of CMV measured with polymerase chain reaction (PCR) was very high (Fig. 2).

Table 1 Laboratory study of four hospitalization times
Figure 1
Figure 1

A computed tomography (CT) scan of the chest was obtained at five months. a Left axillary lymph nodes (arrows). b Jagged shadows scattered in the lungs

Table 2 Immune function tests
Figure 2
Figure 2

Changes in viral load (VL) of cytomegalovirus (CMV) and antiviral therapy

The patient was intubated and artificially ventilated due to respiratory distress. A standard INH-RIF-EMB-PZA anti-tuberculosis treatment regimen was provided. Antiviral treatment with GCV (5 mg/kg, 2 times a day) and antibiotic therapy with vancomycin, meropenem, and cefoperazone/sulbactam were started. She was discharged with oral V-GCV (16 mg/kg, twice daily) from our hospital on admission day 50 with improvement and CMV VL level decreased to 5010 copies/mL in blood (Fig. 2) when I was five months old.

When he was seven months old, he was admitted to the hospital with a fever, shortness of breath, abnormal vision, and drowsiness. Blood tests showed anemia and liver dysfunction (Table 1). A physical examination revealed that the malnourished condition was not corrected; the girl had poor light reflection and poor visual acuity. Brain magnetic resonance imaging revealed backward cerebral myelination, whose levels of mature myelination were equivalent to those of a three-month-old infant (Fig. 3). The visual evoked potential (VEP) was abnormal, while the auditory evoked potentials (AEP) were normal. Cardiac ultrasound demonstrated enlargement of the left ventricle with a small amount of pericardial effusion. Ophthalmologic examination revealed retinal detachment, effusion, and necrosis. Whole exon WES and trios sequencing did not confirm the existence of genetic variations strongly related to disease characteristics. The elevated CMV CV was 94,200 copies/ml (Fig. 2). Refractory disseminated CMV disease was associated with organ involvement (pneumonitis, hepatitis, and retinitis).

figure 3

Brain magnetic resonance imaging (MRI) of the patient at seven months. T1-weighted images (a Y C) and T2-weighted images (b). a The posterior limb of the internal capsule partially shows high intensity, suggesting myelination (arrows). b The posterior limb of the internal capsule shows low intensity, suggesting delayed myelination (arrows). C The gyri enlarged and the sulci deepened, while the hypoplastic corpus callosum showed hypointensity, suggesting progressive myelination (arrows)

Alternative therapies failed to treat the immunodeficiency, and a panel of lymphocyte subsets demonstrated worsening T-cell lymphopenia (Table 2). Given the refractory CMV infection, we added foscarnet (FCV, 60 mg/kg, qd) with V-GCV to the therapy regimen without drug titer determination or viral genetic alterations. GCV was injected into the vitreous cavity of the eyes, while there were 1.84E + 08 copies of CMV VL per milliliter of vitreous fluid. Antituberculous and antibiotic therapies were originally planned. During the 50-day treatment, the condition improved, including a decrease in VL and better liver function and pneumonia. Her guardian requested discharge from the hospital without FCV.

A month later, the girl was readmitted to the hospital for drowsiness and pneumonia. The patient presented severe global developmental delay with regression and her weight dropped to 4.4 kg. The chest X-ray showed severe pulmonary inflammation (fig. 4). During the illness she had intermittent fever, septic shock (vital signs were as follows: blood pressure 78/54 mmHg, heart rate 170 per minute, respiratory rate 73 per minute, and body temperature 38.5°C). She was transferred to the ICU to receive advanced life support measures. Her viral load has continued to increase with worsening of symptoms due to antiviral treatment with V-GCV, reaching 6.98E + 06 copies/ml (Fig. 2). The patient developed pneumothorax and subcutaneous emphysema, and she died of progressive respiratory failure and septic shock at 10 months of age.

Figure 4
Figure 4

Chest X-ray images of the patient at three (a) and nine (b) months. Sparse, irregular shadows and interstitial changes


An autopsy with organ involvement, including lungs, heart, liver, kidneys, and glands (pancreas, thyroid, and salivary gland tissues), was performed to confirm disseminated CMV infection. Inclusion bodies such as nucleolar cells were found in the tissues (Fig. 5). H&E staining of the thymus revealed a reduction in the number of thymic lobes with cortical predominance, with the medulla showing a poorly formed disappearance of the thymic corpuscle, all of which indicated dysplasia of the thymus. Immunohistochemistry showed a greater number of CD3-positive T cells than CD20-positive B cells (Fig. 5).

Figure 5
Figure 5

200 × Hematoxylin and eosin (H&E) stained appearance of CMV-infected tissues containing inclusion bodies such as nucleolar cells (arrows): a lungs; b heart; C liver; d kidney; me scam F The number of thymic lobes is reduced, the malformed medullary gland disappears into the thymic corpuscle, and lymphocytes are significantly reduced, suggesting thymic dysplasia. gram CD3 cells with 100 × immunohistochemical (ICH) staining in the thymus. gram 100 × CD20 immunohistochemical (ICH) staining, suggesting more CD3-positive T cells than CD20 cells (yellow-brown)

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