Systemic BK Virus Infection in a Pediatric Patient With Severe Combined Immunodeficiency

Introduction

Human polyomaviruses comprise a large family, with 13 species having been proven to cause human infection. ¹ The most common and best characterized are BK virus (BKV) and JC virus. Their seroprevalence seems to be high, up to 90% in the general adult population, ¹ and primary infection is believed to occur early in childhood through the respiratory route. ² BKV is then known to establish latent infection in different tissues, with the kidneys, central nervous system (CNS), and lymph nodes having been reported. Although usually infection remains latent, under conditions of immunosuppression, high-scale replication occurs, leading to inflammatory tissue damage. ² BKV is now known to cause specific clinical conditions, the most widely reported being BKV nephropathy, as well as ureteric stenosis and hemorrhagic cystitis among kidney transplant recipients. Nevertheless, other conditions associated with immunosuppression can result in BKV inflammatory damage, such as human immunodeficiency virus (HIV) infection ³ and systemic lupus erythematosus (SLE). ⁴

We present here the autopsy findings of a pediatric patient known to have severe combined immunodeficiency (SCID) who was found to have systemic BKV infection. To the extent of our knowledge, there is no other similar case reported in the literature.

Case Report

A 12-month-old male infant was admitted because of recurrent diagnoses of gastroenteritis and typhoid fever at the age of 6 months. He had also had, at the age of 9 months, a vesicular rash that began on the left upper extremity, which on biopsy had revealed the presence of multiple acid-fast bacilli, which proved through polymerase chain reaction (PCR) to be Mycobacterium bovis. He had a family history with a 4-month-old brother who deceased due to bronchopneumonia and septic shock and 3 healthy female sisters. He had no previous medical history and had received vaccination against tuberculosis, hepatitis B, polio, diphtheria, tetanus, Bordetella pertussis, and type B Haemophilus influenzae. During his stay, bloodwork revealed low immunoglobulin levels (IgG 96.8 mg/dL, IgM below 18.6 mg/dL, and IgA below 23.6 mg/dL), and flow cytometry revealed the absence of CD3+CD4+, CD8+ cells, with CD19+ and CD16+56+ cells present. A serum HIV enzyme-linked immunosorbent assay test gave a negative result, and he was diagnosed with SCID. Stool analysis revealed the presence of rotavirus and Salmonella enterica type C, for which treatment with meropenem and 2 doses of intravenous immunoglobulin were given, after which he was discharged home. Six days later, he was readmitted due to a new episode of gastroenteritis and treated with ceftriaxone. Stool culture revealed the presence of Salmonella type C, and ciprofloxacin was added. He was then found to have acute kidney injury (with an increase in serum creatinine from 0.3 to 0.6 mg/dL) which was presumed to be drug-related. He then developed sepsis secondary to a central venous catheter infection (5 months into his hospitalization), and blood cultures revealed the presence of Enterococcus faecalis, and vancomycin was added. Four months later, he was diagnosed with bronchopneumonia and admitted to the pediatric intensive care unit (ICU). While on the ICU, a new episode of acute kidney injury was evidenced by a rise in serum creatinine to 1.48 mg/dL, with a clinical diagnosis of acute tubular necrosis. At this point, physical examination revealed the presence of hepatosplenomegaly, as well as an elevation on liver enzymes, and the diagnosis of hemophagocytic syndrome was established. He was given etoposide and steroids, with no clinical response.

He continued to show respiratory distress. Chest X-rays showed the presence of basal infiltrates, for which treatment with thrimetoprim-sulfametoxazole was begun. He eventually showed multiple organ failure and died 8 months after his second admission.

Autopsy features corroborated the clinical SCID diagnosis: thymic dysplasia, rudimentary tonsils, absence of Peyer’s patches in the terminal ileum, and lymph nodes showing scant follicles and no germinal centers.

Further histologic findings showed necrotizing bronchiolitis of possible viral origin, disseminated anergic-type tuberculous dermatitis, and hemophagocytic syndrome. Disseminated BKV was detected, with involvement of the kidneys, bladder, pancreas, and leptomeninges.

The gross aspect of left kidney showed an accentuated lobular pattern, with a firm consistency and a pale brown color; there was dilatation of the pyelocaliceal system, and scant hemorrhagic mottling in the tips of the renal pyramids. Histological examination revealed the presence of multiple intranuclear viral inclusions in tubular epithelial cells and podocytes, with variable appearances: eosinophilic, basophilic, and ground glass. There was also necrosis and detachment of epithelial cells (Figure 1(A)) as well as pseudocrescent formation. Immunohistochemistry with anti-SV40 large T antigen showed positivity in all these cells (Figure 1(B)). Transmission electron microscopy revealed nuclear viral particles in a paracrystalline arrangement (Figure 1(C) and (D)). Furthermore, end-point PCR confirmed the presence of BKV DNA (Figure 2). Macroscopic examination of the pancreas revealed smooth, yellow-colored external and cut surfaces with interspersed whitish, firm areas with a fibrous appearance, predominantly in the head of the pancreas. Histologically, all this was seen as chronic pancreatitis with fibrosis and inflammatory infiltrate that contained almost exclusively macrophages. Viral nuclear inclusions were observed in ductal and acinar cells, similar to those observed in the kidney (Figure 3(A)); the presence of BKV was confirmed by immunohistochemistry (Figure 3(B)). In the CNS, the leptomeninges were diffusely opacified, and BKV inclusions were identified in arachnoid cells (Figure 3(C) and (D)). The presence of BKV was also demonstrated in urothelial cells of the renal pelvis and bladder. OPEN IN VIEWER

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Figure 2.

Histological diagnosis was confirmed with PCR amplification of BKV DNA. BKV, BK virus; MPM, molecular weight marker.

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Figure 3.

Viral nuclear inclusions were observed in pancreatic ductal and acinar cells (A: hematoxylin-eosin). Immunohistochemistry against SV40 confirmed the presence of BKV in these inclusions (B: SV40 immunohistochemistry). Nuclear inclusions were also seen in arachnoid cells (C: hematoxylin-eosin), which also stained positively with immunohistochemistry against SV40 (D: immunohistochemistry against SV40).

Discussion

Although, as mentioned previously, most of the literature focuses on specific causes of immunosuppression, chiefly kidney transplant recipients, there are some reports of BKV disease among patients undergoing hematopoietic stem cell transplants, ⁵ and patients with HIV infection. ⁶ Patients with autoimmune diseases, such as SLE, by themselves immunosuppressant, have been found to have higher rates of BKV viremia and viruria.^4,7

SCID with a T− B+ natural killer (NK)+ immunoprofile is a rare autosomal recessive form of the disease, involving the interleukin-7 receptor, resulting in a failure of signaling for T cell proliferation. ⁸ Despite the fact that these cell population has been proven to be involved in controlling latent BKV infections, ² there are no reports of polyomavirus-mediated disease among this population. The only reported case of BKV infection among patients with congenital immunodeficiencies, to the extent of our knowledge, was a patient with common variable immunodeficiency (CVI) and BKV meningoencephalitis. ⁹ This would indeed sound counterintuitive, and further research is needed, one possible explanation being the absence of routine BKV testing among these individuals, as several more common intracellular pathogens are usually suspected. Another cause could be the age of presentation itself, since by 3 to 4 years of age the prevalence of BKV infection is much lower than in adults, around 50%. ¹⁰ Since patients with SCID commonly present recurrent infections and possible death by 2 years of age, ⁹ it would be reasonable to assume the rate of infection among these infants were lower.

Apart from the common diseases known to be associated with BKV, there have been reports of BKV-associated encephalopathy, ¹¹ gastrointestinal bleeding, ¹² and pneumonitis. ¹³ And although BKV is known to infect mononuclear cells of the immune system, with the possibility of then disseminating throughout the whole bloodstream, ² this is one of the very few cases of a patient with proven BKV systemic infection as well as the only reported case of BKV-associated pancreatitis. Although there are other reported cases of BKV-associated hemophagocytic syndrome, ¹⁴ this patient was known to have other bacterial and viral infections, and therefore causation could not be established.

As to the clinical data available before the death of the patient, the usual findings of kidney damage associated with BKV nephritis were present, but the complex medical history of the patient may have hindered clinical data that could arise suspicion of BKV-associated disease.

Histological confirmation of the diagnosis was undertaken through immunohistochemistry, using antibodies directed against the large T antigen, known to cross-react with other polyomavirus-infected tissues, ² and was therefore confirmed through detection of specific BKV DNA sequences.