Sex: M
Vaccine: DTAPHEPBIP, FLUX, HIBV, PPV
Symptoms: Enterovirus test negative, Epstein-Barr virus test negative, Focal segmental glomerulosclerosis, Gene sequencing, Generalised oedema
Clinical narrative: Fever; poor oral intake; blisters at the site of the immunizations; ulceration at the site of the immunizations; focal glomeruli showed areas of segmental glomerulosclerosis/APOL1-Associated Collapsing Focal Segmental Glomerulosclerosis; worsening digital ischemia leading to autoamputation; had worsening digital ischemia leading to autoamputation; generalized edema; proteinuria; high blood pressure; collapse of the glomerular tuft associated with prominent epithelial cell hyperplasia and hypertrophy; collapse of the glomerular tuft associated with prominent epithelial cell hyperplasia and hypertrophy; tubular atrophy/Atrophic tubules showed a thyroidization pattern of atrophy with focal microcystic tubular dilatation; tubulointerstitial  inflammation; scarring; swelling of the tubular epithelium; nephrotic syndrome; two sclerotic glomeruli; interstitial fibrosis; This case was reported in a literature article and described the occurrence of fever in a 14-month-old male patient who received DTPa-HBV-IPV (Pediarix) for prophylaxis.   Co-suspect products included Flu unspecified (Influenza vaccine) for prophylaxis, Haemophilus influenzae type b vaccine for prophylaxis and PNEUMOCOCCAL VACCINE for prophylaxis.   The patient's past medical history included swelling (of a digit from his left hand, at the age of 4 weeks), skin lesion (multiple recurrent), blister, ulcer, inflammation (dermal perivascular and interstitial), anemia (hemoglobin count: 6.8-10.4 g/dL), thrombocytopenia (platelet count: 36-130 x10e3/µL), fever (high), ischemia (of his digits and toes), sepsis (ischemic changes of his digits and had multiple admissions to the hospital for suspected sepsis), failure to thrive, respiratory symptom (at the age of 7 months), pneumonia (at the age of 7 months and admitted twice to the hospital), ill-defined disorder (diffuse parenchymal and interstitial abnormalities , at the age of 7 month), inflammation (at the age of 7 month), focal seizures and gliosis (MRI revealed multiple areas in the superior vermis, occipital lobe and right thalamus). Previously administered products included corticosteroids, sildenafil (0.5 mg/kg daily (3.7 mg per day) with partial response), ruxolitinib (1 mg twice daily) and JANUS kinase (JAK) inhibitor (1 mg twice daily). Concurrent medical conditions included peripheral ischemia, vascular disorder (stimulator of interferon genes associated vasculopathy with onset in infancy, at the age of 8 months) and immunocompromised.   On an unknown date, the patient received Pediarix at an unknown dose, Influenza vaccine at an unknown dose, Haemophilus influenzae type b vaccine at an unknown dose and PNEUMOCOCCAL VACCINE at an unknown dose. On an unknown date, less than 9 months after receiving Pediarix, Influenza vaccine and Haemophilus influenzae type b vaccine, the patient experienced fever (serious criteria hospitalization), oral intake reduced (serious criteria hospitalization), injection site blisters (serious criteria hospitalization), injection site ulcer (serious criteria hospitalization), focal segmental glomerulosclerosis (serious criteria hospitalization), nephrotic syndrome (serious criteria GSK medically significant), glomerular vascular disorder (serious criteria GSK medically significant), pulmonary fibrosis (serious criteria GSK medically significant), peripheral ischemia (serious criteria hospitalization), condition aggravated (serious criteria hospitalization), generalized edema, proteinuria, blood pressure high, hyperplasia, hypertrophy, atrophy, inflammation, scar and swelling. The patient was treated with enalapril, methylprednisolone and ruxolitinib. On an unknown date, the outcome of the fever, oral intake reduced, injection site blisters, injection site ulcer, focal segmental glomerulosclerosis, nephrotic syndrome, glomerular vascular disorder, pulmonary fibrosis, peripheral ischemia, condition aggravated, generalized edema, proteinuria, blood pressure high, hyperplasia, hypertrophy, atrophy, inflammation, scar and swelling were unknown.   It was unknown if the reporter considered the fever, oral intake reduced, injection site blisters, injection site ulcer, focal segmental glomerulosclerosis, nephrotic syndrome, glomerular vascular disorder, pulmonary fibrosis, peripheral ischemia, condition aggravated, generalized edema, proteinuria, blood pressure high, hyperplasia, hypertrophy, atrophy, inflammation, scar and swelling to be related to Pediarix, Influenza vaccine and Haemophilus influenzae type b vaccine.  Additional details were provided as follows: This case was reported in a literature article and described the occurrence of fever and poor oral intake in a 14-month-old male, who was vaccinated with Pediarix vaccine (GlaxoSmithKline), unspecified pneumococcal vaccine (manufacturer unknown), unspecified influenza vaccine (manufacturer unknown), and unspecified Haemophilus influenzae type B vaccine (manufacturer unknown) for prophylaxis.  The patient was boy and one of fraternal twins. At the age of 4 weeks, the patient was presented with swelling of a digit from his left hand. The patient subsequently developed multiple recurrent skin lesions, characterized by blisters that progressed to ulcers. Skin biopsy was performed which showed dermal perivascular and interstitial inflammation with vasculopathy. The patient also developed recurrent ischemic changes of his digits and toes. Initial laboratory evaluation showed persistently elevated levels of inflammatory markers and unexplained anemia (hemoglobin, 6.8-10.4 g/dL). The patient was subsequently developed thrombocytopenia (platelet count, 36-130 x10e3/µL), elevated ferritin level (630-21,804 ng/mL), prolonged prothrombin time and partial thromboplastin time, and low fibrinogen level (1.06-1.80 g/L) that was concerning for macrophage activation syndrome. The patient was initially treated with high-dose corticosteroids followed by a slow tapering dose and 0.5 mg/kg daily of sildenafil (3.7 mg per day), with partial response. The patient continued to develop skin lesions associated with high fevers and ischemic changes of his digits and had multiple admissions to the hospital for suspected sepsis in an immunocompromised patient. The patient also had failure to thrive. At 7 months of age, the patient developed respiratory symptoms and was admitted twice to the hospital for pneumonia. Computed tomography of the chest showed diffuse parenchymal and interstitial abnormalities and findings suggestive of both acute and chronic inflammation. At the age of 8 months, the diagnosis of stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) was made by targeted genetic testing of transmembrane protein 173 (TMEM173), which showed a heterozygous variant predicted to lead to a valine to leucine substitution at amino acid 147 (V147L). Genetic testing for familial hemophagocytic lymphohistiocytosis (HLH), periodic fever syndromes, and deficiency of adenosine deaminase 2 was negative. Based on these findings, the patient was started on treatment with ruxolitinib, a JANUS kinase (JAK) inhibitor, 1 mg twice daily. The development of new skin lesions became less frequent, as well as the frequency of hospitalizations. The ruxolitinib dose was increased to 2.5 mg and the patient did well for a few months before an acute episode of focal seizures. At that time, magnetic resonance imaging of the brain revealed multiple areas suggestive of gliosis in the superior vermis, occipital lobe, and right thalamus from a prior event such as ischemia. However, magnetic resonance angiography and magnetic resonance venography results were normal. An electroencephalogram was also unremarkable. Before immunizations, the patient's ruxolitinib treatment had been on hold for 11 days. No information on patient's family history was provided.  On an unspecified date, the patient received Pediarix vaccine (GlaxoSmithKline), unspecified pneumococcal vaccine, unspecified influenza vaccine, and unspecified Haemophilus influenzae type B vaccine (administration route and site unspecified, dosage unknown; batch number not provided for all). The age of vaccination was not provided. On an unspecified date, at the age of 14 months, an unknown period after routine immunization, the patient was admitted to the hospital for fevers and poor oral intake. During this hospitalization, the patient developed blisters and ulceration at the site of the immunizations, which later worsened and became more diffuse. The patient also had worsening digital ischemia leading to autoamputation. Workup for infection included blood culture; urine culture; a respiratory polymerase chain reaction panel that included influenza, parainfluenza, adenovirus, coronavirus, respiratory syncytial virus, rhinovirus, enterovirus, Bordetella pertussis, and Mycoplasma pneumoniae; and serologic testing for cytomegalovirus, Epstein-Barr virus, and parvovirus. This workup failed to show an infectious cause. During this flare, the patient developed generalized edema, proteinuria, and serum albumin level of 0.8 to 1.9 g/dL, consistent with nephrotic syndrome. Urinalysis showed protein (3+), and protein-creatinine ratio was 34 mg/mg. Before this hospitalization, he had had multiple urinalyses performed that had never shown proteinuria. The patient also developed high blood pressure, and treatment with 0.25 mg/kg daily of enalapril was started. The patient was treated with methylprednisolone, 30 mg/kg daily, and treatment with ruxolitinib (2.5 mg twice daily) was restarted. He continued to have nephrotic range proteinuria and a kidney biopsy was performed. One core of renal cortex was available for light microscopy; this contained 23 glomeruli, 2 of which were globally sclerotic. Nonsclerotic glomeruli frequently showed collapse of the glomerular tuft associated with prominent epithelial cell hyperplasia and hypertrophy. Reactive epithelial cells showed numerous cytoplasmic protein droplets. Additionally, focal glomeruli showed areas of segmental glomerulosclerosis. Otherwise, glomeruli showed no evidence of mesangial or endocapillary hypercellularity. Moderate interstitial fibrosis and tubular atrophy were present, involving 30% of the cortical surface. Mild mixed tubulointerstitial inflammation was noted predominantly within areas of scarring. Atrophic tubules showed a thyroidization pattern of atrophy, with focal microcystic tubular dilatation. Nonatrophic tubules showed marked swelling of the tubular epithelium with large numbers of cytoplasmic protein resorption droplets. Arteries and arterioles were unremarkable. Six glomeruli were available for immunofluorescence, none of which were globally sclerotic. All staining, including for immunoglobulin A (IgA), IgG, IgM, C3, C1q, fibrinogen, and kappa and lambda light chains, was negative within glomeruli. For IgG and kappa and lambda light chain, the proximal tubule protein resorption droplets stained strongly positive. Ultrastructural examination of a glomerulus using electron microscopy showed uniform glomerular basement membranes of normal thickness. No immune electron-dense deposits were present. Epithelial foot processes were moderately effaced, involving 30% of available capillary loops. Few endothelial tubuloreticular inclusions were noted. Tubular basement membranes were unremarkable. Two glomeruli were examined using electron microscopy and both showed a similar degree of epithelial foot-process effacement. Deoxyribonucleic acid (DNA) from the patient's peripheral blood was genotyped for Apolipoprotein L1 (APOL1) risk alleles using TaqMan primer/probe custom design assays. One of the G1 risk variants (rs73885319, encoding a serine to glycine substitution at amino acid 342) and the G2 risk variant (the insertion/deletion encoded by rs71785313) showed compound heterozygosity.  This case has been considered as serious due to hospitalization.  The outcome of the event was not reported.  The author did not comment relationship between the events and pediarix vaccine, unspecified influenza vaccine, and unspecified Haemophilus influenzae type B vaccine.  The authors stated, "This case of a patient heterozygous for the G1 and G2 risk alleles of APOL1 who has a high interferon (IFN) state due to his underlying condition of SAVI provides further support for IFN as an inducer of collapsing glomerulopathy in individuals with the APOL1 high-risk genotype. As such, patients with type 1 interferonopathies who are affected by the upregulation of type I IFN signaling have persistent systemic inflammation. There is a growing body of evidence implicating IFN pathways in the pathogenesis of APOL1-associated collapsing glomerulopathy. Collapsing glomerulopathy is the most fulminant histopathologic form of APOL1-associated nephropathy. It was reported a case of APOL1-associated nephropathy in the setting of the genetic disease SAVI, a type I interferonopathy syndrome, which raises the possibility of increased risk for kidney disease in patients with this disease. In addition, this case further establishes the pathogenic role of IFN in patients with 2 APOL1 risk alleles. Similar to patients with exogenous IFN therapy, this patient with a condition that leads to increased endogenous IFN levels developed the most fulminant form of APOL1-associated nephropathy, collapsing glomerulopathy."      Lab Comments: Lab test were performed on an unspecified date. Renal biopsy showed one core of renal cortex was available for light microscopy; this contained 23 glomeruli, 2 of which were globally sclerotic. Nonsclerotic glomeruli frequently showed collapse of the glomerular tuft associated with prominent epithelial cell hyperplasia and hypertrophy. Reactive epithelial cells showed numerous cytoplasmic protein droplets. Focal glomeruli showed areas of segmental glomerulosclerosis. Otherwise, glomeruli showed no evidence of mesangial or endocapillary hypercellularity. Moderate interstitial fibrosis and tubular atrophy were present, involving 30% of the cortical surface. Mild mixed tubulointerstitial inflammation was noted predominantly within areas of scarring. Atrophic tubules showed a thyroidization pattern of atrophy, with focal microcystic tubular dilatation. Nonatrophic tubules showed marked swelling of the tubular epithelium with large numbers of cytoplasmic protein resorption droplets. 6 glomeruli were available for immunofluorescence, none of which were globally sclerotic. All staining, including for immunoglobulin A (IgA), IgG, IgM, C3, C1q, fibrinogen, and kappa and lambda light chains, was negative within glomeruli. No immune electron-dense deposits were present. Epithelial foot processes were moderately effaced, involving 30% of available capillary loops. Few endothelial tubuloreticular inclusions were noted. Tubular basement membranes were unremarkable. Deoxyribonucleic acid (DNA) from the patient's peripheral blood was genotyped for Apolipoprotein L1 (APOL1) risk alleles using TaqMan primer/probe custom design assays. One of the G1 risk variants (rs73885319, encoding a serine to glycine substitution at amino acid 342) and the G2 risk variant (the insertion/deletion encoded by rs71785313) showed compound heterozygosity.