Sex: F
Vaccine: HEPA, HIBV, MMR, UNK, VARCEL
Symptoms: Inflammation, Intensive care, Interleukin-2 receptor assay, Irritability, Lethargy
Clinical narrative: erythematous rash; human herpes virus type 6; Hemophagocytic lymphohistiocytosis; desaturation; apnea; fever; diarrhea; vomiting; nasal congestion; cough; irritability; lethargy; Escherichia coli; Rhinovirus infection; enterovirus; tachycardia; varicella-zoster virus; vesicular rash; otitis media; papular; urticarial rash; parainfluenza virus; human metapneumovirus; This case was reported in a literature article and described the occurrence of hemophagocytic lymphohistiocytosis in a infant female patient who received Hepatitis A vaccine for prophylaxis.   Co-suspect products included Hib UNK (Hib vaccine) (batch number UNK, expiry date unknown) for prophylaxis, MEASLES MUMPS RUBELLA (batch number UNK, expiry date unknown) for prophylaxis, LIVE VARICELLA VIRUS VACCINE (VARIVAX) (batch number UNK, expiry date unknown) for prophylaxis and PNEUMOCOCCAL 13 VALENT CONJUGATE VACCINE (batch number UNK, expiry date unknown) for prophylaxis.   The patient's past medical history included viral infection (at 9 m;onths of age), fever (triggered by seasonal coronavirus HKU1), seizure (triggered by seasonal coronavirus HKU1 (non-COVID-19) infection.), influenza a virus infection (severe), pneumonia (with very high fever) and respiratory failure (treated with oseltamivir, ceftriaxone, methylprednisolone). Concurrent medical conditions included immunodeficiency (STAT2 Deficiency.).   On an unknown date, the patient received Hepatitis A vaccine, Hib vaccine, MEASLES MUMPS RUBELLA, VARIVAX and PNEUMOCOCCAL 13 VALENT CONJUGATE VACCINE. On an unknown date, 6 days after receiving Hepatitis A vaccine and Hib vaccine, the patient experienced hemophagocytic lymphohistiocytosis (serious criteria hospitalization, GSK medically significant and life threatening), parainfluenzae virus infection (serious criteria GSK medically significant and life threatening), fever (serious criteria hospitalization), diarrhea (serious criteria hospitalization), vomiting (serious criteria hospitalization), nasal congestion (serious criteria hospitalization), cough (serious criteria hospitalization), irritability (serious criteria hospitalization), lethargy (serious criteria hospitalization), escherichia coli infection (serious criteria hospitalization and GSK medically significant), rhinovirus infection (serious criteria hospitalization), enterovirus infection (serious criteria hospitalization and GSK medically significant), tachycardia (serious criteria hospitalization), red rash (serious criteria hospitalization), human herpesvirus 6 infection (serious criteria hospitalization), metapneumovirus infection (serious criteria GSK medically significant), oxygen saturation decreased (serious criteria hospitalization), apnea (serious criteria hospitalization and GSK medically significant), varicella zoster virus infection, vesicular rash, otitis media, papular rash and urticarial rash. The patient was treated with ceftriaxone (Ceftriaxone Sodium) and acyclovir. On an unknown date, the outcome of the hemophagocytic lymphohistiocytosis, parainfluenzae virus infection, fever, diarrhea, vomiting, nasal congestion, cough, irritability, lethargy, escherichia coli infection, rhinovirus infection, tachycardia, red rash, human herpesvirus 6 infection, metapneumovirus infection, oxygen saturation decreased, apnea, varicella zoster virus infection, vesicular rash, otitis media, papular rash and urticarial rash were recovered/resolved and the outcome of the enterovirus infection was unknown.   It was unknown if the reporter considered the hemophagocytic lymphohistiocytosis, parainfluenzae virus infection, fever, diarrhea, vomiting, nasal congestion, cough, irritability, lethargy, escherichia coli infection, rhinovirus infection, enterovirus infection, tachycardia, red rash, human herpesvirus 6 infection, metapneumovirus infection, oxygen saturation decreased, apnea, varicella zoster virus infection, vesicular rash, otitis media, papular rash and urticarial rash to be related to Hepatitis A vaccine and Hib vaccine.  Additional details were provided as follows: This case was reported in a literature article and described the occurrence of hemophagocytic lymphohistiocytosis (HLH) in a female patient aged between 12-13 months old, who was vaccinated with unspecified hepatitis A vaccine and unspecified Haemophilus influenzae type B vaccine (manufacturer unknown for all) for prophylaxis.  The patient was born to distantly related but healthy parents at 38 weeks of gestation. Her own medical history was remarkable for significant viral illness: at 9 months of age, the patient had a prolonged febrile illness with seizures, triggered by seasonal coronavirus HKU1 (non-COVID-19) infection. At 10 months of age, the patient experienced severe influenza A (H3) pneumonia with very high fever and progressive respiratory failure despite treatment with oseltamivir, ceftriaxone, methylprednisolone and oxygen delivered by high-flow nasal cannulae. The patient required intubation and mechanical ventilation for 3 days but recovered. Whole exome sequencing of DNA extracted from whole blood of the proband was performed commercially on the Illumina platform by Invitae Corporation. Carriage of the STAT2 variant by the proband, and all family members, was tested by Sanger sequencing of DNA isolated from whole blood by local diagnostic genetic laboratories according to standard methodologies. Suspecting a genetic aetiology in this case, whole exome sequence analysis and addition/deletion testing of 207 genes associated with primary immunodeficiency was undertaken on whole blood DNA from the proband, identifying a homozygous predicted pathogenic variant in STAT2 (c.1999C less than T [p.Arg667Ter]) and a heterozygous variant in DOCK2 [c.54-1Gless than T], the latter of unlikely clinical relevance. Sanger sequencing analysis confirmed the presence of STAT2 c.1999C less than T in the homozygous state in the proband. This variant was heterozygous in both parents and a clinically unaffected sibling, consistent with segregation of an autosomal recessive trait. No information on patient's medical history, family history, concurrent condition or concomitant medication was provided. On an unspecified date, 6 days before onset of illness, the patient received unspecified measles, mumps, and rubella (MMR) vaccine, unspecified hepatitis A vaccine, unspecified Haemophilus influenzae type B vaccine, varivax (varicella zoster virus) vaccine and 13-valent pneumococcal conjugate vaccine (administration route and site unspecified, dosage unknown; batch number not provided for all). The age of vaccination was not provided but it could be 12 months or 13 months. [Six days before onset of this illness, she had been inoculated with age-appropriate vaccines (MMR, varicella zoster virus, hepatitis A, Haemophilus influenzae type B, and the 13-valent pneumococcal conjugate vaccines) despite nasal congestion and clear rhinorrhea]. On an unspecified date, 6 days after the vaccination, the patient presented with high fever, diarrhea, new onset vomiting, nasal congestion, cough, irritability, and lethargy. On admission, her physical examination only showed nasal congestion. The laboratory parameters were largely unremarkable. On day 4 (d4), the patient's laboratory parameter showed: hemoglobin was 12.1 g/dL (normal range: 10.2-14.7), hematocrit was 34.4 % (normal range: 30.8-43.7), white blood cell count was 7.6x10e9/L (normal range: 6.0-17.5), absolute neutrophil count was 4x10e9/L (normal range: 1.5-8.5), absolute lymphocyte count was 2.3x10e9/L (normal range: 4.0-10.5), absolute monocyte count was 1.2x10e9/L (normal range: 0.3-0.9), platelet count was 242x10e9/L (normal range: 150-450), AST was 66 U/L (normal range: 10.0-37.0), and ALT was 57 U/L (normal range: 5.0-30.0). On day 6 (d6), the patient's laboratory parameter showed: hemoglobin was 10.4 g/dL , hematocrit was 30.1 %, white blood cell count was 3.5x10e9/L, absolute neutrophil count was 2.2x10e9/L, absolute lymphocyte count was 1x10e9/L , absolute monocyte count was 0.2x10e9/L, platelet count was 144x10e9/L , AST was 57 U/L, ALT was 38 U/L  and C-reactive protein was 76 mg/L (normal range: 0.0-8.0). On day 7 (d7), the patient's laboratory parameter showed: hemoglobin was 10.1 g/dL (normal range: 10.2-14.7), hematocrit was 29.2 % (normal range: 30.8-43.7), white blood cell count was 2.3x10e9/L (normal range: 6.0-17.5), absolute neutrophil count was 1.2x10e9/L (normal range: 1.5-8.5), absolute lymphocyte count was 1x10e9/L (normal range: 4.0-10.5), absolute monocyte count was 0.1x10e9/L (normal range: 0.3-0.9), and platelet count was 127x10e9/L (normal range: 150-450). On day 8 (d8), the patient's laboratory parameter showed: hemoglobin was 9.4 g/dL (normal range: 10.2-14.7), hematocrit was 26.9 % (normal range: 30.8-43.7), white blood cell count was 1.4x10e9/L (normal range: 6.0-17.5), absolute neutrophil count was 0.8x10e9/L (normal range: 1.5-8.5), absolute lymphocyte count was 0.6x10e9/L (normal range: 4.0-10.5), absolute monocyte count was 9.1x10e9/L (normal range: 0.3-0.9), and platelet count was 107x10e9/L (normal range: 150-450). On day 9 (d9), the patient's laboratory parameter showed: hemoglobin was 9.7 g/dL (normal range: 10.2-14.7), hematocrit was 27 % (normal range: 30.8-43.7), white blood cell count was 1.5x10e9/L (normal range: 6.0-17.5), absolute neutrophil count was 0.8x10e9/L (normal range: 1.5-8.5), absolute lymphocyte count was 0.7x10e9/L (normal range: 4.0-10.5), absolute monocyte count was 0, platelet count was 85x10e9/L, AST was 221 U/L , ALT was 100 U/L, ferritin was 1980 ng/ml, lactate dehydrogenase was 1043 U/L , and triglycerides was 289 mg/dL. On day 10 (d10), the patient's laboratory parameter showed: hemoglobin was 9.8 g/dL, hematocrit was 26.3 %, white blood cell count was 2.7x10e9/L, absolute neutrophil count was 1.1x10e9/, absolute lymphocyte count was 1.3x10e9/L, absolute monocyte count was 0.2, platelet count was 85x10e9/L, AST was 125 U/L, ALT was 94 U/L, D-dimer was more than 9999 ng/ml, fibrinogen was 71 mg/dLand soluble interleukin-2 receptor was 14740 pg/ml. On day 11 (d11), the patient's laboratory parameter showed: hemoglobin was 8.9 g/dL (normal range: 10.2-14.7), hematocrit was 25.7 %, white blood cell count was 3.5x10e9/L, absolute neutrophil count was 1.4x10e9/L, absolute lymphocyte count was 1.7x10e9/L, absolute monocyte count was 0.3, platelet count was 101x10e9/L, AST was 104 U/L, ALT was 85 U/L , and fibrinogen was 65 mg/dL. On day 12 (d12), the patient's laboratory parameter showed: hemoglobin was 8.1 g/dL , hematocrit was 24.5 % , white blood cell count was 5.6x10e9/L, absolute neutrophil count was 2.4x10e9/L (normal range: 1.5-8.5), absolute lymphocyte count was 2.6x10e9/L , absolute monocyte count was 0.4, platelet count was 135x10e9/L, AST was 82 U/L, and ALT was 78 U/L. On day 15 (d15), the patient's laboratory parameter showed: hemoglobin was 8.9 g/dL, hematocrit was 27.3 %, white blood cell count was 9.1x10e9/L, absolute neutrophil count was 3.1x10e9/L, absolute lymphocyte count was 4.6x10e9/L, absolute monocyte count was 0.7, platelet count was 534x10e9/L AST was 73 U/L and ALT was 55 U/L A partial septic screen yielded more than 100,000 colony forming units/ml of Escherichia coli from urine and a positive PCR for rhinovirus/enterovirus RNA from a nasopharyngeal swab sample. Blood cultures collected on days 4 and 6 and were sterile. High fever continued despite intravenous ceftriaxone for presumed pyelonephritis. The patient was on the Paediatric ward for 2 days with continuing high fever up to 41 degree Celsius. On day 3, the patient was transferred to the Paediatric Intensive Care Unit (PICU) because of poor bilateral lower extremity perfusion that failed to improve on multiple fluid boluses. This was accompanied by persistent tachycardia, increased work of breathing, and a diffuse erythematous rash. Extensive imaging revealed no evidence of an infective focus in the renal tract (ultrasonography), chest (repeated plain x-radiography), abdomen/pelvis (contrast CT) or heart (echocardiography). Virology investigations were consistent with human herpes virus type 6 (HHV6) reactivation, based on positive blood PCR (23,500 (log 4.4) copies/ml of HHV-6 type B), positive HHV6 IgG at 1:80 (negative if less than 1:10) and negative IgM (less than 1:20) on day 6. Testing was not undertaken for MMR viruses; samples were not stored to enable retrospective testing. Persistent high fever was accompanied by worsening cytopenias, elevated triglycerides, elevated ferritin to more than or equal to 500 ng/ml, and elevated soluble interleukin-2 receptor level. These results met 5 of 8 criteria for the diagnosis of hemophagocytic lymphohistiocytosis (HLH). An attempt at bone marrow aspiration on day 9 of admission was aborted due to apnea and profound desaturation. The patient was quickly resuscitated and returned to baseline within a few hours while hematologic parameters began spontaneously improving by day 10. Fever abated after 15 days and the patient was discharged on no antibiotics. Treatment with corticosteroids and/or other immunomodulators was planned after the bone marrow aspiration, but not administered because of clinical and laboratory evidence suggestive of spontaneous HLH resolution on day 10. The diagnosis was considered to be transient HLH triggered by HHV6 infection. Immediately after hospital discharge the patient developed a diffuse vesicular rash from which varicella-zoster virus (VZV) DNA was detected by PCR. This occurred 20 days after receiving the varicella vaccine. The patient was treated with acyclovir for 5 days (20 mg/kg every 6 h) without complication. There was no attempt to ascertain by molecular testing whether VZV was the vaccine strain. However the patient had no exposure to individuals with chickenpox or shingles at home or in hospital. Based on molecular typing of rash-associated virus in post-marketing varicella vaccine surveillance in two countries, the timing of this rash was more consistent with vaccine-strain varicella (median onset 17-21 days post-vaccination) than with wild type varicella (median interval: 7-8 days post-vaccination). Thus on a balance of probabilities, the patient likely experienced dissemination of vaccine-strain VZV rather than wild type varicella. At 14 months of age, immunological work up was undertaken which revealed a polyclonal increase in IgG, protective antibody levels against measles, VZV, diphtheria, and tetanus and normal lymphocyte subset analysis. Immunophenotyping results, (patient II:3) showed total lymphocytes was 3,600 (normal range: 1600-6,700), CD3+ CD4+ was 1,008 (normal range: 1,000-4,600), CD3+ CD8+ was 756 (normal range: 400-2,100), CD3 was 1,368 (normal range: 600-2,700), CD19+ CD3- CD56+ was 216 (normal range: 200-1,200), IgG (mg/dL) was 1,170 (normal range: 300-900), IgG1 was 979 mg/dL (normal range: 160-562), IgG2 was 218 mg/dL (normal range: 24-98), IgG3 was 90 mg/dL (normal range: 17-64), IgG4 was 201 mg/dL (normal range: 0-22), IgM was 63 mg/dL (normal range: 15-70), IgA was 40 mg/dL (normal range: 40-160), IgE was 6 IU/ml (normal range: 0.62-1.6), Tetanus IgG was 4.5 IU/ml (normal range: more than 0.1), Diphtheria IgG was 0.8 IU/ml (normal range: more than 0.1), Measles IgG was more than 300 AU/ml (normal range: more than or equal to 30) and VZV IgG was 1033 Index units (normal range: more than or equal to 135). At 14 months of age, the patient had pulmonary consolidation and fever for 4 days associated with rhinovirus/enterovirus. At 15 months of age, the patient had rhinovirus/enterovirus upper respiratory tract infection with fever for 7 days. At 17 months of age, the patient had suppurative otitis media with fever. At 24 months of age, the patient had febrile parainfluenza virus type 3 upper respiratory tract infection. At 25 months of age, the patient had mixed upper respiratory tract infection with parainfluenza virus type 3, human metapneumovirus, and rhinovirus/enterovirus. At 26 months of age, the patient had upper respiratory tract infection with rhinovirus/enterovirus, with 5 days of fever up to 39.3 degree C and development of lower extremity papular and urticarial rash. Now 3 years of age, her physical growth and developmental milestones had been normal. Further live vaccines had been withheld. Prophylactic immunoglobulin therapy was not felt to be indicated. This case has been considered as serious due to hospitalization. The author commented, "This case informs understanding of the function of STAT2 in both antiviral immunity and immunoregulation. STAT2 is unique among human STATs, by virtue of both its narrow spectrum of activity (within IFN-I/III pathways) and its direct participation in both positive and negative regulation. Defining the molecular and clinical consequences of STAT2 variants provides not only clinically relevant information, but also fundamental insight into the involvement of STAT2, and IFNI/III more generally, in human immunity. It should be noted that severe IAV displays incomplete clinical penetrance in patients with mutated TLR3, IRF7, IRF9, or STAT2. This is not unexpected, since in the context of defects of pathogen defence there are multiple factors that likely contribute to variable expressivity, including: variable pathogen exposure, infecting dose, prior vaccination and compensation by adaptive immunity. Disease caused by live-attenuated parenteral viral vaccines continues to serve as a clear signal of compromised IFNAR signaling. Another novel observation in this case is the occurrence of clinical varicella following VZV immunization, which has not previously been described in STAT2 deficiency. The implication is that vaccine-strain VZV may, like other live-attenuated vaccines such as MMR, be effectively controlled by innate IFNs in vivo, consistent with a previous report of VZV dissemination in a child with IRF9 deficiency. Regrettably in our case, molecular analysis was not undertaken at the time of varicella diagnosis to definitively prove the vaccine origin of VZV, nor was material stored to enable retrospective analysis. It is also notable that dissemination of MMR virus was not identified in this case, despite a suggestive temporal association between administration of MMR and the onset of clinical disease. MMR dissemination is strongly associated with defects of IFN-I/III immunity, but is not inevitable. Again, it should be noted that in our case, blood and/or mucosal samples were not analyzed by PCR for MMR viral detection, and no clinical material was available to retrospectively test. Therefore occult MMR viral replication cannot be excluded as a potential contribution to HLH. The capacity of IFN gamma to compensate for antiviral activity in vitro might suggest a potential therapeutic role in controlling viral replication, however this approach may come at a cost of enhancing hyperinflammation. There have been clinical reports of responsiveness to IVIG or steroids, although in our case the hyperinflammation resolved without specific treatment. More work is needed to dissect the pathomechanism and inform therapeutic strategies." The author concluded, "In summary, this case significantly expands our clinical understanding of STAT2 deficiency. As the first report of life-threatening IAV in STAT2 deficiency, we can now add STAT2 to the list of genes implicated in this phenotype - a list that increasingly emphasizes the importance of IFN-I/III. We also report the first instance of disseminated vaccine-strain VZV in STAT2-deficiency, suggesting a role for innate IFNs in control of live-attenuated VZV vaccines. Finally, as only the second report of HLH in a patient with STAT2-deficiency, this case strengthens the notion that STAT2-deficient patients are vulnerable to hyperinflammation, motivating further investigation of the underlying mechanism(s) and highlighting the enduring capacity of monogenic diseases to uncover novel areas for scientific exploration."