Sex: M
Vaccine: HEP
Symptoms: Computerised tomogram thorax abnormal, Cough, Cytomegalovirus infection, Cytomegalovirus test positive, Cytomegalovirus viraemia
Clinical narrative: suspected vaccination failure; HBV; Cytomegalovirus; Aspergillus fumigatus; cough; wheezing; shortness of breath; intermittent chills; Possible bronchitis; influenza A; fever; productive cough/progressive cough; brain abscesses; brain lesions; nausea; This case was reported in a literature article and described the occurrence of suspected vaccination failure in a 54-year-old male patient who received Hepatitis B vaccine for prophylaxis.   Co-suspect products included maraviroc unknown (batch number UNK, expiry date unknown) for hiv infection, dolutegravir unknown (batch number UNK, expiry date unknown) for hiv infection, darunavir unknown (batch number UNK, expiry date unknown) for hiv infection and ritonavir unknown (batch number UNK, expiry date unknown) for hiv infection.   The patient's past medical history included smoker. Concurrent medical conditions included acquired immunodeficiency syndrome (HIV-1 approximately 25 years prior, his CD4 count was 12 cells/mm3).   On an unknown date, the patient received Hepatitis B vaccine, maraviroc at an unknown dose and frequency, dolutegravir at an unknown dose and frequency, darunavir at an unknown dose and frequency and ritonavir at an unknown dose and frequency. On an unknown date, unknown after receiving Hepatitis B vaccine and not applicable after starting maraviroc and dolutegravir, the patient experienced vaccination failure (serious criteria hospitalization and GSK medically significant), hepatitis b (serious criteria hospitalization and GSK medically significant), cytomegalovirus infection (serious criteria hospitalization and GSK medically significant), aspergillus fumigatus infection (serious criteria hospitalization and GSK medically significant), cough (serious criteria hospitalization), wheezing (serious criteria hospitalization), shortness of breath (serious criteria hospitalization), chills (serious criteria hospitalization), bronchitis (serious criteria hospitalization), influenza a virus infection (serious criteria hospitalization), fever (serious criteria hospitalization), productive cough (serious criteria hospitalization), brain abscess (serious criteria GSK medically significant), brain lesion and nausea. The patient was treated with levofloxacin, sulfamethoxazole + trimethoprim (Trimethoprim-Sulfamethoxazole), prednisone, piperacillin + tazobactam (Piperacillin-Tazobactam), vancomycin, voriconazole, micafungin and emtricitabine + tenofovir. The action taken with maraviroc was unknown. The action taken with dolutegravir was unknown. The action taken with darunavir was unknown. The action taken with ritonavir was unknown. On an unknown date, the outcome of the vaccination failure, hepatitis b, cytomegalovirus infection, aspergillus fumigatus infection, cough, wheezing, shortness of breath, chills, bronchitis, influenza a virus infection, fever, productive cough, brain abscess, brain lesion and nausea were unknown.   It was unknown if the reporter considered the vaccination failure, hepatitis b, cytomegalovirus infection, aspergillus fumigatus infection, cough, wheezing, shortness of breath, chills, bronchitis, influenza a virus infection, fever, productive cough, brain abscess and brain lesion to be related to Hepatitis B vaccine. The reporter considered the nausea to be related to maraviroc and dolutegravir.  Additional details were provided as follows: This was reported in a literature article and described the suspected vaccination failure, in a male patient aged 54-year-old, who was vaccinated with unspecified Hepatitis B vaccine (manufacturer unknown) for prophylaxis.  The patient was a man with a history of acquired immunodeficiency syndrome (AIDS). At the time of initial diagnosis of HIV-1 approximately 25 years prior, his CD4 count was 12 cells/mm3. The patient had poor adherence to antiretroviral therapy (ART). The patient reported stopping his ART (maraviroc, dolutegravir, darunavir, and ritonavir) for approximately 4 months prior to presentation due to nausea, but he had restarted again two months prior to admission. Social history was significant for smoking. The patient worked as a nurse in a prison facility for several years. The patient was in a monogamous relationship with 1 male partner. The patient had 4 dogs and 1 pet cat. No information on patient family history was reported.  On an unknown date, the patient received unspecified hepatitis B vaccine (administration route and site unspecified, dosage unknown; batch number not provided). The age at vaccination was not reported. Since 2009, the patient had positive surface antibody titers noted.  On an unknown date, an unknown time after vaccination, the patient experienced cough, wheezing, shortness of breath, and intermittent chills. The patient was evaluated in the emergency department and was given trimethoprim-sulfamethoxazole for possible bronchitis. The patient symptoms did not improve, and presented again after 1 week at which time he was tested positive for influenza A. When symptoms still persisted, the patient was then started on prednisone and levofloxacin 1 week later. The patient had some relief from his symptoms but soon after his fevers recurred with productive cough and shortness of breath. The patient was therefore admitted and noted to have a fever of 102F. Piperacillin-tazobactam and vancomycin were started in addition to trimethoprim-sulfamethoxazole for broad empiric treatment. The patient left against medical advice on day 3, only to be readmitted to the hospital after cell free DNA (cfDNA) testing of plasma returned positive for Aspergillus fumigatus, HBV, and Cytomegalovirus (CMV) within 72 hours of specimen collection. On an unknown date, the patient presented with progressive cough, wheezing, shortness of breath, and intermittent chills for 1 month. Computed tomography (CT) of the chest was done which showed a left lower lobe 4 centimeter necrotic cavitary mass-like consolidation with thickened irregular walls, shaggy inner linings and septations, ground glass halo, as well as pericavitary irregular nodules and consolidations. The appearance of the cavity was consistent with angioinvasive aspergillosis. cfDNA next generation sequencing (NGS) was sent and revealed the presence of Aspergillus fumigatus, HBV, and cytomegalovirus (CMV). Aspergillus fumigatus was detected at 242 DNA molecules per microliter (MPM; reference level less than 10) and CMV level was 378 MPM. DNA sequencing detected HBV, but MPM was not reported as there is no environmental control for this virus. A sputum fungal culture eventually returned positive for heavy Aspergillus fumigatus after approximately 2 weeks, with a voriconazole MIC of 0.5 ug/mL. Levels of Serum Tests at presentation Aspergillus Galactomannan was 0.660 (ref range less than 0.5), Beta-d Glucan was more than 500 pg/mL ref range less than 80 pg/ml). Histoplasma urine antigen testing was negative. Serum CMV PCR testing showed a low-level viremia of 256 IU/ml. Repeat HBV testing demonstrated positive surface antigen, loss of surface antibody, positive core antibody, and positive E antigen. Hep B DNA was more than 1000,000,000 IU/mL, which along with elevated liver enzymes (aspartate aminotransferase (AST) of 55 U/L; alanine amino transferase (ALT) was 73 U/L) suggested active infection. The patient was admitted and during this admission, the patient was noted to have a CD4 count of 76 cells/mm3 with undetectable HIV viral load. Four months prior, the patient CD4 count was 379 cells/mm3. A magnetic resonance imaging (MRI) of the brain was done due to concern for central nervous system involvement. It showed 8, scattered, small nodular rim-enhancing lesions in bilateral cerebral and cerebellar hemisphere. Lumbar puncture was performed that showed total nucleated cell count of 2 with 88% neutrophils on differential. Cerebro-spinal fluid (CSF) glucose was 42 mg/dl, protein level was 28.9 mg/dl, and no growth of fungus was noted from CSF culture. Toxoplasma IgG and IgM were negative. Given the overall clinical picture, these brain lesions were consistent with brain abscesses due to disseminated aspergillosis from the lungs. CMV infection was assessed to be a result of reactivation in the setting of immunodeficiency, and not likely a contributing cause of lung or brain infection. A repeat chest x-ray 2 weeks after discharge showed improvement in bilateral consolidations. Repeat serum aspergillus antigen level in 1 month was undetectable. During follow up, 4 months later, Levels of Serum Tests showed Aspergillus Galactomannan was less than 0.50, Beta-d Glucan was 63 pg/mL, Hep B DNA was 541000 IU/mL and alanine amino transferase (ALT) was 49 U/L. HBV DNA PCR repeated after 4 months was 5.75 log IU/ml, and the CD4 count improved to 265 cells/mm3. CT scan of the chest was done 6 months after starting treatment and showed regression of the irregular cavitary consolidation within the superior segment of the left lung. The case was considered as suspected vaccination failure being time to onset and dosing schedule unknown. The case was considered as serious due to suspected vaccination failure and hospitalization. Treatment included: Given the result of cfDNA NGS, along with imaging and history suggestive of invasive aspergillosis of the lungs and brain,  the patient's treatment was changed to voriconazole given as a loading dose of 6 mg/kg every 12 hours intravenously (IV) and then continued at 4 mg/kg every 12 hours after the initial 2 loading doses. Micafungin was added for synergy with voriconazole. He was switched to oral voriconazole 200 mg twice daily after 2 weeks of IV treatment with plans to continue treatment for at least 12 months. The patient was also started on emtricitabine-tenofovir treatment for HBV infection. Antiretroviral therapy was resumed with maraviroc, dolutegravir, darunavir, and ritonavir.  The authors commented "NGS of cfDNA has another advantage of detecting co-infections. Our patient, who reported prior immunization to HBV with documented protective titers, tested positive for this virus as an incidental finding. Subsequently, HBV DNA detected in the blood by PCR and elevated liver transaminases confirmed active infection. The patient's HBV infection could be explained by the loss of immune response from initial vaccination with subsequent exposure in the setting of lowered CD4 count off of ART. This case highlights that the HBV co-infection could have been missed if the focus was on obtaining bronchoscopy-guided tissue sampling due to high suspicion of invasive aspergillosis on presentation. There is, therefore, potential utility of using NGS of cfDNA to rapidly diagnose multiple co-infections in severely immunocompromised patients without the need for invasive diagnostic procedures. In this case, the patient benefited from early Hepatitis B treatment because of this test. Frequently, this test can detect DNA viruses, such as CMV and herpes simplex virus 1, which could be present in the blood of immunocompromised hosts without clinical manifestations indicative of active disease to warrant directed treatment. Our case reflected that as well; the patient improved with ART and did not need directed CMV treatment. It is also possible that infections in certain organ systems may result in lower levels of pathogen cfDNA, reducing the sensitivity of the test. Thus, the clinical utility of plasma cfDNA testing should be assessed for usefulness on a case-by-case basis and needs to be interpreted cautiously within the clinical context". The authors concluded "Plasma NGS testing of cfDNA has been helpful in diagnosing invasive fungal infections, including Rhizopus, Scedosporium, and Aspergillus.6 In order to maximize sensitivity, it is best if this test is sent early and prior to initiating antimicrobial therapy. The advantage of the test is that it is non-invasive and can potentially help with pathogen identification with results available within 72 hours. This may provide significant diagnostic value even if sent after initiation of empiric antimicrobial therapy. Another advantage is its capacity to detect co-infections, which is important in immunocompromised patients who can present with multiple opportunistic infections as well as reactivation of prior infections, as seen in our patient. Several limitations of NGS should be kept in mind. At this time, more research is needed to determine the appropriate Plasma NGS testing of cfDNA has been helpful in diagnosing invasive fungal infections, including Rhizopus, Scedosporium, and Aspergillus.6 In order to maximize sensitivity, it is best if this test is sent early and prior to initiating antimicrobial therapy. The advantage of the test is that it is non-invasive and can potentially help with pathogen identification with results available within 72 hours. This may provide significant diagnostic value even if sent after initiation of empiric antimicrobial therapy. Another advantage is its capacity to detect co-infections, which is important in immunocompromised patients who can present with multiple opportunistic infections as well as reactivation of prior infections, as seen in our patient. Several limitations of NGS should be kept in mind. At this time, more research is needed to determine the appropriate." This article is not available for regulatory submission due to copyright restriction.