Role of Hologic® Panther AptimaTM SARS-CoV-2 assay in the detection of SARS-CoV-2: screening or diagnostic technique?

During the multiple waves of COVID-19 suffered all over the world, having a rapid and sensitive diagnostic test has become a priority for microbiology laboratories. The AptimaTM SARS-CoV-2 transcription-mediated amplification (TMA) assay running on the Panther system (Hologic) was presented as a very good option to cover this need. To evaluate this system, 570 respiratory samples were included in the study and were processed both by the Panther (Hologic) system and by qRT-PCR (Thermo Fisher Science, Waltham, USA), current assay for the diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A high number of false positives (n=76) was obtained with Panther system (Hologic), but the number of false positives decreases as the relative light units (RLU) value increases. These results show that this technique can be a good option for sample screening but checking for positive results should be mandatory, especially those with low RLU values.

Stakeholders' perception of a total market approach to HIV self-testing (HIVST) for the private sector in Nigeria.

BACKGROUND: The continuous supply of affordable and quality HIV self-test (HIVST) is a key pillar toward achieving the global HIV 95-95-95 target in Nigeria. This was a descriptive qualitative study that explored private sector stakeholders' perceptions of the enablers and barriers of the HIVST market in Nigeria. METHODS: A total of 29 In-depth interviews (IDIs) were conducted with HIVST supply chain stakeholders and private sector providers (PPMVs and Community Pharmacies). Responses were analyzed using Nvivo software and we systematically developed a total market approach analysis for supply chain stakeholders and archetypes for community Pharmacies and PPMVs based on insights gathered from their journey map. RESULTS: Challenges to the supply side dynamics include forecasting, point of care service delivery, the availability of free and subsidized HIVST kits in the market, neglect of private sector providers (Community Pharmacists and PPMVs) in the healthcare delivery system, limited demand for HIVST, and regulatory bottlenecks influences the overall market dynamics. High cost of the HIVST kit, which triggers low availability, accessibility and affordability from the demand side, depicts the need to understand the market dynamics. Addressing the barriers and optimizing the enablers of the three-model pharmacist and PPMV's will change the market dynamic and service delivery to generate demand. CONCLUSION: To address challenges which already exist, the government need to revise the process guidelines for introducing new HIVST products in the Nigerian market, developing contingency plans to ensure the supply of HIVST remains sufficient when experiencing economic shocks, and create a sustainable roadmap toward optimizing the market for HIVST kits.

Renal Thrombotic Microangiopathy: A Review.

Thrombotic microangiopathy (TMA), a pathological lesion observed in a wide spectrum of diseases, is triggered by endothelial injury and/or dysfunction. Although TMA lesions are often accompanied by clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. The presence of renal-limited manifestations can be diagnostically challenging, often delaying the initiation of targeted therapy. Prompt investigation and empirical treatment of TMA is warranted to reduce associated morbidity and mortality. Major advances have been made with respect to the pathophysiology of primary TMA entities, with the subsequent development of novel diagnostic tools and lifesaving therapies for diseases like thrombotic thrombocytopenic purpura and complement-mediated TMA. This article will review the clinical presentation and pathologic hallmarks of TMA involving the kidney, and the disease-specific mechanisms that contribute to the endothelial injury that characterizes TMA lesions. Diagnostic approach and both empirical and disease-specific treatment strategies will be discussed, along with the potential role for emerging targeted disease-specific therapies.

Hemolytic uremic syndrome in the setting of COVID-19 successfully treated with complement inhibition therapy: An instructive case report of a previously healthy toddler and review of literature.

Introduction: As the global pandemic continues, new complications of COVID-19 in pediatric population have turned up, one of them being hemolytic uremic syndrome (HUS), a complement-mediated thrombotic microangiopathy (CM-TMA) characterized by triad of thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury (AKI). With both multisystem inflammatory syndrome in children (MIS-C) and HUS sharing complement dysregulation as one of the key factors, the aim of this case report is to highlight differences between these two conditions and also emphasize the importance of complement blockade as a treatment modality. Case report: We describe a 21-month-old toddler who initially presented with fever and confirmed COVID-19. His condition quickly deteriorated and he developed oliguria, accompanied with diarrhea, vomiting and oral intake intolerance. HUS was suspected, supported with compelling laboratory findings, including decreased platelets count and C3 levels, elevated LDH, urea, serum creatinine and sC5b-9 and presence of schistocytes in peripheral blood, negative fecal Shiga toxin and normal ADAMTS13 metalloprotease activity. The patient was given C5 complement blocker Ravulizumab and started to display rapid improvement. Conclusion: Although reports of HUS in the setting of COVID-19 continue to pour in, the questions of exact mechanism and similarities to MIS-C remain. Our case for the first time accentuates the use of complement blockade as a valuable treatment option in this scenario. We sincerely believe that reporting on HUS as a complication of COVID-19 in children will give rise to improved diagnosis and treatment, as well as better understanding of both of these intricating diseases.

Atypical Hemolytic Uremic Syndrome Occurring After Receipt of mRNA-1273 COVID-19 Vaccine Booster: A Case Report.

Atypical hemolytic uremic syndrome (aHUS) is a subtype of thrombotic microangiopathy (TMA) characterized by a dysregulation of the alternative complement pathway. Here, we report a previously healthy 38-year-old woman in whom aHUS developed after a COVID-19 vaccine booster. One day after receipt of a booster dose of mRNA-1273 vaccine, she felt ill. Because of persistent headache, nausea, and general malaise, she went to her general practitioner, who referred her to the hospital after detecting hypertension and acute kidney injury. A diagnosis of TMA was made. Her treatment consisted of blood pressure control, hemodialysis, plasma exchange, and respiratory support. Kidney biopsy confirmed the diagnosis of acute TMA. The patient was referred for treatment with eculizumab, and kidney function improved after initiation of this therapy. Genetic analysis revealed a pathogenic C3 variant. SARS-CoV-2 infection as a trigger for complement activation and development of aHUS has been described previously. In addition, there is one reported case of aHUS occurring after receipt of the adenovirus-based COVID-19 vaccine ChAdOx1 nCoV-19, but, to our knowledge, this is the first case of aHUS occurring after a booster dose of an mRNA COVID-19 vaccine in a patient with an underlying pathogenic variant in complement C3. Given the time frame, we hypothesize that the vaccine probably was the trigger for development of aHUS in this patient.

Arrival flight efficiency in pre- and post-Covid-19 pandemics

Covid-19 pandemic affected aviation severely, resulting in unprecedented reduction of air traffic. While aviation is slowly re-gaining traffic volumes, we use the opportunity to study the arrival performance in the Terminal Maneuvering Area (TMA) in non-congested scenarios. Applying flight efficiency and environmental performance indicators (PIs) to the historical data of arrivals to Stockholm Arlanda and Gothenburg Landvetter airports, we discover noticeable inefficiencies, despite significant reduction of traffic intensity. We analyze the impact of such factors as weather and traffic intensity on arrival efficiency in isolated scenarios when only one factor dominates: isolated scenario with low traffic and isolated scenario with good weather conditions. Our analysis uncovers that weather has a stronger influence than traffic intensity on the vertical efficiency, while traffic intensity has stronger effect on the lateral efficiency. Impact of traffic intensity on the lateral efficiency might be explained by frequent hold-on patterns and flight trajectory extensions due to vectoring in high traffic conditions. Further investigation is needed to explain weather and vertical/lateral efficiency correlations, the conclusions might be country-specific.

Prior COVID-19 infection may increase risk for developing endothelial dysfunction following hematopoietic cell transplantation.

Endothelial dysfunction underlies many of the major complications following hematopoietic cell transplantation (HCT), including transplant-associated thrombotic microangiopathy (TA-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), and engraftment syndrome (ES). Emerging evidence similarly implicates endothelitis and microangiopathy in severe COVID-19-related multi-system organ dysfunction. Given the overlap in these two illness states, we hypothesize that prior COVID-19 infection may increase risk for HCT-related endotheliopathies. This retrospective, multicenter study included patients aged 0-25 years who underwent autologous or allogeneic HCT for any indication between January 1, 2020 and September 21, 2021, with close attention to those infected with COVID-19 in either the six months prior to transplant or twelve months following transplant. Incidences of TA-TMA, VOD/SOS, and ES were compared among patients with COVID-19 infection pre-HCT and post-HCT, as well as with historical controls who were never infected with SARS-CoV-2. Those who underwent HCT following COVID-19 infection displayed significantly increased rates of TA-TMA compared to those who were never infected. Additionally, our data suggests a similar trend for increased VOD/SOS and ES rates, although this did not reach statistical significance. Therefore, a history of COVID-19 infection prior to undergoing HCT may be a nonmodifiable risk factor for endothelial-related complications following HCT. Further studies are warranted to better clarify this relationship among larger cohorts and in the era of the Omicron SARS-CoV-2 variants.

Similar Sensitivity of SARS-CoV-2 Detection in Oropharyngeal/Nasopharyngeal and Saliva Samples on the Hologic Panther Platform.

BACKGROUND: Oropharyngeal (OP) and nasopharyngeal (NP) sampling has historically been considered the reference specimen type used for respiratory virus detection. Saliva could be a less invasive alternative for SARS-CoV-2 detection, but limited evidence is available. METHODS: The technical and clinical performance of saliva was compared to OP/NP on the Hologic Panther platform with two Aptima assays, the End-Point Transcription-Mediated Amplification assay (EP-TMA) and Real-Time Transcription-Mediated Amplification assay (RT-TMA). The samples were collected at the Public Health Service Testing Site XL location in Schiphol Amsterdam Airport. At the site, the Regional Public Health Laboratory Kennemerland (RPHLK) has a fully equipped laboratory facility. RESULTS: A total of 374 samples (187 OP/NP swabs and 187 saliva samples) were collected from 187 unique patients. The Real-Time Transcription-Mediated Amplification assay (RT-TMA) resulted in comparable sensitivities for the detection of SARS-CoV-2 in both the OP/NP swabs (88.3%; 113/128) and saliva samples (87.5%; 112/128). The End-Point Transcription-Mediated Amplification assay (EP-TMA) analyses showed a similar sensitivity (86.7%; 111/128) in the OP/NP swabs but a lower sensitivity in the saliva samples (80.5%; 103/128). Within the discordant analyses, we found no associations in the symptoms, earlier SARS-CoV-2 infections and eating, smoking, drinking and tooth brushing habits within one hour before testing. CONCLUSIONS: The Hologic Panther platform Real-Time Transcription-Mediated Amplification assay (RT-TMA) yields a sensitivity for the detection of SARS-CoV-2 in saliva that is comparable to the OP/NP swabs derived from participants presenting themselves at a public health testing facility with minimal or mild symptoms.

Arrival flight efficiency in pre- and post-Covid-19 pandemics

Covid-19 pandemic affected aviation severely, resulting in unprecedented reduction of air traffic. While aviation is slowly re-gaining traffic volumes, we use the opportunity to study the arrival performance in the Terminal Maneuvering Area (TMA) in non-congested scenarios. Applying flight efficiency and environmental performance indicators (PIs) to the historical data of arrivals to Stockholm Arlanda and Gothenburg Landvetter airports, we discover noticeable inefficiencies, despite significant reduction of traffic intensity. We analyze the impact of such factors as weather and traffic intensity on arrival efficiency in isolated scenarios when only one factor dominates: isolated scenario with low traffic and isolated scenario with good weather conditions. Our analysis uncovers that weather has a stronger influence than traffic intensity on the vertical efficiency, while traffic intensity has stronger effect on the lateral efficiency. Impact of traffic intensity on the lateral efficiency might be explained by frequent hold-on patterns and flight trajectory extensions due to vectoring in high traffic conditions. Further investigation is needed to explain weather and vertical/lateral efficiency correlations, the conclusions might be country-specific.

Acute Kidney Injury Following Posaconazole for Mucormycosis: SARS-CoV-2 as a Back-Seat Driver.

Viruses have been implicated in the causation of several systemic illnesses, either directly or by immune modulation. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not an exception. Due to altered immune regulation, it is often associated with novel clinical manifestations and complications which have not been reported before. SARS-CoV-2 induces a pro-inflammatory state which makes the patient vulnerable to developing a variety of previously unreported adverse reactions to medications. Coronavirus disease 2019 (COVID-19) and its treatment have provided a fertile ground for various opportunistic infections including mucormycosis. The standard treatment for mucormycosis is surgical debridement and liposomal amphotericin B. Triazole antifungals such as posaconazole and isavuconazonium are the second-line agents for those intolerant to first-line therapy. Posaconazole is safer than amphotericin B as far as renal adverse effects are concerned. We report the case of a 60-year-old lady with type 2 diabetes mellitus, hypertension, ischemic heart disease, and osteoarthritis. She had severe COVID-19 requiring non-invasive ventilation four months ago. She presented with right rhino-orbital swelling, diplopia, and serosanguinous discharge from the right nostril. She had right third, sixth, and seventh cranial nerve palsies. Magnetic resonance imaging revealed right maxillary, ethmoid, and frontal sinusitis. Biopsy from the right nostril confirmed mucormycosis. Having normal renal and liver functions, she was started on oral posaconazole as she had an allergic reaction to a test dose of 1 mg amphotericin B (non-liposomal) in 20 mL of 5% dextrose water infused over 30 minutes. On day five, she developed acute kidney injury requiring renal replacement therapy. Her posaconazole was stopped. As she was not improving with conservative treatment, an ultrasound-guided, percutaneous renal biopsy was performed from the left kidney. The renal biopsy revealed thrombotic microangiopathy. She was started on liposomal amphotericin B as decided by the multidisciplinary team. Her renal function improved, and she continued on liposomal amphotericin B. We conclude that thrombotic microangiopathy, in this case, was likely due to posaconazole. This is a novel adverse effect presumably of posaconazole. This case report will alert physicians to be vigilant of the renal adverse effects of posaconazole in patients who have had COVID-19. Patients who develop renal injury while on posaconazole should undergo an early renal biopsy to ascertain the exact histopathology.

Atypical Hemolytic Uremic Syndrome after SARS-CoV-2 Infection: Report of Two Cases.

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease causing systemic thrombotic microangiopathy (TMA) due to the fact of complement dysregulation. Immune activation by viruses, including SARS-CoV-2, can lead to the development of an episode of aHUS against a background of genetic dysregulation in the complement pathway. This paper presents an analysis of two cases of aHUS-siblings diagnosed with familial disease, with a genetic predisposition to aHUS, in whom infection with SARS-CoV-2 was a strong trigger of disease recurrence. The quick recognition and treatment with eculizumab in the early stage of the disease resulted in a rapid improvement in clinical conditions and laboratory parameters.

Atypical HUS Triggered by COVID-19: A Case Report.

We hereby present a case of an atypical hemolytic uremic syndrome (aHUS) precipitated by coronavirus disease 2019 (COVID-19). A 26-year-old male was diagnosed with COVID-19 and acute kidney injury. His kidney biopsy was suggestive of thrombotic microangiopathy. Five sessions of plasmapheresis were done but were discontinued in view of nonrecovery of kidney function. He was then referred for a kidney transplant. On genetic analysis, he was found to have mutations in the complement system (CFHR1 and CFHR3), which suggested this was a case of aHUS precipitated by COVID-19. In view of the high risk of recurrence of the primary disease in live-related kidney donor transplantation, he was advised for simultaneous liver and kidney transplants.

Unique Presentation of Bortezomib-Associated Thrombotic Microangiopathy Responsive to Therapeutic Plasma Exchange and Eculizumab Therapy.

Thrombotic microangiopathies (TMA) are a rare group of life-threatening hematological conditions characterized by thrombocytopenia and microangiopathic hemolytic anemia. Although our understanding of the pathophysiology and the availability of diagnostic testing has improved for primary TMAs, such as thrombotic thrombocytopenic purpura, the pathophysiology underlying secondary TMAs, including drug-induced TMAs (DITMAs), remains less clear. In this case report, we present the unique case of a patient with a history of multiple myeloma that presented four months after the initiation of bortezomib therapy with a bortezomib-associated TMA that responded to therapeutic plasma exchange (TPE) with plasma replacement and eculizumab therapy. This case demonstrates the possible utility of TPE with plasma replacement and eculizumab therapy in DITMA patients that fail to respond following a trial of holding the suspected medication.

COVID-19 and thrombotic microangiopathy

As shown by numerous studies conducted during the pandemic, the severe course of COVID-19 is accompanied by multiple organ failure. Cytokine storm, hypercoagulation, complement hyperactivation and other arms comprise the overall picture of the pathogenesis of the severe disease course. The frequent diagnosis of multiple microvascular thrombosis in lung, heart, and kidneys, as well as the presence of platelet-fibrin thrombi there and signs of terminal organ damage, suggest a possible involvement of thrombotic microangiopathy (TMA) in the development of multiple organ failure. In this regard, it is especially important to timely diagnose TMA and start pathogenetic therapy. These measures can significantly reduce mortality due to the novel disease. Heparins and direct oral anticoagulants are the mainstay for prevention and treatment of venous thromboembolism in patients with COVID-19, but their effectiveness in the presence of TMA is questionable. It has been proven that anticoagulants use in critically ill patients with COVID-19 for prevention of large vessel thrombosis is effective, but their role in the prevention of microthrombosis is not clear. Here we review the currently available information on thrombotic microangiopathy, as well as a review of literature data describing TMA-like conditions in COVID-19, discuss potential pathophysiology of the condition development and proposed therapeutic approaches. © Obstetrics, Gynecology and Reproduction 2021.

Pathology findings in pediatric patients with COVID-19 and kidney dysfunction.

BACKGROUND: Acute kidney injury (AKI) is seen in one-fifth of pediatric patients with COVID-19 requiring hospital admission, and is associated with increased morbidity, mortality, and residual kidney impairment. The majority of kidney pathology data in patients with COVID-19 is derived from adult case series and there is an overall lack of histologic data for most pediatric patients with COVID-19. METHODS: We assembled a multi-institutional cohort of five unvaccinated pediatric patients with COVID-19 and associated kidney dysfunction with available histology. RESULTS: Three complex patients with current or prior SARS-CoV-2 infection had multifactorial thrombotic microangiopathy with clinical features of hemolytic uremic syndrome (in two) or disseminated intravascular coagulation (in one); one died and another developed chronic kidney disease stage 5. Two with recently preceding SARS-CoV-2 infection presented with nephrotic syndrome; one had IgA vasculitis and one had minimal change disease. Within a short follow-up time, none has returned to baseline kidney function. CONCLUSION: Although uncommon, COVID-19-associated kidney injury can have significant morbidity in the unvaccinated pediatric and adolescent population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Thrombotic Microangiopathy Causing Acute Kidney Injury in a COVID-19 Patient.

Acute Kidney Injury (AKI) in COVID-19 patients is common and independently associated with higher mortality. The pathophysiology of AKI is multifactorial and may be either direct viral trophism or immune mediated injury and hypercoagulability. This case highlights AKI in a young female with severe COVID-19 due to complement-3 mediated thrombotic microangiopathy with pre-existing chronic kidney disease likely because of IgA nephropathy.

Clinical evaluation of the Procleix SARS-CoV-2 assay, a sensitive, high-throughput test that runs on an automated system.

Testing is crucial in controlling COVID-19. The Procleix® SARS-CoV-2 assay, a transcription-mediated amplification nucleic acid test that runs on an automated system, was evaluated using inactivated virus and clinical samples. The sensitivity of the assay was assessed using heat-inactivated SARS-CoV-2 and compared to 3 other tests. Clinical validation utilized 2 sets of samples: (1) Nasal, nasopharyngeal and oropharyngeal samples (n = 963) from asymptomatic individuals, and (2) nasopharyngeal samples from symptomatic patients: 100 positive and 100 negative by RT-PCR. The Procleix assay had greater sensitivity (3-fold to 100-fold) than the comparators and had high specificity (100%) in asymptomatic subjects. In symptomatic patients, the Procleix assay detected 100% of PCR-positives and found 24 positives in the initial PCR-negatives. Eighteen of these were confirmed positive and 6 were inconclusive. These studies showed that the Procleix SARS-CoV-2 assay was a sensitive and specific tool for detecting COVID-19.

Comparative study of different SARS-CoV-2 diagnostic techniques.

The rapid spread of SARS-CoV-2 led to the necessity of developing diagnostic tests for rapid virus detection. Many commercial platforms have appeared and have been approved for this purpose. In this study, 95 positive and 5 negative retrospective samples were analyzed by 4 different commercial RT-qPCR kits (TaqMan 2019nCoV Assay, Allplex™SARS-COV-2 Assay, FTD SARS-COV-2 Assay and qCOVID-19). The Hologic Aptima SARS-COV-2 and the Clart-COVID-19 system were also tested. serial dilutions of SARS-COV-2 standard control were included for sensitivity analysis. Among the qPCR tested qCOVID19 and Allplex™SARS-COV-2 Assay were both able to detect all the clinical samples included in the study. All four qPCR evaluated showed high sensitivity for samples with Ct<33. Clart-COVID-19 microarrays detected all samples and controls used in this study whereas Hologic Aptima Panther failed with one of the clinical samples. However, the main problem with this system was the number of invalidated samples despite avoiding the use of medium with guanidine isothiocyanate as recommended by the manufacturer. All the techniques tested were of value for SARS-CoV-2 detection.

Diagnosing SARS-CoV-2 with Antigen Testing, Transcription-Mediated Amplification and Real-Time PCR.

This study was performed as a head-to-head comparison of the performance characteristics of (1) two SARS-CoV-2-specific rapid antigen assays with real-time PCR as gold standard as well as (2) a fully automated high-throughput transcription-mediated amplification (TMA) assay and real-time PCR in a latent class analysis-based test comparison without a gold standard with several hundred samples in a low prevalence "real world" setting. Recorded sensitivity and specificity of the NADAL and the LumiraDx antigen assays and the Hologic Aptima SARS-CoV-2 TMA assay were 0.1429 (0.0194, 0.5835), 0.7644 (0.7016, 0.8174), and 0.7157 (0, 1) as well as 0.4545 (0.2022, 0.7326), 0.9954 (0.9817, 0.9988), and 0.9997 (not estimable), respectively. Agreement kappa between the positive results of the two antigen-based assays was 0.060 (0.002, 0.167) and 0.659 (0.492, 0.825) for TMA and real-time PCR. Samples with low viral load as indicated by cycle threshold (Ct) values > 30 were generally missed by both antigen assays, while 1:10 pooling suggested higher sensitivity of TMA compared to real-time PCR. In conclusion, both sensitivity and specificity speak in favor of the use of the LumiraDx rather than the NADAL antigen assay, while TMA results are comparably as accurate as PCR, when applied in a low prevalence setting.

Thrombotic Thrombocytopenic Purpura Presentation in an Elderly Gentleman Following COVID Vaccine Circumstances.

Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder that results in the formation of thrombi in the small blood vessels throughout the body. The two primary forms of TTP are acquired and familial forms. The acquired form usually presents in late childhood or adulthood. Almost 95% of the cases are due to an autoantibody directed against ADAMTS13, and the remaining 5% are due to drugs like ticlopidine, quinine, cyclosporine, gemcitabine, bevacizumab, and certain recreational drugs like ecstasy and cocaine. The familial forms present in infancy or early childhood, but sometimes they can present later in life. Management for acquired forms includes therapeutic plasma exchange and immunosuppressive agents. While for the hereditary forms, the mainstay of treatment is plasma infusion. We present a case of an 80-year-old male with a known medical history of hypertension, type II diabetes mellitus, hyperlipidemia, gout, iron deficiency anemia, and Pfizer-BioNTech COVID-19 (coronavirus disease-19) vaccine administered two weeks before presentation to the ER for evaluation of generalized weakness and malaise. Laboratory findings showed severe anemia with hemoglobin of 4.8 g/dl, platelet count of 48 x 10^3/mcL, elevated lactate dehydrogenase (LDH), decreased haptoglobin, and peripheral smear showing schistocytes. The serum creatinine, total bilirubin, and troponin were elevated. All these findings were raising concern for presumptive diagnosis of TTP, which was confirmed with ADAMTS13 levels less than 10%. TTP was temporarily resolved in 10 days with plasma exchange therapy and high-dose corticosteroids. It is difficult at this time to differentiate vaccine-induced TTP from coincidental TTP presenting soon after vaccination. Further studies would be needed to understand better if this relationship between vaccination and TTP was coincidental or causal.