The effect of pneumococcal conjugated vaccines on occurrence of recurrent acute otitis media among infants diagnosed with acute otitis media at an age younger than 2 months.

To examine the impact of pneumococcal conjugate vaccines (PCV) on the occurrence of recurrent acute otitis media (rAOM) among infants diagnosed with an early acute otitis media (AOM) episode. Retrospective cohort study of pediatric patients with a first episode of AOM at an age < 2 months. Data included clinical, demographic, and microbiological findings at the first AOM episode. In addition, a 5-year follow-up after the patient's first episode was completed from the medical records. This information included documentation of rAOM episodes and complications of AOM (hearing loss, speech disturbance, mastoiditis, and tympanic membrane perforation) and of ear-related surgical procedures (ventilation tube placement, adenoidectomies, and mastoid surgery). Two groups were studied: patients diagnosed between 2005 and 2009 (representing the unvaccinated group, group 1) and those diagnosed in 2010-2014 (the vaccinated group, group 2). A total of 170 infants were diagnosed with a first AOM episode at an age < 2 months; 81 of them belonged to group 1 and 89 to group 2. Streptococcus pneumoniae was isolated in the middle-ear fluid in the first AOM episode in 48.1% of the patients in group 1 and in 30.3% in group 2 (P = 0.0316). 49/81 (60.5%) infants in group 1 were diagnosed with rAOM versus 39/80 (43.8%) in group 2 (P = 0.0298). No statistical differences were found between the groups with respect to long-term complications or need for surgery later in life.   Conclusion: Our study showed a significant decrease in the occurrence of rAOM in infants diagnosed with AOM during the first 2 months of life and timely immunized with PCVs following this initial AOM episode. What is Known: • 30% of children experience recurrent AOM (rAOM) at the first year of life. The earlier the age of the first AOM, the greater the risk for future complications. • After the introduction of PCVs, the overall pneumococcal AOM incidence declined. We investigated the future effect of PCVs on rAOM occurrence, when administered after the first AOM episode. What is New: • A retrospective cohort of 170 infants with a first AOM episode at an age <2 months and followed for 5 years, showed a significant decrease (28.0%) of rAOM in immunized infants following the initial AOM episode. • Our findings supplement previous data suggesting that the widespread PCVs use prevents rAOM by preventing early AOM and emphasize the importance of timely administration of the PCVs.

Inhaled Corticosteroids in Patients with Chronic Obstructive Pulmonary Disease and Risk of Acquiring Streptococcus pneumoniae Infection. A Multiregional Epidemiological Study.

Background: Inhaled corticosteroids (ICS) are associated with an increased risk of clinical pneumonia among patients with chronic obstructive pulmonary disease (COPD). It is unknown whether the risk of microbiologically verified pneumonia such as pneumococcal pneumonia is increased in ICS users. Methods: The study population consists of all COPD patients followed in outpatient clinics in eastern Denmark during 2010-2017. ICS use was categorized into four categories based on accumulated use. A Cox proportional hazard regression model was used adjusting for age, body mass index, sex, airflow limitation, use of oral corticosteroids, smoking, and year of cohort entry. A propensity score matched analysis was performed for sensitivity analyses. Findings: A total of 21,438 patients were included. Five hundred and eighty-two (2.6%) patients acquired a positive lower airway tract sample with S. pneumoniae during follow-up. In the multivariable analysis ICS-use was associated with a dose-dependent risk of S. pneumoniae as follows: low ICS dose: HR 1.11, 95% CI 0.84 to 1.45, p = 0.5; moderate ICS dose: HR 1.47, 95% CI 1.13 to 1.90, p = 0.004; high ICS dose: HR 1.77, 95% CI 1.38 to 2.29, p < 0.0001, compared to no ICS use. Sensitivity analyses confirmed these results. Interpretation: Use of ICS in patients with severe COPD was associated with an increased and dose-dependent risk of acquiring S. pneumoniae, but only for moderate and high dose. Caution should be taken when administering high dose of ICS to patients with COPD. Low dose of ICS seemed not to carry this risk.

Rapid Diagnostic Tests to Guide Case Management of and Improve Antibiotic Stewardship for Pediatric Acute Respiratory Illnesses in Resource-Constrained Settings: a Prospective Cohort Study in Southwestern Uganda.

Pediatric acute respiratory illness (ARI) is one of the most common reasons for evaluation at peripheral health centers in sub-Saharan Africa and is frequently managed based on clinical syndrome alone. Although most ARI episodes are likely caused by self-limited viral infections, the majority are treated with antibiotics. This overuse contributes to the development of antimicrobial resistance. To evaluate the preliminary feasibility and potential impact of adding pathogen-specific and clinical biomarker diagnostic testing to existing clinical management algorithms, we conducted a prospective, observational cohort study of 225 children presenting with malaria-negative, febrile ARI to the outpatient department of a semi-urban peripheral health facility in southwestern Uganda from October 2019 to January 2020. In addition to routine clinical evaluation, we performed influenza and Streptococcus pneumoniae antigen testing and measured levels of C-reactive protein, procalcitonin, and lactate in the clinic's laboratory, and conducted a follow-up assessment by phone 7 days later. Almost one-fifth of participants (40/225) tested positive for influenza. Clinical biomarker measurements were low with C-reactive protein of >40 mg/L in only 11% (13/222) of participants and procalcitonin >0.25 ng/mL in only 13% (16/125). All but two children received antibiotic treatment; only 3% (7/225) were admitted. At follow-up, 59% (118/201) of caregivers reported at least one persistent symptom, but fever had resolved for all children. Positive influenza testing was associated with persistent symptoms. In summary, we demonstrate that simple, rapid pathogen-specific testing and biomarker measurement are possible in resource-limited settings and could improve syndromic management and, in turn, antibiotic stewardship. IMPORTANCE Globally, respiratory illness is one of the most common reasons that children seek care. It is often treated inappropriately with antibiotics, which can drive the development of antibiotic resistance. In resource-rich settings, testing for specific pathogens or measurement of clinical biomarkers, such as procalcitonin and C-reactive protein, is often employed to help determine which children should receive antibiotics. However, there are limited data on the use of these tests in resource-constrained, outpatient contexts in sub-Saharan Africa. We enrolled children with respiratory illness presenting to a clinic in southwestern Uganda and performed testing for influenza, Streptococcus pneumoniae, C-reactive protein, and procalcitonin on-site. Almost all children received antibiotics. We demonstrate that employing clinical algorithms that include influenza and clinical biomarker testing could significantly decrease antibiotic prescriptions. Our study therefore provides preliminary data to support the feasibility and potential utility of diagnostics to improve management of respiratory illness in resource-constrained settings.

Infected simple renal cyst due to Streptococcus pneumoniae rapidly diagnosed by the melting temperature mapping method: a case report.

BACKGROUND: Spontaneous infection of preexisting solitary renal cysts has been documented in adults but is extremely rare in children. To date, no cases of simple renal cysts infected with Streptococcus pneumoniae have been described. Recently, reports have described the diagnosis of bacterial infection using the 16 S rRNA gene as well as the accompanying antimicrobial stewardship for microorganisms that are difficult to culture and for culture-negative cases after preceding antibacterial administration. CASE PRESENTATION: A four-year-old Japanese girl who had a pleuroperitoneal shunt inserted to drain a right pleural effusion due to occlusion of the hepatic portion of the inferior vena cava at three years old visited our hospital due to fever and respiratory discomfort. She was incidentally found to have a right simple renal cyst 10 months before admission. The patient was suspected to have pneumonitis or catheter-related blood stream infection on chest X-ray, which showed right-side pleural effusion. She was diagnosed with invasive pneumococcal infection, as Streptococcus pneumoniae was detected from blood culture on admission. Transient improvements in her symptoms and decreases in the white blood cell count and C-reactive protein level were observed after effective antibiotic administration, but her respiratory condition deteriorated. Enhanced CT showed right renal cyst enlargement and enhancement and thickening of the surrounding wall. Using the melting temperature (Tm) mapping method, S. pneumoniae was rapidly detected directly from pus 4.5 hours after drainage. The specimen culture was negative, but the extracted 16 S rDNA sequence revealed 100 % identity for S. pneumoniae from the same specimen the subsequent day. We successfully performed optimal treatment and reduced medical cost based on the positive Tm mapping method result. CONCLUSIONS: We report the first case of a S. pneumoniae-infected simple renal cyst. The drainage culture was negative, but the Tm mapping method rapidly detected S. pneumoniae directly from the drainage. The Tm mapping method may have great impacts on rapid diagnosis and effective antimicrobial stewardship.

Underutilised human immunodeficiency virus testing in the setting of invasive pneumococcal disease.

People living with human immunodeficiency virus (HIV) are at increased risk of invasive pneumococcal disease (IPD). We assessed whether patients with invasive Streptococcus pneumoniae, in blood or cerebrospinal fluid, underwent HIV serology testing over a 5-year period. We found that only 39 inpatients out of 156 (25%) with IPD were tested for HIV and thus conclude that such testing is not being undertaken according to some guidelines in patients with IPD. Education and implementation strategies are required to increase testing.

Prognostic factors for mortality in invasive pneumococcal disease in adult: a system review and meta-analysis.

Risk factors associated with mortality in invasive pneumococcal disease remain unclear. The present work is a meta-analysis of studies that enrolled only patients with invasive pneumococcal disease and reported on mortality. Potentially eligible reports were identified from PubMed, CHAHL, and Web of Science, comprising 26 reports in total. Overall mortality for invasive pneumococcal disease was reported as 20.8% (95% confidence interval (CI) 17.5-24%). Factors associated with mortality were age (odds ratio (OR) 3.04, 95% CI 2.5-3.68), nursing home (OR 1.62, 95% CI 1.13-2.32), nosocomial infection (OR 2.10, 95% CI 1.52-2.89), septic shock (OR 13.35, 95% CI 4.54-39.31), underlying chronic diseases (OR 2.34, 95% CI 1.78-3.09), solid organ tumor (OR 5.34, 95% CI 2.07-13.74), immunosuppressed status (OR 1.67, 95% CI 1.31-2.14), and alcohol abuse (OR 3.14, 95% CI 2.13-4.64). Mortality rates with invasive pneumococcal disease remained high, and these findings may help clinicians provide appropriate initial treatment for this disease.

Primary pneumococcal peritonitis with a fulminant course.

INTRODUCTION: Primary peritonitis is an inflammation of the peritoneal cavity in the absence of a localized intra-abdominal source. It is included in the differential diagnosis of acute abdomen and can be potentially life-threatening. Pneumococci were a frequent pathogen causing primary peritonitis especially in the preantibiotic era. Nowadays, they act as an uncommon primary pathogen. Pneumococcal peritonitis in adults is more frequently seen in cases of liver cirrhosis with ascites and other pre-existing conditions. Primary pneumococcal peritonitis is uncommon in healthy individuals and therefore its diagnosis is difficult. Secondary peritonitis has to be excluded. CASE REPORT: A 36-year-old woman was admitted to our surgery department with symptoms of severe sepsis. She reported a sudden onset of diffuse abdominal pain and was eight weeks after delivery per vias naturales. A computed tomography scan of the abdomen with intravenous contrast has not demonstrated any pathology explaining the condition of our patient. Empiric anti-microbial therapy with broad-spectrum antibiotics was commenced and a laparotomy was performed, which also did not reveal any source of infection. Purulent odorless fluid was found in the peritoneal cavity. Peritoneal lavage with an antiseptic was performed. Cultures from peritoneal fluid demonstrated a monobacterial growth of Streptococcus pneumoniae. The condition of our patient improved after continued adequate antibiotic therapy and lavage. CONCLUSION: Primary pneumococcal peritonitis is difficult to diagnose in healthy individuals, since it is mimicking secondary peritonitis that has to be excluded. A clinical diagnose without surgical intervention is impossible in most cases. Surgical treatment has an important role in both the diagnosis and management of primary pneumococcal peritonitis, same as adequate antibiotic therapy. Primary peritonitis should be a part of the differential diagnosis of patients presenting with acute abdominal pain.

Changes in vaccination strategies contribute to the development of invasive pneumococcal disease in allogeneic hematopoietic stem cell transplantation recipients: a retrospective study for promoting vaccination.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are at high risk of developing invasive pneumococcal disease (IPD) with substantial morbidity and mortality. Pneumococcal polysaccharide vaccine (PPSV23) and pneumococcal conjugate vaccine (PCV13) are the primary prevention strategy. The difference between the Japanese and international guidelines is limited except when to start PCV13. However, Japanese data regarding the incidence of IPD after allo-HSCT that include vaccination status are limited. Therefore, we aimed to study the clinical characteristics of patients with IPD following allo-HSCT, focusing on unvaccinated patients. We retrospectively reviewed allo-HSCT recipients between April 2005 and December 2018 at Komagome Hospital. Among 1,091 recipients, 11 (1008/100,000 recipients) developed 13 episodes of IPD. The median period from the first allo-HSCT to the first IPD episode was 686 days (10-3040 days). Ten patients developed IPD before vaccination, and seven of these unvaccinated patients with late-onset IPD were ineligible for vaccination based on domestic guidelines. Although appropriate treatments resulted in a good short-term prognosis, most episodes of IPD developed in unvaccinated allo-HSCT recipients. Our data support the promotion of better adherence to the current guidelines and the importance of pneumococcal vaccination even years after allo-HSCT to protect against late-onset IPD.

Cardiovascular complications of Streptococcus pneumoniae bacteraemia.

The incidence of Streptococcus pneumoniae bacteraemia has risen due to a worldwide increase in immunocompromised patients and antibiotic resistance. We describe three patients who experienced severe, including cardiovascular, complications of pneumococcal bacteraemia. Cardiovascular complications related to pneumococci may run a fulminant course. However, some of these life-threatening complications (eg, endocarditis and aortitis) may long remain unnoticed or be misdiagnosed and therefore delay correct treatment. We review the literature with regards to the incidence, diagnosis and treatment of these rare but possibly lethal and hence important cardiovascular complications.

A Rare Case of Pyopericardium After Blunt Thoracic Trauma.

The bacterial purulent pericarditis is rapidly progressive and represents a highly fatal infection, with mortality rates reaching up to 100% if untreated. Approximately 40% to 50% of all cases are caused by Gram-positive bacteria, especially Streptococcus pneumoniae. We describe an extremely rare case of S. pneumoniae purulent pericarditis as a delayed complication of a blunt thoracic trauma. The patient was successfully treated with urgent pericardiocentesis, thoracoscopic pericardial fenestration, and broad-spectrum antibiotics. Owing to the high mortality rate of a purulent pericarditis, a high index of suspicion is needed in order to instaurate an appropriate therapy with drainage and antibiotics.

Case Report: Analysis of Preserved Umbilical Cord Clarified X-Linked Anhidrotic Ectodermal Dysplasia With Immunodeficiency in Deceased, Undiagnosed Uncles.

Family history is one key in diagnosing inborn errors of immunity (IEI); however, disease status is difficult to determine in deceased relatives. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is one of the hyper IgM syndromes that is caused by a hypomorphic variant in the nuclear factor kappa beta essential modulator. We identified a novel IKBKG variant in a 7-month-old boy with pneumococcal rib osteomyelitis and later found that his mother has incontinentia pigmenti. Genetic analysis of preserved umbilical cords revealed the same variant in two of his deceased maternal uncles. Analysis of preserved umbilical cord tissue from deceased relatives can provide important information for diagnosing IEI in their descendants.

Suspension microarray-based comparison of oropharyngeal swab and bronchoalveolar lavage fluid for pathogen identification in young children hospitalized with respiratory tract infection.

BACKGROUND: Respiratory tract infection (RTI) in young children is a leading cause of morbidity and hospitalization worldwide. There are few studies assessing the performance for bronchoalveolar lavage fluid (BALF) versus oropharyngeal swab (OPS) specimens in microbiological findings for children with RTI. The primary purpose of this study was to compare the detection rates of OPS and paired BALF in detecting key respiratory pathogens using suspension microarray. METHODS: We collected paired OPS and BALF specimens from 76 hospitalized children with respiratory illness. The samples were tested simultaneously for 8 respiratory viruses and 5 bacteria by suspension microarray. RESULTS: Of 76 paired specimens, 62 patients (81.6%) had at least one pathogen. BALF and OPS identified respiratory pathogen infections in 57 (75%) and 49 (64.5%) patients, respectively (P > 0.05). The etiology analysis revealed that viruses were responsible for 53.7% of the patients, whereas bacteria accounted for 32.9% and Mycoplasma pneumoniae for 13.4%. The leading 5 pathogens identified were respiratory syncytial virus, Streptococcus pneumoniaee, Haemophilus influenzae, Mycoplasma pneumoniae and adenovirus, and they accounted for 74.2% of etiological fraction. For detection of any pathogen, the overall detection rate of BALF (81%) was marginally higher than that (69%) of OPS (p = 0.046). The differences in the frequency distribution and sensitivity for most pathogens detected by two sampling methods were not statistically significant. CONCLUSIONS: In this study, BALF and OPS had similar microbiological yields. Our results indicated the clinical value of OPS testing in pediatric patients with respiratory illness.

Hemophagocytic lymphohistiocytosis complicating invasive pneumococcal disease: a pediatric case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is an infrequent but life-threatening disease due to excessive immune activation. Secondary HLH can be triggered by infections, autoimmune diseases, and malignant diseases. Streptococcus pneumoniae is a pathogenic bacterium responsible for invasive pneumococcal disease (IPD) such as meningitis and bacteremia. Although the pneumococcal conjugate vaccine (PCV) has led to reductions in IPD incidence, cases of IPD caused by serotypes not included in PCV are increasing. There are few reports of secondary HLH caused by IPD in previously healthy children. We herein report a rare case of a previously healthy boy with secondary HLH complicating IPD of serotype 23A, which is not included in the pneumococcal 13-valent conjugate vaccine (PCV-13). CASE PRESENTATION: An 11-month-old boy who had received three doses of PCV-13 was hospitalized with prolonged fever, bilateral otitis media, neutropenia and elevated C-reactive protein (CRP) levels. Blood culture on admission revealed S. pneumoniae, leading to a diagnosis of IPD. HLH was diagnosed based on a prolonged fever, neutropenia, anemia, hepatosplenomegaly, hemophagocytosis in the bone marrow, and elevated serum levels of triglycerides, ferritin, and soluble interleukin-2 receptor. He received broad-spectrum antibiotics and intravenous immunoglobulins for IPD and high-dose steroid pulse therapy and cyclosporine A for HLH; thereafter, his fever resolved, and laboratory findings improved. The serotype of the isolated S. pneumoniae was 23A, which is not included in PCV-13. CONCLUSIONS: It is important to consider secondary HLH as a complication of IPD cases with febrile cytopenia or hepatosplenomegaly, and appropriate treatment for HLH should be started without delay.

A Case Report of Pneumococcal Septic Arthritis Following a Respiratory and Gastrointestinal Prodrome with Accompanying Literature Review.

We report an uncommon case of septic arthritis of the ankle from a Streptococcus pneumoniae infection and provide an update of the literature reported since 2002. A 58-year-old female presented to the hospital with right ankle pain and an inability to bear weight. She reported a history of productive cough, vomiting, diarrhea, and subjective fevers 4 days earlier. Streptococcus pneumonia was identified in her ankle aspirate, and she was treated urgently with operative incision and debridement, followed by postoperative intravenous antibiotics. At her 7-week follow-up, she demonstrated complete resolution of symptoms and near-complete recovery of range of motion. This case demonstrates the importance of early identification, as the majority of patients recover fully with prompt treatment. The literature review included 44 cases of pneumococcal septic arthritis and found that the knee was the most commonly affected joint, followed by the shoulder and ankle. Blood cultures were positive for S. pneumoniae in 27 of 38 adults (71%) and 4 of 6 children (67%). Comorbid conditions were present in 32 of 38 adults (84%) and 4 of 7 children (57%), the most frequent of which were alcoholism and osteoarthritis in adults and malignancy or immunosuppression in children. Additionally, roughly half of included adults had an extra-articular focus of pneumococcal disease, most frequently pneumonia. Operative treatment was undertaken in 32 of 38 adults (84%) and all 7 children. Of adults with data available, 24 of 33 (73%) recovered with complete joint function, compared with 5 of 7 children (71%).

Streptococcus pneumoniae as a Cause of Mycotic and Infected Aneurysms in Patients without Respiratory Features: Challenging Diagnoses Aided by 16S PCR.

BACKGROUND: Streptococcus pneumoniae is considered a rare cause of mycotic aneurysms. The microbiological diagnosis of mycotic aneurysms can be difficult, and many patients have negative blood culture results. METHODS: We describe a series of four consecutive cases of mycotic aneurysms caused by S. pneumoniae with no respiratory features or extravascular septic foci. In two patients with negative blood culture results, 16S PCR was used for the diagnosis of S. pneumoniae infection. RESULTS: Four men with mycotic aneurysms affecting the aorta, axillary, and popliteal arteries caused by S. pneumoniae presented to our center between 2015 and 2016. All were treated with at least one month of intravenous antibiotics, followed by at least 4 weeks of oral antibiotics. Two were additionally managed using endovascular surgical techniques, and one underwent an open surgical repair. The fourth patient presented with bilateral popliteal aneurysms, one of which ruptured and was managed using surgical ligation and bypass, whereas the other side subsequently ruptured and was repaired endovascularly. Three of the four patients are currently off antibiotics and considered cured, while one died of an unrelated cause. CONCLUSIONS: S. pneumoniae should be considered a potential causative agent of mycotic aneurysms. Diagnosis can be confirmed using 16S PCR, especially in patients where peripheral blood cultures are uninformative.

Pneumococcal Bacteremia Complicated by Hemophagocytic Lymphohistiocytosis.

From pneumonia to pericarditis, from sepsis to splenic abscess, Streptococcus pneumoniae is the causative agent of a diverse array of pyogenic disease. With the introduction of vaccines and effective antibiotic treatments, the incidence of complicated streptococcal infection has declined. We report a case of S. pneumoniae bacteremia, in the setting of occult sinusitis, complicated by hemophagocytic lymphohistiocytosis (HLH), disseminated intravascular coagulation (DIC), and recurrent pneumococcal infection. Although severe streptococcal infection has been associated with immunodeficiency or splenectomy, no such predisposition was identified in our patient. We discuss the association of streptococcal infection with HLH and DIC and review occult sinusitis as a source of pneumococcal bacteremia, with the goal of enhancing the "illness scripts" of general medical practitioners to include such entities.

Associação de meningite e pericardite na doença pneumocócica invasiva: um caso raro / Association of meningitis and pericarditis in invasive pneumococcal disease: a rare case

RESUMO Objetivo: Relatar um caso raro de uma criança com meningite associada a pericardite na doença pneumocócica invasiva. Descrição do caso: Este relato descreve uma evolução clínica desfavorável de um lactente feminino de 6 meses de idade, previamente hígido, que apresentou inicialmente sintomas respiratórios e febre. A radiografia de tórax revelou um aumento da área cardíaca sem alterações radiográficas nos pulmões. Após a identificação do derrame pericárdico, o paciente apresentou convulsões e entrou em coma. Pneumonia foi descartada durante a investigação clínica. Contudo, foi identificado Streptococcus pneumoniae nas culturas de líquor e sangue. O exame neurológico inicial foi compatível com morte encefálica, posteriormente confirmada pelo protocolo. Comentários: A pericardite purulenta tornou-se uma complicação rara da doença pneumocócica invasiva desde o advento da terapia antibiótica. Pacientes com pneumonia extensa são primariamente predispostos e, mesmo com tratamento adequado e precoce, estão sujeitos a altas taxas de mortalidade. A associação de meningite pneumocócica e pericardite é incomum e, portanto, de difícil diagnóstico. Por isso, uma alta suspeição diagnóstica é necessária para instituir o tratamento precoce e aumentar a sobrevida.

ABSTRACT Objective: To report a rare case of a child with invasive pneumococcal disease that presented meningitis associated with pericarditis. Case description: This report describes the unfavorable clinical course of a previously healthy 6-months-old female infant who initially presented symptoms of fever and respiratory problems. A chest X-ray revealed an increased cardiac area with no radiographic changes in the lungs. After identifying a pericardial effusion, the patient experienced seizures and went into coma. Pneumonia was excluded as a possibility during the clinical investigation. However, Streptococcus pneumoniae was identified in the cerebrospinal fluid and blood cultures. An initial neurological examination showed that the patient was brain dead, which was then later confirmed according to protocol. Comments: Purulent pericarditis has become a rare complication of invasive pneumococcal disease since the advent of antibiotic therapy. Patients with extensive pneumonia are primarily predisposed and, even with early and adequate treatment, are prone to high mortality rates. The association of pneumococcal meningitis and pericarditis is uncommon, and therefore difficult to diagnose. As such, diagnostic suspicion must be high in order to institute early treatment and increase survival.