Fever of unknown origin revealing testicular nocardiosis: a case report and literature review.

BACKGROUND: Nocardia is an ubiquitous soil organism. As an opportunistic pathogen, inhalation and skin inoculation are the most common routes of infection. Lungs and skin are the most frequent sites of nocardiosis. Testis is a highly unusual location for nocardiosis. CASE PRESENTATION: We report the case of an immunocompromised 75-year-old-man admitted for fever of unknown origin. He presented with skin lesions after gardening and was first suspected of Mediterranean spotted fever, but he did not respond to doxycycline. Then, physical examination revealed new left scrotal swelling that was compatible with a diagnosis of epididymo-orchitis. The patient's condition did not improve despite empirical antibiotic treatment with the onset of necrotic scrotal abscesses requiring surgery. Nocardia brasiliensis yielded from the removed testis culture. High-dose trimethoprim-sulfamethoxazole and ceftriaxone were started. Multiple micro-abscesses were found in the brain and spinal cord on imaging studies. After 6 weeks of dual antibiotic therapy for disseminated nocardiosis, slight regression of the brain abscesses was observed. The patient was discharged after a 6-month course of antibiotics and remained relapse-free at that time of writing these lines. Trimethoprim-sulfamethoxazole alone is meant to be pursued for 6 months thereafter. We undertook a literature review on previously reported cases of genitourinary and urological nocardiosis; to date, only 36 cases have been published with predominately involvement of kidney, prostate and testis. CONCLUSIONS: To the best of our knowledge, this is the first case of Nocardia brasiliensis simultaneously infecting skin, testis, brain and spinal cord in an immunocompromised patient. Knowledge on uncommon forms of nocardiosis remains scarce. This case report highlights the difficulty of diagnosing atypical nocardiosis and the importance of prompt bacteriological sampling in case of empirical antibiotics failure.

Fever of Unknown Origin in a Renal Transplant Recipient: Lactate Dehydrogenase as an Important Clue to Diagnosis.

Histoplasmosis is a rare disease in nonendemic areas. We report a case of a 23-year-old male patient who presented with fever of unknown origin, cytopenias, organomegaly, and allograft dysfunction 4 months after renal transplant with father as donor. Bone marrow examination showed intracellular budding yeast cells, which was confirmed as histoplasmosis by culture of bone marrow biopsy sample. The patient was treated with intravenous liposomal amphotericin and responded well.

Combined Laboratory Approach to Detection of Parvovirus B19 and Coxiella Burnetii in Patients with Fever of Unknown Origin.

BACKGROUND: Fever of unknown origin (FUO) is one of the greatest challenges for clinicians and patients. There are more than 200 etiological agents of FUO, among these the most common is the role of infection, neoplasms, and diseases of connective tissue. The aim of the present study is to investigate the role of the infectious agents parvovirus B19 (B19V) and Coxiella burnetii (C. burnetii) in the development of fever of unknown origin by a set of immunoenzymatic and molecular methods. METHODS: The present study included a total of 70 adult patients diagnosed with FUO and hospitalized in Bulgarian Hospitals. A control group of 26 healthy people were also included. Serological (indirect enzyme immunoassay test for detection of B19V and C. burnetii Ph. II specific IgM/IgG) and molecular (extraction and detection of infectious nucleic acids) methods were used. RESULTS: From all patients with FUO, a positive result for B19V-IgM was obtained in 18/70 (25.71%, 95% CI: 15.47 - 35.95) and the highest percentage was found in age groups 0 - 9 and 10 - 19 years. Protective B19V immunity and past viral infection was reported in 41/70 (58.57%, 95% CI: 47.03 - 70.11), and this percentage corresponded with the control group 16/26 (61.54%, 95% CI: 42.84 - 80.24). Anti-C. burnetii Ph. II-IgM was demonstrated in 13/70 (18.57%, 95% CI: 9.46 - 27.68). A relatively high percentage of affected patients were ≤ 40 years. Anti-C. burnetii Ph. II-IgG was detected in 24/70 (34.29%, 95% CI: 23.17 - 45.41). The control group has a 100% negative result for acute B19V and C. burnetii infection. A positive B19V-DNA result was obtained in 12/70 (17.14%, 95% CI: 8.31 - 25.97) patients. In 11/12 (91.67%) it was in combination with positive B19V-IgM marker. Of the total 70 sera tested, a positive PCR results for C. burnetii-DNA were obtained in 11 (15.71%, 95% CI: 7.18 - 24.24). According to clinical manifestation and concomitant symptoms, a high percentage of B19V and C. burnetii positives were associated with FUO and fever, headache, chills, and rash. CONCLUSIONS: It is of particular importance for a correct diagnosis of FUO to use a combined laboratory approach to prove acute or persistent infection and to test for a set of etiological agents.

Diagnostic utility of bone marrow examination in evaluation of fever: a descriptive study on 98 immunocompetent adults from a tertiary care institute in south India.

Five-year clinico-laboratory data from 99 (one HIV seropositive) adults (mean age = 41.3 ± 20.4 years) who underwent bone marrow examination for fever persisting for ≥ 1 week were analysed and correlated with microbiological characteristics. Infections, reactive marrow changes and haematolymphoid malignancies were most commonly associated with fever. A high concordance rate of 71% was noted between aspiration and trephine biopsies. Bone marrow granulomas (BMG) were seen exclusively on sections and were most commonly of tubercular and typhoidal in origin (two Salmonella Typhi, one Salmonella Paratyphi A). The common aetiologies associated with fever and cytopenia(s) were BMG, acute leukaemia and haemophagocytic lymphohistiocytosis (HLH; n = 3). The yield from bone marrow culture was inferior compared to other body fluids. In conclusion, bone marrow histology is superior to smears in the evaluation of prolonged fever. Marrow culture may not be useful in immunocompetent individuals other than if Salmonellosis is suspected.

Molecular diagnosis and source tracing of an infection of Aureobasidium pullulans.

Aureobasidium pullulans (A. pullulans) is a dematiaceous, yeast-like fungus that is ubiquitous in nature, which can colonize the human hair and skin. A. pullulans has been clinically implicated to cause skin and soft tissue infections, meningitis, splenic abscesses, and peritonitis. Herein, molecular diagnostic of internal transcribed spacer (ITS) sequencing was used to investigate a suspected case of A. pullulans infection, and the infection source had been traced. A 27-year-old female case was suspected of kala-azar due to the recurrent fever. Bone marrow specimens were analyzed. The samples were negative for Leishmania, Penicillium marneffei and Histoplasma capsulatum. DNA was extracted from the bone marrow specimens, and the 583-bp sequence was amplified with the fungal ITS universal primers. The sequence was compared by Blast query to be identified as A. pullulans. A strain of A. pullulans was also isolated from the kitchen of the patient's living room. Culture characteristics were the same as the human pathogens of A. pullulans, and the ITS sequence was identical to the bone marrow ITS amplification. In conclusion, a deep infection caused by A. pullulans is rare, often occurring in the indwelling catheter, which may cause peritonitis and other symptoms. ITS sequencing of fungi can be used as a diagnostic reference. As A. pullulans is a common fungus in environment, amplification of ITS sequence of A. pullulans in the aseptic body fluid would be necessary to make a comprehensive diagnosis based on the clinical symptoms and signs.

Lessons learned from splenic infarcts with fever of unknown origin (FUO): culture-negative endocarditis (CNE) or malignancy?

Culture negative endocarditis (CNE) is a common concern in patients with fever, heart murmur, cardiac vegetation, and negative blood cultures. The diagnosis of CNE is not based only on negative blood cultures and a cardiac vegetation. The clinical definition of CNE is based on negative blood cultures plus the findings of culture positive infective endocarditis (IE), e.g., fever, cardiac vegetation, splenomegaly, peripheral manifestations. Because embolic splenic infarcts may occur with culture positive IE, some may assume that splenic infarcts are a sign of CNE. Previously, CNE was due to fastidious and non-culturable organisms. With current diagnostic methods, fastidious organisms grow in 2-3 days. Therefore, fastidious IE are a subset of culture positive IE, but do not represent true CNE. We describe a case of an elderly female who presented with a fever of unknown origin (FUO) and multiple splenic infarcts thought by some to represent CNE. An extensive workup for CNE pathogens was negative. The final cause of her splenic infarcts was a diffuse large B-cell lymphoma (DLBCL). Review of the literature, as well as this case, confirms that splenic infarcts are not a feature of CNE. In patients with fever, splenic infarcts, and negative blood cultures, physicians should search for an alternate explanation rather than CNE, e.g., malignancy and hypercoaguable state (lupus anticoagulant).

Recurrent FUO due to intermittent Enterobacter cloacae bacteremias from an infected pacemaker lead diagnosed by gallium scan.

Fever of unknown origin (FUO) refers to fevers of ≥101° F that persist for ≥3 weeks and remain undiagnosed after a focused inpatient or outpatient workup. FUO may be due to infectious, malignant/neoplastic, rheumatic/inflammatory, or miscellaneous disorders. Recurrent FUOs are due to the same causes of classical FUOs. Recurrent FUOs may have continuous or intermittent fevers and are particularly difficult to diagnose. With intermittent fever, recurrent FUO diagnostic tests are best obtained during fever episodes. With recurrent FUOs, the periodicity of febrile episodes is unpredictable. We present a case of a 70-year-old male who presented with recurrent FUO. Multiple extensive FUO workups failed to determine the source of his fever. During his last two episodes of fever/chills, blood cultures were positive for Enterobacter cloacae. Episodic E. cloacae bacteremias suggested a device-related infection, and the patient had a penile implant and permanent pacemaker (PPM). Following febrile episodes, he was treated with multiple courses of appropriate antibiotics, but subsequently fever/chills recurred. Since a device-associated infection was suspected, indium and PET scans were done, but were negative. The source of his intermittent E. cloacae bacteremias was finally demonstrated by gallium scan showing enhanced uptake on a cardiac lead, but not the penile implant or PPM. Gallium scanning remains useful in workup of FUOs, particularly when false-negative indium or PET scans are suspected. The involved pacemaker lead was explanted, grew E. cloacae and the patient has since remained fever free.

Miliary pulmonary infection after BCG intravesical instillation: a rare, misdiagnosed and mistreated complication.

Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy decreases the progression risk of non-muscle-invasive bladder cancer, but potentially yields a broad spectrum of side effects. We report the case of a 73-year-old man affected by miliary pulmonary BCG infection, whose microbiological diagnosis was probably hindered by empiric fluoroquinolones, focusing on imaging and clinical work-up.

Pulmonary tuberculosis presenting as post-operative fever of unknown origin.

Post-operative fever is common following emergency surgery. Investigation and management of post-operative fever can be challenging when a clear source of sepsis is not evident or the underlying source of infection is not recognised. We herein report a case of secondary pulmonary tuberculosis presenting as post-operative fever following emergency laparotomy for a perforated duodenal ulcer. This case of tuberculosis was diagnosed on day 41 post-operatively and prior inconclusive results meant that we relied mainly on re-visiting history and examination in order to identify 3 targeted investigations: plain chest X-ray, sputum sample and blood test. Accordingly, the co-management of this complex patient achieved a good outcome.

Adrenomedullin predicts high risk and culture positivity in children with solid tumors suffering from neutropenic fever.

AIM OF STUDY: Neutropenic fever is a source of morbidity and mortality in children with cancer. It is not possible to detect the causative agent in cultures in most cases; the research for a marker that can show the severity of the disease is ongoing. We evaluated the role of adrenomedullin (ADM) at predicting prognosis on patients with febrile neutropenia, which has been proven to be a good prognostic marker for diseases with high morbidity and mortality, such as heart failure, ischemic ventricular dysfunction, sepsis, and systemic inflammatory response syndrome. MATERIALS AND METHODS: We recorded the 36 febrile episodes of 14 children receiving chemotherapy due to solid tumors. There were 10 events with unknown origin in the low-risk group, while in the high-risk group, there were 17 events with unknown origin, 8 events with microbiological origin and 1 event with clinically proven infection. Cultures were positive only in the high-risk group. However, the changes of ADM levels through time periods (first, second, third, and seventh days) were not significant. RESULTS: The first-day plasma ADM levels significantly predicted the presence of culture positivity (AUC 0.628, 95% CI 0.40-0.85, p = 0.303) and high-risk patients with neutropenic fever (AUC 0.76, 95% CI 0.56-0.97, p = 0.016). CONCLUSION: Our study showed that increased plasma ADM was correlated with high-risk neutropenic fever and culture positivity. The ADM levels in the high-risk group were clearly high at the diagnosis and continued to the end of the treatment.

Lack of Effectiveness of Neutropenic Diet and Social Restrictions as Anti-Infective Measures in Children With Acute Myeloid Leukemia: An Analysis of the AML-BFM 2004 Trial.

PURPOSE: Although nonpharmacologic anti-infective measures are widely used in children treated for acute myeloid leukemia (AML), there is little evidence of their effectiveness. PATIENTS AND METHODS: We analyzed infectious complications in children during intensive treatment of AML according to the AML-BFM 2004 trial and surveyed sites on institutional standards regarding recommended restrictions of social contacts (six items), pets (five items), and food (eight items). A scoring system was developed with a restriction score for each item. Multivariable Poisson regression adjusted for sex, age, weight group, risk stratification, and prophylactic antibiotics was used to estimate the impact of the restrictions on the incidence ratios of fever of unknown origin, bacteremia, pneumonia, and gastroenteritis. RESULTS: Data on recommendations of nonpharmacologic anti-infective measures and infectious complications were available in 339 patients treated in 37 institutions. Analyses did not demonstrate a significant benefit of any of the restrictions regarding food, social contacts, and pets on the risk of fever, bacteremia, pneumonia, and gastroenteritis. In contrast, age, weight group, risk stratification, and nonabsorbable antibiotics had some influence on infections complications. CONCLUSION: The lack of effectiveness of dietary restrictions and restrictions regarding social contacts and pets should result in reconsideration of anti-infective policies.

Repeat blood cultures in children with persistent fever and neutropenia: Diagnostic and clinical implications.

BACKGROUND: Repeat blood cultures are frequently obtained in children with persistent fever and neutropenia (FN), but their clinical impact is uncertain. METHODS: We identified children with persistent FN in the context of hematologic malignancy or hematopoietic stem cell transplantation from July 2006 to June 2012. For each episode, we reviewed blood cultures to determine the yield of true positive and false positive results. We then examined episode-level and culture-level predictors to determine factors associated with new bloodstream infections (BSI). RESULTS: Among 135 children who met inclusion criteria, there were 184 persistent FN episodes, during which 17 new BSI were diagnosed after the first 24 hr of fever (9.2%; 95% CI 5.4-15.3%). After the first 24 hr, the incidence of new BSI was 1.5% (95% CI 1.0-2.4%) per day and the incidence of blood culture contamination was 1.1% (95% CI 0.6-2.1%) per day. Of 17 new BSI identified, 14 (82%) required changes in therapy, while all 12 contaminant blood cultures were followed by additional antibiotic therapy. Increased odds of new BSI were associated with a history of BSI within 30 days of the episode (OR 5.18; 95% CI 1.29-20.8) and increasing time between recurrent fevers (OR 1.29; 95% CI 1.06-1.57). CONCLUSIONS: Repeat blood cultures have an important role in diagnosing new BSI and directing therapy in children with persistent FN. The current strategy could be improved by reducing the frequency of blood cultures after the first 24 hr, and targeting repeat cultures by risk.

Utility of adding Pneumocystis jirovecii DNA detection in nasopharyngeal aspirates in immunocompromised adult patients with febrile pneumonia.

Detection of viral and bacterial DNA in nasopharyngeal aspirates (NPAs) is now a routine practice in emergency cases of febrile pneumonia. We investigated whether Pneumocystis jirovecii DNA could also be detected in these cases by conducting retrospective screening of 324 consecutive NPAs from 324 adult patients (198 or 61% were immunocompromised) admitted with suspected pulmonary infections during the 2012 influenza epidemic season, using a real-time quantitative polymerase chain reaction (PCR) assay (PjqPCR), which targets the P. jirovecii mitochondrial large subunit ribosomal RNA gene. These NPAs had already been tested for 22 respiratory pathogens (18 viruses and 4 bacteria), but we found that 16 NPAs (4.9%) were PjqPCR-positive, making P. jirovecii the fourth most prevalent of the 23 microorganisms in the screen. Eleven of the 16 PjqPCR-positive patients were immunocompromised, and five had underlying pulmonary conditions. Nine NPAs were also positive for another respiratory pathogen. Six had PjqPCR-positive induced sputa less than 3 days after the NPA procedure, and five were diagnosed with pneumocystis pneumonia (four with chronic lymphoproliferative disorders and one AIDS patient). In all six available pairs quantification of P. jirovecii DNA showed fewer copies in NPA than in induced sputum and three PjqPCR-negative NPAs corresponded to PjqPCR-positive bronchoalveolar lavage fluids, underscoring the fact that a negative PjqPCR screen does not exclude a diagnosis of pneumocystosis. Including P. jirovecii DNA detection to the panel of microorganisms included in screening tests used for febrile pneumonia may encourage additional investigations or support use of anti-pneumocystis pneumonia prophylaxis in immunocompromised patients.

Utility of bone marrow examination for workup of fever of unknown origin in patients with HIV/AIDS.

AIMS: The utility of bone marrow aspiration and biopsy (BMAB) as a diagnostic tool in patients with HIV/AIDS and fever of unknown origin (FUO) is a subject of debate. Because highly active antiretroviral therapy has reduced incidence of opportunistic infections, it is important to reassess the efficacy of BMAB for this diagnostic purpose. To our knowledge, no such studies have been performed in Harris County which has the highest incidence of HIV in the state of Texas. METHODS: We reviewed all BMABs from patients with HIV/AIDS and FUO or persistent cytopenia(s) from 2007 to 2011. RESULTS: Of 57 evaluable patients, BMAB was positive in 24 samples by acid fast bacilli (AFB) or Gomori methenamine silver (GMS) stains (17.5%), presence of granuloma and/or lymphohistiocytic aggregates (31.6%), culture (21.0%) or a combination. Cultures demonstrated Mycobacterium avium/intracellulare (4), M tuberculosis (2), M gordonae (1), Histoplasma capsulatum (3) and Cryptococcus neoformans (2). There were three cases in which a pathogen was grown in culture but that had a negative of 'direct examination' on tissue sections (negative AFB and GMS special stains, no morphological evidence of granuloma/lymphohistiocytic infiltrates). CONCLUSIONS: This study supports the use of diagnostic BMAB as a rapid decision-making tool in patients with HIV and FUO in the proper clinical setting. BMAB demonstrated infection-related evidence prior to positive bone marrow culture in 75% of cases. Special stains and blood cultures had similar diagnostic yield, but BMAB offers faster results. Thus, this procedure assists in clinical decision making and the refinement of treatment in a more timely manner.

Consensus guidelines for the use of empiric and diagnostic-driven antifungal treatment strategies in haematological malignancy, 2014.

Invasive fungal disease (IFD) causes significant morbidity and mortality in patients undergoing allogeneic haemopoietic stem cell transplantation or chemotherapy for haematological malignancy. Much of these adverse outcomes are due to the limited ability of traditional diagnostic tests (i.e. culture and histology) to make an early and accurate diagnosis. As persistent or recurrent fevers of unknown origin (PFUO) in neutropenic patients despite broad-spectrum antibiotics have been associated with the development of IFD, most centres have traditionally administered empiric antifungal therapy (EAFT) to patients with PFUO. However, use of an EAFT strategy has not been shown to have an overall survival benefit and is associated with excessive antifungal therapy use. As a result, the focus has shifted to developing more sensitive and specific diagnostic tests for early and more targeted antifungal treatment. These tests, including the galactomannan enzyme-linked immunosorbent assay and Aspergillus polymerase chain reaction (PCR), have enabled the development of diagnostic-driven antifungal treatment (DDAT) strategies, which have been shown to be safe and feasible, reducing antifungal usage. In addition, the development of effective antifungal prophylactic strategies has changed the landscape in terms of the incidence and types of IFD that clinicians have encountered. In this review, we examine the current role of EAFT and provide up-to-date data on the newer diagnostic tests and algorithms available for use in EAFT and DDAT strategies, within the context of patient risk and type of antifungal prophylaxis used.

Consensus guidelines for the treatment of yeast infections in the haematology, oncology and intensive care setting, 2014.

Pathogenic yeast forms are commonly associated with invasive fungal disease in the immunocompromised host, including patients with haematological malignancies and patients of haemopoietic stem cell transplants. Yeasts include the Candida spp., Cryptococcus spp., Pneumocystis jirovecii and some lesser-known pathogens. Candida species remain the most common cause of invasive yeast infections (and the most common human pathogenic fungi). These guidelines present evidence-based recommendations for the antifungal management of established, invasive yeast infections in adult and paediatric patients in the haematology/oncology setting. Consideration is also given to the critically ill patient in intensive care units, including the neonatal intensive care unit. Evidence for 'pre-emptive' or 'diagnostic-driven antifungal therapy' is also discussed. For the purposes of this paper, invasive yeast diseases are categorised under the headings of invasive candidiasis, cryptococcosis and uncommon yeast infections. Specific recommendations for the management of Pneumocystis jirovecii are presented in an accompanying article (see consensus guidelines by Cooley et al. appearing elsewhere in this supplement).

Comparative microbiological features of Bartonella henselae infection in a dog with fever of unknown origin and granulomatous lymphadenitis.

We report the first documented case of Bartonella henselae infection in a dog from France and the first isolation of B. henselae from a dog with fever of unknown origin. This observation contributes to the "One Health" concept focusing on zoonotic pathogens emerging from companion animals. A 1-year-old female German shepherd dog was referred for evaluation of fever of unknown origin of 1 month duration. Diagnostic investigations confirmed diffuse pyogranulomatous lymphadenitis. The dog became afebrile, and lymph node size normalized in response to a 6-week course of doxycycline. Retrospectively, Bartonella DNA was amplified from an EDTA-anticoagulated blood sample obtained before antimicrobial therapy, with the gtlA fragment sharing 99 % identity with the 350-bp gtlA fragment of the B. henselae Houston-1 strain. The same strain was isolated in the blood of three healthy cats from the household. Two months after discontinuation of doxycycline, the dog experienced a febrile relapse. Bartonella DNA was again amplified from blood prior to and immediately after administration of a 6-week course azithromycin therapy. However, without administration of additional medications, PCR was negative 9 months after azithromycin therapy and the dog remains clinically healthy 12 months following the second course of antibiotics. The medical management of this case raises several clinically relevant comparative infectious disease issues, including the extent to which Bartonella spp. contribute to fever of unknown origin and pyogranulomatous inflammatory diseases in dogs and humans, and the potential of doxycycline and azithromycin treatment failures. The possibility that dogs could constitute an underestimated reservoir for B. henselae transmission to people is also discussed.