Chapter Controlled Human Infection with Bordetella pertussis.

Bordetella pertussis, a slow-growing Gram-negative coccobacillus and the causative agent of whooping cough, is one of the leading causes of vaccine-preventable death and morbidity globally. A state of asymptomatic human carriage has not yet been demonstrated by population studies but is likely to be an important reservoir for community transmission of infection. Such a carriage state may be a target for future vaccine strategies. This chapter presents a short summary of the characteristics of B. pertussis, which should be taken into account when developing a human challenge model and any future experimental medicine interventions. Three studies involving deliberate infection with B. pertussis have been described to date. The first of these was a scientifically and ethically unacceptable paediatric challenge study involving four children in 1930. The second was an investigation of a putative live vaccine using a genetically modified and attenuated strain of B. pertussis. Finally, a systematically constructed human challenge model using a wild-type, potentially pathogenic strain has been established. The latter study has demonstrated that deliberate induction of asymptomatic colonisation in humans is safe and immunogenic, with colonised participants exhibiting seroconversion to pertussis antigens. It has also shown nasal wash to be a more sensitive method of detecting the presence of B. pertussis than either pernasal swab or throat swab, and that B. pertussis carriage can be cleared effectively with Azithromycin. The development of this wild-type B. pertussis human challenge model will allow the investigation of host-pathogen and facilitate future vaccine development.

Exploring the acceptability of controlled human infection with SARSCoV2-a public consultation.

Rapid development of an effective vaccine for SARSCoV2 is a global priority. A controlled human infection model (CHIM) would accelerate the efficacy assessment of candidate vaccines. This strategy would require deliberate exposure of volunteers to SARSCoV2 with no currently available treatment and a small but definite risk of serious illness or death. This raises complex questions about the social and ethical acceptability of risk to individuals, given the potential benefit to the wider population, and as such, a study cannot be done without public involvement. We conducted a structured public consultation with 57 individuals aged 20-40 years to understand public attitudes to a CHIM, and pre-requisites for enrolment. The overall response to this strategy was positive, and many would volunteer altruistically. Carefully controlled infection is viewed as safer than natural exposure to wild virus. The prolonged social isolation required for the proposed CHIM is considered an obstacle but not insurmountable, with reasonable compensation and supportive care. Given the significant level of public interest, a CHIM should be done as open science with regular, controlled dissemination of information into the public domain. Importantly, there was a strong view that the final decision whether to conduct a CHIM should be in the hands of qualified and experienced clinician-scientists and the authorities.

Effect of ethnicity on care pathway and outcomes in patients hospitalized with influenza A(H1N1)pdm09 in the UK.

Data were extracted from the case records of UK patients admitted with laboratory-confirmed influenza A(H1N1)pdm09. White and non-White patients were characterized by age, sex, socioeconomic status, pandemic wave and indicators of pre-morbid health status. Logistic regression examined differences by ethnicity in patient characteristics, care pathway and clinical outcomes; multivariable models controlled for potential confounders. Whites (n = 630) and non-Whites (n = 510) differed by age, socioeconomic status, pandemic wave of admission, pregnancy, recorded obesity, previous and current smoking, and presence of chronic obstructive pulmonary disease. After adjustment for a priori confounders non-Whites were less likely to have received pre-admission antibiotics [adjusted odds ratio (aOR) 0·43, 95% confidence interval (CI) 0·28-0·68, P < 0·001) but more likely to receive antiviral drugs as in-patients (aOR 1·53, 95% CI 1·08-2·18, P = 0·018). However, there were no significant differences by ethnicity in delayed admission, severity at presentation for admission, or likelihood of severe outcome.

Risk factors for hospitalisation and poor outcome with pandemic A/H1N1 influenza: United Kingdom first wave (May-September 2009).

BACKGROUND: During the first wave of pandemic H1N1 influenza in 2009, most cases outside North America occurred in the UK. The clinical characteristics of UK patients hospitalised with pandemic H1N1 infection and risk factors for severe outcome are described. METHODS: A case note-based investigation was performed of patients admitted with confirmed pandemic H1N1 infection. RESULTS: From 27 April to 30 September 2009, 631 cases from 55 hospitals were investigated. 13% were admitted to a high dependency or intensive care unit and 5% died; 36% were aged <16 years and 5% were aged > or = 65 years. Non-white and pregnant patients were over-represented. 45% of patients had at least one underlying condition, mainly asthma, and 13% received antiviral drugs before admission. Of 349 with documented chest x-rays on admission, 29% had evidence of pneumonia, but bacterial co-infection was uncommon. Multivariate analyses showed that physician-recorded obesity on admission and pulmonary conditions other than asthma or chronic obstructive pulmonary disease (COPD) were associated with a severe outcome, as were radiologically-confirmed pneumonia and a raised C-reactive protein (CRP) level (> or = 100 mg/l). 59% of all in-hospital deaths occurred in previously healthy people. CONCLUSIONS: Pandemic H1N1 infection causes disease requiring hospitalisation of previously fit individuals as well as those with underlying conditions. An abnormal chest x-ray or a raised CRP level, especially in patients who are recorded as obese or who have pulmonary conditions other than asthma or COPD, indicate a potentially serious outcome. These findings support the use of pandemic vaccine in pregnant women, children <5 years of age and those with chronic lung disease.

Cytokine production by activated T cells in common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency. It is characterized by hypogammaglobulinemia, increased susceptibility to recurrent infections, autoimmunity, and malignancies. OBJECTIVES: To determine whether patients with CVID have cytokine production defects after T-cell activation and to assess whether or not these are correlated with markers of severe disease. METHODS: Twenty-seven patients with CVID and 17 healthy volunteers were investigated. Peripheral blood mononuclear cells were cultured under standard conditions in the presence and absence of phytohemagglutinin. Subsequent cell proliferation and cytokine release were measured and compared between stimulated and unstimulated cells. RESULTS: A general enhancement in cytokine production was observed in both CVID patients and controls after stimulation. However, we detected a lower production of interferon-gamma in CVID patients than in controls (P = .026). A production defect for at least 1 cytokine was observed in 12 patients. Ten of these failed to generate protective titers in response to the polysaccharide vaccine, and the frequency of bronchiectasis in this group of patients was 91.7%. Cytokine release correlated strongly with cell proliferation. CONCLUSIONS: This study indicates that some CVID patients have T-cell proliferation and secretory defects and that these may be associated with severe manifestations of disease. Screening for such defects could permit more effective monitoring and therapeutic strategies for CVID patients.

Mannose-binding lectin is present in human semen and modulates cellular adhesion of Neisseria gonorrhoeae in vitro.

Mannose-binding lectin (MBL) is an innate immune molecule present in blood and some mucosal tissues, which can influence microbial attachment and inflammatory responses of host cells during infection. In this study MBL was found to be present at a low concentration in semen samples in the range 1.2-24.9 ng/ml. Co-incubation of bacteria with semen resulted in the binding of MBL to the bacterial surface. Neisseria gonorrhoeae is a common cause of genitourinary infection. MBL bound to N. gonorrhoeae with strain-to-strain variation in the intensity of binding and nature of the bacterial receptor. Pretreatment with MBL concentrations similar to those found in human serum modulated the adhesion of N. gonorrhoeae strain FA1090 but not strain MS11 to epithelial cells. This effect was dose-dependent. This work demonstrates that MBL is present in human semen and modifies cellular responses to N. gonorrhoeae in a concentration-dependent manner.

Signs of herniosis in women with vaginal prolapse and/or stress incontinence.

Gynecological literature pertaining to prolapse or stress urinary incontinence published over the past four decades was reviewed to determine whether signs of herniosis, the systemic connective tissue co-morbidity known to play a significant role in abdominal herniation, were present and differed from controls. A total of eight indications were reported: (1) Genetic factors, i.e., family history and race, were predictive. (2) An increase in the incidence was observed in association with heritable diseases of collagen and their formes frustes (e.g., joint laxity). (3) Recurrence rate after repair was high (30%). (4) Fragmentation and degeneration of smooth muscle and collagen fibers were observed histologically. (5) Biochemistry demonstrated a decline of 24-40% in collagen content of skin, round ligament, cardinal ligament, periurethral vaginal wall, cervix, pubocervical, cervicococcygeal, and vesicovaginal fasciae. (6) In patients with stress urinary incontinence, collagen content decreased 60%. This change was independent of age, parity, menopausal status, and weight. (7) Matrix metalloproteinase (MMP-2 and MMP-9) activity increased fourfold and that of their inhibitor TIMP-1 decreased. (8) Cigarette smoking, an acquired factor, increased the incidence of stress urinary incontinence. This commonality with the etiology of abdominal herniae explains why gynecologists have decreased their emphasis on childbirth injury and, like herniologists, have moved to discard the dogma "prolapse" as a designate for extraperitoneal herniation in the pelvis.

Archaic terms and dogmas impeding care of abdominal and pelvic herniation.

During the past 5000 years, ancient nomenclature and dogmas regarding the etiology of protrusions have accumulated. Whereas, in the abdomen, the Latin "hernia" supplanted Greek, it, based on content, persists in the pelvis as cystocele, rectocele, etc. Russell (Lancet 1:1519-1523, 1902) championed the congenital saccular theory of herniae, denying they could ever be acquired pathologically. Barring technical error, removal of the sac would cure. Despite dissent in the 1920s by Harrison, Keith, and Andrews, Russell's concepts held late into the twentieth century. We now know that pathology - systemic connective tissue disease - plays an important role in adult herniation. Tensionless prosthetic repair is usually required since the healing of damaged musculo-aponeurotic structures in abdomen or pelvis is impaired. Laparoscopists have declared sliding extraperitoneal prolapse of sacless kidney, ureter, bladder, and fat pad to be herniae. Similar vaginal protrusions should be denoted likewise. It is time gynecologists and herniologists join in the effort to develop antidotes for combating this pernicious co-morbidity which has been shown also to cause aneurysms, diverticulosis coli, skin changes, and emphysema. Prophylaxis should include exercise and going without cigarettes.

Co-morbidity and interstitial herniation in the adult: an hypothesis.

Whereas interstitial hernias of infancy are a result of congenital abnormalities, those in adults have been blamed on anatomical banding. Many of the latter are associated with systemic, genetic, or acquired connective tissue disease, however. This results in attenuated aponeuroses, ruptured tendons, and atrophied fascia from collagen malformation and destruction. Muscle contractility is compromised by loss of connective tissue septae, reducing capillary density. The result is wasting and disaggregation, which explains interstitial defects filled with herniated extraperitoneal fat, which account for 1% of primary inguinal herniae. These were originally described in the transversus and internal oblique musculature by Hessert (Surg Gyn Obstet 16:566-568, 1913). Similar slits are seen with Spigelian herniae, all of which are interstitial. This hypothesis, if proven, would imply treatment of the pervasive co-morbidity with the protrusions.

The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults.

Bacterial meningitis and meningococcal sepsis are rare conditions with high case fatality rates. Early recognition and prompt treatment saves lives. In 1999 the British Infection Society produced a consensus statement for the management of immunocompetent adults with meningitis and meningococcal sepsis. Since 1999 there have been many changes. We therefore set out to produce revised guidelines which provide a standardised evidence-based approach to the management of acute community acquired meningitis and meningococcal sepsis in adults. A working party consisting of infectious diseases physicians, neurologists, acute physicians, intensivists, microbiologists, public health experts and patient group representatives was formed. Key questions were identified and the literature reviewed. All recommendations were graded and agreed upon by the working party. The guidelines, which for the first time include viral meningitis, are written in accordance with the AGREE 2 tool and recommendations graded according to the GRADE system. Main changes from the original statement include the indications for pre-hospital antibiotics, timing of the lumbar puncture and the indications for neuroimaging. The list of investigations has been updated and more emphasis is placed on molecular diagnosis. Approaches to both antibiotic and steroid therapy have been revised. Several recommendations have been given regarding the follow-up of patients.

The preperitoneal approach to the groin and the inferior epigastric vessels.

Preperitoneal, a word coined by Nyhus in the 1960s, has been applied not only to posterior approaches that he, Stoppa, and Wantz popularized but to anterior exposures of the groin, which divide the transversalis fascia. This assumes that all give similar views of the easily cleaved space of Bogros. However, accumulated anatomical observations reveal the transversalis fascia as having not one but two layers. The inferior epigastric vessels run between rather than in the preperitoneal space, which is avascular and has its own fascia lining the peritoneum. Historical evidence shows that both the midline Cheatle-Henry and lateral Ugahary-Kugel approaches, which transect the abdominal wall, provide excellent exposure of the avascular preperitoneal space. However, neither the unilateral posterior McEvedy approach nor the anterior approach does, as only part of the musculature and fasciae are retracted. The inferior epigastric vasculature and posterior lamina transversalis fascia, which remain in situ, block the view. Unless they are disrupted or circumvented, neither of the latter approaches or subsequent repairs should be labeled preperitoneal.

British contributions to modern herniology of the groin.

Traditional disdain for groin repair stifled recognition of British innovations. Some, relating to modern herniology, are remembered herein. Morton (1841) and Mackay (1889) showed the epigastric artery piercing Cooper's transversalis fascia (1807). Bilaminarity (Cooper, 1807) was confirmed in 1992 (Read). Thomson's iliopubic tract (1838) became part of Nyhus' repair (1960) [derived from McEvedy's repair (1950)] and laparoscopy (Ger, 1982). Retzius' space (Edinburgh, 1858) with Lister's antisepsis (1865) enabled preperitoneal herniorrhaphy (Annandale, 1876). He participated (1873) in intraperitoneal release of incarceration and reducible protrusions (Tait 1883). Cheyne's pectineus muscle plug (1893) preceded Kelly's marble prosthesis for femoral herniation (1898). Cheatle (1920) introduced posterior preperitoneal repair-ignored, rediscovered (Henry, 1936), and adopted (1952) at the Mayo clinic. Calne (1967) pioneered retrorectus Mersilene and was followed by Stoppa (1969) and Wantz (1989). Brandon (1945) blamed failure of modified Bassini's herniorrhaphies on closure at the intermediate inguinal ring instead of the internal. A similar mechanism may explain interstitial recurrence (Gilbert, 2003) after Amid-Lichtenstein repair. Lytle (1896-1986) described a muscle shutter at the internal ring, course of genitofemoral nerve, and orifice of femoral canal. Russell's congenital saccular theory (1906) was questioned by Keith (1924). Acquired connective-tissue pathology was later shown to play a systematic role in adult groin herniation (Read, 1970), confirmed by Jackson and colleagues (1996) and others.

Management of nonsmall cell lung carcinoma with solitary brain metastasis.

Cushing's group, operating on metastatic brain tumors in the 1920s, was the first to point out that lung cancer (usually adenocarcinoma in an upper lobe) was the most common primary tumor. Excision of a solitary metastasis could result in long-term survival. Magilligan and coworkers (J Thorac Cardiovasc Surg 1976;72:690) introduced the modern era of large series of combined lung-brain resection with low mortality (3%) and a 5-year outcome of 21%. Our results (92 patients) confirm their experience. Presenting symptoms were pulmonary (53), synchronous (28), or neurologic (11). Nonsquamous cell (48) predominated. Pulmonary resections (45) were pneumonectomy (five), lobectomy (27), segmentectomy (five), and wedge biopsy (eight). Craniotomy (68) and irradiation resulted in recurrence in seven patients. There was no operative mortality. The survival rate after curative lung and brain resection (27) was 52% at 1 year, 35% at 2 years, and 21% at 5 years. Median survival in noncurative combined resection (eight), craniotomy only (27), thoracotomy only (eight), or no surgery (22) groups, with or without irradiation or chemotherapy, averaged 6.4 months. Every effort should be made to give patients with this syndrome the benefit of combined surgery, which was not offered or agreed on in more than a third of our cases.

Changes in arterial oxygenation and pulmonary shunt during thoracotomy with endobronchial anesthesia.

Eight-five veterans underwent thoracic operations, mainly for carcinoma of the lung, with the aid of endobronchial anesthesia. Changes in arterial oxygenation (PaO2) and pulmonary shunt (Qs/Qt) were determined sequentially. Mean PaO2 after both lungs were ventilated for 20 minutes, supine, with 100% oxygen was 433 +/- 8 mm Hg. Selective ventilation of one bronchus dropped this value significantly (p less than 0.01) to 247 +/- 13 mm Hg. PaO2 did not change appreciably when the patient was turned to the lateral position; however, following pleurotomy there was a significant (p less than 0.01) decline in mean PaO2 to a nadir of 178 +/- 17 mm Hg at 90 minutes. Transient hypoxemia (PaO2 less than 60 mm Hg) occurred in 11 of 85 patients, most frequently (7/11) during positioning. Preoperative PaO2 PaCO2, forced expiratory volume in 1 second, forced vital capacity, or medical status did not predict hypoxemia. Qs/Qt increased significantly (p less than 0.01) at the onset of atelectasis from 18% +/- 0.9% to 25.4% +/- 0.9% but did not change with turning. The maximal mean Qs/Qt (30.3% +/- 1.1%) occurred immediately after opening the pleura and then decreased significantly (p less than 0.05), despite the fall in PaO2. Blood loss greater than 1,000 cc (n = 10), especially with hypotension, resulted in a significant increase (p less than 0.05) in Qs/Qt and a fall in PaO2. Thus pulmonary vascular adaptation to acute atelectasis has been demonstrated in man, and this, as in animal models, fails with hemorrhage.

Primary pulmonary plasmacytoma: a case report.

Most extramedullary plasmacytomas are associated with the upper respiratory tract. Primary pulmonary plasmacytomas are rare, and the treatment is surgical excision. This malignancy advances to multiple myeloma in a minority of patients. The patient in our case report is the first to experience renal failure due to hematologic monoclonal gammopathy. Postoperatively, serum protein electrophoresis reverted to normal.

Survival of men treated for chronic stable angina pectoris. A cooperative randomized study.

During 1972 to 1974, 686 men aged 27 to 67 years, admitted to thirteen Veterans Administration Hospitals with stable angina, resting or exercise electrocardiographic abnormalities, "graftable" arteries, and abnormal left ventricular function (80 percent) were randomly assigned to surgery (332) or medical (354) treatment. There was no significant difference in clinical, angiographic, and ventriculographic characteristics. The over-all operative mortality rate (30 days) was 5.8 percent, 5 percent in the 95 percent who had saphenous vein aorta-coronary bypass alone. Eighty-nine percent of the 79 percent recatheterized at 1 year had at least one patent graft. Longevity for patients with one, two, and three vessel disease who were treated surgically was comparable to that previously described, but did not differ from that of the medically treated groups. Survival in the over-all surgical group was 86 percent at 4 years as compared to 83 percent in the medical group, which in these "operative candidates" is better than usually cited. This difference was eliminated when the 90 patients (13 percent) with left main disease, whose longevity was significantly improved (p = 0.005) by the operation, were excluded. Despite this exclusion, a slight trend in favor of surgery was still discernible in the largest subgroup, those having triple vessel disease with an abnormal left ventricle.

Left ventricular--right atrial shunt: an unusual cause of hemodynamic deterioration following aortic valve surgery.

Two cases of left ventricular-right atrial shunts inadvertently produced during aortic valve replacement are described. It is surprising that this complication is not more prevalent considering the close proximity of the aortic and mitral valves to the atrioventricular portion of the membranous septum. A left-to-right shunt should be a consideration in patients who fail to improve following aortic valve surgery, especially if the valve and subaortic region were heavily calcified or septal trauma occurred during the surgical procedure.

Cardiovascular effects of protamine sulfate are dependent on the presence and type of circulating heparin.

Man's response to clinical doses of protamine is highly variable. We investigated the influence of circulating heparin in nine swine (mean age 6 weeks, weight 10 kg). Through a sternotomy we implanted an electromagnetic flow probe around the pulmonary artery for cardiac output determination and catheters into the ascending aorta, pulmonary artery, right atrium, and left atrium for pressure monitoring. Each animal was allowed to recover and was studied awake on 3 consecutive days. Protamine, 3 mg/kg, beef lung heparin, 300 U/kg, and pork mucosal heparin, 300 U/kg, followed by protamine, were given in rotation by intravenous bolus. Protamine alone had no effect. Beef lung heparin followed by protamine induced a marked increase in pulmonary artery pressure (mean 38 +/- 3 to 51 +/- 5 mm Hg in 3 minutes). Pulmonary vascular resistance doubled (mean 0.12 +/- 0.01 to 0.23 +/- 0.04 R within 4 minutes), returning to normal within 15 minutes. Cardiac index and aortic pressure changed minimally. Pork mucosal heparin followed by protamine induced a similar but greater increase in mean pulmonary arterial pressure; however, cardiac index fell significantly (p less than 0.05, 207 +/- 16 to 117 +/- 16 ml/kg/min-1 at 1 minute) despite a regular rhythm and adequate left atrial filling pressure. Thus cardiac contractility was depressed. Systemic hypotension occurred in three of nine pigs. Both mean pulmonary vascular resistance and systemic vascular resistance increased (0.12 +/- 0.01 to 0.67 +/- 0.25 R and 0.40 +/- 0.04 to 1.09 +/- 0.25 R, respectively), significantly (p less than 0.05) more with pork than beef heparin. These data demonstrate that cardiovascular response to protamine neutralization varies significantly in regard to the type of heparin used. Furthermore, circulating heparin is required to produce those effects previously attributed to protamine alone.

Outcomes of lower extremity amputations.

In an effort to identify variables that could be used to predict outcomes of amputation, a cohort of 97 veteran amputees with a median age of 64 years who underwent 155 lower extremity procedures during 1984 was followed for 15 months. A high incidence of postoperative complication, revision, and mortality with poor quality of life confirm the serious prognosis of these individuals. Regression analyses indicated that peripheral vascular disease and prolonged preoperative hospitalization were associated with complications. Preoperative gangrene and peripheral vascular disease were associated with the need for revision. Complications, a low body mass index, and multiple diseases were related to death. Those with multiple diseases and extensive atherosclerosis were less likely to walk. Ability to perform activities of daily living was the most important predictor of quality of life. Patients at higher risk for these adverse outcomes need to be identified early in their hospital stay. The involvement of the patient or his or her surrogate in decisions regarding the course of treatment and the level of amputation is essential.