Febrile Phase Research Articles

Kawasaki Disease and Chlamydia Pneumoniae Infection

Chlamydia pneumoniae infections have been associated with coronary artery disease. Although Kawasaki disease is characterized by an association with coronary artery disease in children predominantly under the age of 5, the etiology is still unknown. Serum samples were obtained from 72 infants and children, aged 5 months to 7 years, in the active febrile phase of Kawasaki disease and tested for the presence of C. pneumoniae serum antibodies. Twenty-seven (37.5%) serum samples were positive for an IgG antibody, 22 (30.6%) were positive for an IgA antibody, and 11 (15.3%) were positive for an IgM antibody to C. pneumoniae. The presence of serum IgM antibodies to C. pneumoniae in infants and children in the acute phase of Kawasaki disease was significantly higher than that of age-matched healthy controls ( P<0.01).

781 Infection during severe neutropenia in 182 patients with acute myeloid leukemia (AML)–morbidity and mortality

Infections still remain the major cause of morbidity and mortality in neu-tropenic patients with leukemia. Especially fungal infections are critical during neutopenia. 487 febrile phases were evaluated retrospectively during 377 neutropenic episodes (leukocytes < 0.5×10⁹/l) of 182 AML-patients treated in our institution from 1982–1993. We observed 16 neutropenic phases without fever. In 156 episodes (32%) the origin remained unknown (FUO), but 331 (68%) were clinically or microbio-logically identified infections mostly gram-positive bacterial (37%), followed by fungal (31%) and gram-negative bacterial infections (21%). Sepsis (220) and pneumonia (86) represented the major type of infections. 70% of pneumonia were caused by fungi. Urinary tract infections (27), tonsillitis (17), oesophagitis (16) and abscesses (13) turned out to be the other main infection sites. 48 patients died during neutropenia. The leading cause of death was fungal sepsis or pneumonia in 73% (29). 38% (11) of lethal fungal infections were discovered at autopsy; in 9 of these 11 patients mixed infections were observed—frequently a combination of fungal and gram-negative infection. To conclude all patients with pneumonia in neutropenia should be treated early with high dosage antimycotic therapy; in addition a mixed infection should be considered.

Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain; its possible role in the febrile response

Cyclooxygenase 2 (COX-2) is a newly discovered isoform of cyclooxygenase that is inducible by lipopolysaccharide (LPS) or cytokines. This enzyme is considered to play a major role in inflammatory processes by catalyzing the production of prostaglandins. In the present study, induction of COX-2 mRNA in the rat brain by intraperitoneal injection of LPS was studied by the in situ hybridization technique with special attention paid to timing and sites of induction along with the time course of fever. In situ hybridization was carried out on sections of rat brain, 1 h (latent phase), 2.5 h (maximally febrile phase), 4 h (plateau phase), and 7 h (recovery phase) after the LPS injection, as well as on those from the brains of untreated and saline-injected rats. Injection of LPS induced COX-2 mRNA in the brain in two different constituents: neuronal cells and non-parenchymal cells of the blood vessels and leptomeninges. Induction in the neuronal cells was restricted to some telencephalic areas where the COX-2 mRNA signal was also detected in control animals. The signal was maximally enhanced by 50 to 80% over the basal level 1 h after LPS injection. The COX-2 mRNA signal was hardly detectable in neuronal and glial cells in other brain regions, including the preoptic area, either in control or LPS-injected rats. Strong COX-2 mRNA signals, however, appeared in the inner surface of blood vessels and the leptomeninges over the entire brain, including the preoptic area and its vicinity. The signals were not detectable in the brains of control rats and were most intense in the brains of rats treated with LPS for 2.5 h or 4 h. These results demonstrate that two major cell groups in the brain, neuronal cells and non-parenchymal cells, are responsible for the enhanced production of prostaglandins after systemic LPS treatment. Considering the site and timing of induction, we propose a possible role for blood vessels and leptomeninges as the source of prostaglandin E 2 in the genesis of fever.

Biphasic fever: what triggers the second temperature rise?

The mechanism of initiation of the second body temperature (Tb) rise of the typically biphasic lipopolysaccharide (LPS) fever is not known. This study was undertaken to test the hypothesis that the second Tb rise during fever may be initiated as a direct consequence of the elevated Tb of the first febrile rise. Experiments were conducted in conscious guinea pigs implanted with intraperitoneal thermodes, intravenous catheters, and intrahypothalamic thermocouples. Intraperitoneal cooling (IPC) was performed by perfusing water (22 degrees C) through the thermode under afebrile conditions during the first (0-40 min after pyrogen injection) or second (80-120 min) phase of the biphasic LPS (2 g/kg iv) fever or during a monophasic LPS (0.5 g/kg iv) fever. Throughout IPC, the rate of heat withdrawal was maintained at 11.6 +/- 1.2 mW/g. No IPC was performed in the corresponding controls. When started immediately after LPS administration at the higher dose, IPC completely blocked the first phase of the biphasic fever. This blockade was followed by a Tb rise, which, although similar to the rise in the second phase, might alternatively be interpreted as the delayed occurrence of the first phase previously suppressed by IPC. However, we excluded the later possibility by showing the absence of an overshoot in Tb restoration after IPC applied during the second phase of biphasic fever, during monophasic fever, or under afebrile conditions. We conclude, therefore, that the second Tb rise of biphasic LPS fever is not induced by the elevated Tb of the first febrile phase. The cause of the second peak of the characteristic biphasic febrile response to intravenous LPS remains speculative.

Ampicillin plus Mecillinam vs. Cefotaxime/Cefadroxil Treatment of Patients with Severe Pneumonia or Pyelonephritis: a Double-Blind Multicentre Study Evaluated by Intention-to-Treat Analysis

In this double-blind multicentre study, using the intention-to-treat approach, a total of 293 patients with fever (> or = 38.5 degrees C), symptoms of sepsis and signs of pneumonia or pyelonephritis were randomly assigned to treatment with ampicillin and mecillinam (A+M) or cefotaxime followed by cefadroxil. In the febrile phase, treatment was given intravenously twice daily, either with 1,200 mg ampicillin together with 600 mg mecillinam or with 2 g cefotaxime alone. When the patients stayed afebrile, the intravenous administration was replaced by oral treatment twice daily for 14 days, either with 500 mg pivampicillin and 400 mg pivmecillinam or 1 g cefadroxil. In the A+M group, 33% (48/144) of the patients did not complete the full course of treatment as compared with 32% (47/149) in the cephalosporin group, the reasons being treatment failure in 27 and 29, respectively, or adverse effects (n = 16 in both groups). The median duration of fever was 47 h in the A + M group and 50 h in the cephalosporin group. Of 135 patients with pneumonia, 68% were completely cured in the A + M group, and 65% in the cephalosporin group, the main reasons for treatment failure being Mycoplasma pneumonia or ornithosis. Of 136 patients with pyelonephritis, 63% were cured in each group. The main reason for failure was bacteriological relapse. Side-effects were reported by 32 patients (22%) of the A+M group, as compared with 41 (28%) of the cephalosporin group. Epigastric complaints were equally frequent in both groups, but there was a tendency for a higher frequency of exanthema in the A+M group, and for antibiotic-associated diarrhoea and fungal superinfections in the cephalosporin group.

Inflammatory cytokine responses in juvenile chronic arthritis.

The inflammatory cytokines interleukin 1 beta (IL-1 beta) interleukin 6 (IL-6), tumour necrosis factor alpha (TNF alpha) and the anti-inflammatory peptide--the interleukin 1 (IL-1) receptor antagonist--were measured in the plasma of children with juvenile chronic arthritis (JCA). In the two subgroups studied (polyarticular JCA and systemic JCA), there was good correlation between laboratory measures of disease activity C-reactive protein (CRP), erythrocyte sedimentation rate and clinical scores for disease activity. Despite higher levels of CRP in the systemic group IL-1 beta levels were lower and regression analysis recorded a difference in the relationship between CRP and IL-1 beta within the two clinical groups. In contrast, IL-6 levels were high in the systemic group and correlated with disease activity. No such correlation was observed in the polyarticular group. Five children with systemic JCA were studied during the febrile phase of their illness. IL-6 levels rose and fell with the fever. TNF alpha levels also rose and fell but out of phase with the fever. In contrast IL-1 beta levels were either undetectable throughout the febrile episode or only became detectable as the temperature reduced to normal. The IL-1 receptor antagonist was usually found in 1000-fold excess over IL-1 beta, levels rising and falling with the fever. These results demonstrate difference in the cytokine profiles and acute phase protein responses in polyarticular and systemic JCA. This would suggest different pathogenic mechanisms for these two groups of JCA with IL-6 being the more important cytokine in systemic JCA.

Haemorrhagic fever with renal syndrome in Korean children

Haemorrhagic fever with renal syndrome (HFRS) is an acute disease caused by Hantavirus and clinically characterised by abrupt onset of fever, various haemorrhagic manifestations and transient renal and hepatic dysfunction. We retrospectively reviewed 63 cases of HFRS in children from 13 different hospitals in Korea who presented over a 15-year period. The age of the patients ranged from 7 to 15 years, with a male to female ratio of 8 to 1. Fifty-four (86%) patients were 10 years or older. On admission, 24 (38%) were in the febrile phase and 35 (56%) were in the oliguric phase. Fever (100%) abdominal pain (91%), headache (76%) and vomiting (73%) were the most common symptoms. Backache, subconjunctival haemorrhage and hypertension were also noted in about one-third of patients. Hypotension was documented in only 7 (11%) patients. Leucocytosis (> 10,000/mm3) and thrombocytopenia (< 150,000/mm3) were noted in more than two-thirds of patients. Elevated blood urea nitrogen and serum creatinine was observed in 94% by the 7th (median) day of illness. Elevated aspartate aminotransferase and/or alanine aminotransferase were found in more than two-thirds of patients. Renal biopsy was performed in 12 patients and revealed various stages of acute tubular necrosis with occasional interstitial cell infiltration and oedema. Only 2 showed evidence of interstitial haemorrhage. Eleven patients required 1-3 days of dialysis and the remaining patients required only conservative management. Three (5%) patients died of shock, respiratory failure and pulmonary haemorrhage. All other patients recovered without sequelae. Although childhood cases were much less common than adults, clinical and laboratory findings were in general similar between children and adults.

Probable role of Streptococcus pyogenes in Kawasaki disease.

Over the past 25 years, the clinical course of Kawasaki disease has been defined, the prevalence and nature of the cardiovascular effects widely understood, and pathological changes in the most severe cases well described. However, the aetiology and pathogenesis of this puzzling disease have remained unclear, thus specific therapy is not yet available. Because of some close clinical similarities between this disease and streptococcal scarlet fever, particular attention has been paid to the possible role of Streptococcus pyogenes as an aetiological agent in this illness. Until now, however, group A beta-haemolytic streptococci have never been consistently isolated from any patients; in addition, the titre of anti-streptolysin 0 is not raised, and lack of response to antibiotics is a feature of this disease. Our long series of investigations over more than 10 years, which will be covered in the present review, were performed in an attempt at elucidating causative agent(s) of Kawasaki disease. This has led to our firm belief in the probable role of S. pyogenes in the pathogenesis of this disease, despite the lack of fulfillment of Koch's postulates, on the basis of the following findings. Patients with Kawasaki disease recovering from the acute, febrile phase of the illness exhibited an exaggerated cell-mediated reactivity, as measured by the macrophage migration inhibition test, to group A beta-haemolytic streptococci, their pyrogenic exotoxin and streptolysin 0 as well as to several mammalian muscle cell extracts which are allegedly related antigenically to the cell wall and/or cytoplasmic membrane of S. pyogenes. Protoplast-like "spherical bodies" varying in diameter from 0.5 to 1.5 microns, and devoid of cell walls, were detected in the buffy coats of peripheral blood from patients with this disease, and stained distinctly by immuno-electron microscopy using, as a primary antibody, a rabbit antiserum to S. pyogenes- derived protoplasts, and followed by absorption with protoplasts from Staphylococcus aureus and Escherichia coli. Newborn mice infected with S. pyogenes having no capacity to confer cell-mediated immunity even in adult murine hosts, and reinfected 4-6 weeks later with another strain of the same species of bacteria which is able to elicit cellular immunity, showed a lack of humoral response to streptococcal antigens, leaving intact cell-mediated immunity. Such a biased immunological characteristic is an exact counterpart of that of Kawasaki disease patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for a viral aetiology of Jembrana disease in Bali cattle

Jembrana disease is an acute infectious disease of Bali cattle ( Bos javanicus) in Indonesia. High titres of the infectious agent are present in plasma during the febrile phase of the disease. The size of the agent determined by membrane filtration was between 50 and 100 nm, indicating it is a virus and not a rickettsia as previously proposed. Spherical virus-like particles of 75 to 130 nm diameter with a smooth membrane and frequently with an eccentric nucleoid were detected by electron microscopy in plasma from infected animals. The virus replicated in mononuclear cell cultures of peripheral blood origin but not in other cell cultures. The virus and the associated disease have characteristics consistent with virus in the family Retroviridae.

The inflammatory cytokines in measles: correlation between serum interferon-gamma levels and lymphocyte subpopulations.

Interleukin-1 (IL-1 beta), tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) were measured in serum from children with measles using an immunoradiometric assay. The IFN-gamma level was increased in 52 out of 54 patients in the acute phase of measles (less than 7 days of illness), and then declined to an undetectable level in the convalescent phase. Neither IL-1 nor TNF could be detected during the course of the illness. The mean serum IFN-gamma level was at its peak on day 4 and could be detected over a 7-day period after the onset of fever, coinciding with the febrile period (6.9 +/- 1.5 days). In the acute phase, the phytohaemagglutinin responses, absolute number of platelets, total lymphocyte counts, CD3+, CD4+, CD8+ cell counts and the CD4/8 ratio were depressed, while stab cell number and lactate dehydrogenase levels were higher than those in the convalescent phase. Using Spearman rank sum test, the IFN-gamma level was correlated negatively with the peripheral lymphocyte (P less than 0.01), CD3+ (P less than 0.05), CD4+ (P less than 0.05) cell counts and the CD4/8 ratio (P less than 0.05) and correlated positively with the stab cell count (P less than 0.01) but not with any other parameter. When the acute phase findings were compared between 28 complicated and 40 uncomplicated patients, the former were younger (P less than 0.01) and had higher maximum body temperature during the illness (P less than 0.05) than the latter, there was no difference in their IFN-gamma levels. These results show that endogenous IFN-gamma appears in the circulation during the acute febrile phase of measles, but does not contribute directly to any complication of the disease.

Interferon and natural killer cell activity in patients with exanthem subitum.

Early immune response was studied by assessing interferon (IFN) and natural killer cell activity in 13 patients with exanthem subitum associated with human herpesvirus 6 infection during the acute and convalescent phases. Only IFN-alpha showed a significant increase in the plasma of patients during the acute febrile phase compared with the convalescent period. The inhibitory effect of IFN-alpha and IFN-beta on human herpesvirus 6 replication was demonstrated in vitro with cord blood mononuclear cells. Natural killer cell activity was also significantly augmented in the acute phase, especially in the exanthem period, rather than in the convalescent phase (P less than 0.01). These results suggest that the enhanced IFN-alpha response and natural killer cell activity in the acute early phase of the disease may play pivotal roles in the recovery from exanthem subitum.

Haemorrhagic fever with renal syndrome: clinical aspects.

Based on clinical and pathological features a typical case of haemorrhagic fever with renal syndrome passes through five phases: (1) febrile phase, (2) hypotensive phase, (3) oliguric phase, (4) diuretic phase and (5) convalescent phase. The major manifestations are fever, pain in the back and abdomen, flushed face, prostration, proteinuria, purpura and haemorrhage and acute renal failure. Selective right auricular haemorrhage, marked congestion and haemorrhage in the renal medulla and necrosis of the anterior lobe of the pituitary gland are the three prominent pathological findings. The clinical severity depends upon the causative agents, namely Hantaan virus, Seoul virus and the European form in that order. Specific serological diagnosis of haemorrhagic fever with renal syndrome is made by demonstrating a rise in titre of specific immunofluorescent antibody against Hantaan and related viruses. The management is supportive, based on an understanding of the pathophysiology of the disease.

重症蚊アレルギーを伴い，成長ホルモン治療中に周期性の発熱で発症した悪性組織球症の１例

A 17 years old male who had been receiving growth hormone treatment for pituitary dwarfism for 20 months developed malignant histiocytosis (MH). He had had a history of severe hypersensitivity to mosquito bites since the age of 4. Before and upon admission he had 5 episodes of high fever which occurred cyclically about 4 weeks apart. The febrile phase was associated with hepatosplenomegaly, pancytopenia, marked elevation of serum LDH activity and ferritin level, all of which almost subsided or became normal during the afebrile phase. Accordingly, it was difficult to diagnose him as having MH. During the fifth episode of fever, hepatosplenomegaly increased markedly, atypical, immature monocytoid cells appeared in the bone marrow, and serum ferritin and LDH activity were extraordinarily elevated, strongly suggesting a diagnosis of MH. Combination chemotherapy resulted in a marked decrease in hepatosplenomegaly. However, MH was complicated with cerebral hemorrhage, and he died 3 months after admission. Immunohistochemical results showing positivity for lysozyme and α1 antichymotrypsin and negativity for pan T antigen confirmed the diagnosis of MH. Of several serum cytokines assayed, M-CSF and IFN γ showed increase during the febrile phase and normalization during the afebrile phase.

The effects of experimentally induced fever on the estimated blood flow to and oxygen utilization by the liver and the viscera drained by the portal vein in sheep

Intrajugular injection of a purified E. coli lipopolysaccharide induced a biphasic fever in sheep after a latent period of 12 to 20 min. The changes in the blood flow from the liver and from the viscera drained by the portal vein were: (a) in the latent period, decreases in total hepatic blood flow (THF) due to decreased portal venous blood flow (PVF); (b) during the first febrile phase, increases in THF due to increased hepatic arterial blood flow and, (c) in the second febrile phase, decreases in THF due to decreased PVF. Although there were large variations in the oxygen supply to the viscera drained by the portal vein and to the liver, there were relatively small or no changes in their oxygen consumption.

Ultrastructural localization of immunoglobulin M in activated B-cells in patients with epidemic hemorrhagic fever using gold probe

Our previous electron microscopic studies have shown for the first time that the atypical lymphoid cells in the peripheral blood of patients with epidemic hemorrhagic fever (EHF) during the acute febrile phase of the illness appeared to be activated B-cells and plasma cells of various developmental stages. But it is still not a tall clear whether those initially activated cells were actually B-cells. In this study, an indirect immuno gold staining method for the detection of B-cell surface antigen was used.Peripheral blood mononuclear cells were isolated from anticoagulated venous blood of 3 EHF patients (2—7 days of illness) and control donors by centrifugation at 2,500 Xg for 15 min. The cells obtained from the buffy coat were washed in TBS and resuspended in TBS-5% BSA. Unfixed cells were in cubated insuspension in step I with monoclonal antibody (MS27) directed against human IgM (μ Chain) for 30 min at 37±C. After washing in TBS—BSA, the gold probe was applied to the cells in step II incubation with GAM-G15 reagent for 45 min at RT. The gold probe was prepared in our laboratory according to Slot and Geuze. After the third washing in TBS-BSA, the cell pellets were fixed, dehydrated and embedded in Epon 812.

Monokine Production by Malnourished Nursing Home Patients

Protein malnutrition is associated with a decreased febrile and acute phase response to infection and increased mortality. To elucidate a cause for this poor response, we assessed the effect of chronic protein malnutrition on monocyte production of the pyrogens interleukin-1 (IL-1) and tumor necrosis factor (TNF). Thirteen malnourished nursing home residents, 11 age-matched controls, and 9 young controls were studied. Production of IL-1 and TNF in vitro was not diminished in the malnourished group when compared with the age-matched and young controls. Causes other than diminished IL-1 or TNF production should be sought to explain decreased resistance to infection in the malnourished nursing home resident.

Spontaneous tumor necrosis factor production in Kawasaki disease

Tumor necrosis factor production by peripheral blood mononuclear cells was measured in 18 patients with Kawasaki disease. In patients studied during the acute febrile phase of their disease, there was increased spontaneous TNF production (mean 26.9 +/- 40.3 U/ml) compared with that of control subjects (1.0 +/- .86 U/ml) (p less than or equal to 0.025). Spontaneous TNF production by patients tested in the subacute or convalescent phase of the illness was significantly lower than that in patients tested during the acute illness (p less than or equal to 0.025). In all patients studied with serial acute and subacute-convalescent samples, TNF production was normal in the follow-up samples. Because TNF is a potent mediator of inflammation and causes damage to vascular endothelial cells, we suggest that TNF may be important in the pathogenesis of both the immune activation and endothelial cell damage characteristic of this illness.

Determinants of low serum concentrations of salicylates in patients with Kawasaki disease

The mechanisms leading to the previously reported difficulties in achieving therapeutic serum concentrations of salicylates in Kawasaki disease were studied in eight children, once during the acute (febrile) phase and again during the nonfebrile (subacute) phase of the disease. Salicylate bioavailability was impaired during the acute phase of the disease (47.7% +/- 6.6%), and increased significantly thereafter to 75.1% +/- 9.3%. During the febrile phase there was a significant correlation between salicylate bioavailability and steady-state serum concentrations. Salicylate renal clearance was significantly higher during the febrile phase (14.45 +/- 2.5 mL/kg.h), compared with the nonfebrile phase (7 +/- 1.6 mL/kg.h, P less than 0.05). The change in salicylate clearance could be explained by decreased protein binding in the acute phase (82.5% +/- 1.9%) with substantially more free salicylates caused by significantly lower serum albumin concentrations. Changes in urine metabolites during the acute and subacute phases were consistent with the changes in dose administered (100 mg/kg in the acute phase vs 10 mg/kg in the subacute phase). The pattern of metabolites excreted in the urine of children with Kawasaki disease receiving 100 mg/kg was similar to that in children with juvenile rheumatoid arthritis receiving the same dose.

Kawasaki disease: Review of risk factors for coronary aneurysms

Between June 1, 1979, and May 31, 1984, at The Hospital for Sick Children in Toronto, Kawasaki disease was diagnosed in 163 patients (112 boys, 51 girls, P less than 0.001). Fifteen percent of the children had coronary artery aneurysms. Prior to diagnosis, 24% had been given low doses of aspirin, and 50% acetaminophen. Children with coronary aneurysms had significantly higher temperature during days 10 to 13 of the disease. The febrile phase of the disease was also significantly longer in these children. Coronary artery involvement occurred with equal frequency in boys and girls. There was no significantly greater incidence of coronary artery involvement in infants younger than 1 year of age than in older children. Duration of fever (greater than or equal to 14 days vs less than 14 days) was equally as predictive of the eventual occurrence of coronary aneurysms as the modified Asai score.

Probable Efficacy of High-Dose Salicylates in Reducing Coronary Involvement in Kawasaki Disease

The efficacy of high-dose salicylates in reducing the coronary artery involvement of Kawasaki disease was compared in 36 children who received acetylsalicylic acid, 80 to 180 mg/kg/day, and in 18 who did not receive high-dose salicylates during the febrile phase of the disease and whose fever was controlled mainly with acetaminophen. The two groups were comparable with respect to age and body weight. In the acetylsalicylic acid-treated group, the dose was adjusted to meet the therapeutic serum concentration range (greater than or equal to 20 mg/dL). There were significantly more cases of coronary involvement in the nontreated group (50%) than in the salicylate-treated group (16.6%) and of coronary aneurysms (39% vs 3%). During the febrile phase of the disease, salicylate serum concentrations achieved with a given dose were on the average twofold lower than during the nonfebrile phase, owing to impaired absorption of acetylsalicylic acid. It is suggested that despite the difficulty in achieving therapeutic serum concentrations of salicylate during the febrile phase of Kawasaki disease with a dose as high as 100 mg/kg/day, this dose is potentially capable of preventing the associated coronary disease.