Afebrile Subjects Research Articles

Assessment of the burden of malaria and bacteraemia by retrospective molecular diagnosis in febrile illnesses and first-line anti-infectives in Côte d'Ivoire

BackgroundThe aetiologies of fever are poorly understood in sub-Saharan Africa. We aimed to assess the burden of malaria and bacteria in Côte d’Ivoire. MethodsBlood samples from 438 febrile and 346 afebrile people were screened using molecular tools. ResultsPlasmodium falciparum was the most common microorganism associated with fever (46.8% in febrile, 23.4% in afebrile people; p < 0.001). Bacteraemia was detected in 21.7% of febrile people and 12.7% of afebrile people (p = 0.001). Streptococcus pneumoniae was the main cause of bacteraemia (7.1% of febrile and 0.6% of afebrile individuals; p < 0.001). Non-typhoidal Salmonella spp. was detected in 4.5% of febrile people and 1.2% of afebrile individuals (p < 0.001). Salmonella enterica Typhi and S. enterica Paratyphi were only detected in febrile subjects (1.4% and 2.1%), as well as Tropheryma whipplei (0.9%), Streptococcus pyogenes (0.7%), and Plasmodium ovale (4.6%). The prevalence in febrile and afebrile people was similar for Staphylococcus aureus (3.6–4.9%), Rickettsia felis (5.5–6.4%), Mansonella perstans (3.0–3.2%), and Plasmodium malariae (1.6–2.3%). Comorbidities were higher in febrile than in afebrile subjects (10.3% versus 5.5%; p = 0.01); 82% involving P. falciparum. All patients co-infected with P. falciparum and S. pneumoniae were febrile whereas 30% of those infected by P. falciparum alone were not (p = 0.02). Among febrile participants, 30.4% with malaria and 54.7% with bacteraemia had received neither antimalarial nor antibiotic therapy. ConclusionIdentification of etiologies of acute febrile diseases in sub-Saharan Africa proposes keys to successful treatment and prevention of infectious diseases. Vaccination campaigns may decrease the morbidity of mono- and co-infections by preventable microorganisms.

Investigation of Chest X-Ray Use in the Emergency Department in Pediatric Patients with Sickle Cell Disease Presenting with Fever Compared to Age Matched Controls

Background In sickle cell disease (SCD), acute chest syndrome (ACS) is associated with prolonged hospitalization, increased risk of respiratory failure, future lung disease and 25% mortality in hospitalized patients(Bakshi, &amp; Krishnamurti, 2017; Vinchinsky et al. 1997). Pediatric patients with SCD frequently present to the Pediatric Emergency Department (PED) with complaints of fever, chest pain, and cough, all of which may or may not be related to ACS. It is challenging for PED providers to determine which patients are at highest risk of ACS, so chest X-Rays (CXR) are frequently ordered which increases radiation exposure and healthcare costs. The objective of this study was to identify incidence of CXR performance, as well as ACS diagnosis, in SCD patients presenting to our PED with or without fever. Our goal was to identify significant clinical predictors of ACS in this population in order to implement a diagnostic algorithm for PED providers. Methods This was an IRB-approved retrospective medical record review of subjects diagnosed with SCD with inclusion criteria: ages 2-12 years, who presented to the University of Maryland PED between 2016-2018. We performed bivariate analyses comparing these variables between subjects who were febrile vs. afebrile on presentation to the PED, as well as those who were ultimately diagnosed with ACS compared to those who were not. Analysis of categorical variables was performed using Chi-square or Fischer exact test as appropriate. We performed a multivariable logistic regression model to identify significant predictors of ACS diagnosis. Analyses performed using SAS 9.4. Results We identified 424 SCD subjects who presented to our PED meeting inclusion criteria, with 25% (n=108) presenting with fever. Of these, 69% received a CXR on presentation vs. 42% of afebrile subjects (p=&amp;lt;0.0001). In our febrile group 21% (n=23) patients had more than 2 febrile episodes and 100% received CXRs. There were no significant differences between the febrile and afebrile subjects when it came to sex, asthma diagnosis/comorbidity, hydroxyurea use, folic acid supplementation, or pneumococcal prophylaxis. Overall, 10% of patients presenting to the PED were diagnosed with ACS (n=42), made up of 13% of those presenting with fever vs. 9% of those presenting without fever. Those subjects ultimately diagnosed with ACS were significantly more likely to present with chest pain (p=0.003), tachypnea (p=0.001), and hypoxia (p&amp;lt;0.0001), and were more likely to have a past history of asthma (p=0.0085). Sickle cell variant, home medications, and history of splenectomy were not significantly associated with ACS diagnosis. Upon multivariable modeling, when adjusting for fever and pre-existing asthma diagnosis, the only significant predictors of ACS diagnosis were chest pain and hypoxia. Patients without chest pain had an odds ratio (OR) =0.3 of ACS diagnosis [95% Confidence Interval, CI 0.14-0.67], indicating they had 70% lower odds of ACS compared to patients with chest paint. Patients without hypoxia had OR=0.12 of ACS compared to those with hypoxia [CI 0.06-0.25], indicating an 88% reduced odds of ACS diagnosis. Conversely, those with chest pain had 3.3x the odds of ACS diagnosis [CI 1.5-7.4] and those with hypoxia had 8.4x the odds of ACS diagnosis [CI 4-17.9] compared to those without these symptoms. Conclusion In ACS, current guidelines recommend that patients presenting with fever, hypoxia, tachypnea, tachycardia and abnormal respiratory exam findings should be treated empirically as well as receive a CXR. However radiological signs can be delayed compared to physical signs so a normal CXR does not preclude the diagnosis of ACS if there is clinical suspicion(Howard et al. 2015). Our data demonstrate that clinical findings such as chest pain, tachypnea and hypoxia were most likely to correlate to a diagnosis of ACS. While 69% of our febrile patients received a CXR in the PED, only 13% were ultimately diagnosed with ACS, indicating that more CXRs and radiation exposure occurred in the febrile population than may have been necessary. When adjusting for fever and asthma, the most notable predictors of ACS were hypoxia and chest pain. When present, these findings are significant predictors of ACS; when absent, subjects had significantly decreased odds of ACS. Incorporating the presence or absence of chest pain and hypoxia may help focus the use of CXR on the appropriate patient population. Disclosures No relevant conflicts of interest to declare.

Malaria and haematologic parameters of pupils at different altitudes along the slope of Mount Cameroon: a cross-sectional study

BackgroundHaematologic abnormalities are features in Plasmodium falciparum infection, and anaemia is an inevitable outcome. This study examines the influence of malaria status and altitude on haematologic parameters in school-aged pupils.MethodsA cross-sectional study was conducted among 728 school pupils aged between four and 15 years at three different altitudinal ranges along the slope of the Mount Cameroon region. The investigative methods included the use of questionnaire, clinical evaluation and laboratory investigations. Blood sample collected from each child was used for the preparation of blood films for detection of malaria parasites and assessment of malaria parasite density as well as full blood count determination using an automated haematology analyzer.ResultsThe prevalence of malaria in the study population was 33.8% and 64.2% (158/246) of these were asymptomatic (AM). Pupils in lowlands had a significantly (P <0.05) prevalence (95% confidence interval, CI) of malaria (60.6%, CI = 54.6–65.9%) than those in middle belt (29.1%, CI = 23.9–34.8%) and highlands (7.7%, CI = 6.1–9.8%), while those in middle belt had significantly higher geometric mean parasite density (475) than those in lowlands (233) and highlands (388). The prevalence of malaria was significantly higher in children that presented with fever (40.4%, CI = 33.8–47.2%) when compared with afebrile subjects (31%, CI = 27–35.2%). Pupils with AM had a higher prevalence of leucopaenia (43.7%, CI = 35.8–51.8%), microcytosis (27.2%, CI = 20.5–34.9%), hypochromasia (27.8%, CI = 21–35.5%) and thrombocytopaenia (14.9%, CI = 8.9–22.8%) when compared with those with clinical malaria (CM). All mean haematological parameters were comparable in pupils with CM and AM, except for the mean white blood cell (WBC) counts. Pupils with AM had significantly lower (P = 0.02) mean WBC counts (5.1 ± 2.5 × 109/L) than those with CM (5.9 ± 2.3 × 109/L). Age, altitude and malaria parasitaemia was of significant influence on several haematological parameters.ConclusionAltitude influenced the distribution and density of malaria parasites and was of confounding influence on the haematologic profiles. These results highlight the insidious effects of AM on the haematologic components.

It's Just a Virus! Viral Etiologies of Fever Without a Source

Colvin JM, Muenzer JT, Jaffe DM, et al. Detection of viruses in young children with fever without an apparent source. Pediatrics. 2012; 130(6): e1455-e1462; doi: 10.1542/peds.2012-1391Investigators from Washington University, St. Louis and Biological Mimetics, Inc., Frederick, MD conducted a study to better understand the viral etiologies of fever without an apparent source (FWS) in young children. Children aged 2 to 36 months who presented to the emergency department (ED) at St. Louis Children’s Hospital with a temperature of ≥38°C without an apparent source and who had blood obtained for clinical management were enrolled. Children with symptoms suggestive of a viral respiratory infection or who had a positive rapid test for influenza were excluded. Two comparison groups of children were also enrolled: (1) children aged 2 to 36 months who presented to the ED with a temperature of ≥38°C but had a probable or definite bacterial infection, and (2) afebrile children aged 2 to 36 months who were having an ambulatory surgical procedure. Blood and/or nasopharyngeal (NP) specimens were collected from study children. Polymerase chain reaction (PCR) testing was used to identify viruses. The main outcome was the type and frequency of viruses detected in each study group. Secondary outcomes were antibiotic utilization among children with FWS and demographic and clinical variables associated with viral infection.A total of 206 children were enrolled: 75 with FWS, 15 with fever and a probable or definite bacterial infection, and 116 who were afebrile. All children with bacterial infection and 29% of children with FWS were hospitalized. Viruses were detected in 76% of children with FWS, 40% with bacterial infection, and 35% who were afebrile (P < .001). The viruses identified most frequently in children with FWS were adenovirus, human herpesvirus-6 (HHV-6), and enterovirus. Each was detected significantly more frequently in those with FWS (identified in 57%) than in those with bacterial infection (13%) or who were afebrile (7%). Epstein-Barr virus was the most commonly detected virus in children with bacterial infection (23%) and rhinovirus was the most commonly detected in afebrile subjects (16%). Children with FWS were significantly more likely to have >1 virus identified and to have a virus detected from their blood or NP specimen than children in the bacterial or control groups. Among children with FWS, 45% received antibiotics, including 91% of those who had adenovirus. The only significant demographic or clinical characteristic of children who had adenovirus, HHV-6, or enterovirus infection compared to children with no virus detected was that the white blood count was more likely to be >15,000 cells/mm3 in children who had adenovirus (P = .003).The authors conclude that viruses are frequently detected in children aged 2 to 36 months with FWS and that use of blood specimens for virus detection could increase virus identification and decrease empiric antibacterial treatment.This important study has several limitations. First, the investigators did not enroll all eligible children with FWS but only those who presented to the ED when study personnel were working. This introduces selection bias. Second, the inclusion criterion requiring that blood work be ordered by the treating provider as part of the clinical work-up introduces additional bias, as those with FWS for whom no blood work was ordered were excluded. Third, detection of a virus does not mean that the virus was responsible for the child’s fever, although the viruses most frequently identified in the febrile children are typically thought to be pathogenic (and many of those found in the afebrile cohort are thought to have low pathogenicity). Finally, virus detection was limited to blood and NP specimens in this study. Notably, stool specimens, which may increase virologic yield, were not included.The management of FWS has evolved along with the vaccination landscape: occult bacteremia has essentially disappeared in highly-vaccinated populations.1 Increasingly, febrile infants and young children with an unrevealing physical examination may have either a urinary tract infection2 or “a virus.” While worried parents may balk at the “it’s just a virus” diagnosis, this study gives it credence. Of note, the yield of virus-specific diagnoses increased from 49% with the use of PCR on NP specimens (which is the standard of care in most pediatric hospitals) to 76% when both NP and blood were assayed by PCR. These findings suggest, among other things, that the application of new technologies will improve our ability to render a specific diagnosis for febrile illnesses in young children. (See also AAP Grand Rounds, June 2012;27[6]:65.3)

Coronary Artery Dimensions in Febrile Children Without Kawasaki Disease

Coronary artery (CA) dilatation on echocardiography is a criterion for treatment with intravenous immunoglobulin for incomplete Kawasaki disease (KD). However, CA dimensions for febrile children are unknown. We compared CA dimensions in children with febrile illnesses other than KD to those of normal afebrile children and to KD patients. We performed echocardiograms in 43 patients who met the following inclusion criteria: (1) age 3 months to 18 years, (2) daily fever >38°C for ≥96 hours, and (3) a diagnosis other than KD. These subjects had mean CA z scores greater than normative values (left main CA=0.66±0.75, P<0.001; right CA=0.28±0.81, P=0.03; left anterior descending CA=0.35±1.0, P=0.03). Maximum CA z score >2 was found in 2 subjects (osteomyelitis, Mycoplasma pneumonia). Among demographic and laboratory measures, only higher platelet count was associated with greater left anterior descending CA z scores (P=0.004) and maximum CA z score (P=0.03). Non-KD febrile subjects, compared with 144 KD patients, had smaller CA z scores (P=0.04, P<0.001, and P<0.001 for left main CA, right CA, and left anterior descending CA, respectively), and lower white blood cell count, erythrocyte sedimentation rate, and platelet count (all P<0.001). A maximum CA z score cutoff of 2.0 had specificity of 95% (95% confidence interval, 84%-99%) and sensitivity of 32% (95% confidence interval, 25%-41%) in distinguishing non-KD febrile from KD patients; for maximum CA z score of 2.5, specificity was 98% and sensitivity was 20%. This pilot study found that mean CA dimensions in children with non-KD febrile illnesses are larger than those in normative afebrile subjects but smaller than dimensions in patients with KD. Future studies should augment the available data on CA dimensions in children with more severe febrile illnesses.

Central Nervous System Herpes Simplex Virus Infection in Afebrile Children With Seizures

Central nervous system herpes simplex virus infection is suspected in patients presenting with acute-onset seizures and lethargy. The potential neurologic sequelae from untreated herpes infection can prompt empirical acyclovir therapy, even in afebrile subjects. The objectives of this study were to determine the frequency of central nervous system herpes simplex virus infection in children presenting with afebrile seizures and to assess the need for empirical acyclovir therapy. Clinical and laboratory data of children with acute-onset afebrile seizures and children with central nervous system herpes simplex virus infection were compared. Polymerase chain reaction and viral cultures of the cerebrospinal fluid for herpes simplex virus infection were negative in all subjects with afebrile seizures; 32.7% of these subjects were empirically treated with acyclovir. In conclusion, central nervous system herpes simplex virus infection is uncommon in children presenting with afebrile seizures, and acyclovir therapy is rarely necessary in subjects with normal neurologic examination and cerebrospinal fluid analysis.

The incidence and significance of acute post-hysterectomy pelvic collections

In a prospective study, 32 consecutive patients underwent endovaginal pelvic scanning in the first post-operative week following hysterectomy. Twenty-four attended for a further scan at clinical follow up. Vaginal vault fluid collections were identified in 19 women (59%) on the first post-operative scan. Fifteen of the 19 with collections had no significant pyrexia. Out of the entire sample of 32 subjects, six patients (19%) had significant post-operative pyrexia of whom four were in the group with post-hysterectomy vaginal vault collection and two had no collection on their early post-operative scans. All collections detected on the early scans had resolved or were smaller on follow-up scan but two asymptomatic patients who had no collection on the early scan had developed vaginal vault fluid collections on the late follow-up scan. No statistically significant association was demonstrated between the presence of a collection and post-operative pyrexia, surgical approach or operative blood loss The results of this study indicate that the demonstration of vaginal vault collection following hysterectomy is a frequent finding in both febrile and afebrile subjects and does not indicate the need for drainage.

Endogenous haemopoietic growth factors in neutropenia and infection.

Haemopoietic growth factors (HGFs) are being administered to patients with neutropenic fever; however, little is known about the endogenous HGF response in these patients. Specific assays were used to study four HGFs, granulocyte (G-) CSF, granulocyte-macrophage (GM-) CSF, macrophage (M-) CSF and interleukin (IL-) 6 levels in the blood of patients with neutropenic fever (46 episodes). For comparison, levels were also measured in three control populations: normals (20), afebrile neutropenic (14), and bacteraemic but not neutropenic patients (20). In febrile patients, levels of G-CSF (median, range) (0.46, < 0.10-142 ng/ml). IL-6 (0.054, 0.005-24.3 ng/ml) and M-CSF (18.5, 9.9-79.1 ng/ml) were elevated compared with afebrile subjects (< 0.10, < 0.10-1.62 ng/ml). (0.008, 0.002-0.024 ng/ml) and (6.45, < 5.0-31.3 ng/ml) respectively. GM-CSF was not elevated (< 0.02, < 0.02-8.0 ng/ml) compared with afebrile subjects (0.021, < 0.02-0.20 ng/ml). Variables significantly associated (P < 0.05) with elevated cytokine levels were determined by multiple regression analyses. Factors associated with G-CSF elevation were fever, neutropenia, pathogen type and raised bilirubin and creatinine. In contrast, neutropenia was not associated with IL-6 elevation although there was an association between IL-6 elevation and fever, Gram-negative and fungal infections and raised creatinine and bilirubin. M-CSF elevation was associated with fever, renal impairment and known pathogen. Elevated G-CSF and IL-6 levels normalized rapidly (hours-days) with the resolution of infection, whereas M-CSF concentrations remained elevated for up to 10 d. Cytokine levels remained elevated in septic neutropenic patients who did not recover. In summary, G-CSF, IL-6 and M-CSF levels were significantly elevated in sepsis. In contrast, GM-CSF levels were not elevated. These studies should assist the development of therapeutic strategies using HGFs in the treatment of sepsis.

Pneumocystis carinii antigenemia in adults with malignancy, infection, or pulmonary disease.

A counterimmunoelectrophoresis test for Pneumocystis carinii antigenemia was employed to assess the extent of subclinical infection or colonization with this agent in adults with infection, pulmonary disease, or malignancy and in healthy homosexual men. Antigenemia was detected in 6 of 208 (3%) of normal controls, 3 of 28 (11%) of patients with pulmonary infection, 3 of 33 (9%) of those with chronic lung disease, 1 of 36 (3%) of patients with lung cancer, 7 of 271 (3%) of afebrile subjects with malignancy, 6 of 19 (32%) of febrile patients with malignancy, 2 of 22 (9%) of those with nonpulmonary infection, and 0 of 21 (0%) of healthy young homosexual men. These data suggest that P. carinii is a common commensal or saprophyte that becomes clinically significant only when host defenses are impaired. Antigenemia may occur intermittently during various disease states in the absence of positive clinical signs and should alert the physician to subacute infection or colonization. Treatment appears advisable when clinical data and counterimmunoelectrophoresis results concur.

The Effect of Type of Thermometer and Length of Time Inserted on Oral Temperature Measurements of Afebrile Subjects

The Effect of Type of Thermometer and Length of Time Inserted on Oral Temperature Measurements of Afebrile Subjects

Oral Temperature Differences in Relation to Thermometer and Technique

The validity of oral temperature measurements depends on use of an appropriate site, a dependable thermometer, and a proper technique. Fifty febrile patients and 50 afebrile volunteers were studied to determine differences in oral temperature measured in three sublingual sites with three brands of electronic thermometers and with mercury thermometers and to learn whether two methods of probe insertion (slow-slide and direct-placement) with electronic thermometers would result in differences in either the temperature reading obtained or the instrument response time. When measured with the rapidly responding electronic thermometers, temperatures in the right and left posterior sublingual pockets were significantly higher (p less than .01) than in the area under the front of the tongue. The difference was approximately .3 degrees F in the afebrile subjects and approximately .4 degrees F in those with fever. With mercury thermometers, however, the temperature differences were small and not statistically significant. There was no significant difference between temperatures measured in the two posterior pockets using either electronic or mercury thermometers. There was some individual variation in the values registered by electronic thermometers at each site, although the differences between the three sites were consistent with all three instruments. Actual temperature values differed between electronic and mercury thermometers. When electronic thermometer probes were inserted into a posterior pocket using a slow-slide technique, temperature readings were higher by approximately .1 degree F and were obtained a few seconds faster than when the probe was put directly in place without a prewarming procedure. These differences were statistically significant (p less than .01) but of limited clinical importance. Findings emphasized the importance of using the posterior sublingual pocket as the site for oral temperature measurement and the value of using the same instrument to obtain repeated comparable measurements.

The effect of aspirin pretreatment on the sweating response of older female subjects.

Seven healthy female volunteers (aged 50 to 67 years) have been subjected to a thermal stress and their sweat rates evaluated using hygrosensors on five different locations on their body surface. It was found that the sweating rate was highest on the forehead in all but one of the subjects with the chest being the next most prominent site for the response. Five of the subjects were restudied after aspirin pretreatment. In the presence of this drug, resting body temperature was lowered, sweating occurred at a lower oral temperature and the mean sweating rate at a standardized body temperature was significantly higher. These findings are consistent with aspirin's known pharmacological actions, although in this study the increased sweating rate have been demonstrated in afebrile subjects.

Prostaglandins in cerebrospinal fluid of patients during various infectious diseases

Concentrations of prostaglandins of the E and F series were estimated by radioimmunoassay in cerebrospinal fluid (CSF) of 30 febrile patients (infants and adults) and of 19 afebrile, adult patients. In CSF of all feverish patients with meningitis, pneumonia, or pyelonephritis, concentrations of prostaglandins of the E series were about twice higher than those of the afebrile subjects. In contrast, concentrations of prostaglandins of the F series remained largely unchanged during fever. In accord with the results of animal experiments prostaglandins of the E series seem to act as mediators of fever during infectious diseases also in man.

Experimental Exposure of Human Subjects to Viruses of Influenza

Summary An analysis has been made of the effects of exposure of more than 200 human subjects to active viruses of influenza (the PR-8, F-99 and, in a small series, the F-12 strains of influenza A, and the Lee strain of influenza B). The results of the experiments, which were conducted for a number of purposes, may be summarized as follows: All four strains of influenzal virus caused febrile reactions upon inhalation of atomized allantoic-fluid cultures, but very rarely upon intranasal instillation.A febrile response was obtained in susceptible subjects with regularity only when undiluted infected allantoic fluids were atomized. Upon ten- or hundredfold dilution of the viral preparations the incidence of fever decreased markedly.The incubationary period between exposure to the virus and onset of temperature differed with the different strains. It was shorter, as a rule, with the PR-8 and Lee strains (less than 24 hours), and usually more extended (30 to 48 hours) with the F-99 virus. Previous exposure to the F-99 strain seemed to influence the incubationary period in that subjects who were re-exposed after 9 months reacted with fever within 24 hours in contrast to control individuals exposed for the first time, who became febrile generally in 30 to 48 hours.All four strains caused similar clinical manifestations except for the degree of change in the white blood cell picture. When the F-99 strain was employed leucopenia and relative lymphocytosis were frequently marked.Following inhalation, virus was re-isolated from over 50 per cent of the febrile subjects and from about 15 per cent of the afebrile subjects in the cases of the F-99 and F-12 strains, but from only one subject in the Lee series and from none in the PR-8 series. After intranasal instillation the Lee and F-12 viruses were recovered from most of the subjects but not the F-99 strain. The PR-8 virus has not been studied in this respect. Virus was re-isolated under the various conditions in some instances as late as 72 to 96 hours after exposure. Re-isolation was successful most frequently 48 hours after inhalation and 24 hours after intranasal instillation.There was no correlation between the pre-inhalation titer of antibodies and the febrile response in the PR-8 and Lee series. With the F-99 strain a definite inverse relationship was noted in two separate experiments. Thus, fever was observed in almost all subjects who showed a titer of 1:16 as measured by inhibition of agglutination of chicken erythrocytes. With increasingly higher titers the incidence of febrile reactions decreased, and finally no fever was noted in individuals with initial levels higher than 1:128.After exposure to the influenzal viruses most subjects responded with the production of homologous antibodies, i.e., after inhalation of influenza A virus an increase in anti-influenza A antibodies was noted, and conversely in the case of influenza B. A few subjects who inhaled preparations of PR-8 virus showed a rise in anti-influenza B antibodies either with or without a homologous antibody response. A number of febrile cases did not respond with formation of antibodies. The lack of a serological response in febrile cases was not limited to subjects with high titers of antibodies, but was observed also in some cases with low levels. The implications of these findings are discussed in regard to serological observations made during certain epidemics of influenza.Calculation of the geometric mean antibody response in the various groups showed that inhalation or intranasal instillation of active, or of concentrated inactivated virus as a means of immunization does not offer an advantage when compared with the serological results of subcutaneous vaccination. Irradiated allantoic-fluid cultures caused only slight or no rises in antibodies upon inhalation.The clinical data and laboratory findings are discussed in regard to the nature of the febrile response and the suggestion is made that the effects of exposure of human subjects to influenzal viruses may be the composite result of three factors: infection, with propagation of the virus, toxic manifestations, and accelerated reactions in partially immune subjects.