Risks for Developing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in College Students Following Infectious Mononucleosis: A Prospective Cohort Study.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) involves severe fatigue, unrefreshing sleep, and cognitive impairment, leading to functional difficulties; prior studies have not evaluated risk factors with behavioral and immune data collected before developing ME/CFS. Up to 5% of university students develop infectious mononucleosis (IM) annually, and 9-12% meet criteria for ME/CFS 6 months later. We sought to determine predictors of ME/CFS. METHODS: We enrolled college students at the start of the school year (time 1), identified those who developed IM (time 2), and followed them for 6 months (time 3), identifying 3 groups: those who developed ME/CFS, severe ME/CFS (meeting >1 set of criteria), and who were asymptomatic. We conducted 8 behavioral and psychological surveys and analyzed cytokines at 3 time points. RESULTS: 238 of the 4501 students (5.3%) developed IM; 6 months later, 55 of the 238 (23%) met criteria for ME/CFS and 157 (66%) were asymptomatic. 67 of the 157 asymptomatic students served as controls. Students with severe ME/CFS were compared with students who were asymptomatic at 3 time points. The former group was not different from the latter group at time 1 (prior to developing IM) in stress, coping, anxiety, or depression but were different in several behavioral measures and had significantly lower levels of IL-6 and IL-13. At time 2 (when they developed IM), the 2 ME/CFS groups tended to have more autonomic complaints and behavioral symptoms while the severe-ME/CFS group had higher levels of IL-12 and lower levels of IL-13 than the recovered group. CONCLUSIONS: At baseline, those who developed ME/CFS had more physical symptoms and immune irregularities, but not more psychological symptoms, than those who recovered.

A Validated Scale for Assessing the Severity of Acute Infectious Mononucleosis.

OBJECTIVES: To develop a scale for the severity of mononucleosis. STUDY DESIGN: One to 5 percent of college students develop infectious mononucleosis annually, and about 10% meet criteria for chronic fatigue syndrome (CFS) 6 months following infectious mononucleosis. We developed a severity of mononucleosis scale based on a review of the literature. College students were enrolled, generally when they were healthy. When the students developed infectious mononucleosis, an assessment was made as to the severity of their infectious mononucleosis independently by 2 physicians using the severity of mononucleosis scale. This scale was correlated with corticosteroid use and hospitalization. Six months following infectious mononucleosis, an assessment is made for recovery from infectious mononucleosis or meeting 1 or more case definitions of CFS. RESULTS: In total, 126 severity of mononucleosis scales were analyzed. The concordance between the 2 physician reviewers was 95%. All 3 hospitalized subjects had severity of mononucleosis scores ≥2. Subjects with severity of mononucleosis scores of ≥1 were 1.83 times as likely to be given corticosteroids. Students with severity of mononucleosis scores of 0 or 1 were less likely to meet more than 1 case definition of CFS 6 months following infectious mononucleosis. CONCLUSIONS: The severity of mononucleosis scale has interobserver, concurrent and predictive validity for hospitalization, corticosteroid use, and meeting criteria for CFS 6 months following infectious mononucleosis.

Cost analysis of bronchoalveolar lavage and respiratory tract biopsies in the diagnosis and management of suspected invasive fungal infection in children with cancer or who have undergone stem cell transplant.

BACKGROUND: Identification of an organism is the gold standard for the diagnosis of fungal infection; however, we have previously shown that invasive procedures infrequently lead to a change in management in children with cancer or who have undergone stem cell transplant with suspected respiratory tract invasive fungal infection (RT-IFI). There is also a paucity of data on the cost of RT-IFI in this population. We therefore compared the costs of RT-IFI diagnosed based on CT scan alone versus those who underwent a bronchoalveolar lavage (BAL) or respiratory tract biopsy (RTB). PROCEDURE: We collected cost data on patients at a single center undergoing chemotherapy or who were post-hematopoietic stem cell transplant (HSCT) and were suspected of having RT-IFI between 2007 and 2012. Cost data were included for 14 days from the day of their diagnostic CT scan or procedure. RESULTS: Cost data were available for 76 patients. Thirty-six patients were diagnosed with suspected RT-IFI based on CT only, and 40 patients underwent BAL or RTB. Costs related to chest X-rays (CXRs), inpatient/intensive care unit (ICU) beds, anesthesia, operating room (OR) time, and procedures were significantly higher in the BAL/RTB group versus CT scan group (all P < 0.01). Costs related to CT scans were significantly higher in the CT scan group (P = 0.0002). Overall costs were significantly higher for patients who underwent BAL or RTB versus CT scan only (P < 0.0001). CONCLUSION: Our previous data showed that BAL and RTB infrequently led to a change in management in this population. We now demonstrate that this strategy is costly as well.

Operationalizing Substantial Reduction in Functioning Among Young Adults with Chronic Fatigue Syndrome.

PURPOSE: Chronic fatigue syndrome and myalgic encephalomyelitis are fatiguing illnesses that often result in long-term impairment in daily functioning. In reviewing case definitions, Thrope et al. (Fatigue 4(3):175-188, 2016) noted that the vast majority of case definitions used to describe these illnesses list a "substantial reduction" in activities as a required feature for diagnosis. However, there is no consensus on how to best operationalize the criterion of substantial reduction. METHOD: The present study used a series of receiver operating curve (ROC) analyses to explore the use of the Medical Outcomes Study Short-Form-36 Health Survey (SF-36), designed by Ware and Shelbourne for operationalizing the substantial reduction criterion in a young adult population (18-29 years old). We compared the sensitivity and specificity of various cutoff scores for the SF-36 subscales and assessed their usefulness in discriminating between a group of young adults with a known diagnosis of chronic fatigue syndrome or myalgic encephalomyelitis (n = 98) versus those without that diagnosis (n = 272). RESULTS: The four top performing subscales and their associated cutoffs were determined: Physical Functioning ≤ 80, General Health ≤ 47, Role Physical ≤ 25, and Social Functioning ≤ 50. Used in combination, these four cutoff scores were shown to reliably discriminate between the patients and controls in our sample of young adults. CONCLUSION: The implications of these findings for employing the substantial reduction criterion in both clinical and research settings are discussed.

BK polyomavirus infection in pediatric heart transplant recipients: a prospective study.

BKV infection and nephropathy complicate pediatric HTx, but the incidence and time course of the disease are unknown. We assessed the incidence of BKV infection and its association with kidney dysfunction in pediatric HTx recipients. A single center prospective study compared pediatric (<18 years) HTx recipients, with and without BKV infection, who received an allograft between September 2013 and December 2014. Screening of urine for BKV was performed prior to transplant, and at week 1, and at months 3, 6, 9, 12, and 15 months post-transplantation. Serum for BKV DNA was assayed if BK viruria was present. Statistics included Fisher's exact test and Student's t test. Twelve patients were enrolled. Two patients were removed per parent request. Two (20%) had BK viruria and one (10%) had BK viremia. No patients developed BKVN. BK viruria was present within 2 months following transplantation. There were no identifiable risk factors for BKV infection and no statistically significant difference in renal function between the groups; however, there was a trend toward worsening renal function in those with BKV infection. BKV infection can occur early following heart transplantation. Screening for BK viruria should be considered in HTx recipients.

Illness progression in chronic fatigue syndrome: a shifting immune baseline.

BACKGROUND: Validation of biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) across data sets has proven disappointing. As immune signature may be affected by many factors, our objective was to explore the shift in discriminatory cytokines across ME/CFS subjects separated by duration of illness. METHODS: Cytokine expression collected at rest across multiple studies for female ME/CFS subjects (i) 18 years or younger, ill for 2 years or less (n = 18), (ii) 18-50 years of age, ill for 7 years (n = 22), and (iii) age 50 years or older (n = 28), ill for 11 years on average. Control subjects were matched for age and body mass index (BMI). Data describing the levels of 16 cytokines using a chemiluminescent assay was used to support the identification of separate linear classification models for each subgroup. In order to isolate the effects of duration of illness alone, cytokines that changed significantly with age in the healthy control subjects were excluded a priori. RESULTS: Optimal selection of cytokines in each group resulted in subsets of IL-1α, 6, 8, 15 and TNFα. Common to any 2 of 3 groups were IL-1α, 6 and 8. Setting these 3 markers as a triple screen and adjusting their contribution according to illness duration sub-groups produced ME/CFS classification accuracies of 75-88 %. The contribution of IL-1α, higher in recently ill adolescent ME/CFS subjects was progressively less important with duration. While high levels of IL-8 screened positive for ME/CFS in the recently afflicted, the opposite was true for subjects ill for more than 2 years. Similarly, while low levels of IL-6 suggested early ME/CFS, the reverse was true in subjects over 18 years of age ill for more than 2 years. CONCLUSIONS: These preliminary results suggest that IL-1α, 6 and 8 adjusted for illness duration may serve as robust biomarkers, independent of age, in screening for ME/CFS.

Tracking post-infectious fatigue in clinic using routine Lab tests.

BACKGROUND: While biomarkers for chronic fatigue syndrome (CFS) are beginning to emerge they typically require a highly specialized clinical laboratory. We hypothesized that subsets of commonly measured laboratory markers used in combination could support the diagnosis of post-infectious CFS (PI-CFS) in adolescents following infectious mononucleosis (IM) and help determine who might develop persistence of symptoms. METHODS: Routine clinical laboratory markers were collected prospectively in 301 mono-spot positive adolescents, 4 % of whom developed CFS (n = 13). At 6, 12, and 24 months post-diagnosis with IM, 59 standard tests were performed including metabolic profiling, liver enzyme panel, hormone profiles, complete blood count (CBC), differential white blood count (WBC), salivary cortisol, and urinalysis. Classification models separating PI-CFS from controls were constructed at each time point using stepwise subset selection. RESULTS: Lower ACTH levels at 6 months post-IM diagnosis were highly predictive of CFS (AUC p = 0.02). ACTH levels in CFS overlapped with healthy controls at 12 months, but again showed a trend towards a deficiency at 24 months. Conversely, estradiol levels depart significantly from normal at 12 months only to recover at 24 months (AUC p = 0.02). Finally, relative neutrophil count showed a significant departure from normal at 24 months in CFS (AUC p = 0.01). Expression of these markers evolved differently over time between groups. CONCLUSIONS: Preliminary results suggest that serial assessment of stress and sex hormones as well as the relative proportion of innate immune cells measured using standard clinical laboratory tests may support the diagnosis of PI-CFS in adolescents with IM.

Clinical utility of bronchoalveolar lavage and respiratory tract biopsies in diagnosis and management of suspected invasive respiratory fungal infections in children.

BACKGROUND: Bronchoscopy with bronchoalveolar lavage (BAL) and respiratory tract biopsies are important tools for diagnosing fungal infections in children with cancer and hematopoietic stem cell transplant (HSCT) recipients. Our objective was to evaluate the impact of BAL and respiratory tract biopsies on the management of suspected fungal infections in oncology and HSCT patients. PROCEDURE: We retrospectively reviewed the medical records of oncology and HSCT patients with possible, probable, or proven fungal infection of the respiratory tract and determined whether BAL or biopsy following computed tomography (CT) prompted a change in management. RESULTS: Among 101 patients (0.5-29 years of age), 24 underwent a BAL and 31 had biopsies (27 lung and 4 sinus). The remaining 46 patients had CT scans only. Of these, there were radiographic findings suggestive of a fungal infection in 38 patients (83%). Thirty of these 38 patients (79%) had a change in management. BAL provided a diagnosis in 6 of 24 patients (25%). There was a change in management in 2 of the 6 (33%). Respiratory tract biopsy provided a diagnosis in 12 of 31 patients (39%). Biopsy results led to a change in management in 4 of the 12 patients (33%). Significant postoperative morbidity attributed to biopsy occurred in 3 of 31 patients (10%); 2 patients had pneumothorax requiring chest tube and intubation and a patient had prolonged intubation. CONCLUSION: BAL and biopsy in children with an oncological diagnosis or those undergoing HSCT only infrequently lead to changes in management in the era of empiric therapy with broad-spectrum anti-fungal agents.

Navigating the Spectrum of Two Pediatric COVID-19 Complications: Multi-System Inflammatory Syndrome in Children and Post-Acute Sequelae of SARS-CoV-2 Infection.

PURPOSE: This review summarizes the current scope of understanding associated with two common post-infectious complications associated with COVID-19 infection: Multi-System Inflammatory Syndrome in Children (MIS-C) and Post-Acute Sequelae of SARS-CoV-2 infection (PASC). It identifies current gaps in the knowledge and issues that may limit the ability to fill these gaps. This review provides a framework to drive continued research. METHODS: A comprehensive review of the current literature was performed, identifying seminal articles describing the emergence of MIS-C and PASC, and works from the literature focused on the clinical implications and pathophysiologic understanding of these disorders. FINDINGS: Although pediatric patients experienced few severe cases of acute COVID-19 infection, the burden of disease from post-infectious sequelae is substantial. Mortality is low, but morbidity is significant. There are still numerous unknowns about the pathophysiology of both MIS-C and PASC; however, with widespread immunity developing after increased vaccination and prior infection, it may be difficult to perform adequate prospective studies to answer pathophysiologic questions. Long-term sequalae of MIS-C seem to be minimal whereas, by definition, PASC is an ongoing problem and may be severe. IMPLICATIONS: The rapid sharing of information regarding novel conditions such as MIS-C and PASC are key to interventions related to future post-infectious sequelae outside of those stemming from COVID-19. Although MIS-C seems unlikely to return as a clinical condition in substantial numbers, there is still significant learning that can be gleaned from existing patients about general aspects of epidemiology, equity, and pathophysiology. There is significant morbidity associated with PASC and additional resources need to be dedicated to determining appropriate and effective therapies moving forward.

Joint Flexibility and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After Mononucleosis.

PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease characterized by substantial fatigue, postexertional malaise, unrefreshing sleep, and orthostatic intolerance, among other symptoms. Specific risk factors for the development of ME/CFS have not been adequately characterized. It has been suggested that ME/CFS is a connective tissue disorder and that joint hyperflexibility is a risk factor for the development of ME/CFS. METHODS: The goal of this study was to examine whether joint hyperflexibility is a risk factor for the development of ME/CFS after infectious mononucleosis (IM). This study was part of a prospective cohort study. College students were studied for the development of IM and were followed up for the development of ME/CFS 6 months later. Participants in the cohort for the present study included 53 students who met criteria for ME/CFS 6 months after IM and 66 recovered control subjects who had modified Beighton scores (a measure of joint hyperflexibility) available. FINDINGS: No connection was found between joint hyperflexibility and the development of ME/CFS after IM. Differences in joint hyperflexibility (as measured by using the modified Beighton score) in the ME/CFS group and the control group were not statistically significant. Female subjects had significantly higher Beighton scores compared with male subjects. IMPLICATION: After IM, no relationship was found between joint hyperflexibility and the development of ME/CFS.

Indirect protection of adults from rotavirus by pediatric rotavirus vaccination.

BACKGROUND: Pediatric vaccination has resulted in declines in disease in unvaccinated individuals through decreasing pathogen circulation in the community. About 2 years after implementation of pediatric rotavirus vaccination in the United States, dramatic declines in rotavirus disease were observed in both vaccinated and unvaccinated children. Whether this protection extends to adults is unknown. METHODS: The prevalence of rotavirus, as determined by Rotaclone enzyme immunoassay, in adults who had stools submitted for bacterial stool culture (BSC) between February to May to Northwestern Memorial Hospital, Chicago, was compared between the prepediatric impact era (2006-2007) and the pediatric impact era (2008-2010). Isolates were genotyped and clinical characteristics of those with rotavirus were compared. RESULTS: Of the 5788 BSC sent, 4725 met inclusion criteria and 3530 of these (74.7%) were saved for rotavirus testing. The prevalence of rotavirus among adults who had stool sent for BSC declined from 4.35% in 2006-2007 to 2.24% in 2008-2010 (a relative decline of 48.4%; P = .0007). The decline in the prevalence of rotavirus was of similar significant magnitude in both outpatients and inpatients. Marked year-to-year variability was observed in circulating rotavirus genotypes, with strain G2P[4] accounting for 24%; G1P[8], 22%; G3P[8], 11%; and G12P[6], 10% overall. About 30% of adults from whom rotavirus was isolated were immunocompromised and this remained constant. CONCLUSIONS: Pediatric rotavirus vaccination correlated with a relative decline of almost 50% in rotavirus identified from adult BSC during the peak rotavirus season, suggesting that pediatric rotavirus vaccination protects adults from rotavirus.

Chronic fatigue syndrome following infections in adolescents.

PURPOSE OF REVIEW: To review the recent epidemiology, pathophysiology, and treatment of postinfectious chronic fatigue syndrome (CFS) in adolescents. RECENT FINDINGS: Thirteen percent of adolescents (mainly women) met the criteria for CFS 6 months following infectious mononucleosis; the figure was 7% at 12 months and 4% at 24 months. Peak work capacity, activity level, orthostatic intolerance, salivary cortisol, and natural killer cell number and function were similar between adolescents with CFS following infectious mononucleosis and recovered controls. Autonomic system, oxygen consumption, peak oxygen pulse, psychological and cytokine network differences were documented between those who recovered and those who did not. SUMMARY: The prognosis of CFS is better in adolescents than in adults. Activity level, exercise tolerance, and orthostatic testing could not distinguish patients with CFS from adolescents who have recovered from infectious mononucleosis (controls), while certain cytokine network analyses, life stress factors, and autonomic symptoms could.

Cytokine network analysis in a community-based pediatric sample of patients with myalgic encephalomyelitis/chronic fatigue syndrome.

OBJECTIVES: Studies have demonstrated immune dysfunction in adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); however, evidence is varied. The current study used network analysis to examine relationships between cytokines among a sample of pediatric participants with ME/CFS. METHODS: 10,119 youth aged 5-17 in the Chicagoland area were screened for ME/CFS; 111 subjects and controls were brought in for a physician examination and completed a blood draw. Youth were classified as controls (Cs, N = 43), ME/CFS (N = 23) or severe (S-ME/CFS, N = 45). Patterns of plasma cytokine networks were analyzed. RESULTS: All participant groups displayed a primary network of interconnected cytokines. In the ME/CFS group, inflammatory cytokines IL-12p70, IL-17A, and IFN-γ were connected and included in the primary membership, suggesting activation of inflammatory mechanisms. The S-ME/CFS group demonstrated a strong relationship between IL-17A and IL-23, a connection associated with chronic inflammation. The relationships of IL-6 and IL-8 in ME/CFS and S-ME/CFS participants also differed from Cs. Together, these results indicate pro-inflammatory responses in our illness populations. DISCUSSION: Our data imply biological differences between our three participant groups, with ME/CFS and S-ME/CFS participants demonstrating an inflammatory profile. Examining co-expression of cytokines may aid in the identification of a biomarker for pediatric ME/CFS.

Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue.

BACKGROUND: As Chronic Fatigue Syndrome (CFS) has been known to follow Epstein-Bar virus (EBV) and other systemic infections; our objective was to describe differences in immune activation in post-infective CFS (PI-CFS) patients and recovered controls. We studied 301 adolescents prospectively over 24 months following the diagnosis of monospot-positive infectious mononucleosis (IM). We found an incidence of CFS at 6, 12 and 24 months of 13%, 7% and 4% respectively. METHODS: Using chemiluminescent imaging we measured the concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12 (p70), 13, 15, 17 and 23, IFN-γ, TNF-α and TNF-ß in duplicate plasma samples available in bio-bank from 9 PI-CFS subjects and 12 recovered controls at 24 months post-infection. RESULTS: Standard comparative analysis indicated significant differences in IL-8 and 23 across subject groups. In constructing a linear classification model IL-6, 8 and 23 were selected by two different statistical approaches as discriminating features, with IL-1a, IL-2 and IFN-γ also selected in one model or the other. This supported an assignment accuracy of better than 80% at a confidence level of 0.95 into PI-CFS versus recovered controls. CONCLUSION: These results suggest that co-expression patterns in as few as 5 cytokines associated with Th17 function may hold promise as a tool for the diagnosis of post-infectious CFS.

College student symptoms as assessed by a student health survey.

ObjectiveWe sought to identify the general health of college students.ParticipantsA total of 4402 university freshmen and sophomores were recruited to report their general health through an online questionnaire.MethodsResponses from the DePaul Symptom Questionnaire were analyzed. We then conducted latent class analyses to evaluate 54 different symptoms among participants.ResultsA four class solution was identified, consisting of a group of asymptomatic students (35.65%), a second group of students reporting mild fatigue and sleep symptoms (38.87%), a third group reporting moderate sleep and fatigue symptoms (20.36%), and a group reporting moderate and severe complaints on the majority of symptoms (5.11%). Female students had 2.07 times the relative risk of the severe symptom class of men. Indigenous students have 2.88 times the relative risk of occupying the severe symptom class than non-indigenous students.ConclusionsThe results suggest that about 5% of college students have varied symptoms of a moderate to severe degree. Future research is needed to better assess whether there are biological associations with these self-report findings, as well as to determine longer-term implications of these symptoms.

Pre-illness data reveals differences in multiple metabolites and metabolic pathways in those who do and do not recover from infectious mononucleosis.

Metabolic pathways related to energy production, amino acids, nucleotides, nitrogen, lipids, and neurotransmitters in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may contribute to the pathophysiology of ME/CFS. 4501 Northwestern University college students were enrolled in a prospective, longitudinal study. We collected data before illness, during infectious mononucleosis (IM), and at a 6 month follow-up for those who recovered (N = 18) versus those who went on to develop ME/CFS 6 months later (N = 18). Examining pre-illness blood samples, we found significant detectable metabolite differences between participants fated to develop severe ME/CFS following IM versus recovered controls. We identified glutathione metabolism, nucleotide metabolism, and the TCA cycle (among others) as potentially dysregulated pathways. The pathways that differed between cases and controls are essential for proliferating cells, particularly during a pro-inflammatory immune response. Performing a series of binary logistic regressions using a leave-one-out cross-validation (LOOCV), our models correctly classified the severe ME/CFS group and recovered controls with an accuracy of 97.2%, sensitivity of 94.4%, and specificity of 100.0%. These changes are consistent with the elevations in pro-inflammatory cytokines that we have reported for patients fated to develop severe ME/CFS 6 months after IM.

Plasma next-generation sequencing for diagnosis of amebic liver abscess in a non-endemic area.

Amebic liver abscess (ALA) is a common condition in the developing world but is rare in the United States without a clear exposure risk. It is even less common to develop in an infant. The diagnosis of ALA can be logistically difficult and often requires invasive procedures and testing with slow turnaround times. We present an 18-month-old boy initially admitted with fever, abdominal pain, and diarrhea with rapid progression to respiratory failure. He was found to have a significant pleural effusion accompanying a large solitary liver lesion with abdominal ascites. There was no infectious exposure history or travel history, and thus pyogenic liver abscess was suspected, and aspiration performed while he was on empiric antimicrobials. The bacterial culture was negative. Molecular testing with 16 s and 18 s rRNA PCR on the fluid were non-diagnostic. The diagnosis of Entamoeba histolytica was confirmed within 48 hrs via plasma next-generation sequencing. Serum IgG for E histolytica resulted positive multiple weeks after the patient was discharged. The patient made a full recovery after metronidazole and paromomycin. This case illustrates the need to maintain ALA in the differential diagnosis for liver abscess in an infant even in the absence of risk factors. Additionally, plasma next-generation sequencing may play a role in more rapid diagnosis of ALA and has the potential to reduce the need for more invasive testing.

Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Following Infectious Mononucleosis.

Background: About 10% of individuals who contract infectious mononucleosis (IM) have symptoms 6 months later that meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our study for the first time examined whether it is possible to predict who will develop ME/CFS following IM. Methods: We have reported on a prospectively recruited cohort of 4,501 college students, of which 238 (5.3%) developed IM. Those who developed IM were followed-up at six months to determine whether they recovered or met criteria for ME/CFS. The present study focuses on 48 students who after six months had a diagnosis of ME/CFS, and a matched control group of 58 students who had no further symptoms after their IM. All of these 106 students had data at baseline (at least 6 weeks prior to the development of IM), when experiencing IM, and 6 months following IM. Of those who did not recover from IM, there were two groups: 30 were classified as ME/CFS and 18 were classified as severe ME/CFS. We measured the results of 7 questionnaires, physical examination findings, the severity of mononucleosis and cytokine analyses at baseline (pre-illness) and at the time of IM. We examined predictors (e.g., pre-illness variables as well as variables at onset of IM) of those who developed ME/CFS and severe ME/CFS following IM. Results: From analyses using receiver operating characteristic statistics, the students who had had severe gastrointestinal symptoms of stomach pain, bloating, and an irritable bowel at baseline and who also had abnormally low levels of the immune markers IL-13 and/or IL-5 at baseline, as well as severe gastrointestinal symptoms when then contracted IM, were found to have a nearly 80% chance of having severe ME/CFS persisting six months following IM. Conclusions: Our findings are consistent with emerging literature that gastrointestinal distress and autonomic symptoms, along with several immune markers, may be implicated in the development of severe ME/CFS.

Plasmodium infection is associated with cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 Spike protein.

Sero-surveillance can monitor and project disease burden and risk. However, SARS-CoV-2 antibody test results can produce false positive results, limiting their efficacy as a sero-surveillance tool. False positive SARS-CoV-2 antibody results are associated with malaria exposure, and understanding this association is essential to interpret sero-surveillance results from malaria-endemic countries. Here, pre-pandemic samples from eight malaria endemic and non-endemic countries and four continents were tested by ELISA to measure SARS-CoV-2 Spike S1 subunit reactivity. Individuals with acute malaria infection generated substantial SARS-CoV-2 reactivity. Cross-reactivity was not associated with reactivity to other human coronaviruses or other SARS-CoV-2 proteins, as measured by peptide and protein arrays. ELISAs with deglycosylated and desialated Spike S1 subunits revealed that cross-reactive antibodies target sialic acid on N-linked glycans of the Spike protein. The functional activity of cross-reactive antibodies measured by neutralization assays showed that cross-reactive antibodies did not neutralize SARS-CoV-2 in vitro. Since routine use of glycosylated or sialated assays could result in false positive SARS-CoV-2 antibody results in malaria endemic regions, which could overestimate exposure and population-level immunity, we explored methods to increase specificity by reducing cross-reactivity. Overestimating population-level exposure to SARS-CoV-2 could lead to underestimates of risk of continued COVID-19 transmission in sub-Saharan Africa.