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The skin lesion erythema migrans (EM) is an initial sign of the Ixodes tick-transmitted Borreliella spirochetal infection known as Lyme disease. T cells and innate immune cells have previously been shown to predominate the EM lesion and promote the reaction. Despite the established importance of B cells and antibodies in preventing infection, the role of B cells in the skin immune response to Borreliella is unknown. Here, we used single-cell RNA-Seq in conjunction with B cell receptor (BCR) sequencing to immunophenotype EM lesions and their associated B cells and BCR repertoires. We found that B cells were more abundant in EM in comparison with autologous uninvolved skin; many were clonally expanded and had circulating relatives. EM-associated B cells upregulated the expression of MHC class II genes and exhibited preferential IgM isotype usage. A subset also exhibited low levels of somatic hypermutation despite a gene expression profile consistent with memory B cells. Our study demonstrates that single-cell gene expression with paired BCR sequencing can be used to interrogate the sparse B cell populations in human skin and reveals that B cells in the skin infection site in early Lyme disease expressed a phenotype consistent with local antigen presentation and antibody production.

Some patients have residual non-specific symptoms after therapy for Lyme disease, referred to as post-treatment Lyme disease symptoms or syndrome, depending on whether there is functional impairment. A standardized test battery was used to characterize a diverse group of Lyme disease patients with and without residual symptoms. There was a strong correlation between sleep disturbance and certain other symptoms such as fatigue, pain, anxiety, and cognitive complaints. Results were subjected to a Logistic Regression model using the Neuro-QoL Fatigue t-score together with Short Form-36 Physical Functioning scale and Mental Health component scores; and to a Decision Tree model using only the QoL Fatigue t-score. The Logistic Regression model had an accuracy of 97% and Decision Tree model had an accuracy of 93%, when compared with clinical categorization. The Logistic Regression and Decision Tree models were then applied to a separate cohort. Both models performed with high sensitivity (90%), but moderate specificity (62%). The overall accuracy was 74%. Agreement between 2 time points, separated by a mean of 4 months, was 89% using the Decision Tree model and 87% with the Logistic Regression model. These models are simple and can help to quantitate the level of symptom severity in post-treatment Lyme disease symptoms. More research is needed to increase the specificity of the models, exploring additional approaches that could potentially strengthen an operational definition for post-treatment Lyme disease symptoms. Evaluation of how sleep disturbance, fatigue, pain and cognitive complains interrelate can potentially lead to new interventions that will improve the overall health of these patients.

Such surveillance can provide an early warning for emergence of this disease and measure disease underreporting., Human babesiosis is an emerging tick-borne disease caused by the intraerythrocytic protozoan Babesia microti. Its geographic distribution is more limited than that of Lyme disease, despite sharing the same tick vector and reservoir hosts. The geographic range of babesiosis is expanding, but knowledge of its range is incomplete and relies exclusively on reports of human cases. We evaluated the utility of tick-based surveillance for monitoring disease expansion by comparing the ratios of the 2 infections in humans and ticks in areas with varying B. microti endemicity. We found a close association between human disease and tick infection ratios in long-established babesiosis-endemic areas but a lower than expected incidence of human babesiosis on the basis of tick infection rates in new disease-endemic areas. This finding suggests that babesiosis at emerging sites is underreported. Vector-based surveillance can provide an early warning system for the emergence of human babesiosis.

Previous studies in rodents and people have demonstrated that repeated tick exposure is associated with reduced Borrelia burgdorferi transmission but the mechanism of prevention remains unclear. We examined the acute histopathologic reactions to initial and repeated Ixodes scapularis bites in BALB/c mice and in people. Skin biopsies of BALB/c mice infested for the first time by I. scapularis nymphs revealed vascular dilatation and an accumulation of inflammatory cells adjacent to the bite site but absent at the site of tick attachment. Such changes would enhance tick-borne pathogen transmission. Mice reexposed to I. scapularis nymphs experienced a decrease in vascular dilatation and a marked increase in inflammatory cells at the site of tick attachment. Skin biopsies of people with attached I. scapularis nymphs revealed similar histologic patterns. These results indicate that cellular changes at the tick-dermal interface following I. scapularis attachment are likely to allow for successful transmission of tick-borne pathogens in non-tick-immune hosts and to inhibit tick-borne pathogen transmission in hosts that have developed tick immunity.

We used multiparameter flow cytometry to characterize leukocyte immunophenotypes and cytokines in skin and peripheral blood of patients with erythema migrans (EM). Dermal leukocytes and cytokines were assessed in fluids aspirated from epidermal suction blisters raised over EM lesions and skin of uninfected controls. Compared with corresponding peripheral blood, EM infiltrates were enriched for T cells, monocytes/macrophages, and dendritic cells (DCs), contained lower proportions of neutrophils, and were virtually devoid of B cells. Enhanced expression of CD14 and HLA-DR by lesional neutrophils and macrophages indicated that these innate effector cells were highly activated. Staining for CD45RO and CD27 revealed that lesional T lymphocytes were predominantly Ag-experienced cells; furthermore, a subset of circulating T cells also appeared to be neosensitized. Lesional DC subsets, CD11c+ (monocytoid) and CD11c− (plasmacytoid), expressed activation/maturation surface markers. Patients with multiple EM lesions had greater symptom scores and higher serum levels of IFN-α, TNF-α, and IL-2 than patients with solitary EM. IL-6 and IFN-γ were the predominant cytokines in EM lesions; however, greater levels of both mediators were detected in blister fluids from patients with isolated EM. Circulating monocytes displayed significant increases in surface expression of Toll-like receptor (TLR)1 and TLR2, while CD11c+ DCs showed increased expression of TLR2 and TLR4; lesional macrophages and CD11c+ and CD11c− DCs exhibited increases in expression of all three TLRs. These results demonstrate that Borrelia burgdorferi triggers innate and adaptive responses during early Lyme disease and emphasize the interdependence of these two arms of the immune response in the efforts of the host to contain spirochetal infection.

Background. Animal studies suggest that Borrelia burgdorferi, the agent of Lyme disease, may persist after antibiotic therapy and can be detected by various means including xenodiagnosis using the natural tick vector (Ixodes scapularis). No convincing evidence exists for the persistence of viable spirochetes after recommended courses of antibiotic therapy in humans. We determined the safety of using I. scapularis larvae for the xenodiagnosis of B. burgdorferi infection in humans. Methods. Laboratory-reared larval I. scapularis ticks were placed on 36 subjects and allowed to feed to repletion. Ticks were tested for B. burgdorferi by polymerase chain reaction (PCR), culture, and/or isothermal amplification followed by PCR and electrospray ionization mass spectroscopy. In addition, attempts were made to infect immunodeficient mice by tick bite or inoculation of tick contents. Xenodiagnosis was repeated in 7 individuals. Results. Xenodiagnosis was well tolerated with no severe adverse events. The most common adverse event was mild itching at the tick attachment site. Xenodiagnosis was negative in 16 patients with posttreatment Lyme disease syndrome (PTLDS) and/or high C6 antibody levels and in 5 patients after completing antibiotic therapy for erythema migrans. Xenodiagnosis was positive for B. burgdorferi DNA in a patient with erythema migrans early during therapy and in a patient with PTLDS. There is insufficient evidence, however, to conclude that viable spirochetes were present in either patient. Conclusions. Xenodiagnosis using Ixodes scapularis larvae was safe and well tolerated. Further studies are needed to determine the sensitivity of xenodiagnosis in patients with Lyme disease and the significance of a positive result. Clinical Trials Registration {"type":"clinical-trial","attrs":{"text":"NCT01143558","term_id":"NCT01143558"}}NCT01143558.

Physicians must be prepared to provide comprehensive pretravel advice to their patients. Because world conditions are constantly changing, it is necessary to obtain accurate and current information. Common health problems that may be faced by any traveler include accidents, motion sickness, and jet lag. Physicians must familiarize themselves with the many forms of insurance available for the traveler.

Human babesiosis is a tickborne malaria-like illness that generally resolves without complication after administration of atovaquone and azithromycin or clindamycin and quinine. Although patients experiencing babesiosis that is unresponsive to standard antimicrobial therapy have been described, the pathogenesis, clinical course, and optimal treatment regimen of such cases remain uncertain.We compared the immunologic status, clinical course, and treatment of 14 case patients who experienced morbidity or death after persistence of Babesia microti infection, despite repeated courses of antibabesial treatment, with those of 46 control subjects whose infection resolved after a single course of standard therapy. This retrospective case-control study was performed in southern New England, New York, and Wisconsin.All case patients were immunosuppressed at the time of acute babesiosis, compared with10% of the control subjects. Most case patients experienced B cell lymphoma and were asplenic or had received rituximab before babesial illness. The case patients were more likely than control subjects to experience complications, and 3 died. Resolution of persistent infection occurred in 11 patients after 2-10 courses of therapy, including administration of a final antimicrobial regimen for at least 2 weeks after babesia were no longer seen on blood smear.Immunocompromised people who are infected by B. microti are at risk of persistent relapsing illness. Such patients generally require antibabesial treatment foror=6 weeks to achieve cure, including 2 weeks after parasites are no longer detected on blood smear.

Background Typhoid fever is endemic in many parts of the world. In the United States, nearly three quarters of all cases are contracted by persons who traveled to regions with endemic disease. Typhim Vi, a vaccine containing the purified cell surface Vi polysaccharide of the Salmonella enterica serovar Typhi, was developed to provide protection against typhoid fever. We present the results of the largest safety study of this Vi vaccine to date. Methods This open-label, descriptive study assessed safety and reactogenicity following the Vi vaccine administration. Coadministration of other vaccines (at separate sites) was permitted, consistent with clinical practice. Participants aged 2 years or older with no known sensitivities to any vaccine component, who received the Vi vaccine, according to label directions, at a participating travel clinic, were eligible to participate. Information was collected on concurrent medications and medical conditions. The occurrence of solicited injection site reactions and systemic reactions was recorded on diary cards for 7 days following vaccination, along with any unsolicited medical events. Serious adverse events were reported for 30 days postimmunization. Results A total of 1,204 participants (mean age: 37.2 y, range: 2–82 y, 55% female) were enrolled into the study, and 1,111 completed the 7-day follow-up. The most common solicited reactions were injection site pain [850 of 1,111 (76.5%)], tenderness [838 of 1,111 (75.4%)], and muscle aches [434 of 1,111 (39.1%)]. Fever was reported in 18 (1.6%) of 1,111 participants. Coadministration of other common travel vaccines did not affect reactogenicity profiles, except for an increase in the Vi vaccine injection site redness when two vaccines were administered in the same limb. Conclusions The Vi vaccine was well tolerated in an unselected population, aged 2 to 82 years, presenting to a travel clinic for vaccination.

Ticks introduce a variety of pharmacologically active molecules into their host during attachment and feeding in order to obtain a blood meal. People who are repeatedly exposed to ticks may develop an immune response to tick salivary proteins. Despite this response, people usually are unaware of having been bitten, especially if they are not repeatedly exposed to ticks. In order to develop a laboratory marker of tick exposure that would be useful in understanding the epidemiology of tick-borne infection and the immune response to tick bite, we developed an enzyme-linked immunosorbent assay (ELISA) to detect antibody to a recombinant form of calreticulin protein found in the salivary glands of Ixodes scapularis , a member of a complex of Ixodes ticks that serve as the vectors for Lyme disease, human babesiosis, and human granulocytic anaplasmosis. Using this assay, we tested sera obtained from C3H/HeN and BALB/c mice before and after experimental deer tick infestation. These mice developed antibody to Ixodes calreticulin antigen after infestation. We then used the same assay to test sera obtained from people before and after they experienced deer tick bite(s). People experiencing deer tick bite(s) developed Ixodes calreticulin-specific antibody responses that persisted for up to 17 months. This Ixodes recombinant calreticulin ELISA provides objective evidence of deer tick exposure in people.

The foreword to Imported Skin Diseases states, “This book was written and illustrated for the health professional in order to help in the diagnosis and management of patients with diseases acquired in another, often tropical, environment.” The book identifies an important clinical need for practitioners whose patients are traveling to an ever greater degree to more distant and exotic locales. This book is neither an encyclopedic compendium of all tropical skin diseases nor a simple handbook for the house officer or medical student. The breadth of topics is broad, but some topics are discussed in great depth with good authority. The photographic images are clear and well chosen. Chapters that stand out include those on Pigmentary Disorders in Black Skin by J.P.W. van der Veen, M.F.E. Leenarts, and W.W. Westerhof; Coloured versus White Skin by B. Naafs; Buruli Ulcer by F. Portaels and W.M. Meyers; Tungiasis by H. Feldmeier and J. Heukelbach; Myiasis by D.A. Burns; and Beetle Dermatitis by P. Schmid-Grendelmeier and S. Haug. The chapter Persistent Insect Bites by C.L.M. van Hees assumes that all mosquitoes are night biters. The author states that one can prevent mosquito bites by “avoiding being outside from dusk till dawn.” But this message misses the point because anopheline and other species bite from dusk to dawn, and Aedes and other species are day biters. This advice is really intended to help avoid contracting malaria, not being bitten. At times, the writing is puzzling. For example, the chapter, Fever and Rash, by H.G. Schipper and P.A. Kager discusses loiasis and indicates that “fever is absent.” It is unclear why a chapter on fever would include a disease that has no fever. Loiasis is more fully covered in the later chapter, Onchocerciasis/Filariasis, by M. Murdoch, so its discussion in Fever and Rash is superfluous and out of place. Many of the chapters were written by authorities whose first language was probably not English. These chapters could have been edited more carefully because grammatical errors interfere with comprehension. The same applies to the book’s typographical errors, which are too frequent to count. Imported Skin Diseases is organized primarily by diagnosis rather than by syndrome. The disease descriptions are generally complete, with adequate sections on diagnosis and treatment. I discovered at the back of the book, almost by accident, some rather skimpy tables organized by syndrome (fever and rash, ulceration, eschar). I would have preferred this approach to be covered in greater detail because it would be much more useful to the Western practitioner who is confronted with a patient returning from the tropics with an undiagnosed skin disorder. For example, I have a patient in my office with an eschar. The patient has returned from a trip to Africa. What are the diagnostic considerations? Or, a patient has a rash and fever and has traveled widely throughout Asia; how can I approach a proper diagnosis? As the book is written it could be useful as preparation for the Diploma in Tropical Medicine and Hygiene, certification examination of the International Society of Travel Medicine or American Society of Tropical Medicine and Hygiene, or perhaps as a primer for a physician who will travel to the tropics to practice medicine.

To the Editor.— The continuing spread of chloroquine-resistant malaria, combined with unacceptable toxicity of drugs such as Fansidar and amodiaquine for routine use, has restricted the choice of antimalarial regimens that can now be recommended. Many authorities, including the Centers for Disease Control Malaria Branch, 1 now include proguanil (Paludrine, ICI Pharmaceuticals, United Kingdom) among the drugs that may be used for antimalarial prophylaxis. Proguanil is not available in the United States and many physicians are not familiar with its use or how to obtain it. Current Centers for Disease Control recommendations suggest the use of proguanil in certain limited settings. In particular, it may be used by those who will be spending longer than three weeks in rural areas of east Africa (especially Kenya and Tanzania 2,3 ), where much of the falciparum malaria is now resistant to chloroquine. Data do not support its use in other malarious areas such

Excerpt To the editor: I am conducting a research project on various aspects of office practice in primary care. I am interested in communicating with physicians who have recently entered private p...

Gardner et al. failed to show the effectiveness of nebulized racemic epinephrine in the treatment of what they called "croup." Perhaps their study failed as a result of their definition of croup. Croup (subglottic edema) and epiglottitis are each distinct clinical entities by anatomy, etiology, pathophysiology, and, therefore, therapy. It will be interesting to see the fate of the null hypothesis if the data are re-examined from this perspective.