Severe Secondary Infections Research Articles

Pathogenic bacterium Vibrio harveyi: an endosymbiont in the marine parasitic ciliate protozoan Cryptocaryon irritans

Vibrio harveyi, known as a pathogenic bacterium caused severe secondary bacterial infections of the large yellow croaker Larimichthys crocea, was identified as an endosymbiont in the marine parasitic ciliate protozoan Cryptocaryon irritans. Meta 16S sequencing method was used to identify the bacterial flora in C. irritans, and V. harveyi was isolated via culture-dependent method. Vibrio harveyi was observed in cytoplasm of C. irritans at the stage of tomont both by transmission electron microscopy and by Fluorescence in situ hybridization; no signal, however, was detected in nucleus area. The relationship between V. harveyi and C. irritans and the role of endosymbiotic V. harveyi in C. irritans merit further investigation.

Freshwater Catfish Envenoming in a Tropical Country

Freshwater catfish are known to cause painful stings in humans. Stings usually cause mild envenomation and, in some instances, can lead to severe secondary bacterial infections. Sri Lanka is a tropical country where catfish stings are not rare. However, presenting signs and symptoms, complications, and management options are scarce in the literature. A retrospective, descriptive, cross-sectional study was conducted by reviewing patient records in the university surgical units and surgical clinic in the teaching hospital in Anuradhapura, Sri Lanka, during 2015. Ten patients presented to the hospital following catfish stings. The common presenting features following stings were severe pain, swelling, and lymphadenopathy followed by cellulitis. Late complication such as tenosynovitis were also observed. Routine procedures are sufficient to reduce further complications. However, people who are at high risk of encountering catfish, and travelers visiting tropical countries, should be aware of the possibility of stings and take necessary precautions.

Compromised Defenses: Exploitation of Epithelial Responses During Viral-Bacterial Co-Infection of the Respiratory Tract.

Respiratory infections are the greatest single contributor to the overall burden of disease worldwide [1]. Polymicrobial infections are becoming increasingly recognized in terms of both prevalence and their effect on disease severity, causing many common diseases such as oral infections, otitis media, chronic wound infections, and implanted medical device infections, as well as chronic pulmonary disease in cystic fibrosis patients [2,3]. There is a large body of literature demonstrating synergy between viral and bacterial infections at mucosal surfaces; for example, (i) the intestinal microbiota promotes enteric viral infection via direct interactions and modulation of the immune system [4]; (ii) sexually transmitted viruses exploit the altered environment, including altered pH, inflammatory, and oxidative settings, during bacterial vaginosis or aerobic vaginitis to increase infection of the vaginal and cervical epithelium [5]; and (iii) bacteria take advantage of the altered innate and adaptive immune responses of the respiratory tract during viral infection of the respiratory epithelium to increase infectivity and virulence [6]. Many studies have focused on the consequences of influenza infection on secondary bacterial infection in the respiratory tract, where altered lung physiology and immune status increases susceptibility to severe secondary bacterial infections with common commensal organisms of the upper respiratory tract, such as Streptococcus pneumoniae and Staphylococcus aureus [7]. Here, we focus on the role of the respiratory epithelium in defending against microbial pathogens as well as in facilitating synergistic pathogenic interactions (Fig 1). Fig 1 Model of increased susceptibility to secondary bacterial infection after primary viral infection of the respiratory epithelium. Role of the Respiratory Epithelium in Innate and Adaptive Immunity The respiratory epithelium is the primary site of host–pathogen encounter in the respiratory tract and the first line of defense against infection (extensively reviewed [8–10]). The epithelium employs a wide array of tools to inhibit colonization as well as dictate innate and adaptive immune responses to pathogens that overcome these initial barriers. First and foremost, the epithelium is a physical barrier to pathogen invasion, forming cell–cell junctions to exclude pathogens from the underlying tissues and actively restrict nutrient availability. Respiratory epithelial cells maintain an airway surface liquid into which they secrete mucins that form a mucus layer to trap and propel pathogens out of the respiratory tract via mucociliary beat. The epithelium also secretes many additional effectors in the airway surface liquid, including antimicrobial peptides and proteins, such as degradative enzymes, iron sequestration proteins, protease inhibitors, collectin surfactant proteins, chemokines, and various forms of palate-lung-nasal-clone protein (PLUNC). The airway epithelium also produces toxic reactive nitrogen species and reactive oxygen species. These direct antimicrobial effectors are upregulated in response to pathogen or pro-inflammatory signals. Airway epithelial cells also produce cytokines and chemokines in response to pathogens, via pattern recognition receptor (PRR) activation, or to pro-inflammatory signals to shape the innate and adaptive immune responses, leading to an influx of neutrophils and monocytes, differentiation of monocytes into dendritic cells and macrophages, influx and activation of Th cells, and differentiation of B cells. B cell differentiation leads to immunoglobulin (Ig) class switching, and epithelial cells transcytose polymeric IgM and IgA into the airway surface liquid. Despite this array of defense functions, synergistic interactions between viral and bacterial respiratory pathogens can arise when one pathogen is able to suppress the antimicrobial activities of the epithelium or when an epithelial response that is protective against one pathogen makes the airway more permissive for infection by the other pathogen.

The role of dendritic cell alterations in susceptibility to hospital-acquired infections during critical-illness related immunosuppression.

Systemic inflammatory response syndrome (SIRS) is a common condition in critically ill patients. SIRS is characterized by alteration of both innate and adaptive immunity and causes protracted immunosupression, exposing the patients to severe secondary infections. Dendritic cells (DCs), which play a pivotal role bridging innate and T cell-dependent immunity, exhibit prolonged alterations after SIRS. In an early phase, SIRS causes depletion or systemic activation of immature DCs in parenchymal tissues and lymphoid organs, leading to impaired pathogen detection and presentation. Later on, newly formed DCs acquire a poorly immunogenic phenotype, with poor capacity to capture, process and/or present antigens and to stimulate T cells. Here, we review the studies that describe alterations in DC function post-SIRS. Knowledge about the molecular mechanisms involved are still scarce but their understanding might open new therapeutic avenues to prevent or reduce protracted immunosuppression in critically-ill patients.

Phenotypic, molecular and antimicrobial susceptibility assessment in isolates from chronic ulcers of cured leprosy patients: a case study in Southern Brazil.

BACKGROUND One of the most stigmatizing physical sequelaeof leprosy in cured patients is the development of chronic lower extremity ulcers. The bacterial diversity present in ulcers is considered one of the factors that can delay the healing process, as well as serve as a focus for severe secondary infections. OBJECTIVE To identify the microbiota and antimicrobial resistance profile of bacteria isolated from skin ulcers in patients cured of leprosy. METHODSAfter obtaining informed consent, material was collected from ulcers of 16 patients treated at the Outpatient Public Health Dermatology Clinic of Rio Grande do Sul and Hospital Colônia Itapuã. Sampleswere collected during dressing, and the material sent to the Microbiology Laboratory of the Federal University of Health Sciences of Porto Alegre for microbiological culture. Methicillin-resistant Staphylococcus aureus (MRSA) was characterized by two molecular methods, including detection of the mecA gene by PCR and SCCmecgene typing. RESULTS Cultures revealed microorganisms in all ulcers: Gram-negative bacilli in 80%, Gram-positive cocci in 63%, and mixed microflora in 36%. Staphylococcus aureus and Pseudomonas aeruginosa were the most prevalent bacteria. Assessment of the antimicrobial resistance profile was notable for the presence of MRSA. Molecular analysis of this isolate revealed presence of the mecA gene contained in a type IV staphylococcal cassette chromosome mec (SCCmec). CONCLUSIONS In patients with leprosy, laboratory culture of skin ulcers is essential for correct antibiotic selection and to control emerging pathogens, such as MRSA carrying SCCmec type IV.

Innate Immune Function and Mortality in Critically Ill Children With Influenza: A Multicenter Study

MW Hall, SM Geyer, CY Guo; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network PICFlu Study Investigators. Crit Care Med. 2013;41(1):224–236 The influenza virus can inhibit leukocyte function in vitro and in vivo, and is associated with severe secondary bacterial infections. Immunoparalysis is the state marked by reduction in the ability to produce tumor necrosis factor (TNF)-α in response to lipopolysaccharide (LPS). This study sought to test the hypothesis that mortality from influenza in critically ill children and young adults is associated with both hypercytokinemia and innate immune suppression. Patients <18 years old, who were admitted to 1 of the 15 PICUs that belong to the Pediatric Acute Lung …

Age-sex distribution and seasonality pattern among influenza virus infected patients in Delhi, 2009-2010

The sudden rise in the number of novel influenza A (pH1N1) virus infections in India, soon after its emergence in Mexico and USA, raised serious concern about the disease severity and its associated respiratory complications to hospitalized patients. (1) Patients suddenly started reporting to various hospitals with severe respiratory complications. They were tested for the pH1N1 infection and their case history was thoroughly evaluated to characterize the epidemiology and clinical severity of the infection. The worldwide data for influenza infections show that the older people, along with young children, are particularly vulnerable to severe outcomes and secondary infections. (2) The existing surveillance systems have not made adequate use of age-specific data and the importance of understanding age, when estimating the impact of influenza disease burden, needs to be extensively studied. This short communication describes the snapshot of age and sex distribution in pandemic influenza H1N1 virus related respiratory complications and comorbidities that were identified starting from the peak of pandemic to postpandemic phase.

Can Interactions between Timing of Vaccine-Altered Influenza Pandemic Waves and Seasonality in Influenza Complications Lead to More Severe Outcomes?

Vaccination can delay the peak of a pandemic influenza wave by reducing the number of individuals initially susceptible to influenza infection. Emerging evidence indicates that susceptibility to severe secondary bacterial infections following a primary influenza infection may vary seasonally, with peak susceptibility occurring in winter. Taken together, these two observations suggest that vaccinating to prevent a fall pandemic wave might delay it long enough to inadvertently increase influenza infections in winter, when primary influenza infection is more likely to cause severe outcomes. This could potentially cause a net increase in severe outcomes. Most pandemic models implicitly assume that the probability of severe outcomes does not vary seasonally and hence cannot capture this effect. Here we show that the probability of intensive care unit (ICU) admission per influenza infection in the 2009 H1N1 pandemic followed a seasonal pattern. We combine this with an influenza transmission model to investigate conditions under which a vaccination program could inadvertently shift influenza susceptibility to months where the risk of ICU admission due to influenza is higher. We find that vaccination in advance of a fall pandemic wave can actually increase the number of ICU admissions in situations where antigenic drift is sufficiently rapid or where importation of a cross-reactive strain is possible. Moreover, this effect is stronger for vaccination programs that prevent more primary influenza infections. Sensitivity analysis indicates several mechanisms that may cause this effect. We also find that the predicted number of ICU admissions changes dramatically depending on whether the probability of ICU admission varies seasonally, or whether it is held constant. These results suggest that pandemic planning should explore the potential interactions between seasonally varying susceptibility to severe influenza outcomes and the timing of vaccine-altered pandemic influenza waves.

The influence of environmental bacteria in freshwater stingray wound-healing

Invasion by bacteria can influence the course of healing of wounds acquired in aquatic environment. In this study, the bacteria present in Potamotrygon motoro stingray mucus and in the Alto Paraná river water were identified, and their ability to induce tissue injury and resist antibiotics was determined. Biochemical identification analysis showed that 97% of all bacterial isolates were Gram negative, Aeromonas spp., Enterobacter cloacae and Citrobacter freundii being the species most prevalent. Gelatinase and caseinase were produced by Aeromonas hydrophila, Aeromonas sobria and Pseudomonas aeruginosa strains. Erythrocyte hemolysis assay showed that A. sobria, A. hydrophila and to a lesser extent, other Gram-negative bacteria produced hemolysin. It was also observed that molecules released in culture by these bacteria were toxic to human epithelial cells. Antibiogram results showed that 68% of all bacterial isolates were resistant to at least one type of antibiotic, mainly B-lactams. Finally, it was demonstrated that although P. motoro venom was toxic to epithelial cells it did not influence bacterial proliferation. In summary, the results obtained in this work indicate that during the accident, the mucus of P. motoro and the environmental water may transfer into the wound pathogenic multi-resistant bacteria with the potential to cause severe secondary infections.

S25 IL 17 production in primary and secondary Respiratory Syncytial Virus (RSV) infection and neutrophil transmigration

<h3>Introduction and Objectives</h3> RSV causes winter epidemics of respiratory disease particularly in infants and the immunocompromised. Infected ciliated airway epithelial cells, local macrophages and dendritic cells secrete cytokines including interleukins (IL) 6 and 8, promoting a strong neutrophilic response that is important in disease clearance and airway inflammation. The IL 17 inflammatory pathway, which is important in surface immunity, has been little studied in RSV infection to date. The following hypothesis was explored: <i>The IL17 pathway is important in neutrophil chemotaxis and restriction of RSV replication</i>. <h3>Methods</h3> A transwell model of the airway was devised, co-culturing A549s (an immortalised bronchial epithelial cell line) and neutrophils to study the effect of RSV and IL17 on the transmigration of neutrophils. Neutrophil transmigration was assessed using light microscopic immunocytochemistry. Nasal swabs were taken from infants with RSV positive Bronchiolitis (n=49), RSV negative Bronchiolitis (n=12), the symptomatic older siblings of RSV positive infants (n=15) and uninfected, asymptomatic children (n=20). Cytokines released (IL6/IL8/IL17a/IL21/TNF) were analysed by cytokine bead array. <h3>Results</h3> IL 17 and RSV caused significantly increased number of neutrophils to transmigrate compared to either IL 17 or RSV alone. Primary RSV infections which caused hospitalisation, are characterised by high levels of nasal epithelial derived cytokines (IL 6, IL 8). Less severe secondary RSV infections are characterised by relatively low levels of IL 6 and IL 8 and relatively high levels of IL 17. <h3>Conclusions</h3> There is evidence that IL 17 is synergistic with RSV induced IL 8 in promoting neutrophil transmigration <i>in vitro</i>. There is evidence to support IL 17 as an important cytokine restricting RSV production in secondary infection <i>in vivo</i>. This study suggests that the IL 17 pathway is important in the pathogenesis of RSV bronchiolitis and could be potentially important in the development of novel therapies for this ubiquitous and important cause of respiratory disease.

Antibiotics Can Interfere with Priming of Neutrophils by Gut Microbiota

Administering broad-spectrum antibiotics to infected patients can also knock out benign intestinal bacteria, which play a key role in overall immunity by priming neutrophils in bone marrow, say researchers at the University of Pennsylvania (Penn) School of Medicine in Philadelphia. Because such losses of gut flora can disrupt host-immune responses, heavy-duty antibiotic treatments thus raise the risk for such patients of developing severe secondary infections, particularly while in hospital settings. On the plus side, replacing the bacterial signals that routinely prime neutrophils may someday provide a valuable means for offsetting these disruptive effects of broad-spectrum antibiotics, suggests Jeffrey Weiser, a professor of microbiology and pediatrics at Penn, and his collaborators.

Anaplasma phagocytophilum in Ruminants in Europe

The agent that causes tick-borne fever (TBF) in sheep was first described in 1940, 8 years after the disease was first recognized in Scotland. The same agent was soon shown to cause TBF in sheep and pasture fever in cattle in other parts of the UK, Scandinavia, and other parts of Europe. After the initial use of the name Rickettsia phagocytophila, the organism was given the name Cytoecetes phagocytophila to reflect its association with granulocytes and its morphological similarity with Cytoecetes microti. This name continued to be used by workers in the UK until the recent reclassification of the granulocytic ehrlichiae affecting ruminants, horses, and humans as variants of the same species, Anaplasma phagocytophilum. TBF and pasture fever are characterized by high fever, recurrent bacteremia, neutropenia, lymphocytopenia, thrombocytopenia, and general immunosuppression, resulting in more severe secondary infections such as tick pyemia, pneumonic pasteurellosis, listeriosis, and enterotoxemia. During the peak period of bacteremia as many as 90% of granulocytes may be infected. The agent is transmitted transtadially by the hard tick Ixodes ricinus, and possibly other ticks. After patent bacteremia, sheep, goats, and cattle become persistently infected "carriers," perhaps playing an important role in the maintenance of infection, in the flock/herd. Little is known about how efficiently ticks acquire and maintain infection in ruminant populations or whether "carrier" domestic ruminants play an important role as reservoirs of infection, but deer, other free-living ruminants, and wild rodents are also potential sources of infection. During the late 1990s serological evidence of infection of humans was demonstrated in several European countries, creating a renewed interest and increased awareness of the zoonotic potential of TBF variants. More recently, a few cases of human granulocytic anaplasmosis (HGA) have been reported in some European countries, but it remains to be established whether the variants causing HGA in Europe are genetically and biologically different from those causing TBF in ruminants. TBF is readily diagnosed by demonstrating intracytoplasmic inclusions in peripheral blood granulocytes or monocytes of febrile animals or by detecting specific DNA by polymerase chain reaction (PCR), and TBF variants of A. phagocytophilum can be cultivated in tick cell lines, but the differentiation of TBF variants from HGA variants awaits further investigations.

Clinical characteristics of Pneumocystis carinii pneumonia in patients with connective tissue diseases

The characteristics of Pneumocystis carinii pneumonia (PCP) in patients with connective tissue diseases (CTDs) were examined retrospectively. Nine patients were enrolled in this study. Their mean age was 57.1 years. All the patients received a high-dose steroid or immunosuppressant. The onset (mean 6.6 days) of fever, cough, breathlessness, and geographical ground-glass opacities revealed by chest computed tomography was acute. The serum beta-D: -glucan level increased with a simultaneous increase in the Krebs von den Lungen (KL)-6 or surfactant protein D level. The serum immunoglobulin G (IgG) and albumin levels and the peripheral blood lymphocyte count at the onset of PCP were low, but only the serum IgG level decreased significantly. The patients were treated with trimethoprim-sulfamethoxazole or pentamidine isetionate. Six patients died eventually: two patients of progressive respiratory failure, two probably due to a recurrence of the PCP, and two with microbial respiratory infections other than PCP. Five of the six patients required mechanical ventilation. Three patients received secondary prophylaxis and survived. In conclusion, the acute onset was characteristic of PCP in patients with CTDs. High-dose steroids, immunosuppressants, and hypogammaglobulinemia are risk factors; and respiratory failure requiring mechanical ventilation, severe secondary infections, and a lack of secondary prophylaxis are poor prognostic factors. Secondary prophylaxis is recommended for all of these patients.

Clinical characteristics of Pneumocystis carinii pneumonia in patients with connective tissue diseases

The characteristics of Pneumocystis carinii pneumonia (PCP) in patients with connective tissue diseases (CTDs) were examined retrospectively. Nine patients were enrolled in this study. Their mean age was 57.1 years. All the patients received a high-dose steroid or immunosuppressant. The onset (mean 6.6 days) of fever, cough, breathlessness, and geographical ground-glass opacities revealed by chest computed tomography was acute. The serum β-d-glucan level increased with a simultaneous increase in the Krebs von den Lungen (KL)-6 or surfactant protein D level. The serum immunoglobulin G (IgG) and albumin levels and the peripheral blood lymphocyte count at the onset of PCP were low, but only the serum IgG level decreased significantly. The patients were treated with trimethoprim-sulfamethoxazole or pentamidine isetionate. Six patients died eventually: two patients of progressive respiratory failure, two probably due to a recurrence of the PCP, and two with microbial respiratory infections other than PCP. Five of the six patients required mechanical ventilation. Three patients received secondary prophylaxis and survived. In conclusion, the acute onset was characteristic of PCP in patients with CTDs. High-dose steroids, immunosuppressants, and hypogammaglobulinemia are risk factors; and respiratory failure requiring mechanical ventilation, severe secondary infections, and a lack of secondary prophylaxis are poor prognostic factors. Secondary prophylaxis is recommended for all of these patients.

Antibodies against a truncated Staphylococcus aureus fibronectin-binding protein protect against dissemination of infection in the rat

Staphylococcus aureus bacteraemia (SAB) originating from local infections can lead to severe secondary infections such as endocarditis. The protective effect of antibodies against secondary infections was studied in a rat model, where a local joint infection leads to bacteraemia and endocarditis on damaged aortic valves. In this study, immunizations with a truncated D2-domain of the S. aureus fibronectin-binding protein displayed on a cow-pea mosaic virus (CPMV-D) carrier induced protection against endocarditis ( P<0.05). Opsonization of S. aureus with antibodies raised against CPMV-D stimulated both neutrophil activity and macrophage phagocytosis in vitro. Furthermore, intravenous administration of these antibodies protected mice from weight loss due to SAB.

Oro‐pharyngeal protozoa in captive bustards: Clinical and pathological considerations

An oro‐pharyngeal protozoal survey was carried out in captive bustards in the United Arab Emirates. .Endolimax spp., .Entamoeba gallinarum, Acanthamoeba spp., .Naegleria spp. and .Coccidia spp. were the protozoa isolated from the oro‐pharynx of clinically normal birds. The protozoa species involved in oro‐pharyngeal diseases were .Trichomonas gallinae and .Entamoeba anatis. Most of the protozoa observed in clinical cases were associated with severe secondary bacterial infections possibly due to the suppression of normal oro‐pharyngeal bacterial flora which includes .Escherichia coli, Enterobacter spp., .Klebsiella spp. and .Citrobacter spp. In this respect, .Pseudomonas spp., and .Staphylococcus spp., were isolated from individuals affected with oro‐pharyngeal diseases. In such cases, inflammatory changes in the oro‐pharynx were detected associated with white‐yellow caseous nodular lesions, mucous discharge, exfoliation of epithelial cells and the presence of inflammatory cells.

Retrovirus-like activity in an immunosuppressed dog: Pathological and immunological findings

A putative retrovirus was isolated from a dog with a severe, acquired immunodeficiency-like syndrome. The haematological abnormalities and immunological deficiencies included anaemia, leucopenia (lymphopenia and neutropenia), thrombocytopenia, decreased humoral immunity, and ineffective T-cell responses in-vitro. The necropsy findings included generalized lymphoid depletion, severe bone marrow hypoplasia, plasmacytic infiltrates in lymphoid and non-lymphoid organs, and severe secondary infections. Supernates of peripheral blood mononuclear cell cultures from the affected dog contained an agent with manganese-dependent reverse transcriptase (RT) activity that sedimented at a density of 1.122 g/ml. RT activity was also found post-mortem in extracts prepared from the bone marrow, lymph nodes, and small intestine. The lymph nodes and small intestine expressed a 3.8 kb mRNA that was recognized by a bovine leukaemia virus (BLV) pol DNA probe by Northern blotting. DNA isolated from the lymph nodes and small intestine from the affected dog showed distinct band patterns by Southern analysis, suggesting an exogenous retrovirus. The retrovirus could be propagated in normal canine peripheral blood mononuclear cells or short-term canine lymphocyte cell lines in-vitro, and was cytopathogenic for cells of canine, but not human, origin. These results suggest the existence of a pathogenic canine retrovirus capable of producing disease of the type associated with retroviruses in other species.

EPIDEMIOLOGY, CLINICAL FEATURES, AND PROGNOSTIC FACTORS OF PAEDIATRIC HIV INFECTION

486 children born to HIV-positive mothers, 57 children infected by blood products, and 1 child for whom the personal history was not available were studied. Perinatal infection had a more varied clinical picture and a worse outcome compared with infection acquired later in childhood. Severe secondary infections, neurological disorders, and hepatitis (but not lymphoid interstitial pneumonia) were linked to a high mortality rate in perinatally infected children, in whom an early onset of symptoms was also a bad prognostic factor. Perinatal HIV infection occurred in 32·6% of children born to seropositive mothers, with a higher transmission rate in children born by vaginal delivery and then breast-fed. Preterm delivery and low birthweight seemed to be related to drug abuse during pregnancy, not to intrauterine HIV infection. Girls had a higher rate of perinatal infection and, of those infected, had an increased mortality.

An evaluation of topical mupirocin in moderately severe primary and secondary skin infections.

Five days' treatment with topical mupirocin, applied twice daily, in 36 patients with moderately severe primary and secondary skin infections, resulted in resolution/much improvement of skin lesions in 75.0% of patients and bacterial eradication in 83.9% of cases. Penicillin-resistant and penicillin-sensitive staphylococci were most commonly implicated. No adverse effects were reported in any of the patients treated. Physicians' assessment of cure/improvement was recorded in 91.7% of patients.

Solid-phase radioimmunoassay of human immunoglobulin M and immunoglobulin G antibodies against herpes simplex virus type 1 capsid, envelope, and excreted antigens

A solid-phase radioimmunoassay developed in our laboratory for detection of human viral immunoglobulin M (IgM) and IgG antibodies was applied to demonstrate human class-specific antibody response against capsid, envelope, and excreted antigens of herpes simplex virus type 1. In primary infections, a clear IgM and IgG antibody response was found predominantly against the envelope components, whereas the IgM and IgG antibodies to the capsid antigen appeared more slowly. Increasing IgG antibody titers to the excreted antigen were also found in primary infections, though appearing more slowly than antibodies to the other subunit antigens. The antibody response against capsid and envelope antigens was not type specific, whereas in primary infections IgG class antibodies against the excreted antigen showed distinct type specificity. In recurrent infections, no significant level of IgM class antibodies was demonstrated, but in the patients with a severe secondary herpes simplex virus infection a definite IgM class antibody response was found against the envelope antigen. In addition, during severe secondary infections the antibody response against the excreted antigen was enhanced. The host IgG antibody response in recurrent infections was directed against the envelope and excreted antigens, whereas the level of the capsid antibodies was relatively stable.