Human parechoviruses (HPeVs) are newly recognized single-stranded RNA viruses that were formerly classified in the Enterovirus genus1). Among 16 HPeV serotypes, HPeV-3 infection occurs most frequently among infants below the age of 3 months2). Since HPeV-3 was first isolated in Japan in 19991), the HPeV serotype has been increasingly identified as an important pathogen of sepsis-like illness and central nervous system infections in neonates and young infants3). Life-threatening illnesses such as hemophagocytic lymphohistiocytosis have been reported in neonatal HPeV-3 infection4). However, the major clinical features displayed by patients with HPeV-3 infection are also common in those suffering from severe infectious diseases caused by other pathogens5). Thus, the diagnosis of HPeV-3 infection is difficult based only on clinical signs.

Recent studies have reported several clinical findings that are characteristic of HPeV-3 infection4678). Clinical features such as palmar-plantar erythema and hyperferritinemia might be diagnostic indicators of an HPeV3 infection in febrile neonates and young infants67). This report describes 2 young infants with an HPeV3 infection who presented with a prolonged fever, palmar-plantar erythema, and hyperferritinemia (>500 ng/mL). These cases may enhance our understanding of the unique features of HPeV-3 infection in young infants.

Streptococcus equi subspecies equi is the causative agent of strangles, a highly contagious upper respiratory tract infection of horses. Typical clinical signs of disease include fever, inappetance, lethargy, submandibular or retropharyngeal lymphadenopathy or purulent drainage, or purulent nasal discharge. Complications of S. equi infection can occur and include airway obstruction from lymphadenopathy, disseminated abscesses from hematogenous spread, or purpura hemorrhagica and various diseases caused by immune‐mediated processes.1, 2, 3, 4, 5

Streptococcus equi M protein (SeM) antibody titers are typically measured to determine if a horse has developed a complication of strangles, such as purpura hemorrhagica or metastatic abscess formation, or to determine if a horse is at risk of purpura hemorrhagica if they were to be vaccinated. Both the 2005 and 2018 American College of Veterinary Internal Medicine consensus statements on strangles state that a very high titer (≥1:12 800) is associated with metastatic abscess formation or purpura hemorrhagica and that high titers (1:3200‐1:6400) are detected 4‐12 weeks after infection.1, 2 Anecdotally, horses can have high titers (≥1:12 800) 4‐8 weeks after infection and no signs of complications (authors' personal observations, KMD, LAB, ACT). The objective of this study was to measure SeM antibody titers on horses after outbreak to determine if titers detect the presence of complications.2 An additional objective was to follow SeM antibody titers out to 7 months after infection to determine immunoglobulin decay and to monitor for development of additional complications. We hypothesized that the magnitude of SeM antibody titer after infection (SeM titer ≥1:12 800) will be useful to monitor for the presence of complications or for the risk of development of complications.

Human cytomegalovirus (CMV) is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. Primary infection by CMV is usually asymptomatic as the intact immune system limits active viral replication effectively. Initial infection by CMV can rarely cause a self-limiting mononucleosis-like illness associated with fever, fatigue, myalgias and hepatosplenomegaly. However, CMV is capable of multiple immune evasion mechanisms and complete eradication of the virus may not be achieved. Instead, the virus remains quiescent within endothelial cells, stem cells of the bone marrow and peripheral blood monocytes, establishing a lifelong latent infection. The seroprevalence of CMV varies greatly between races and population groups. Older age, low socio-economic status, lower education levels and HIV-infection were most commonly associated with greater CMV seroprevalence.

When the immune system is suppressed, latent CMV can reactivate and replicate rapidly. This can result in high levels of CMV viremia and infection of multiple organ systems. The populations who are most at risk of CMV infection are the individuals with active haematological malignancies, HIV infection, recipients of hematopoietic stem cell transplant or solid organ transplant and individuals on significant immunosuppressive therapy for autoimmune disorders and connective tissue disease. CMV infections are also increasingly recognised amongst critically ill patients in intensive care units, the majority of whom are immunocompetent prior to illness.

In the advanced stages of HIV infection, T-Helper cell function is impaired and there is a decline of the adaptive immune response which is crucial to CMV disease control. Prior to the use of highly active antiretroviral therapy (HAART), the prevalence of CMV opportunistic infection (OI) in acquired immune deficiency syndrome (AIDS) was very high. Up to 90% of patients with AIDS were found to have evidence of disseminated CMV infection at time of autopsy.

The predominant manifestation of CMV in HIV-infection is CMV retinitis, affecting up to 40% of patients and accounting for 85% of all CMV related complications [[10],,]. The other organs that are affected by CMV disease in AIDS include the gastrointestinal tract, peripheral and central nervous system, liver, kidneys, adrenals and lungs.

The advent of HAART in the 1990s has resulted in a substantial decrease in incidence of severe OI caused by CMV in AIDS. CMV OI typically occurs in individuals presenting with AIDS-defining illness and possessing a CD4 lymphocytes count of below 100/μl. In a large epidemiological study of AIDS-defining opportunistic OI from 18,733 HIV-infected residents diagnosed from 1993 to 2008, only 0.6% had CMV infection as the initial OI and there were nil reports on CMV pneumonia.

Herein, we describe a very rare case of CMV pneumonia and review the literature on diagnosing this rare clinical entity in HIV-infected patients.

6.What are the most common clinical findings of FeL due to L. infantum?

Detailed case reports of FeL have been available in recent years mainly from European countries where pet cats typically have a higher standard of health care. In the New World, other Leishmania spp. are endemic and may co-infect cats and complicate the clinical picture. Therefore, we have only reviewed case reports or case series originally from European countries. A total of 46 clinical cases have been published between 1989 and 2014, where the diagnosis of FeL was confirmed by serological and/or parasitological methods [11–14, 21, 26, 36, 37, 50–67].

The most common clinical signs reported in FeL include skin or mucocutaneous lesions and lymph node enlargement, and they have been described in more than half of the cases (Table 4). Some cats showed only dermatological lesions alone [13, 52, 56, 58], while others with skin lesions showed a combination with systemic signs [12, 14, 21, 26, 36, 51, 60, 62–64, 68]. Conversely, other cats did not have any skin detectable lesions on clinical presentation [11, 36, 50, 54, 55, 57, 66, 69, 70].

The cutaneous and mucocutaneous lesions are described in Question 7. Lymphadenomegaly may be solitary or multicentric. Ocular lesions have been reported in approximately one third of the affected cats. Uveitis, either unilateral or bilateral (Fig. 1), is the most common ocular lesion described, with occasionally a pseudotumoral granulomatous pattern and eventually progress to panophthalmitis [50, 53, 55, 64, 69]. Blepharitis and conjunctivitis have also been described in a number of clinical cases [66, 68, 70]. Amastigotes have been found by cytology in conjunctival nodules, corneal infiltrates and aqueous humor, and by histopathology after enucleation of the eye or post mortem even in uveal tissue [50, 53, 55, 64, 69]. Chronic gingivostomatitis is also a common clinical finding and has been found in about one fourth of the cats so far studied with leishmaniosis (Fig. 2) [11, 26, 53, 55, 63, 66, 70]. Nodular lesions are unfrequently seen on the gingival mucosa or the tongue [60, 66, 69, 71], where infected macrophages may be visualized in lesion biopses [60, 69].

Non specific signs such as weight loss, reduced appetite, dehydration, and lethargy also have been reported. A list of other sporadic clinical manifestations described includes: pale mucous membranes, hepatomegaly, jaundice, cachexia, fever, vomiting, diarrhea, chronic nasal discharge, splenomegaly, polyuria/polydipsia, dyspnea, wheezing, abortion and hypothermia.

The implication of Leishmania as a cause of some of these clinical signs has been associated with the presence of the parasite in cytological or histopathological examinations of liver, spleen, lymph nodes, stomach, large bowel, kidney, oral mucosa, nasal exudate and eye tissues [13, 14, 36, 50, 57, 63, 66, 68, 72]. However, clinical disease is commonly associated with an impaired immunocompetence due to several causes including retroviral infections (FIV and FeLV), immunosuppressive treatment and concomitant debilitating diseases such as malignant neoplasia or diabetes mellitus.

As also found in dogs, FeL does not exclude the possibility of concurrent diseases or co-infections. This fact may influence the clinical presentation and prognosis. The cause-effect relationship between various etiological and pathogenic factors is not always easy to establish.7.What are the most common dermatological findings of FeL due to L. infantum and to other Leishmania species?

Cutaneous lesions predominate in the clinical picture of FeL due to L. infantum. Dermal abnormalities include nodules, ulcerations or more rarely exfoliative dermatitis. They are generalized or localized, symmetrical or asymmetric and may, though less frequently, appear all over the body in a focal, multifocal, regional or diffuse pattern [12–14, 26, 36, 37, 51, 52, 56, 58, 60, 62, 64, 68, 70]. Some cats may harbour different types of skin lesions at the same time or develop them subsequently; they may coexist with mucocutaneous lesions (Fig. 3). Cutaneous and mucocutaneous nodules, of variable size, are more often localized on the head, including eyelids, nose and lips, or on the distal parts of the limbs. Nodules have also been reported in the anal mucosa and they are usually small (less than 1 cm), non painful or pruritic and have a normal, ulcerated or alopecic surface [26, 50, 51, 56, 60, 62–64, 66, 68, 70].

Ulcerations which may be diffuse and superficial or focal and deep (Fig. 4) are localized on the same body sites as nodules, and may be complicated by bacterial infections that explain why they are covered by hemorrhagic crusts and/or purulent material [13, 14, 52, 53, 56, 58, 60–62, 64, 65, 68, 70]. However, ulcerative dermatitis is sometimes diffuse and can be observed on the body trunk or on bony prominences [14, 36, 58, 62, 63].

In contrast to CanL, exfoliative dermatitis (Fig. 5) is rare in the feline disease [36, 52, 68]. Other uncommon dermatologic presentations include hemorrhagic papules and nodules where Leishmania amastigotes can be found [37, 52]. Alopecia (Fig. 6), which is also uncommon in FeL [12, 36, 52, 62, 64], may be associated with other skin diseases concurring in L. infantum infected cats such as demodicosis. Mild to severe pruritus is rare in FeL [58, 64, 65] and in some cases with a pruritic syndrome other compatible causes co-existed such as flea allergy, pemphigus foliaceus (PF) or neoplasia (squamous cell carcinoma).

Clinical disease caused by natural infection with species other than L. infantum is typically reported as nodular or ulcerative dermatitis with no systemic clinical signs. Skin lesions are often single but they can metastatize (Table 5) [73–76].8.What are the most common dermatopathological features of FeL?

Skin histopathology of lesions associated with L. infantum has shown that the most commonly observed alteration is a granulomatous dermatitis [26, 51, 56, 59, 60, 68]. It often has a diffuse pattern and the epidermis may present hyperkeratosis, acanthosis and ulceration [56, 68]. A nodular to diffuse arrangement of the granulomatous dermatitis is also reported [26, 60]. However, in a retrospective case series from Spain, two cats presented different histological findings. The first one had granulomatous perifolliculitis with a high number of lymphocytes and plasma cells surrounding the cutaneous adnexa. It was associated with a marked hyperplasia of epidermis and sebaceous glands. The other cat was diagnosed with a lichenoid interface dermatitis typically represented by infiltration of lymphocytes, plasma cells and a few neutrophils and macrophages at the dermoepidermal junction. In this case, epidermal necrosis and epidermal microabscesses were also observed. A perivascular infiltration of superficial skin layers by macrophages, mast cells, neutrophils and eosinophils was also observed in another case.

Leishmania amastigotes have always been identified in the affected skin. A semiquantitative estimation of amastigotes was also performed with the aid of immunohistochemistry (IHC), in which the parasitic load of the skin ranged from high (>50 immunolabelled amastigotes/field at x400) to moderate (10–50 immunolabelled amastigotes/field) in cases of diffuse granulomatous dermatitis. Conversely, it was low (1–9 immunolabelled amastigotes/field) in cases of granulomatous perifolliculitis or lichenoid interface dermatitis .

In biopsy samples taken from cases with ulcerative dermatitis, eosinophilic granulomatous dermatitis with a severe dermo-epidermal necrosis were found without the presence of amastigotes, but with a positive quantitative Leishmania PCR.

In some FeL cases, other dermatological diseases such as eosinophilic granuloma and PF were also diagnosed [52, 56, 68].

Interestingly, amastigotes were also found associated with neoplastic tissue in the lesion of two cats with squamous cell carcinoma (SCC). In one other case, SCC was diagnosed in a cat presenting concurrent Leishmania skin lesions [14, 59].

In two cases of skin disease caused by L. braziliensis, a mononuclear and neutrophilic inflammatory infiltrate of the dermal tissue was seen in histological sections.9.What are the most common differential diagnoses in L. infantum endemic areas for dermatological features?

The commonly seen cutaneous nodular form in FeL cases should be distinguished from nodules caused in cats with cryptococcosis, sporotrichosis, histoplasmosis, sterile or eosinophilic granuloma, mycobacterioses, and a wide variety of cutaneous neoplasms (e.g. feline sarcoids, mast cell tumor, fibrosarcoma, basal cell carcinoma, bowenoid in situ carcinoma and lymphoma). The main differentials of the ulcerative lesions include squamous cell carcinoma with which however it may co-exist [13, 14, 59], idiopathic ulcerative dermatitis, indolent ulcer, mosquito-bite dermatitis, atypical mycobacteriosis and feline leprosy, cutaneous vasculitis, erythema multiforme and cold-agglutinin disease. Finally, skin diseases such as dermatophytosis, systemic or cutaneous lupus erythematosus, exfoliative dermatitis due to thymoma or due to immune-mediated pathomecanisms, PF, sebaceous adenitis/mural folliculitis complex and paraneoplastic alopecia could be included in the differential list of those leishmanial cats that are admitted with the rare exfoliative/crusting dermatitis which may also be alopecic and erythematous. It has been postulated that PF and FeL may share a common pathomechanism (molecular mimicry) when they co-exist in the same cat.10.What clinicopathological findings may alert the clinician to the possibility of FeL due to L. infantum?

Limited information is available about clinicopathological abnormalities in cats and it is only based on case reports. Mild to severe normocytic normochromic non-regenerative anemia is the most frequent haematological abnormality reported in clinical cases. Moderate to severe pancytopenia may be observed [37, 50, 57] in association with aplastic bone marrow, but some of the cats reported with pancytopenia were FIV positive [37, 50, 57]. Curiously, in one of these cases, amastigotes were found in 4 % of neutrophils in buffy coat smears.

Hyperproteinemia with hypergammaglobulinemia is a common finding in FeL as also found in dogs, and hypoalbuminemia is occasionally reported [37, 50].

Renal proteinuria and increased serum creatinine are also reported at diagnosis or during follow-up in some cases [37, 68].

Relative lymphocytosis and an increase in serum ALT activity were significantly associated with seroreactivity to L. infantum.

The type of inflammatory infiltrate found in tissue cytology (aspirates, impression smears) or histopathology in organs such as skin, eye, oral mucosa, liver, spleen and kidney is commonly pyogranulomatous to granulomatous [66, 68, 72]. There was also lymphoid reactive hyperplasia in lymphoid organs such as lymph nodes and spleen, with variable numbers of Leishmania amastigotes observed (Fig. 7).11.What are the most common differential diagnoses in endemic areas for systemic illness caused by L. infantum in cats?

As lymph node enlargement is the most common sign, apart from skin and mucocutaneous lesions, FeL should be included in the differential list when this finding is noted on physical examination as solitary or generalized lymphadenomegaly. This list mainly includes infections with other infectious agents (FIV, FeLV, FCoV, Bartonella, Mycobacteria, T. gondii, Cryptococcus or other systemic mycoses), lymphoma or metastatic involvement from other neoplasia.

FeL should also be considered in cats with ophthalmologic disease, mainly in cats with acute, recurring or chronic uveitis and differentiated from similar clinical conditions caused by FIV, FeLV, FCoV, Bartonella, T. gondii, fungal infections, neoplasia or paraneoplastic syndrome. Some feline uveitis cases are considered idiopatic and treated with corticosteroids. A diagnosis of idiopatic uveitis was initially made in some cases of ocular FeL and corticosteroids worsened the disease [50, 55, 69]. This fact warrants a careful investigation to exclude FeL before treating ocular disease with corticosteroids.

Proliferative and ulcerative chronic inflammation of the oral mucosa associated with FeL can be included in the list of possible causes of the feline chronic gingivostomatitis syndrome (FCGS). This painful and common immune-mediated disease is considered multifactorial in cats and treated by full mouth teeth extraction for eliminating oral plaque antigenic stimulation. Corticosteroids are frequently used to improve the clinical signs; however, when this was tried in some cats with oral disease associated with L. infantum infection it induced worsening of FeL [11, 66].

Hyperglobulinemia with increased gammaglobulin level reported in FeL is usually found in chronic infections caused by viruses, bacteria or systemic fungi, or inflammation associated with FCGS or inflammatory bowel disease, or in neoplasia such as lymphoma, or multiple myeloma.

avium subspecies hominissuis’ infection in a domestic

cat

Various studies have been carried out to find out the etiology of Kawasaki disease (KD). Viral infection is thought to be one of the causes of KD, but it is still controversial1234). Although several potential viral causes of KD are identified, the diagnosis of KD with concomitant viral infection is a little unclear to confirm KD.

Adenoviral infection is frequently involved in young children less than 3 years and is characterized with prolonged high fever, upper and lower respiratory tract symptom, conjunctivitis and gastrointestinal symptom with hepatic involvement. Inflammatory biomarker such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are mostly elevated in patients with adenoviral infection. Because of strong inflammatory response, adenoviral infection closely resembles bacterial infection and KD5678). Although the majority patients of adenoviral infection presented respiratory condition, extrapulmonary manifestation of conjunctivitis, skin rash, mucous membrane changes, cervical lymphadenopathy and encephalitis can be associated. The various clinical manifestation of adenovirus infections are particularly similar to KD regarding the clinical aspects910111213).

A recent study demonstrated the distinction of clinical and virologic characteristics of adenoviral infection differentiating from KD with incidental adenoviral detection14). Because of clinical similarities, early and acute diagnosis and intravenous immunoglobulin (IVIG) therapy are essential to prevent coronary artery abnormalities in KD. The aim of this study is to compare the clinical and laboratory characteristics of KD patients with adenovirus detection and those with only adenoviral infection and to identify biomarkers that can differentiate KD from adenovirus infections at the initial hospitalization stage. In addition, we also assessed the clinical and laboratory distinction of KD with adenovirus from KD without adenovirus infection.

A 42-day-old male neonate was admitted to Gyeongsang National University of Hospital due to high fever and irritability. He was born at full-term gestational age at a weight of 3,200 g, and he was thriving until this hospital visit. Localized symptoms were not detected, and the results of a physical examination were unremarkable. His healthy older sister was reported to have had a recent febrile respiratory infection. The patient's initial vital signs were as follows: blood pressure 80/50 mmHg, heart rate 168 beats/min, respiratory rate 38 breaths/min, and body temperature 38.8℃. The laboratory findings at admission were as follows: hemoglobin, 9.0 g/dL; white blood cell (WBC) count, 1,990/mm3; absolute neutrophil count, 670/mm3; platelet count, 390×103/mm3; aspartate aminotransferase (AST), 42 U/L (range, 22–63 U/L); alanine aminotransferase (ALT), 23 U/L (range, 12–45 U/L); γ-glutamyl transferase (γ-GT), 36 U/L (range, 12–123); creatine kinase (CK), 147 U/L (range, 5–130 U/L); lactate dehydrogenase (LDH), 283 U/L (range, 170–580 U/L); ferritin, 385 ng/mL (range, 0–400 ng/mL); protein, 5.5 g/dL (range, 4.6–7.4 g/dL); albumin, 4.0 g/dL (range, 1.9–5.0 g/dL); and C-reactive protein (CRP), 0.5 mg/L (range, <7.9 mg/L). No cerebrospinal fluid (CSF) pleocytosis or pyuria was observed. Cefotaxime and ampicillin/sulbactam were administered.

No bacteria were found in blood, CSF, or urine samples. HPeV-3 was detected in CSF and serum samples by reverse transcription polymerase chain reaction (PCR) as described in our previous study9). CSF PCR tests were negative for herpes, enterovirus, cytomegalovirus, Epstein-Barr virus, and HPeV1. In addition, we found no respiratory viruses such as adenovirus, coronavirus, parainfluenza virus, rhinovirus, respiratory syncytial virus, influenza virus, bocavirus, and metapneumovirus. High fever and irritability persisted. At day 5 of admission, an erythematous rash and swelling were observed on the patient's hands and feet. The laboratory findings were as follows: hemoglobin, 8.7 g/dL; WBC count, 3,930/mm3; absolute neutrophil count, 260/mm3; platelet count, 160×103/mm3; protein, 4.4 g/dL; albumin, 2.9 g/dL; AST, 658 U/L; ALT, 162 U/L; γ-GT, 147 U/L; CK, 321 U/L; LDH, 1,324 U/L; ferritin, 2,581 ng/dL; and CRP, 0.3 mg/dL. Intravenous immunoglobulin (IVIG) was administrated because severe systemic inflammatory responses were considered in the patient. After IVIG treatment, the patient's fever subsided gradually and the erythematous rash disappeared. The patient was discharged on day 8 of admission.

Kawasaki disease (KD) is an acute systemic vasculitis mostly affecting children younger than 5 years old. It is the most important cause of acquired heart disease in children in developed countries. Concomitant respiratory viral infections have been described in 8–42% of patients, and bacterial infections were found in 33% of patients [2–8]. The clinical presentation of patients with and without concomitant infection is similar. In one study, bacterial co-infection alluded to a trend towards a higher rate of resistance to intravenous immunoglobulin (IVIG), without reaching statistical significance (26% vs 15%, odds ratio 1.77 (95% confidence interval 0.71–4.41)). The accepted definition of IVIG resistance is based on the persistence or recrudescence of fever 36 hours after the end of IVIG infusion. However, it is unclear how concomitant infection influences the resolution of fever and response to IVIG treatment. The aim of this study was to determine the impact of concurrent infection on the prevalence of IVIG resistance and coronary outcome.

Because results of bacterial culture and antimicrobial susceptibility testing from specimens collected from the nasal cavity are difficult to interpret, monitoring the efficacy of treatment of cats with suspected chronic bacterial URI is usually based on clinical signs of disease.

Systemic inflammation (SI), as indicated by clinical signs such as fever and increased respiratory and heart rates, can be due to a variety of underlying non-infectious or infectious causes including trauma, thermal burns, surgery, ischemia-reperfusion events and viral or bacterial infections. Patients presenting with SI can pose a diagnostic challenge for clinicians in determining the underlying etiology; consequently it can be difficult to select the most appropriate options for treatment and patient management1–5. There is a clinical need for rapid diagnostic tests that can help clinicians distinguish between non-infectious, viral and bacterial etiologies of SI in (critically ill) patients. Without such tests, patients may be over-prescribed antibiotics when there is little clinical evidence of infection4, 6. Reducing inappropriate and unnecessary use of antibiotics, the concept of antibiotic stewardship, is essential in slowing the spread of resistant bacteria7.

Traditional reference methods for determining bacterial or viral causes of SI involve the culture, isolation and identification of causative pathogens from multiple specimens from a patient. Such an approach, however, has several limitations: (i) the causative pathogen might not be present in the specimens taken for examination; (ii) the specimens may become contaminated by organisms unrelated to the cause of infection; (iii) multiple organisms may be present in the specimens (e.g. due to contamination or non-harmful microbiota) and it can be difficult to determine which organism is the cause of the presenting clinical signs8–10. Furthermore, (iv) some sampling techniques (e.g. bronchoalveolar lavage, lumbar puncture) are relatively invasive. Finally, (v) some pathogens are not easily cultured. Although traditional culture-based methods are steadily being supplemented or displaced by immunological and molecular methods such as rapid immunoassays and polymerase chain reaction (PCR)11, 12, these newer methods also suffer from limitations, for example: (i) an inability to detect organisms not represented in an immunoassay or PCR panel; (ii) an inability to discriminate between live and dead organisms in a specimen; and (iii) a tendency to detect low levels of virus that may not be clinically relevant13.

Given these limitations, increasing attention is being paid to an alternative approach: that of identifying biomarkers that reflect the differential host response to underlying non-infectious, bacterial, or viral conditions14–23. Our current investigation builds upon and extends previous host biomarker studies by identifying a molecular signature that is demonstrably specific to SI caused by a broad range of pathogenic viruses that represent all seven Baltimore virus classification groups and that cause infection in different tissues in multiple mammalian species. We used, as a discriminating function, the Area Under Curve (AUC) in Receiver Operating Characteristic Curve (ROC) analysis, and boosted specificity by employing a filtering step in our discovery process whereby biomarkers with high AUCs for non-viral causes of SI were removed. Independent validation of the signature in adult and pediatric cohorts demonstrated a strong discrimination of viral vs. non-viral causes of SI. Notably, this viral signature relies on only four biomarkers, and this high degree of parsimony should help to ensure the performance robustness necessary for effective translation to a rapid point-of-care format.

Hemotropic mycoplasmas (the so-called hemoplasmas) are small wall-less bacteria that attach to the erythrocytes, causing anaemia in different mammalian species, including cats. Three hemoplasma species have been typically detected in cats: Mycoplasma haemofelis (Mhf), “Candidatus Mycoplasma haemominutum” (CMhm) and “Candidatus Mycoplasma turicensis” (CMt). Another species, “Candidatus Mycoplasma haematoparvum-like”, has also been reported in cats [5–7]. Although these bacteria are distributed worldwide, the prevalence varies geographically [7–11].

It is still unknown how feline hemoplasmas are transmitted. Vector transmission through fleas [12–16] or ticks [17, 18] has been suggested, but direct transmission through aggressive interactions or blood transfusion have also been hypothesized as potential sources of infection.

Clinical presentation varies from absence of clinical signs to the existence of acute haemolytic anaemia, showing the affected cats pallor, depression, lethargy, weight loss, anorexia, dehydration and intermittent pyrexia or even sudden death. In this sense, Mhf seems to be the most pathogenic of the three main feline hemoplasmas. The clinical presentation can vary depending not only on the pathogenicity of the haemoplasma species, but also on host factors, such as the presence of concurrent disease. Younger cats are more susceptible to clinical haemoplasmosis. Other factors such as infecting organisms’ dose or route of infection may also impact on outcome.

There are just a few studies reporting hemoplasma infection in cats in Spain [9, 20, 21] and, to our knowledge, no epidemiological studies on these bacteria have been performed in the central region of the country. The objective of this study was to determine the prevalence of feline hemoplasmas (Mhf, CMhm and CMt) in cats from Madrid, central Spain, and to characterize risk factors and clinical signs associated with these feline infections in the area.

CMV is a very rare cause of pulmonary OI in the setting of HIV-infection. CMV pneumonia should be carefully evaluated amongst patients with AIDS who are critically ill and not responding to treatment of other diagnosed pulmonary infections. The diagnosis of CMV pneumonia can only be made with consistent clinical, radiological, microbiological and cyto-histopathologic features. A high degree of clinical vigilance for this rare clinical entity must be maintained as prompt treatment with anti-CMV therapy is effective and can augment clinical recovery.

Acute respiratory infection is a major cause of morbidity, hospitalization, and mortality with a worldwide disease burden estimated at 113 million disability-adjusted life years and 3.5 million deaths. Respiratory infection is caused by various pathogens, but approximately 80% of cases are viral. Because respiratory viral infection is characterized by a wide range of similar respiratory symptoms, it is difficult to make an etiologic diagnosis based solely on observable symptoms.

Recently, widespread use of multiplex reverse transcription polymerase chain reaction (RT-PCR)-based methods has greatly improved the diagnostics for respiratory viral infections. It provides a more accurate diagnosis of causative pathogens and a better understanding of the etiology of infection. However, most epidemiologic investigations of respiratory virus infections have focused on children, and few studies have been conducted with an adult population. Yet, understanding the etiologies and clinical profiles of respiratory viral infections are essential for improving preventive and therapeutic strategies.

Here, we report a retrospective observational study that describes the viral etiologies of acute respiratory infections in children and adults and the clinical features of respiratory viral infections for adults.

Inflammation of the lungs (pneumonia) can occur after a variety of insults. In dogs and cats, although uncommon, primary bacterial pneumonia can occur after infection with B. bronchiseptica, Mycoplasma spp., S. equi zooepidemicus, S. canis, and Yersinia pestis.61, 62, 63, 64, 68

,

78, 79, 80 Of 65 puppies <1 year of age with “community acquired” pneumonia in the United States, 49% were infected with B. bronchiseptica.80 Dogs with B. bronchiseptica infection were younger and had more severe disease than dogs from which other bacteria were cultured. Most cases of bacterial pneumonia in dogs and cats are secondary to other primary inflammatory events like viral infections or aspiration of oral, esophageal, or gastric contents during vomiting or regurgitation (commonly associated with megaesophagus), after aspiration because of pharyngeal or laryngeal function abnormalities, during anesthesia recovery, and after inhalation of foreign bodies.81, 82, 83 In addition, bacterial pneumonia can develop in the presence of immunodeficiency syndromes. Secondary bacterial pneumonia potentially could develop as a result of other pulmonary or airway diseases like neoplasia, ciliary dyskinesia, bronchiectasis, and collapsing airways.

Common organisms isolated from dogs and cats with lower respiratory disease include E. coli, Pasteurella spp., Streptococcus spp, B. bronchiseptica, Enterococcus spp., Mycoplasma spp., S. pseudintermedius and other coagulase‐positive Staphylococcus spp., and Pseudomonas spp.78, 79, 80, 84, 85, 86, 87

The Zika virus, discovered in Uganda in 1947, was shown to be endemic through Sub-Saharan Africa and tropical areas of Southeastern Asia in studies through the second half of the 20th century. Isolated outbreaks occurred in Yap Island in 2007 and on French Polynesia in 2014. Starting in mid-2015, Zika virus infection achieved epidemic status, spreading rapidly through South America, Central America, and the Caribbean Islands. It was soon recognized that Zika virus infection occurring during pregnancy caused microcephaly and other congenital disorders in the developing fetus, the latter being the primary reason for the World Health Organization (WHO) labelling Zika as an international threat in early 2016. Beginning in late 2015, numerous academic labs and pharmaceutical companies initiated work to develop a vaccine against Zika, however, by the time the first vaccines entered clinical trials, the Zika epidemic had started to wane creating significant challenges to vaccine assessment that has engendered discussion of other regulatory pathways to licensure.

In this paper, we provide a brief update of current progress in Zika virus vaccine development and explore the challenges to vaccine assessment and eventual licensure.

Human bocavirus (HBoV) (genus Bocavirus, family Parvoviridae) has been recently identified in children with respiratory tract infection (RTI), first in Sweden, and subsequently in different parts of the world [2–10]. However, most studies so far have only retrospectively studied virus prevalence and only a few have addressed whether HBoV infection is associated with respiratory disease symptoms.

The aim of the present study was to define the epidemiological profile and the clinical characteristics associated with HBoV in hospitalized children with respiratory tract infection (RTI) in Greece.

On January 9 2020, the World Health Organization (WHO) declared the identification, by Chinese Health authorities, of a novel coronavirus, further classified as SARS-CoV-2. This new virus, initially emerged in the Chinese city of Wuhan in December 2019, led to a sharply spreading outbreak of human respiratory disease (COVID-2019), both within People’s Republic of China and in several other countries worldwide. On March 9 2020, WHO declared COVID-19 a global pandemic. Currently, Italy is the second most affected country by COVID-19 infection after China. The first autochthonous infection case was confirmed in Italy on February 21 2020 and up to now (March 12), 12462 cases with 827 deaths have been registered in Italy. Considering the recent evolution of Italian epidemiologic picture, many health-care facilities will be likely in charge of managing patients affected by COVID-19 in the next days. The “L. Spallanzani” National Institute for the Infectious Diseases, IRCCS has been the first Italian hospital to admit patients affected by COVID-19. Therefore, it will be useful to share the protocol for the clinical management of COVID-19 confirmed cases, applied within our Institute, in order to support other facilities that may have a limited experience in treating COVID-19 patients.

Procedures described in the present document are applied in agreement with the “Regional Network for the Infectious Diseases”, the “Regional Hospital and Medical Specialties Network” and with the active cooperation of the “Regional Agency for the Health Emergencies – ARES 118”. This latter is in charge for the response to the territorial health emergencies and for the transport of patients within the hospital network. Recommendations described within this document are based on very limited clinical evidences. Consequently, they should be considered as expert opinions, which may be modified according to newly produced literature data.

a. A person with an acute respiratory infection (defined as acute onset of at least one of the following sign/symptoms: fever, cough, respiratory difficulty breathing)

and without another etiology which completely explains the clinical presentation

and history of travels/stay in countries where there has been documented local transmission* within the 14 days preceding symptoms onset

OR

b. A person with an acute respiratory infection

and

history of close contact with a probable or confirmed COVID-19 case in the within the 14 days preceding symptoms onset

OR

c. A person with a severe respiratory infection (fever and at least one sign/symptom of respiratory disease e.g. cough or difficulty breathing)

and

who require hospital admission

and

another etiology which completely explains the clinical presentation

In the setting of primary care/AE department in countries/areas where autochthonous transmission has been observed, all patients with sings/symptoms of acute respiratory infection should be considered as suspected cases.

*According to WHO reports available at: https://www.who.int/emergencies/diseases/ novel-coronavirus-2019/situationreports/

15.What is the prognosis of clinical leishmaniosis ?

Some consideration can be extrapolated from information reported on 14 cats affected by FeL and followed up until death or euthanasia. On the basis of these reported cases, prognosis appears to vary from good to poor. In fact, five cats died a few days or weeks after diagnosis [12, 26, 36, 37, 65]. Some were affected by chronic renal failure or hepatic disease, but the real influence of Leishmania infection on mortality was not clearly demonstrated in these cases [36, 37, 65]. In other cases, euthanasia was performed after diagnosis because of a rapid clinical worsening [54, 57, 62] or due to a concurrent neoplasia. Post mortem evaluation was obtained in three cats that died or were euthanized shortly after diagnosis, and all of them had visceral dissemination of Leishmania amastigotes found in the spleen, lymph nodes, liver, stomach or in the large bowel [13, 36, 57].

Records of a long-term follow up (13–60 months) are available for nine cats and in four of the cases they were followed up until death or euthanasia [11, 37, 50, 56, 60, 66, 69, 70]. Their age ranged between 5 and 12 years at diagnosis and only one had been found positive for FIV antibodies. Clinical presentation varied but visceral dissemination of Leishmania infection was investigated and confirmed in all but one case. This latter cat had a diagnosis of PF associated with Leishmania infection confirmed by serology and PCR on skin biopsies, but the potential extra-cutaneous dissemination of infection was not investigated. Four of these followed up cats were treated with allopurinol for 24–40 months [37, 50, 56, 66].

It is noteworthy that three cats which were never treated with anti-Leishmania drugs after diagnosis died or were euthanized 1–5 years later and one was reported alive after 4 years. In these untreated cases, FeL progressed with time and chronic renal disease developed in two cats that were not treated. Untreated ocular FeL may cause vision loss and may require ocular enucleation due to panophthalmitis [50, 53, 55, 68, 69].

The retrospective evaluation of single case reports did not provide clear evidence about the prognosis of FeL because the clinical data available are heterogeneous and sometimes incomplete; however, some conclusions can be inferred. Both treated and untreated cats may live for years before the deterioration of their health status mainly due to renal and heart injuries that might be unrelated to L.infantum infection. The exact role of L. infantum infection in the development of multiorgan injury causing renal, cardiac or hepatic disease has to be confirmed. However, it can significantly influence life expectancy and any concurrent diseases should be treated if detected. In case of renal disease, the International Renal Interest Society (IRIS) staging system is recommended for therapy, follow-up and prognosis (http://www.iris-kidney.com).

Bovine respiratory syncytial virus (BRSV) is an important respiratory pathogen in cattle, detrimentally affecting the economy and animal welfare. The virus is distributed worldwide and is a major pathogen of the bovine respiratory disease complex [1, 2]. Viral respiratory infections are also of concern with regards to antibiotic resistance, as they predispose cattle to secondary bacterial infections that are commonly treated with antibiotics. Bovine respiratory disease is traditionally handled with management measures, vaccination and metaphylactic antibiotic treatment. Another possible strategy is to prevent inter-herd transmission of the main pathogens by increasing biosecurity measures at herd level. Because live animal transport is considered one of the main modes of BRSV transmission between herds [5, 6], proper mitigation must ensure that live animal transport be performed without compromising biosecurity. This requires knowledge on transmission risk associated with animal contact at different stages of infection. Knowledge of BRSV shedding related to clinical features would also be useful in order to assess the transmission risk of an infected herd without the use of viral diagnostic assays. For both of these areas, several knowledge gaps exists. Although way of infection may affect both viral shedding and clinical signs compared to naturally exposed animals, challenge studies are superior in the sense that aetiology and time of exposure is known and clinical features and virus excretion can be followed closely. Challenge studies, many of them aiming to evaluate the efficacy of vaccines [7–11] seldom last longer than one to two weeks. Grissett et al. and Gershwin concluded that shedding of BRSV begins on day three or four post-infection (p.i.) and usually lasts until day nine or ten. Grissett et al. summarized that the median time to appearance, peak and resolution of clinical signs was 3, 6 and 12 days, respectively, based on information from 22 inoculation studies [7–11, 14–22]. As studies outlasting the acute phase of infection are lacking, it is not known how long an animal can transmit infectious viruses to other animals. Appearance of clinical signs is usually the only information available in the field, and finding a clinical parameter that indicates shedding of infectious BRSV would be valuable. The existence of chronic or persistent infections in individuals is likewise still unclear [23–26].

During the acute phase of a BRSV infection, immunological protection develops, but it is assumed to be short-lived. This might enable early reinfection and new shedding of the infective virus, which complicates the risk assessment. A few BRSV studies have been performed to shed light on this. In a study by Kimman et al. they reported a strong local IgA response in the respiratory tract, but no virus shedding, when calves were re-exposed 3–4 months after primary BRSV infection. Stott et al. indicated, referring to their own unpublished results, that reinfection in calves and heifers may occur as early as three weeks post-infection. However, early reinfection with BRSV is not well-documented, and more precise knowledge of the occurrence is needed.

The existing literature on BRSV shedding and transmission is based on various laboratory methods, such as detection of viral RNA and culturing of the virus. Although resource-demanding, virus transmission studies are preferably performed using live animals in sentinel trials.

The aim of the present study was, therefore, to study basic features of BRSV infection in calves infected by exposure to BRSV-shedding calves. This was performed by:Investigating the shedding of viral RNA and infective virions:related to clinical outcome during the experimental period, lasting for two monthsin calves rechallenged by inoculation seven weeks p.i.Investigating whether the calves and their environment are not infectious to naïve in-contact calves four to nine weeks post-infection despite rechallenge with BRSV and mild stress induction.

Respiratory viruses are ubiquitous and cause a large variety of clinical symptoms. Respiratory tract infection (RTI) is undoubtedly common, and the recognition of a causative pathogen contributes to the appropriate management. In addition to the well-known respiratory viruses, such as respiratory syncytial virus (RSV) and influenza virus, human metapneumovirus (MPV) was identified in 2001, followed by the discovery of other respiratory viruses. Currently, the disease burden of respiratory viruses is beyond our knowledge. Respiratory viruses have been detected in more than two-thirds of children with radiographically confirmed community-acquired pneumonia (CAP). Similarly, in the United States, molecular diagnostics revealed viral infection in 43%–67% of pediatric CAP cases. Respiratory viruses also play an important role in adult pneumonia and are detected in 15%–56% of adult CAP cases. Viruses are responsible for the majority of respiratory infectious diseases in both children and adults, causing a massive disease burden. Furthermore, the identification of causative viruses enables the accurate diagnosis of respiratory infections and prescription of specific antiviral agents against certain viruses, such as oseltamivir for influenza viruses, and improves evaluation of the prognosis. Recognizing causative viruses can also provide information on the appropriate infection control measures, which can potentially reduce unnecessary hospital stays and allow discontinuation of unnecessary antibiotics. In summary, respiratory virus infection is common, and testing for respiratory pathogens can improve understanding of the roles of pathogens in respiratory diseases and contribute to their better clinical management.

A timely and accurate diagnosis of viral infection can be challenging. Rapid antigen tests are used to detect influenza virus infection worldwide, but there are some concerns regarding the sensitivity of currently available viral antigen tests. Technological advances have improved the sensitivity, accessibility, and utility of viral diagnostic tools. Molecular assays have been developed and progressively multiplexed to diagnose a large number of respiratory viruses in a single assay with excellent sensitivity and specificity. The importance of molecular-based diagnostic modalities is currently on the rise, and polymerase chain reaction (PCR) technology is being increasingly used in the clinic to rapidly diagnose respiratory infections. This study aims to detect respiratory viruses in children using PCR and to compare the detection power of this technique against that when using traditional antigen tests and virus cultures. The clinical conditions were also investigated.

The porcine circovirus (PCV) belongs to the family Circoviridae and contains a single-stranded circular DNA genome. There are three types of PCV: porcine circovirus type 1 (PCV1), porcine circovirus type 2 (PCV2) and porcine circovirus 3 (PCV3). During the past few decades, PCV2 has been widely studied and is considered to be the main pathogen responsible for porcine circovirus diseases and porcine circovirus-associated diseases (PCVD/PCVAD), which are characterized as clinical or subclinical PCV2 infections among pigs. The most representative symptoms of the diseases include porcine dermatitis and nephropathy syndrome (PDNS), which mainly occurs during the growing or finishing stage of pigs; postweaning multisystemic wasting syndrome (PMWS), which affects nursery and growing pigs; and porcine respiratory disease complex (PRDC), which usually occurs in pigs 14–20 weeks of age.

To date, the exact mechanisms of PCVD/PCVAD are currently unknown. However, many studies have reported co-infection with other swine pathogens, such as porcine reproductive and respiratory syndrome virus, porcine parvovirus, swine influenza virus, Mycoplasma hyopneumoniae, and Salmonella spp., are important cofactors that may enhance PCV2 infection and the severity of PCVD/PDVAD. Furthermore, vaccination failure, stress or crowding together with PCV2-infected animals also cause PCVD/PCVAD. As co-infections with viruses are frequently detected in domestic pigs and wild boars, we discuss co-infections of pigs with PCV2 and other swine viruses in this review. Furthermore, co-infections of different PCV2 strains, which cause recombination and genomic shifts in recent years, are also reviewed.

Molecular techniques including polymerase chain reaction (PCR) have increased the sensitivity of detection for common and emerging respiratory viruses, and often reveal the presence of more than one pathogen in respiratory patients.[1],[2] The importance of viral co-infections in the pathogenesis, severity or course of respiratory infections is not well established. The high sensitivity of molecular techniques raises questions about the clinical relevance of positive test results. The presence of a virus does not necessarily indicate causation of clinical symptoms or disease. On the contrary, bacterial co-infection is usually associated with a more severe diseases course and worse prognosis, despite the precise interaction between bacteria and viruses is not always clear.

Our study aims to analyze the relationship between viral or bacterial co-infection detected by molecular methods, and the clinical phenotype of children admitted to hospital with lower tract acute respiratory infections (LT-ARI).

Human parainfluenza viruses (HPIVs) are RNA viruses in the genus Paramyxoviridae. Four HPIV types have been identified. HPIVs are important causes of upper respiratory tract illness (URTI) and lower respiratory tract illness (LRTI), especially in children. An estimated five million LRTI occur each year in the United States in children under 5 years old, and HPIVs have been isolated in up to one third of these infections. The HPIV-1, HPIV-2 and HPIV-3 are second only to respiratory syncytial virus (RSV) as a cause of hospitalizations (2%–17%) for acute respiratory infection among children aged younger than 5 years in the United States.

Compared with studies of HPIV infection in children, less is known about infections in adults. Most HPIV infections in adults cause mild upper respiratory tract symptoms, but the elderly or those with compromised immune systems are at increased risk for severe HPIV infection. Compared with types 1−3, only a small number of reports have studied HPIV-4, and the lack of epidemiologic data on HPIV-4 prevents a clear understanding of the full clinical pattern of HPIVs. In addition, any differences in the clinical presentation of the four HPIV types are still largely unknown.

The aims of this study were to explore the epidemiologic features and clinical manifestations of HPIVs and other common respiratory pathogens in children and adults with acute respiratory tract illness (ARTI) in Guangzhou, southern China, and to uncover clues that might help to establish clinical distinctions between different HPIV types.

This retrospective study included children with a diagnosis of KD between 2008 and 2016 followed at the Sainte-Justine’s University Hospital Center (Montreal, Canada). Inclusion criteria were a diagnosis of KD maintained at discharge based on current clinical practice and recommendations; and echocardiography measurements of the coronary artery (CA) at onset, 1–2 weeks and >3 months after diagnosis. The main outcome was resistance to IVIG treatment in children with, versus those without concurrent infection. Secondary outcomes included duration of fever, progress of inflammatory markers and coronary artery complications. This study was approved by the institutional Research Ethics Committee of the CHU Sainte-Justine. The institutional Research ethics Committee waived the requirement for informed consent.