ITP is characterized by isolated low levels of circulating platelets (PLT <100,000/μl) secondary to autoimmune destruction of platelets or inhibition of synthesis. It varies from mild to severe disease with lethal sequelae. The severe form includes bleeding requiring treatment which usually occurs with a platelet count <20,000/μl. ITP may present acutely or chronically; the chronic form is defined as thrombocytopenia of more than 6 months’ duration since initial clinical presentation. Acute ITP is common in children (<10 years) in contrast to the chronic form which is more common in adults.

The exact mechanism of ITP is poorly understood, with many hypotheses claiming that viral infection triggers the disease after which preformed antibodies cross-react with platelet antigens[1,2].

Clinical presentation varies from the more common petechiae, purpura and mucous membrane bleeding (epistaxis or gum bleeding) to the rare severe gastrointestinal or intracranial bleeding, which has been reported in 1.4% of patients[3].

Viruses thought to cause ITP include HIV, HCV, CMV, EBV, herpes viruses and VZV[4–6]. In 1992, Wright[7] reported a case of severe thrombocytopenia secondary to asymptomatic CMV infection. In 2004, Hamada et al. described a patient with severe thrombocytopenia associated with varicella zoster infection whose platelet count returned to normal after antiviral treatment. Interestingly, Zea-Vera and Parra[9] reported a case of ITP exacerbation that was secondary to Zika virus infection.

An association between ITP and some bacterial infections such as tuberculosis and Helicobacter pylori has been documented[10]. However, a connection between ITP and infection with coronavirus, even though the virus is common, has not previously been reported in the literature.

Infection with coronavirus (CoV) has been associated with severe acute respiratory syndrome (SARS). Haematological changes in patients with SARS are common and notably include lymphopenia and thrombocytopenia. The development of thrombocytopenia may involve a number of mechanisms. Although the development of autoimmune antibodies or immune complexes triggered by viral infection may play a significant role in inducing thrombocytopenia, SARS-CoV may also directly infect haematopoietic stem/progenitor cells, megakaryocytes and platelets, inducing their growth inhibition and apoptosis[11]. In contrast, we report severe thrombocytopenia following mild coronavirus upper respiratory tract infection.

Coronavirus infections were considered benign until the SARS outbreak of 2003 when the their virulence attracted increased attention and new group members like Cov.HKU1 were identified. Cov.HKU1 was discovered in 2005 in Hong Kong in an adult with chronic pulmonary disease[12] and is now considered to be associated with acute respiratory infections.

Coronavirus is not a well-known cause of immune thrombocytopenia even though it may possibly cause severe ITP. Therefore, a respiratory viral panel test should be used in the initial assessment of a patient with immune thrombocytopenia.

During the study 50 JIA flares or worsening of JIA activity parameters were observed in 44/70 patients included in at least one of two surveillance periods, and 10 of them (20%) were temporally associated with respiratory infection episodes (7 classified as ILI). In 8 of those episodes we could not identify any other triggering factor possibly associated with the flare (Table 3).

The possible factors associated with the 40 JIA flare episodes not related to respiratory infections were suspension or nonadhearance to medication in twelve episodes, and intercurrent infections in seven episodes: otitis, chickenpox, parotiditis (2), gastroenterocolitis (2) and infection sacroiliitis. In twelve-one episodes there were no identifiable causes for the flares.

There was no significant difference in the total number of flares related to gender, age (< 9 years old and ≥ 9 years old), JIA type of onset (oligoarticular, polyarticular or systemic), use of immunosuppressive therapy, period of surveillance (SV1 or SV2) or administration of influenza vaccine. Flares or worsening of JIA activity parameters associated with ARI were more frequently observed in patients with systemic JIA (5 of the 16 flares that occurred in this group) as compared to patients with polyarticular JIA (2/14 flares, p = 0.03).

This case is, to our knowledge, the first report of ARDS due to fulminant pulmonary blastomycosis in the emergency medicine literature. While this entity is uncommon, it has been described in ICU patients. Of note, an experienced EP, faced with a young patient with undifferentiated, near-fatal CAP, recognized the importance of definitive antimicrobial therapy and prescribed broad spectrum antibiotics including doxycycline (for zoonotic bacterial pathogens), as well as empiric antiviral and antifungal therapy. This patient’s blastomycosis was covered empirically (and as it turns out, definitively) with amphotericin from the time of his arrival in the ED. This report addresses one potential approach to fulminant pneumonitis from an unknown pathogen, which represents an important gap in existing guidelines on early antimicrobial therapy.

There is ample evidence that a delay in definitive antibiotic therapy negatively affects outcomes in severe bacterial infection. This delay is most often due to unrecognized infection, failure to initiate antibiotic therapy in the ED, or failure to anticipate antimicrobial resistance. In fact, among hypotensive ICU patients with septic shock (nearly 40% of whom had pneumonia), each hour delay in effective antimicrobial therapy after the first hour was associated with an average decrease in survival of 8%.3 The Surviving Sepsis Campaign, while not addressing fulminant pneumonia specifically, does recommend that empiric antimicrobial therapy include one or more drugs that have activity and adequate tissue penetration against “all likely pathogens,” including viruses and fungi.5 Professional society guidelines on the management of critically ill patients with severe CAP highlight the need to cover empirically for resistant organisms including Pseudomonas aeruginosa and community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA).6 In our experience, patients with septic shock rarely receive antifungal or antiviral therapy. Besides knowledge of non-bacterial pathogens endemic to a certain geographic area (e.g. Coccidioides spp. and hantavirus in the southwestern U.S.), these guidelines are of limited utility to an EP caring for an intubated patient because treatment is initiated before a detailed travel and exposure history can be obtained.

A diverse list of pathogens can cause fulminant pneumonia and ARDS in an immunocompetent host. In fact, there is evidence that multilobar lung involvement is independently associated with a twofold increased likelihood of treatment failure in CAP.7,8 Usual pathogens include standard or atypical bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Group A Streptococcus, Legionella spp., or aerobic gram-negative bacteria, including Pseudomonas aeruginosa. Massive aspiration can lead to a polymicrobial pneumonia that often includes anaerobes, or in the case of freshwater aspiration, infection with Aeromonas hydrophila.9 In our case, antibacterial coverage included piperacillin-tazobactam, levofloxacin, and vancomycin. Endemic fungal infections, such as blastomycosis, histoplasmosis, or coccidioidomycosis, have also been associated with fulminant pneumonia; thus, we gave amphotericin. One must also consider viruses such as influenza A and B (for which we gave oseltamivir), but also varicella zoster virus10 or herpes simplex,11 and thus it may be prudent to administer acyclovir in the appropriate setting. Respiratory viruses that are prevalent, detectable on polymerase chain reaction-based assays but without specific treatment include respiratory syncytial virus, parainfluenza virus, rhinovirus, adenovirus, human metapneumovirus, multiple coronaviruses (the etiologic agents of severe acute respiratory syndrome [SARS] and of Middle East respiratory syndrome [MERS]), and hantaviruses (responsible for the hantavirus pulmonary syndrome [HPS]). Fulminant pneumonia can also be caused by rare zoonotic bacteria often recognized in the U.S. for their potential as biological weapons, namely Bacillus anthracis (anthrax), Francisella tularensis (tularemia), and Yersinia pestis (pneumonic plague), for which we gave doxycycline. Lastly, fulminant pneumonitis can be due to non-infectious vasculitic or idiopathic disorders, which are typically corticosteroid-responsive, and methylprednisolone was given in this case.

Blastomycosis can be asymptomatic or mimic bacterial pneumonia following the inhalation of aerosolized spores from the Blastomyces dermatitidis mold living in moist soil. This endemic fungus is found most commonly surrounding the Great Lakes and the St. Lawrence, Ohio, and Mississippi Rivers.12 In states where blastomycosis is a reportable disease (Arkansas, Louisiana, Michigan, Minnesota, and Wisconsin), it is relatively rare; annual incidence rates vary from 1–2 cases per 100,000 population to as high as 10–40 cases per 100,000 population in several northern Wisconsin counties.13,14 Fulminant pneumonia leading to ARDS and respiratory failure occurs in a minority of cases, with mortality of 50–89%. (Contemporary mortality may be lower in the era of extracorporeal membrane oxygenation support).15,16 Extrapulmonary blastomycosis can occur by hematogenous spread of yeast to the skin, bones, and joints. Delay in diagnosis is relatively common; clinicians even in endemic areas often fail to consider blastomycosis in the initial differential for severe CAP. The diagnosis is made by isolating the organism in culture. Rapid evidence of blastomycosis is often obtained by visualizing the broad-based budding yeast forms in a sputum smear or potassium hydroxide prep. In severe infections, Blastomyces can cross-react with the urine Histoplasma antigen assay yielding a positive result before the final culture is available, as occurred in our case. Treatment of severe pulmonary or disseminated blastomycosis is with liposomal amphotericin B for 1–2 weeks until clinical improvement is noted, then daily itraconazole for at least one year.17

Bronchiectasis caused by immune-related mechanisms including autoimmunity, immunodeficiencies and hematologic malignancies were identified as predominant aetiologies in the United States. This work demonstrates a low rate of idiopathic bronchiectasis and importantly reveals that systematic evaluation may identify an aetiology in a high proportion of cases suggested by an earlier UK study. In the US, immune dysfunction was frequently associated with bronchiectasis including that among stem-cell transplant recipients who suffered graft versus host disease. Outside of indigenous Canadian cohorts, where high rates of childhood bronchiectasis are reported, data on aetiology of adult Canadian non-CF bronchiectasis is rather limited and the precise nature of aetiology in this country is largely uncertain [34, 35]. In Latin America aetiology is, like elsewhere, driven by infection and influenced by infectious disease epidemiology such as that in endemic TB regions or against backdrops of higher rates of pertussis and measles which in turn relate to the lower vaccine uptake rates. Higher rates of pneumonia and tuberculosis in childhood are also likely key contributing factors to bronchiectasis in this region.

Despite not being included in most classifications of pulmonary complications after HSCT, pulmonary edema (PE) as a consequence of a fluid overload (FO) is extremely frequent (Rondón et al. 2017).

Widespread alveolar injury in absence of active lower respiratory tract infection, cardiac or renal dysfunction, and iatrogenic fluid overload (Clark et al. 1993; Panoskaltsis-Mortari et al. 2011)

The true prevalence of bronchiectasis in communities in the Asia-Pacific region is largely unknown and should be considered a potential diagnosis in all populations. Important aetiologies of bronchiectasis seen in other regions including immunodeficiency syndromes such as, common variable immunodeficiency, secondary immunoglobulin disorders (frequently drug related) and mucociliary defects including primary ciliary dyskinesia, chronic aspiration, autoimmune/connective tissue diseases, particularly rheumatoid arthritis, and ABPA are described and in some cases result in a delayed diagnoses. In Japan, a less studied inflammatory disease, sinobronchial syndrome is documented in many cases of bronchiectasis.

While geographic variation in bronchiectasis aetiology is described, selection or referral biases, and, the extent of testing to seek a diagnosis of bronchiectasis in individual patients may have resulted in the observed patterns in the populations reported. Figure 2 illustrates the existing literature of available studies focused on bronchiectasis aetiology based on geography.

Pre-vaccination geometric mean titers (GMT) with 95% confidence interval (95% CI) for H1N1, H3N2 and B/Florida in JIA patients were 13.3 (11-21.5), 12.4 (10.5-21) and 14.1 (12.2-23.3) respectively; and 43.4 (41.7-46.5), 33.2 (31.5-38.7) and 33.6 (31.9-37.6) in post vaccine period. Vaccine response of the patients and controls is described in Table 4.

Thirty-one of 44 patients (70%) who received influenza vaccine were using methotrexate or leflunomide, one patient was on cyclosporine, and five were receiving anti-TNFα drugs at the time of vaccination. Six patients were using corticosteroids at mean daily dose of 0.3 (0.1-0.6) mg/kg/day, with mean duration of treatment of 16.8 (10-24) months.

In general, response to influenza vaccine was not influenced by age, JIA type of onset, therapeutic regimens or disease activity. Patients on anti-TNFα drugs presented lower seroconversion (p = 0.03) and seroprotection (60%) responses to H1N1 strain, but the seroprotection above the cut-off levels to the other strains: H3N2 (100%) and B/Florida (80%).

The vaccine was considered safe. Pain at the injection site was described in 6/44 (13.6%) JIA patients and 1/10 (10%) healthy children; other local changes (redness and swelling or warmth) were reported by 2/44 (4.5%) of JIA patients and in 1/10 healthy children. Six patients developed cough and rinorrhea, without fever, during the first ten days after receiving the vaccine.

No significant differences were found in JIA activity index (ACRPed30) or doses of prednisone used by patients before and after 30, 90 and 180 days of vaccination (p = 0.22), Table 5. Methotrexate weekly dose was significantly lower 30 and 90 days after vaccination when compared to the pre vaccination dose (p = 0.03).

No patient reported ILI symptoms during the 6-month post-vaccine follow-up period.

A balanced intestinal microbial community is essential for the development and maintenance of immune function and health. The respiratory microbiome develops in tandem with that of the gut. There is clear cross-talk between the two compartments (the “gut–lung axis”) and manipulation of the gut microbiome, by changes in diet or drugs, can alter the microbiome of the lung, providing beneficial effects in asthma and protection against respiratory viruses. Direct seeding of bacteria from the gastrointestinal tract into the airways may play a role in shaping the respiratory microbiome and triggering local immune responses (Figure 1). However, it is now clear that the gastrointestinal tract can direct immune responses in remote environments by the systemic dissemination of bacterial metabolites via the bloodstream, as has been shown for short-chain fatty acids (SCFAs). The beneficial effects of dietary-fibre fermentation products are now well documented in a number of chronic inflammatory diseases. Dysbiosis of the gut microbiota has been associated with a number of local and systemic conditions, including respiratory diseases. It is the case of asthma, wherein the gut microbiota of patients is enriched for histamine-producing bacteria compared to healthy controls. Dysbiotic gut microbiota has also been shown in patients with systemic sclerosis, particularly those with extra-intestinal manifestations, including lung fibrosis and silicosis. In experimental systemic sclerosis, manipulation of intestinal microbiota through early-life antibiotic administration was associated with dysregulated T-cell responses in the lung and altered expression of fibrosis-related genes. Moreover, early-life dysbiosis was associated with adult-onset lung fibrosis. The hypothesis that early-life intestinal dysbiosis is durable and confers susceptibility to late-onset lung fibrosis in human disease is intriguing. However, while the role of the gut–lung axis in pulmonary inflammation has been studied, little is known about the impact of microbial metabolites on the development of pulmonary fibrosis.

Severe community-acquired pneumonia (CAP) is a frequent cause of sepsis and the acute respiratory distress syndrome (ARDS).1 However, a fulminant presentation of these syndromes in an otherwise healthy patient in the emergency department (ED) is uncommon.2 Severe CAP is usually due to one of a familiar list of bacterial and viral pathogens (Streptococcus pneumoniae, Staphylococcus aureus, Legionella sp., and influenza A&B viruses), and effective antimicrobial therapy in the first hour after presentation to the ED improves the likelihood of a good outcome.3,4 Furthermore, seasoned emergency physicians (EP) understand the importance of matching the intensity and timeliness of their interventions (including empiric antimicrobial therapy) to the severity and tempo of the patient’s illness; in general, a fulminant presentation of sepsis and pneumonia in a young adult demands rapid, definitive intervention to preserve life. Surprisingly, existing literature and guidelines give little guidance to the EP regarding an approach to empiric antimicrobial therapy for fulminant, immediately life-threatening pneumonia.

The general characteristics of hMPV and HCoV-NL63 highlighted by this study show strong similarities with those that have emerged from broad, previously published studies. hMPV was detected in 8.3% of those hospitalized with LRTIs. These figures are similar to those reported in Europe,12 the United States,3 and Australia.4 HCoV-NL63 was detected in 2.8% of specimens tested and was associated with both URTIs and LRTIs. These findings are similar to those of previous studies that reported detection rates ranging from 1.3% to 3.6% in various sample sets.56 We found the proportion of patients with hMPV infection was significantly higher among children 1 to 3 years old in comparison with that among younger or older children. Our results are comparable with those of van den Hoogen et al.7 The seasonality of hMPV is becoming evident. In our study, the peak incidence was in March, August and September, but there were hMPV isolates from every month of the year except for July and October. A broad seasonal activity of hMPV with distinctive pattern in different years was reported by Sloots et al.3 A previous report states that HCoV-NL63 peaked in summer, which is similar to our finding.

hMPV was associated with acute URTIs and LRTIs in our immunocompromised children. The hMPV-associated disease in hematologic malignancy and related disorders was characterized by several respiratory symptoms, including fever, nasal congestion, cough, and shortness of breath. Seven patients developed rapidly progressive respiratory failure associated with pneumonia and culture-negative shock. All patients were admitted to intensive care units. hMPV was the only respiratory pathogen detected by NPA or BAL in 4 of these patients. These findings are similar to those reported by Williams et al89 and Englund et al.10 Three immunocompromised patients with idiopathic pneumonia died despite aggressive therapy, suggesting involvement of hMPV as a cause of total idiopathic pneumonia. Our findings are consistent with those of investigators who have demonstrated that HCoV-NL63 was a cause of URTIs in hospitalized children with acute respiratory infection and can be associated with high risk of respiratory complications in high-risk patients.11

In summary, our data suggest that hMPV and HCoV-NL63 may play a significant role in acute respiratory illness of hospitalized Saudi children. These data support the hypothesis that hMPV is a significant pathogen in immunocompromised children, with a risk of increased morbidity and mortality. HCoV-NL63 may cause severe lower respiratory disease in those with underlying conditions. Our study has a number of limitations. It is not an epidemiological study and so may not reflect prevalence in the community; in fact, the frequency of viruses detected by molecular biological techniques are of those sampled and not of all those who are symptomatic. In addition, this study was conducted in a tertiary care facility with many immunocompromised children, a group not reflective of the general population. More comprehensive studies are needed to determine the full spectrum of presentation of hMPV and HCoV-NL63 and the impact of these viruses on the health care system in Saudi Arabia.

Acute exacerbations of IPF (AE-IPF) are episodes of acute respiratory worsening with a median survival following the event of approximately three to four months. According to the recently revised definition and diagnostic criteria, they can be either idiopathic or triggered (for instance, by infection), but cardiac failure, fluid overload or extra-parenchymal causes, such as pulmonary embolism, pneumothorax or pleural effusion, need to be excluded. Notably, because the original diagnostic criteria for AE-IPF required these events to be idiopathic, studies published before the 2016 revised document have been conducted in patients without overt clinical infection.

Several studies have reported an association between subclinical or occult viral infection and AE-IPF, although the causal role of this association remains to be proven. A study of 43 subjects with AE-IPF failed to clearly identify a viral or other infectious aetiology for the acute event in the vast majority of patients. In addition, all subjects (n = 43) had negative bacterial cultures and negative viral serology. By PCR analysis of BAL fluid, 4/43 patients tested positive for common respiratory viruses (e.g., parainfluenza (n = 1), rhinovirus (n = 2) and coronavirus (n = 1)), while no viruses were detected in the BAL fluid from stable patients (n = 40). Pan-viral microarrays revealed the presence of HSV (n = 1), EBV (n = 2) and Torque Teno virus (TTV) virus (n = 12) in patients with AE but not in the stable disease group (p = 0.0003), but TTV infection was present in a similar percentage of diseased controls with acute lung injury. Deep sequencing of a subset of AE cases confirmed the presence of TTV but did not identify additional viruses. A Japanese study of 78 patients with AE of ILD, including 27 with IPF, found viruses in the respiratory samples of 15 of them (19.2%), including HHV7 (n = 4) and HHV7 plus CMV (n = 3), but the proportions of virus infections in the IPF and non-IPF ILD groups were similar. Moreover, while the probability of survival over 60 days was lower in the virus positive group, virus isolation itself did not predict 60-day survival, questioning the clinical relevance of these findings. More recently, viral sequences were detected in the nasopharyngeal swab of 18/30 (60%) patients with AE-IPF and 13/30 (43.3%) cases with stable disease (p = 0.2). AE-IPF showed increased levels of the inflammatory cytokines IL-6, IFN-gamma, MIG, IL-17 and IL-9 compared to IPF patients with stable disease and controls. HHV and Influenza virus A accounted for the majority of the viral burden. Interestingly, AE-IPF following influenza A vaccination has been reported.

Until recently, there has been little focus on the role of bacterial infection as the trigger of AE-IPF.

Molyneaux and colleagues used culture-independent techniques to explore changes in the BAL microbiota from patients with stable IPF (n = 15) and subjects experiencing AE-IPF (n = 20). Despite negative BAL bacterial cultures and virus screens, the bacterial burden of patients with AE-IPF was over four times higher than that of patients with stable disease. In addition, while the bacterial community of patients with stable disease contained Streptococcus, Prevotella, Veillonella, Haemophilus and Psedomonas, following AE-IPF the microbiota changed substantially, with an increase in Campylobacter and Stenotrophomonas spp. and a decrease in Veillonella sp.. More recently, Weng and colleagues looked at the presence of pathogens and specific IgM against microbial pathogens in sputum, and sequences of pathogens in nasopharyngeal swabs from 170 IPF patients (122 with stable disease and 48 with AE-IPF) and 70 controls. Bacterial IgM was higher in stable IPF than in controls and in AE-IPF than in stable patients, with Mycoplasma displaying the highest IgM positive rate in both disease subsets (12.2% and 5.6%, respectively). Thirty-eight different bacterial strains (mainly Gram-negative) were detected in the sputum of patients with IPF but the total detection rates did not differ between patients with AE-IPF and those with stable disease (18.8% versus 21.3%, respectively).

Taken together, these observations suggest that alterations in pulmonary microbiome play a causative role in at least some cases of AE-IPF. However, theoretically, the higher bacterial load and altered microbiome found during an AE could be the consequence (rather than the cause) of the diffuse alveolar damage characteristic of AE. Ideally, future studies should collect paired samples from the same patients when stable and during the acute event to prove any changes from the baseline microbiota, forcing the relationship from association to causation.

Clinical characteristics of HCoV-NL63 infections are listed in Table 2. All 4 HCoV-NL63–positive children had underlying medical conditions. Two of them had cystic fibrosis, 1 patient had Sweet syndrome, and 1 patient had asthma. The clinical diagnosis of these patients included pneumonia in 2 and viral pneumonia causing chronic lung disease exacerbation in 2 patients. Their common presentation included fever and cough in 4 patients, wheezing in 3 patients, and crepitations in 2 patients. One patient with Sweet syndrome required admission to the intensive care unit for 4 days.

Figure 5 shows the effect of H5N1 viral infection on lung wet-to-dry weight ratios and dry lung-to-body weight ratios. In H5N1-infected mice, two ratios did not change obviously on day 3 p.i., but dramatically elevated on day 7 p.i., suggesting the severe edema and inflammatory exudates of the lung. Both ratios of infected mice returned to control levels on day 14 p.i., indicating that edema and inflammatory exudates had been reabsorbed. On day 30 p.i., the survived mice showed the significantly decreased lung wet-to-dry weight ratios but dramatically increased dry lung-to-body weight ratios, which might be associated with the formation of PF in H5N1-infected mice.

We described a case series of sixty patients who were hospitalized in the Unit of Infectious diseases from 10th August to 31st December 2009 with flu-like symptoms and were tested with RT-PCR for H1N1 virus. Of these, 33 patients were positive for H1N1, while the remaining 27 were negative. The main differences between these two groups and corresponding clinical messages are summarized underneath.

In this case control study we included all patients with influenza symptoms admitted to the emergency flu department according to their attendance. Limitations of the study include that our data represent the experience of a single center, that procalcitonin test was given only in 51/60 patients and also Erythrocyte Sedimentation Rate (ESR) was sporadically collected during the follow up of the patients and so was not evaluated. Bacterial pneumoniae in association with influenza has been considered a important factor leading to poor patients outcomes in prior pandemics. Even though none of the blood cultures were positive, we were unable to evaluate the effect of bacterial co-infection on patient outcomes, since blood cultures were obtained in only 17% of the study population (when fever ≥38°C) and workup for atypical pathogens was not performed. Although bacterial co-infection was not documented, the majority of the study population was treated with antibiotics. Prior publications failed to demonstrate any significant involvement of bacterial pathogens in hospitalized patients with 2009 H1N1 virus pneumonia. During the initial evaluation in 4/27 patients of group B and 6/33 of group A an antibiotic treatment was prescribed by a General Practitioner and none of these patients had a sputum culture at that time. Furthermore, we did not receive cultivable sputum samples from all patients. We supposed that false negative culture in pneumonia patients is mainly due to mixed microbial flora or the natural colonization admixture of the upper airway. The subgroup of patients with pneumonia in both groups is so small that any statistical analysis is impossible and the power of the sample is quite small. Future studies are necessary to define the best treatment of 2009 H1N1 virus pneumonia and the role of combination antiviral therapy.

The lack of significant differences in the percentages of patients with hypoxemia between the two groups is probably due to the proximal number of patients with local patchy shadowing observed in group B and group A. (Table 2.)

Obesity is known to be associated with influenza A (H1N1) viral infection, but in this cohort we observed that in group B there was a larger number of obese patients in opposition to group A (88.8% vs. 54.5%) (p = 0.009). We were unable to explain the reason that the majority of H1N1 patients were not obese in our study as in previous reported studies. Obesity is not a risk factor for poor outcomes in patients with seasonal influenza, but obesity has been suggested as a risk factor for poor outcomes in patients with 2009 H1N1 influenza infection in the USA.

In our case control study a large number patients suffering from lymphoma were observed, because these patients received chemotherapy regimen making them vulnerable to respiratory infections. Patients in group B had elevated C-reactive protein (mean 12.8 vs. 5.74) and white blood count WBC in comparison to group A (mean 10.528 vs. 7.114) suggesting a microbial infection already upon admission. These elevated values (C-reactive protein and WBC) are known to be associated with bacterial infection and early antibiotic treatment prevents progression of the disease as reported in previous studies.

Symptoms from oseltamivir were mainly observed in group A (nausea 4.5% vs. 1.5%, diarrhea 4.5% vs. 1.5%, vomiting 1.4 vs. 0.5%) probably because of the larger dose and prolonged treatment with oseltamivir (5.8 vs. 1.93) as previously reported. However, it was difficult to distinguish the pharmaceutical side effects of osetalmivir (tamiflu) from influenza symptoms in patients receiving antiviral treatment for less than 5 days. Oseltamivir should be given until proof of negative RT-PCR result, since if a patient is positive, it prevents progression of the disease as shown in previous observational studies.

Moreover, mean duration of hospital stay was 5.85 in group B vs. 6.11 days in group A, because of the time needed for normalization of chest radiographs. Nevertheless, there were no significant differences between the two groups and the days of hospitalization were limited due to early oseltamivir for group A and antibiotic treatment for group B as previously explained.

Lastly the mean young age of the patients in both groups, and the small number of co-morbidities observed in our sample of patients, possibly were also responsible for having overall mild clinical course.

TRIs were originally believed to be viral particles, but were later described as discrete microstructures that directly originate from endoplasmic reticulum or as condensed material within its cisterns [1, 2]. They have been proposed to signify a response to cellular injury [3, 4]. Their formation was shown to occur in response to endogenous elevation of α- and β-interferon and they are currently considered the footprint of interferons (IFNs). Moreover, the presence of TRIs in renal biopsies of patients with idiopathic membranous nephropathy has been shown by Yang et al to indicate the existence of underlying autoimmune or viral etiology. TRIs have been historically associated with SLE and HIV infection since the late 20th century.

In the early 1980s, Rich et al. demonstrated the association between secretion of IFN and the formation of TRIs, which were named “lupus inclusions” at the time. Subsequently, Kim et al., in the late 1980s, reported increased levels of IFN-α in patients with SLE. Furthermore, IFN-α has been shown to induce SLE through the activation of antigen-presenting cells and autoimmunity. Moreover Nakahara et al. described TRIs as an earlier sign of SLE that can even precede glomerulonephritis with “full-house” IF staining. None of our 3 cases had positive serology for lupus, nor did they show clinical signs and or symptoms of SLE during the follow-up period.

TRIs have been also associated with HIV infection since the late 1980s. Strauss et al. reported the presence of TRIs in 10 out 10 patients with HIVAN, and Cohen et al. considered the combination of renal lesions including FSGS and TRI specific for HIVAN diagnosis. Later, the presence of TRIs and the collapsing variant of FSGS was linked to HIV infection.

Although the pathogenesis of HIVAN remains unclear, there is recent evidence for direct infection of the renal epithelial cells as the underlying etiology. Our 3 patients were investigated for HIV infection and found to be negative.

Bromfield et al. reported a case of FSGS and TRIs in a renal biopsy from a patient with cytomegalovirus (CMV) infection. They concluded that CMV might have triggered an exaggerated T-cell response that led to the development of podocyte injury as well as the TRIs. All of our cases were tested for CMV and found to be negative.

INFs α and β have been shown to induce podocyte loss, proteinuria, and glomerular sclerosis. Wallbach et al. described the ability of INF to either suppress or augment immune response, and in their case report of a multiple sclerosis patient treated with INF, they concluded that proteinuria, nephrotic syndrome, and lupus nephritis should be regarded as uncommon adverse effects of INF-β therapy. Similarly, Markowitz et al. reported 11 cases of collapsing FSGS after treatment with IFNs. Ten out of 11 had endothelial TRIs. The authors emphasized the importance of considering collapsing FSGS with TRIs as a well-recognized consequence of INF therapy.

The underlying etiology for the formation of TRIs in our patients remains unclear. Although all 3 of our patients were negative for HIV and CMV, they did test positive for other common viruses (Table 1). Viral infections induce IFN production triggering signaling systems linked to toll-like receptors (TLRs) [18, 19]. Our 3 patients may have had elevated endogenous IFN triggered by an exaggerated immune response to common viral infections. Serological studies to determine IFN levels and immunohistochemical (IHC) staining to detect enhanced TLR expression in our patients may have been very informative. A finding of elevated IFN and positive TLR tissue staining would have added valuable evidence in support of our hypothesis that common viral infections as found in our patients can result in formation of TRIs. Unfortunately, by the time these cases were examined for publication, it was too late to perform serological studies and TLR staining was not available to us.

In conclusion, the presence of TRIs in renal biopsies of children without underlying autoimmune or viral etiologies remains obscure. We propose a possible role for excess IFN triggered by an abnormal immune response to common viral infections in the formation of TRIs and the renal injury. Performing serological testing for IFN levels and TLR IHC stains in patients similar to the ones we have described may be useful in future studies if performed immediately after discovery of TRIs within the renal biopsy.

ARDS: acute respiratory distress syndrome; PF: pulmonary fibrosis; IPF: idiopathic pulmonary fibrosis; SARS: severe acute respiratory syndrome; Chicken/HB/108: A/Chicken/Hebei/108/2002 (H5N1); SPF: specific pathogen-free; MID50: mouse infectious doses; p.i.: postinoculation; H-E: hematoxylin and eosin; TGF-β: transforming growth factor-β; IL-10: interleukin-10; PDGF: platelet-derived growth factor.

We present a case of genotype 3a HEV infection in a lung transplant recipient with MS on immunosuppressive therapy. The patient’s symptoms and lymphocytic pleocytosis on admission were consistent with acute viral meningitis. Tacrolimus toxicity may have also contributed to her presentation because she improved rapidly after tacrolimus discontinuation. The patient’s persistent low-level transaminitis for several years before admission and subsequent evidence of cirrhosis suggest that she was likely chronically infected with HEV. Although initial testing for HEV IgG was negative, serologies can be unreliable in immunosuppressed patients. Her prior episodes in 2013 and 2016 of seizure and “encephalopathy” are also suggestive of chronic neuroinvasive HEV disease with intermittent flares.

Although the development of chronic HEV infection is infrequent in the general population, solid organ transplant (SOT) recipients are at greater risk. In 1 series of 85 SOT recipients with HEV infection, >60% developed chronic hepatitis. In some of these patients, cirrhosis can develop within several years. Neurologic manifestations of HEV infection, including inflammatory polyradiculopathy, encephalitis, and Guillain-Barré syndrome, have been seen in 5.5% of cases. The timing of neurological manifestations after HEV infection has not been well described, but ranged from 12–60 months in 1 review of 6 cases in immunosuppressed patients. In animal models, HEV is able to cross the blood–brain barrier, replicate in the central nervous system, and cause neuronal necrosis and myelin degeneration.

Hepatitis E virus infection is infrequently considered as an infectious cause of meningoencephalitis and specific diagnostic testing is not routinely done, underscoring the benefit of an unbiased approach such as mNGS for pathogen detection. Hepatitis E virus infection may be detected through serological testing, but concurrent blood and stool HEV RNA testing is recommended, especially in immunosuppressed patients. Clinicians should consider HEV in the differential diagnosis for SOT or other immunosuppressed patients with unexplained hepatitis, particularly those taking calcineurin inhibitors. The treatment of chronic HEV infection includes reduction in immunosuppression, enabling viral clearance in approximately 30% of SOT patients. Ribavirin monotherapy has achieved sustained virologic response in approximately 85% of patients and was initiated in this patient. New antivirals such as sofosbuvir may have a future role in treatment.

Notably, our patient appears to have contracted HEV from her donor. Supporting evidence includes the positive anti-HEV IgG/IgM testing of the donor’s serum and the patient’s persistent low-level transaminase elevations that began after transplant. Of only 2 published reports of donor-derived HEV transmission, 1 liver transplant recipient developed cirrhosis and death from septic shock within 15 months of transplantation, and 2 renal transplant recipients (with the same donor) developed cholestatic hepatitis at 9 and 11 months after transplantation [14, 15]. This is the first report of presumptive HEV transmission through lung transplantation. Transplant centers and clinicians should be aware of the potential for HEV infection in donors judged to be at elevated risk.

M. Määttä1, H.P. Laurila1, S. Holopainen1, L.I. Lilja‐Maula1, M. Melamies1, S.J. Viitanen1, L.R. Johnson2, N. Koho1, M. Neuvonen1, M. Niemi1, M.M. Rajamäki1

1University of Helsinki, Helsinki, Finland,2University of California, Davis, USA

Gastroesophageal reflux and microaspiration (MA) of small amounts of gastric juice have been associated with various human respiratory diseases, including idiopathic pulmonary fibrosis and asthma. MA can be documented by measuring proteins originating from the gastrointestinal tract in bronchoalveolar lavage fluid (BALF). In this study, bile acids were measured by mass spectrometry in BALF from West‐Highland White Terriers (WHWTs) with canine idiopathic pulmonary fibrosis (CIPF, n = 33), healthy WHWTs (n = 13), dogs with bacterial pneumonia (BP, n = 11), healthy Irish Wolfhounds (IWHs) with previous BPs (n = 8), dogs with chronic bronchitis (CB, n = 13), dogs with eosinophilic bronchopneumopathy (EBP, n = 9), dogs with laryngeal dysfunction (LD, n = 19), healthy English Bulldogs (EBs, n = 26) and healthy Beagles (n = 6).

Concentrations of 17 different bile acids were determined and total bile acid (TBA) concentration was calculated as a sum of these. TBA was above minimum detection limit in 79 % of CIPF (26/33), 45 % of BP (5/11), 54 % of CB (7/13), 44 % of EBP (4/9) and 63 % of LD (12/19) dogs. In healthy dogs, bile acids in BALF were detected less commonly in IWHs (0%, 0/8), EBs (8%, 2/26) and Beagles (0%, 0/6) than in healthy WHWTs (54 %, 7/13). Results suggest that MA occurs in various canine respiratory diseases. In healthy dogs bile acids were detected only in WHWTs which could be associated to the breed predisposition of CIPF.

Disclosures

Disclosures to report.

Grants: ‐ Finnish Veterinary Foundation 5470 (2016), 5070 (2017) ‐ Finnish Foundation of Veterinary Research 4700 (2016).

HPS can be associated with Leishmania donovani and Leishmania infantum infections, but leishmaniasis may also mimic the syndrome, as it is characteristically associated with organomegaly and pancytopenia. This is particularly important in non-endemic areas, where visceral leishmaniasis is unlikely to be included in the differential diagnosis, and repeated bone marrow smears are often required to identify Leishmania species by means of PCR with species-specific probes. Specific anti-leishmania treatment with amphotericin B is usually sufficient to control HPS. Unfortunately, sporadic cases of undiagnosed leishmaniasis have been treated as HPS with fatal consequences.

Malaria (caused by Plasmodium falciparum and Plasmodium vivax), toxoplasmosis, babesiosis, and strongyloidiasis have been rarely identified in association with HPS: a history of travel from endemic countries may help to identify these triggering agents.

Yeast (Candida spp., Cryptococcus spp. and Pneumocystis spp.) and moulds (Histoplasma spp., Aspergillus spp. and Fusarium spp.) have been associated with the occurrence of HPS, most commonly during HIV infection, neoplastic diseases, protracted corticosteroid administration, and transplantation.

Disseminated Penicillium marneffei infection is common among HIV-infected patients in many regions in Southeast Asia: the first case of HPS associated with penicilliosis in a Thai HIV-infected child was reported in 2001, with complete recovery after antifungal and intravenous immunoglobulin therapy.

Reactive HPS has frequently been associated with intracellular pathogens. The pathophysiology of HPS associated with non-viral agents may be related to the production of high levels of activating cytokines by host lymphocytes and monocytes. Although the pathophysiological response of the host immune system to the infectious agent is not fully understood, it is hypothesised that functional deficiencies in NK and cytoxic T cells may occur during the illness.

HPS can be associated with disseminated Mycobacterium tuberculosis infection. Thirty-six cases (including infants and children) have so far been reported, approximately half of which were accompanied by comorbidities: eight patients had end-stage renal disease and were receiving hemodialysis or had undergone renal transplantation, four had a history of a malignancy, two had AIDS, and one had sarcoidosis. Fever was the most frequent clinical feature upon presentation, combined with visceromegaly and pancytopenia, and all of the patients underwent bone marrow aspirations that confirmed hemophagocytosis. Evidence of extra-pulmonary tuberculosis was found in 83% of cases. The concluding remarks of the report stated that tuberculosis-related HPS has a poor prognosis, with a mortality rate of approximately 50%, although anti-tuberculous and immunomodulatory therapy (consisting of high-dose corticosteroids, intravenous immunoglobulin, anti-thymocyte globulin, cyclosporine A, epipodophyllotoxin or plasma exchange) may lead to a better outcome. Early diagnostic confirmation and the timely administration of anti-tuberculous medication seem to be crucial in these patients. One reported case of HPS occurred after childhood vaccination with the bacillus Calmette-Guérin.

HPS has also been described in association with brucellosis, with Brucella melitensis being the most frequently isolated organism. Leptospirosis can cause life-threatening HPS as a result of an insufficient or misdirected immunological response to Leptospira itself: antibiotic treatment alone is not sufficient in such cases, and treatment with corticosteroids, intravenous immunoglobulin or etoposide is required. Rickettsial diseases, transmitted to humans by arthropod bites and usually controlled at an intracellular level by nitric oxide synthesis, hydrogen peroxide production, and tryptophan degradation have also been related to HPS: overall, 15 cases of rickettsial disease confirmed serologically and complicated by HPS have been published in the period 1990–2010, with only 3 cases occurring in patients less than 15 years and a prognosis influenced by the specific Rickettsia species, patient’s immunologic equipment, and delay in antibiotic therapy or corticosteroid therapy. In 2009, sepsis caused by multidrug-resistant Acinetobacter baumannii following urinary tract infection was reported for the first time in a previously healthy 3-year-old child, who recovered after multiple doses of granulocyte colony stimulating factor and red blood cell/platelet transfusions without any cytotoxic treatment or immunotherapy.

In 1967, Ashbaugh and co-authors described 12 patients with acute respiratory distress. A new definition of lung injury was recommended in 1994 in which these patients were separated into two groups, namely, those patients with less severe hypoxemia being classified as having acute lung injury (ALI), and those with more severe hypoxemia as suffering from ARDS [71, 72]. The most common morphologic pattern of ARDS is DAD, the features of which correlate better with the phases of alveolar damage than with its specific cause. Another histological pattern, which can be clinically and radiologically expressed as ARDS, is AFOP. This pattern does not meet the strict histological criteria for either organizing pneumonia (OP) or DAD and the prognosis of AFOP is better than DAD. DAD has been divided into exudative, proliferative, and fibrotic, or organizing phases [73, 74]. The pathologic alterations seen in ARDS, however, have been shown to be heterogeneous, since in a recent study only half of the patients with ARDS displayed typical DAD in postmortem examination. On the other hand, only less than half of patients with postmortem autopsy findings of DAD that were treated in intensive care unit had been diagnosed clinically as ARDS. Significant differences between ARDS and AIP are supported by the large differences of DAD in the lungs of ARDS patients, and the known etiological trigger in ARDS but not in AIP, which are factors that may account for the variable patient recovery.

A retrospective study on 58 patients with DAD lung histopathology revealed that 60% of them were immunocompromised and 90% of them fulfilled the ARDS criteria at the time of the lung biopsy. The causes of DAD in that particular study were infections (22%), AIP (21%), non-infectious complication of an organ or stem cell transplantation (17%), CVD (16%), AE of IPF (12%), drug reactions (10%) and radiation therapy (2%). The overall mortality for the lung diseases was 53%, with the exception of AE of IPF, in which the mortality was higher, being 86%. The histology of DAD is not able to reveal the cause of alveolar damage, although a recent study depicted two forms of DAD in patients with ARDS showing that interstitial myofibroblast proliferation was more common in patients with chemotherapy or drug toxicity than with severe infections. From the clinical point of view, it is important to understand that the histological pattern of DAD is a non-specific lung reaction, and it does not provide any information to the clinician about the reason for the disease, that is, sepsis, trauma, aspiration, infection, drugs or it can be associated with an idiopathic disease such as AIP.

All the patients in general, had a mild clinical course and none of the patients had to be admitted in the ICU.

An 81-year-old retired female doctor was admitted to our hospital with dry cough, and breathlessness for 1 mo.