Iris W. S. Li

Delayed Clearance of Viral Load and Marked Cytokine Activation in Severe Cases of Pandemic H1N1 2009 Influenza Virus Infection

Abstract Background. Infections caused by the pandemic H1N1 2009 influenza virus range from mild upper respiratory tract syndromes to fatal diseases. However, studies comparing virological and immunological profile of different clinical severity are lacking. Methods. We conducted a retrospective cohort study of 74 patients with pandemic H1N1 infection, including 23 patients who either developed acute respiratory distress syndrome (ARDS) or died (ARDS-death group), 14 patients with desaturation requiring oxygen supplementation and who survived without ARDS (survived-without-ARDS group), and 37 patients with mild disease without desaturation (mild-disease group). We compared their pattern of clinical disease, viral load, and immunological profile. Results. Patients with severe disease were older, more likely to be obese or having underlying diseases, and had lower respiratory tract symptoms, especially dyspnea at presentation. The ARDS-death group had a slower decline in nasopharyngeal viral loads, had higher plasma levels of proinflammatory cytokines and chemokines, and were more likely to have bacterial coinfections (30.4%), myocarditis (21.7%), or viremia (13.0%) than patients in the survived-without-ARDS or the mild-disease groups. Reactive hemophagocytosis, thrombotic phenomena, lymphoid atrophy, diffuse alveolar damage, and multiorgan dysfunction similar to fatal avian influenza A H5N1 infection were found at postmortem examinations. Conclusions. The slower control of viral load and immunodysregulation in severe cases mandate the search for more effective antiviral and immunomodulatory regimens to stop the excessive cytokine activation resulting in ARDS and death.

Viral load in patients infected with pandemic H1N1 2009 influenza A virus.

Viral shedding profile of infections caused by the pandemic H1N1 2009 influenza A virus has not been reported. The aim of this study was to determine the viral load in different body sites. Viral loads of pandemic H1N1 virus in respiratory specimens, stool, urine, and serum were determined by quantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR). Respiratory specimens from patients with seasonal influenza were used as historical controls. Initial pre‐treatment viral load were compared between these two groups. Serial respiratory specimens from patients with pandemic H1N1 virus infection were obtained for analysis of viral dynamics. Twenty‐two pandemic H1N1 cases and 44 seasonal influenza historical controls were included. The mean initial viral load before oseltamivir therapy was 1.84 × 108 copies/ml for pandemic H1N1 virus compared with 3.28 × 108 copies/ml in seasonal influenza historical controls (P = 0.085). Among patients with pandemic H1N1 virus infection, peak viral load occurred on the day of onset of symptoms, and declined gradually afterwards, with no virus being detectable in respiratory specimens by RT‐PCR 8 days and by culture 5 days after the onset of symptoms respectively, except in one patient. Pandemic H1N1 virus was detected in stool and in urine from 4/9 and 1/14 patients, respectively. Viral culture was also positive from the stool sample with the highest viral load. Younger age was associated with prolonged shedding in the respiratory tract and higher viral load in the stool. Data from this quantitative analysis of viral shedding may have implications for formulating infection control measures. J. Med. Virol. 82:1–7, 2010.

The Natural Viral Load Profile of Patients With Pandemic 2009 Influenza A(H1N1) and the Effect of Oseltamivir Treatment

Background The natural history of viral shedding from the upper respiratory tract of the new pandemic 2009 influenza A(H1N1) and the effect of oseltamivir treatment were uncertain. Methods A retrospective cohort study involving 145 consecutive patients with specimens positive by reverse transcriptase-polymerase chain reaction for the matrix and new H1 genes was conducted. Results The nontreated and oseltamivir-treated patients were comparable in their viral load at presentation, demography, and the presenting symptoms. No correlation was observed between viral load with age and number of symptoms. Viral load of nasopharyngeal aspirate (NPA) was significantly lower in treated than in nontreated patients at day 5 after symptom onset. When oseltamivir was initiated ≤ 2 days after symptom onset, a greater rate of viral load reduction in NPA of treated patients than that of nontreated patients was observed (−0.638 [95% CI, −0.809 to −0.466] vs −0.409 [95% CI, −0.663 to −0.185] log10 copies/mL/d post-symptom onset), and the viral load was undetectable at day 6 after oseltamivir initiation, which was 1 day earlier than that of those whose treatment was initiated > 2 days of symptom onset. The viral load was inversely correlated with concomitant absolute lymphocyte count in nontreated patients (Pearson correlation coefficient [r] = −0.687, P = .001) and treated patients (Pearson r = −0.365, P < .001). Resolution of fever was 1.4 days later in nontreated than treated patients (P = .012) Conclusions The natural viral load profile was described. Oral oseltamivir suppresses viral load more effectively when given early in mild cases of pandemic 2009 influenza A(H1N1) infections.

Disseminated Penicilliosis, Recurrent Bacteremic Nontyphoidal Salmonellosis, and Burkholderiosis Associated with Acquired Immunodeficiency Due to Autoantibody against Gamma Interferon

ABSTRACT Acquired immunodeficiency due to autoantibody against gamma interferon has recently been associated with opportunistic nontuberculous mycobacteriosis, especially among Southeast Asians. We report another 8 cases, all except one apparently immunocompetent hosts who suffered from concomitant or sequential infections by other intracellular pathogens causing penicilliosis, extraintestinal nontyphoidal salmonellosis, and burkholderiosis. The only case with an underlying immunodeficiency syndrome had systemic lupus erythematosus that was quiescent throughout the multiple infective episodes. Eight out of 10 (80.0%) patients with serological evidence of penicilliosis, 5 out of 7 (71.4%) with culture-positive extraintestinal nontyphoidal salmonellosis, 5 out of 28 (17.9%) with serological evidence of melioidosis, and 7 out of 13 (53.8%) with culture-positive nontuberculous mycobacteriosis possessed autoantibody against gamma interferon, whereas only 1 out of 100 patients with systemic lupus erythematosus did. Our study represents the first and largest case series linking this emerging immunodeficiency syndrome with these atypical infections in apparently immunocompetent hosts. Thus, we advocate that any patient with unexplained recurrent or polymicrobial infections due to these intracellular pathogens should be screened for acquired immunodeficiency due to autoantibody against gamma interferon.

Concurrent comparison of epidemiology, clinical presentation and outcome between adult patients suffering from the pandemic influenza A (H1N1) 2009 virus and the seasonal influenza A virus infection.

Purpose of study The demographics, clinical features and outcome of patients with pandemic influenza A (H1N1) 2009 infection were compared with a concurrent cohort of patients with seasonal influenza A infection. Study design The clinical and microbiological data of hospitalised adult patients admitted between 29 June and 28 October 2009, with pandemic A (H1N1) 2009 or seasonal influenza A infection, were analysed. Results A total of 186 patients including 69 pandemic A (H1N1) and 117 seasonal influenza were analysed. The majority (75%) under 50 years of age had pandemic A (H1N1). Compared with seasonal influenza, pandemic A (H1N1) patients were younger (median age 47 years vs 76 years, p<0.001), less likely to have lower respiratory tract symptoms (46.4% vs 66.7%, p=0.007), but more likely to be obese (5.8% vs 0%, p=0.018), pregnant (7.2% vs 0.9%, p=0.027) or have no underlying predisposing factors (24.6% vs 5.1%, p<0.001). Patients with pandemic A (H1N1) were more likely to receive oseltamivir (91.3% vs 40.2%, p<0.001), but less likely to receive antibiotics (75.4% vs 90.6%, p=0.005). Respiratory failure was the reason for intensive care unit admission for all four patients with pandemic A (H1N1), but only for one of three patients with seasonal influenza. There were no statistical significant differences in the rate of intensive care unit admission or death. Conclusions In addition to age, several clinical parameters were different between pandemic A (H1N1) and seasonal influenza. However, since both seasonal and pandemic influenza can lead to significant morbidity and mortality, the impact of pre-existing seasonal influenza should not be underestimated during the pandemic period.

The Lower Serum Immunoglobulin G2 Level in Severe Cases than in Mild Cases of Pandemic H1N1 2009 Influenza Is Associated with Cytokine Dysregulation

ABSTRACT The majority of patients with pandemic influenza H1N1 2009 had mild illness, but some, including those with no risk factors for severe disease, may succumb to this infection. Besides viral factors such as the D222/225G substitution of the hemagglutinin, host factors such as IgG2 subclass deficiency recently was reported to be associated with severe disease in a cohort of Australian patients besides other known risk factors, including underlying chronic illness, extremes of age, and pregnancy. We conducted a case-control study of 38 Asian patients with respiratory failure due to severe pandemic influenza and compared the results to those for 36 mild cases. None had selective IgG2 deficiency, but the level of IgG2 subclass was significantly lower in the severe cases (3.55 g/liter versus 4.75 g/liter; P = 0.002), whereas the levels of IgG1, IgG3, and IgG4 were not significantly different from those of the mild cases. Previous studies suggested that some IgHG2 and FcγRIIa genotypes were associated with IgG2 deficiency. The allelic frequency of the IgHG2 genotypes in our severe cases was not correlated with their levels of IgG2, while that of FcγRIIa was not significantly different from that of the general Han Chinese population (P = 0.216). Only the overall cytokine/chemokine profile (P = 0.029) and serum globulin level (P = 0.005) were found to be independently associated with the IgG2 level by multivariate analysis. The lower IgG2 level in our severe group might be related to cytokine dysregulation rather than being a significant risk factor for severe pandemic influenza. The importance of this finding for therapeutic intervention will require further studies of larger cohorts of patients.

High Mortality Associated with Catabacter hongkongensis Bacteremia

ABSTRACT Catabacter hongkongensis is a recently described catalase-positive, motile, anaerobic, nonsporulating, Gram-positive coccobacillus that was first isolated from blood cultures of four patients from Hong Kong and Canada. Although DNA sequences representing C. hongkongensis have been detected in environmental sources, only one additional case of human infection has been reported, in France. We describe five cases of C. hongkongensis bacteremia in Hong Kong, two presenting with sepsis, one with acute gangrenous perforated appendicitis, one with acute calculous cholecystitis, and one with infected carcinoma of colon. Three patients, with gastrointestinal malignancy, died during admission. All five isolates were catalase positive, motile, and negative for indole production and nitrate reduction and produced acid from arabinose, glucose, mannose, and xylose. They were unambiguously identified as C. hongkongensis by 16S rRNA gene analysis. Of the total of 10 reported cases of C. hongkongensis bacteremia in the literature and this study, most patients had underlying diseases, while two cases occurred in healthy young individuals with acute appendicitis. Six patients presented with infections associated with either the gastrointestinal or biliary tract, supporting the gastrointestinal tract as the source of bacteremia. C. hongkongensis bacteremia is associated with a poor prognosis, with a high mortality of 50% among reported cases, especially in patients with advanced malignancies. All reported isolates were susceptible to metronidazole. Identification of more C. hongkongensis isolates by 16S rRNA gene sequencing will help better define its epidemiology and pathogenesis.

Epidemiology and clinical features of Shewanella infection over an eight-year period.

Abstract Shewanella is a rare human pathogen that can lead to fatal infections. However, clinical information about this bacterium remains scarce. In this study, we retrospectively reviewed all patients with laboratory isolates of Shewanella over an 8-y period to assess risk factors, clinical manifestations and outcome. Twenty-nine patients were identified. Shewanella was most commonly isolated from intra-abdominal specimens (48.2%), followed by skin and soft tissue specimens (27.6%), blood (13.8%) and sputum (10.3%). Malignancy, hepatobiliary disease and diabetes mellitus were common underlying diseases. The overall 30-day mortality rate was 20.6%. Shewanella was considered a definite causative pathogen in 7 patients, and a recurrent infection occurred in 2 patients. Colonization of the biliary tract was common. Among co-isolated pathogens, the enteric flora was most represented. All isolates were susceptible to ceftazidime and aminoglycosides, but 1 isolate was resistant to imipenem. In conclusion, Shewanella may become a colonizing bacterium, subsequently causing invasive diseases in patients with an underlying disease.

Lipid metabolites as potential diagnostic and prognostic biomarkers for acute community acquired pneumonia

Abstract Early diagnosis of acute community-acquired pneumonia (CAP) is important in patient triage and treatment decisions. To identify biomarkers that distinguish patients with CAP from non-CAP controls, we conducted an untargeted global metabolome analysis for plasma samples from 142 patients with CAP (CAP cases) and 97 without CAP (non-CAP controls). Thirteen lipid metabolites could discriminate between CAP cases and non-CAP controls with area-under-the-receiver-operating-characteristic curve of >0.8 (P ≤ 10−9). The levels of glycosphingolipids, sphingomyelins, lysophosphatidylcholines and L-palmitoylcarnitine were higher, while the levels of lysophosphatidylethanolamines were lower in the CAP cases than those in non-CAP controls. All 13 metabolites could distinguish CAP cases from the non-infection, extrapulmonary infection and non-CAP respiratory tract infection subgroups. The levels of trihexosylceramide (d18:1/16:0) were higher, while the levels of lysophosphatidylethanolamines were lower, in the fatal than those of non-fatal CAP cases. Our findings suggest that lipid metabolites are potential diagnostic and prognostic biomarkers for CAP.

Coccidioidomycosis as a rare cause of pneumonia in non‐endemic areas: A short exposure history should not be ignored

Coccidioidomycosis is endemic in the south‐western USA. Two cases of infection in travellers returning to Hong Kong are described. A previously healthy patient who had travelled to an endemic area for a short time was successfully treated with fluconazole. A second patient with comorbidities and more prolonged exposure had disseminated and eventually fatal disease, despite prolonged administration of anti‐fungal agents. Although coccidioidomycosis is a rare disease in Hong Kong, it should always be considered when there is a relevant travel history. Even a short period of travel to an endemic area should alert clinicians to this possibility when managing patients with severe pneumonia, especially those with multi‐organ involvement. On the other hand, in patients with comorbidities, even aggressive and prolonged anti‐fungal therapy may not guarantee a successful outcome.