Sharifah Faridah Syed Omar

Review of Dengue Hemorrhagic Fever Fatal Cases Seen Among Adults: A Retrospective Study

Background Dengue is a mosquito-borne viral disease endemic in many countries in the tropics and sub-tropics. The disease affects mainly children, but in recent years it is becoming more of an adult disease. Malaysia experienced a large dengue outbreak in 2006 to 2007, involving mostly adults, with a high number of deaths. Methodology/Principal Findings We undertook a retrospective study to examine dengue death cases in our hospital from June 2006 to October 2007 with a view to determine if there have been changes in the presentation of severe to fatal dengue. Nine of ten fatal cases involved adult females with a median age of 32 years. All had secondary dengue infection. The mean duration of illness prior to hospitalization was 4.7 days and deaths occurred at an average of 2.4 days post-admission. Gastrointestinal pain, vomiting, diarrhea, intravascular leakages and bleeding occurred in the majority of cases. DSS complicated with severe bleeding, multi-organ failure and coagulopathy were the primary causes of deaths. Seven patients presented with thrombocytopenia and hypoalbuminemia, five of which had hemoconcentration and increased ALT and AST indicative of liver damage. Co-morbidities particularly diabetes mellitus was common in our cohort. Prominent unusual presentations included acute renal failure, acute respiratory distress syndrome, myocarditis with pericarditis, and hemorrhages over the brain and heart. Conclusions In our cohort, dengue fatalities are seen primarily in adult females with secondary dengue infection. The majority of the patients presented with common clinical and laboratory warning signs of severe dengue. Underlying co-morbidities may contribute to the rapid clinical deterioration in severe dengue. The uncommon presentations of dengue are likely a reflection of the changing demographics where adults are now more likely to contract dengue in dengue endemic regions.

Chikungunya infection in Malaysia: Comparison with dengue infection in adults and predictors of persistent arthralgia

BACKGROUND Chikungunya virus (CHIKV) and dengue virus (DENV) co-circulate in areas endemic with the Aedes mosquito vectors. Both viruses cause similar illnesses which may be difficult to distinguish clinically. CHIKV is also associated with persistent arthralgia. OBJECTIVES To compare and describe factors which differentiate between DENV and CHIKV infections on presentation; and to describe predictors of persistent arthralgia in CHIKV patients. STUDY DESIGN Patients aged >14 years diagnosed with acute CHIKV and DENV infections in Kuala Lumpur, Malaysia were retrospectively identified. Clinical and laboratory data were obtained from medical records, and compared. CHIKV patients were telephoned 15-24 months later and interviewed about persistent symptoms. Logistic regression analysis was performed. RESULTS A total of 53 CHIKV and 113 DENV patients were included. CHIKV patients were older and more likely to be female. CHIKV was independently associated with arthralgia and rash, while DENV was associated with myalgia, raised aspartate transaminase, and leucopaenia. Forty CHIKV patients were followed up, with a median duration of self-reported arthralgia of 3 months (range, 0-24 months). Eighteen (45%) had persistent arthralgia beyond 4 months, for which age >40 years was an independent predictor. At 1 year, 9 (22.5%) patients had arthralgia. CONCLUSION In Kuala Lumpur, selected clinical and laboratory predictors help to distinguish between DENV and CHIKV infections. Persistent arthralgia was a frequent sequel of CHIKV infection in this cohort.

Hemophagocytosis in dengue: Comprehensive report of six cases

Hemophagocytic syndrome is a potentially fatal disorder. It is being increasingly reported but remained under-recognized in dengue. Most reported cases were in association with plasma leakage and shock but multi-organ impairment was also observed. We describe the time-lines of 6 cases of confirmed dengue with varying severities of hemophagocytosis. All had persistent fever, cytopenia and elevated transaminases with markedly elevated ferritin levels during and beyond the plasma leakage phase. Acute renal failure and central nervous system manifestation were observed in two patients. Morphological hemophagocytosis was demonstrated in three patients. All survivors showed clinical and biochemical resolution of hemophagocytosis indicating its transient nature. Persistence of fever and cytopenia together with multi-organ dysfunction, out of proportion to and beyond the plasma leakage phase should prompt clinicians to consider this phenomenon.

Outbreak of Human Infection with Sarcocystis nesbitti, Malaysia, 2012

An outbreak of fever associated with myalgia and myositis occurred in 2012 among 89 of 92 college students and teachers who visited Pangkor Island, Malaysia. The Sarcocystis nesbitti 18S rRNA gene and sarcocysts were obtained from muscle tissues of 2 students. Our findings indicate emergence of S. nesbitti infections in humans in Malaysia.

TLR2-induced cytokine responses may characterize HIV-infected patients experiencing mycobacterial immune restoration disease.

Objectives:Most HIV patients who experience Mycobacterium tuberculosis-associated immune restoration disease (TB IRD) display elevated interferon-gamma (IFN&ggr;) responses against mycobacterial antigens, but these can occur without an IRD. Recognition of mycobacteria-associated molecular patterns through toll-like receptors (TLRs) on dendritic cells and monocytes induces cytokine production. Here, we investigate TLR-induced responses in IRD. Design:Peripheral blood mononuclear cells (PBMCs) were collected at approximately weeks 0, 6, 12, 24 and 48 after antiretroviral therapy from five patients experiencing TB IRD, nine matched non-IRD patients and 15 healthy controls. Methods:IFN&ggr; production by PBMC stimulated with protein purified derivative (PPD) was assessed by ELISpot. TLR2 expression on myeloid dendritic cells (mDCs) and monocytes was assessed by flow cytometry. TNF&agr;, IL-12p40 and IL-10 were measured by ELISA in 24-h cultures of PBMC with lipomannan (mycobacteria-derived TLR2 agonist). Results:TLR2 expression on mDC and monocytes was higher in patients than controls at baseline (P < 0.005). TLR2 expression decreased to normal levels on mDC by week 12, but remained higher on monocytes at week 24 (P = 0.02). At week 24, IRD patients showed higher IFN&ggr; responses to PPD (P = 0.02), TLR2 expression on monocytes (P = 0.006) and lipomannan-induced TNF&agr; production (P = 0.016) than non-IRD patients. Lipomannan-induced TNF&agr; and IL-12p40 responses paralleled TB IRD in the patients with high TLR2 expression. IL-10 levels did not associate with IRD. Conclusion:TLR2-induced pro-inflammatory cytokines by dendritic cells or monocytes may contribute to the pathogenesis of mycobacterial IRD.

Acute respiratory distress syndrome and acute renal failure from Plasmodium ovale infection with fatal outcome

BackgroundPlasmodium ovale is one of the causative agents of human malaria. Plasmodium ovale infection has long been thought to be non-fatal. Due to its lower morbidity, P. ovale receives little attention in malaria research.MethodsTwo Malaysians went to Nigeria for two weeks. After returning to Malaysia, they fell sick and were admitted to different hospitals. Plasmodium ovale parasites were identified from blood smears of these patients. The species identification was further confirmed with nested PCR. One of them was successfully treated with no incident of relapse within 12-month medical follow-up. The other patient came down with malaria-induced respiratory complication during the course of treatment. Although parasites were cleared off the circulation, the patient’s condition worsened. He succumbed to multiple complications including acute respiratory distress syndrome and acute renal failure.ResultsSequencing of the malaria parasite DNA from both cases, followed by multiple sequence alignment and phylogenetic tree construction suggested that the causative agent for both malaria cases was P. ovale curtisi.DiscussionIn this report, the differences between both cases were discussed, and the potential capability of P. ovale in causing severe complications and death as seen in this case report was highlighted.ConclusionPlasmodium ovale is potentially capable of causing severe complications, if not death. Complete travel and clinical history of malaria patient are vital for successful diagnoses and treatment. Monitoring of respiratory and renal function of malaria patients, regardless of the species of malaria parasites involved is crucial during the course of hospital admission.

Sarcocystis nesbitti Causes Acute, Relapsing Febrile Myositis with a High Attack Rate: Description of a Large Outbreak of Muscular Sarcocystosis in Pangkor Island, Malaysia, 2012

Background From the 17th to 19th January 2012, a group of 92 college students and teachers attended a retreat in a hotel located on Pangkor Island, off the west coast of Peninsular Malaysia. Following the onset of symptoms in many participants who presented to our institute, an investigation was undertaken which ultimately identified Sarcocystis nesbitti as the cause of this outbreak. Methodology/Principal Findings All retreat participants were identified, and clinical and epidemiological information was obtained via clinical review and self-reported answers to a structured questionnaire. Laboratory, imaging and muscle biopsy results were evaluated and possible sources of exposure, in particular water supply, were investigated. At an average of 9–11 days upon return from the retreat, 89 (97%) of the participants became ill. A vast majority of 94% had fever with 57% of these persons experiencing relapsing fever. Myalgia was present in 91% of patients. Facial swelling from myositis of jaw muscles occurred in 9 (10%) patients. The median duration of symptoms was 17 days (IQR 7 to 30 days; range 3 to 112). Out of 4 muscle biopsies, sarcocysts were identified in 3. S. nesbitti was identified by PCR in 3 of the 4 biopsies including one biopsy without observed sarcocyst. Non-Malaysians had a median duration of symptoms longer than that of Malaysians (27.5 days vs. 14 days, p = 0.001) and were more likely to experience moderate or severe myalgia compared to mild myalgia (83.3% vs. 40.0%, p = 0.002). Conclusions/Significance The similarity of the symptoms and clustered time of onset suggests that all affected persons had muscular sarcocystosis. This is the largest human outbreak of sarcocystosis ever reported, with the specific Sarcocystis species identified. The largely non-specific clinical features of this illness suggest that S. nesbitti may be an under diagnosed infection in the tropics.

Plasma interleukin-18 levels are a biomarker of innate immune responses that predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome.

Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a substantial problem in HIV/TB coinfected patients commencing antiretroviral therapy (ART). The immunopathogenesis of TB-IRIS includes increased production of proinflammatory chemokines and cytokines, including interleukin-18, which is a signature cytokine of the nucleotide-binding domain and leucine-rich repeat pyrin containing protein-3 inflammasome. We compared plasma levels of interleukin-18 and other biomarkers of monocyte/macrophage activation in the prediction and characterization of TB-IRIS. Methods: Biomarkers were assayed pre-ART and during TB-IRIS, or equivalent time-point, in a case–control study of Malaysian HIV patients with paradoxical or unmasking TB-IRIS (n = 15), TB no IRIS (n = 14), and no TB or IRIS (n = 15). Findings for interleukin-18 were verified in another cohort of patients with paradoxical TB-IRIS (n = 26) and their controls (n = 22) from India. Results: Interleukin-18 was higher in TB-IRIS patients pre-ART and during the event in both Malaysian patients (P < 0.0001) and Indian patients (P < 0.01). CXCL10 was higher pre-ART (P < 0.001), mainly in paradoxical TB-IRIS patients, and during TB-IRIS (P < 0.001), whereas CXCL8 was only higher during TB-IRIS (P < 0.001). Soluble(s) CD14 was increased in all patients with HIV/TB coinfection pre-ART and during TB-IRIS or equivalent time-point, compared with patients without TB. In contrast, interferon-&ggr; was lower before and during TB-IRIS. By receiver operating curve analysis, CXCL10, and/or interleukin-18 pre-ART were predictive of TB-IRIS. Conclusion: Plasma interleukin-18 levels pre-ART are candidate biomarkers for predicting paradoxical and unmasking TB-IRIS and should be investigated for risk stratification and elucidation of disease pathogenesis.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) treatment for uterine fibroids.

Magnetic Resonance-guided focused Ultrasound Surgery (MRgFUS) is gaining popularity as an alternative to medical and surgical interventions in the management of symptomatic uterine fibroids. Studies have shown that it is an effective non-invasive treatment with minimal associated risks as compared to myomectomy and hysterectomy. MRgFUS can be offered to a majority of patients suffering from symptomatic uterine fibroids. It has been suggested that the use of broader inclusion criteria as well as the mitigation techniques makes it possible to offer MRgFUS to a much larger subset of patients than previously believed. This paper will describe how MRgFUS treatment for uterine fibroids is performed at the University of Malaya Medical Centre, Kuala Lumpur, Malaysia.

Molecular diversity of HIV-1 and surveillance of transmitted drug resistance variants among treatment Naïve patients, 5 years after active introduction of HAART in Kuala Lumpur, Malaysia.

Expansion of antiretroviral treatment programs have led to the growing concern for the development of antiretroviral drug resistance. The aims were to assess the prevalence of drug resistant HIV‐1 variants and to identify circulating subtypes among HAART‐naïve patients. Plasma specimens from N = 100 HIV+ HAART‐naïve adult were collected between March 2008 and August 2010 and viral RNA were extracted for nested PCR and sequenced. PR‐RT sequences were protein aligned and checked for transmitted drug resistance mutations. Phylogenetic reconstruction and recombination analysis were performed to determine the genotypes. Based on the WHO consensus guidelines, none of the recruited patients had any transmitted drug resistance mutations. When analyzed against the Stanford guidelines, 35% of patients had at least one reported mutation that may reduce drug susceptibility to PI (24%), NRTI (5%), and NNRTI (14%). The commonly detected mutation that may affect current first line therapy was V179D (3%), which may lead to reduced susceptibility to NNRTI. The predominant circulating HIV‐1 genotypes were CRF01_AE (51%) and CRF33_01B (17%). The prevalence of unique recombinant forms (URF) was 7%; five distinct recombinant structures involving CRF01_AE and subtype B′ were observed, among them a cluster of three isolates that could form a novel circulating recombinant form (CRF) candidate. Transmitted drug resistance prevalence among HAART‐naïve patients was low in this cohort of patients in Kuala Lumpur despite introduction of HAART 5 years ago. Owing to the high genetic diversity, continued molecular surveillance can identify the persistent emergence of HIV‐1 URF and novel CRF with significant epidemiological impact. J. Med. Virol. 86:38–44, 2014.