Are we testing enough?

I had written this as part of my last post but it didn't fit in with that topic...

Yes there was a case of pneumonia in the Kingdom of Saudi Arabia that apparently went untested for all possible/emerging/out-of-the-box pathogens - does that never happen elsewhere?

In defence of the current MERS-CoV hotzone's testing, there are plenty of research and review papers in the scientific literature that show pneumonia is one of those diseases that could really do with better testing and characterisation. Acute brain inflammatory diseases are another bunch. They are scary diseases, they have an immediate impact and sequelae that may not yet be well defined and they are likely to be triggered by 1 or more viruses and or bacteria. And all that sits on top of the highly variable milieu of our genetic (immune defects?), physiological (prior predisposing tissue damage or changes?) and immunological (previous exposures or lack thereof) background.

Is it possible to effectively manage disease prevention and ill patients if you don't know the cause of the disease? Sure, there are no treatments for most viral diseases - but that's an excuse not to uncover the agent likely causing a patient's ills and not a reason. One can never learn the cause if there has been no testing for the most pertinent bugs. Its a vicious and really annoying cycle that seems to be part of a disconnect between the bed and the lab. At least in some places. I'm deliberately leaving aside being unable to prove causality through detection alone. That's for another day.

In the case of diseases that are poorly tested, that list of bugs should include everything relevant and everything that could be relevant. 

It feels (oh very scientific) like its been a while since we've really looked hard at the testing of some acute diseases - we tend to stick with what we knew when it comes to testing panels. Over time new technologies have been developed (PCR - kinda old now) and a lot of new bugs have been (and keep being) found. Are we in need of a shake up? I think "paradigm" should really be a dirty word in the testing for infectious agents right now.

I would personally love to get some good collaborations going and do some comprehensive testing for everything under the sun, plus some next-generation sequencing to find things we don't yet know of, on a large number of such cases (and controls). Finding the funding - and the interested collaborators - now there is a trick worthy of Loki and one I have yet to attain.

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MERS-CoV by the numbers: recent weekly case activity...

Click to enlarge.

Confirmed MERS-CoV cases (green) and

deaths (red) each week. Case numbers

are listed on the y-axis (side), days of each

week along the x-axis (bottom). Case dates

are derived from announced date of onset

but if absent, on the date of reporting.

This follows on from my previous post (you can follow its links to earlier weekly charts) about lab-confirmed Middle East respiratory syndrome coronavirus (MERS-CoV) cases, plotted by week.

These charts are based on the reports that get into the public domain. Those of us trying to follow and deconvolute MERS-CoV case information pretty much all agree that the data are terrible, but they are what they are. For example, the data are currently absent details on 2 MERS-related deaths for which no links to our case lists can be found. There are 85 cases missing date of disease onset data (which makes these charts imperfect), 8 without an age, 10 without a sex and most have no date of hospitalisation or date of lab confirmation. As I've bemoaned before, a standardised numbering of cases would be helpful too. Among other things.

The charts suggest there is not a lot of activity in terms of new cases, and the number of deaths, thankfully, remain much lower than during the weeks preceding my post in early September.

You can see that during the Hajj (13th-18th of October), there were 3 cases and a death described but in the weeks immediately afterwards, there has been no spike in cases of MERS. What makes this a significant development is that, for the second time since we learned of MERS-CoV, countries outside the Kingdom of Saudi Arabia (KSA) have had a direct hand in the observation and testing of pilgrims. This adds some confidence that severe symptomatic MERS is a relatively rare disease and one that does not spread quickly and efficiently. We have no real data to say that virus doesn't spread quick, widely and efficiently however, just that the severe infection outcomes don't.

So, no sign of a major jump in new cases. In this 4-week period there have been 13 cases which is up 2 from the 4-weeks before that. There have been 3 deaths (PFC of 23.1%, well below the total average of 41.3%) in this period, down from 4 in the previous month.

These numbers still have to be considered with care. This week's Spanish case really shone a light on the issue of laboratory unconfirmed cases of clinically diagnosed pneumonia circulating in the KSA. And where there is one such case there are likely to be others. Many others? We don't know.

So with 155 cases and 64 deaths in 87-weeks, MERS seems to be ticking along, but it shows no signs of becoming a widespread health issue. While it has a PFC of 41%, that is a meaningless number until we start testing more widely than is being done now. There are still many questions to answer about its host, how humans acquire it, whether its widespread in the community - but on the topic of transmission, MERS does not look likely to become a pandemic any time soon.

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MGH/MRRH OB/GYN Collaboration: Mbarara Uganda (Sep-Oct 2013)

I can�t say that I was shocked when I got to Mbarara Regional Referral Hospital.  I had been there before, so to speak,  only in a different country on the opposite side of the continent. I knew the stark and dramatic differences. I was however taken aback yet again. It was hard not to compare what I trained in and knew well with what I faced in Mbarara. At MGH we have 11 delivery rooms, each private, with large beds equipped with movable and removable parts. These accommodate 3000 deliveries a year. At MRRH they have 2 delivery beds. Simple steel frames with a thin black pad. 

Delivery bed on the Labour Ward at MRRH

These 2 beds take the hospital through over 8000 deliveries a year.  This most basic difference in physical resources is only just the beginning. In almost every aspect of patient care and management the residents and obstetricians at MRRH make do with so much less � almost zero nursing support, limited supply of drugs and equipment, limited antenatal records, often no dating of pregnancies, no electronic fetal monitoring, limited availability of neonatal resuscitation, limited or no oxygen. This list goes on and on.

Despite the limitations of medical care and lack of � almost everything physical, I have been most impressed by the abundance of fortitude and patience displayed by the women seeking obstetric care at MRRH. After a cesarean section, women simply get on with the necessities of life with very little support. To begin with, they get an astonishingly limited amount of pain medication. At MGH women routinely receive IV toradal, shortly followed by regular doses of oxycodone or dilaudid, which they not only have throughout their hospital stay, but also go home with. Here at MRRH, it is a dose or two of pethidine (demerol) immediately post op, and then rectal diclofenac as needed. That�s it, and no complaints - they just deal with it.  They go to the bathroom themselves, empty their foleys themselves, , provide for their own meals, own sheets, and own supplies as needed.  They get only the basics from the hospital � a �Mama Kit� which includes: a bar of soap, 2 plastic sheets (on which they have their vaginal exams and on which they deliver), a roll of cotton wool (which become their pads), 2 packs of gauze, 2 razor blades, and a health card for their child. 

Mama Kit Provided to Patients on Admission

On top of that, their recovery is far from comfortable.  In a postnatal ward built to accommodate 30 women, there are often as many as 60. When the beds run out, which they always do, women, post vaginal delivery or some even post-cesarean get a mat pad and make a space on the floor � either squeezed in between two beds or at the foot of the beds. This happens every day. In the time I have been here I have never seen any woman complain, argue or express the slightest irritation at being placed on the floor. If they are asked to move to allow a doctor or nurse to get to a patient or a piece of equipment, again no frustration or complaints they simply pick up their mats, their personal belongings and their babies and move.

Postnatal Ward at MRRH

Without a doubt these women display extra-ordinary fortitude in coping with their physical pain and in managing without many of the comforts and support that women in Boston taken for granted. Perhaps even more remarkable is the resilience shown by a significant portion of these women  recovering from a neonatal loss, or delivery of a stillborn child. At this hospital the stillbirth rate has ranged from over 2-6% of deliveries. That is as many as 58 stillbirths per month, with over half of those often occurring intrapartum. Women who have suffered these losses also simply go on, also squeezed into the postpartum ward, perhaps next to, or in between women who are fortunate enough to have their babies well and crying at their sides. Their expressions and demeanor often reveal little and it is so easy to walk past them, or even examine and assess them without recognizing or acknowledging their loss.

 On rounds one day I attempted to ask a woman where her baby was. I was with a resident from India and we both could not communicate well. The woman lying next to her listened to our fumbled attempts, and took pity on us.  She could speak English ��the baby is in the Toto ward� (pediatric ward), she said quite simply, �they�ve taken it for testing�.  We thanked her and continued with our assessment of that patient. About 5 minutes later we got to the woman who had helped us. She also had no baby. We asked and she said � her baby didn�t make it. It was born alive and died shortly afterwards. From our conversation 5 minutes earlier I would never have known. For this woman, I had the opportunity to acknowledge her loss, and express some amount of empathy � though from where I stood I clearly had no concept of how she really felt. I wondered how many other women I had walked past or assessed without any recognition or acknowledgement of their loss. Knowing the stillbirth and neonatal rates, that I had done so was a certainty. 

Adeline Boatin
OB/GYN Global Health Fellow

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MERS-CoV case in Spain, imported from Saudi Arabia during visit for Hajj pilgrimage [UPDATED]

Spain's Ministry of Health, Social Services and Equality (Ministerio de Sanidad, Servicios Sociales e Igualdad) has been reported via the media (not yet on their website) as describing the first case of Middle East respiratory syndrome coronavirus (MERS-CoV) infection.

Click to enlarge.
MERS map of the world. Countries hosting internal
transmission for MERS-CoV are shown in red. Those
hosting imported cases in orange.

The case is being presumed to be imported from the Kingdom of Saudi Arabia (KSA). The subject, a 61-year old Moroccan woman (61F; presumably FluTracker's #153) living in Spain, had spent a month in the KSA (Oct 2 to Nov 1; the Hajj specifically occurred during Oct 13-18) and was showing signs and symptoms of a febrile cough illness on the 15th of October. She did attend the Hajj according to Helen Branswell's article. So can now put the "no cases during the Hajj" story to bed? We don't technically know when the virus was acquired.  61F was in the KSA for a long period so acquisition may have occurred before or after but let's not split hairs, it was a Hajj-related acquisition. 

61F is stable with a diagnosis of pneumonia (chest X-ray) which was made sometime around 28/29 October in a hospital in the KSA.

Timeliness is a big concern here. It seems that 7-days passed between a clinical diagnosis of pneumonia in KSA, a flight from Jeddah to Madrid and a laboratory diagnosis (at the National Center for Microbiology in Spain) of MERS-CoV infection on Nov 5th. That's perhaps 21-days between onset and laboratory confirmation. Spanish contact tracing commenced at the time of confirmation (6-Nov). 

I guess we'll see if there are any more details to be had about the transport process (isolation/containment procedures?). We do know that 61F was symptomatic and needed oxygen during the flight. 

It's a good thing MERS-CoV does not seem to transmit efficiently - there may have been many exposures between the 15th and the final diagnosis and hospitalisation in Spain. And why could the laboratory testing not have been completed in the KSA? Was a swab/aspirate/lavage taken for any testing there? Either this is a political thing or there are (?many) cases of pneumonia in the KSA that are going untested for MERS-CoV....or for any virus or bacterium?

The current MERS-CoV tally is 151 cases, 64 deaths (42.3%)

See Mike Coston's posts of the early reports here and here. Thanks to Helen Branswell (@HelanBranswell) for tweetification.

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Durban, South Africa

Determining HIV-associated cryptococcal disease with clinic-based, point-of-care screening in Durban, South Africa.

In August, I traveled to Durban, South Africa to collect pilot data for a study of diagnostics and to set up a new study related to cryptococcal infections, a common cause of HIV-related mortality.

The global burden of cryptococcal meningitis (CM) is estimated at 958,000 cases and 625,000 deaths per year, making CM a leading cause of AIDS-related mortality. The vast majority of CM occurs among HIV-infected people with advanced immunosuppression or within 3 months of antiretroviral therapy (ART) initiation. In sub-Saharan Africa, an estimated 7-19% of HIV-infected adults have asymptomatic cryptococcal antigenemia (CrAg) at the time of HIV diagnosis, and circulating CrAg predicts onset of CM and mortality. These antigens appear weeks before the onset of neurological symptoms, and among those with circulating antigens oral anti-fungal therapy (fluconazole) reduces the risk of CM and death. Thus, early detection of CrAg and prophylactic anti-fungal therapy might improve health outcomes, but few laboratories in resource-limited settings (RLS) have had the ability to expeditiously test for CrAg in serum.

In the first study, I worked with Ms. Julia Kleene (pictured below), a medical student at Stony Brook School of Medicine, to conduct testing of stored urine samples from a previous cohort (photos below).  In one long, exhausting day we managed to test approximately 800 urine samples using a rapid test for cryptococcal antigens.  This study was the first assessment of cryptoccocal antigen prevalence in the KwaZulu-Natal Province.  We tested participants with a wide range of CD4 counts.  We found about 10% prevalence of cryptococcosis among newly-diagnosed HIV-infected adults, and the results did not differ among people with higher CD4 counts, which is contrary to most other studies.  The results formed the basis for pilot data related to a K23 grant application and are currently being prepared for publication.

In the second study, I used the time to set up a new longitudinal study to determine the impact of clinic-based screening for cryptococcal infections at the time of HIV diagnosis.  During my visit, we were able to hire a local research assistant and a local research nurse.  We spent time at our clinical site arranging the flow of the participants through the stages of the study, preparing documents, and meeting with various research partners.  The study then started enrollment on September 12, and to date we have already enrolled over 200 participants.

The location of this study is the iThembalabantu Clinic in Umlazi, a township of Durban with over 1.2 million people and a very high burden of HIV and TB. The clinic offers HIV testing, counseling, and treatment, and has a pharmacy to dispense ART (first and second line regimens) and therapy for opportunistic infections. The clinic is staffed by 2 full-time physicians, 10 nurses, 4 HIV counselors, and a cadre of community health workers. Each day, clinic counselors test 30-40 adults for HIV, of whom an average of 36% are HIV-infected, and clinicians provide comprehensive care for >100 HIV-infected people.   The results of these studies will help inform future studies of point-of-care CrAg screening in South Africa, as well as other resource-limited settings, to help prevent AIDS-related mortality.

The travel funds provided an essential opportunity for me to travel to Durban to collect pilot data for my K23 application, and at the same time to lay the groundwork to initiate a new prospective clinical study. I have very grateful to Partners for the Global Health Center of Expertise travel grant to help support my clinical research projects.  I would definitely recommend this funding opportunity to other clinical fellows.

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Cape Town, South Africa � Jessica Magidson, Postdoctoral Fellow, Chester M. Pierce, MD Division of Global Psychiatry, MGH

After leaving Harare, the second part of my trip is in Cape Town South Africa. Here I am focusing on clinical research, primarily to build relationships with faculty in the psychiatry department at University of Cape Town (UCT) who are also involved in the capacity building initiatives in Zimbabwe and the clinical research we were working on while in Harare�to train health care workers in empirically supported behavioral interventions for improving antiretroviral therapy (ART) adherence and depression. In addition to discussing with UCT faculty the ongoing progress on the work in Zimbabwe, I am also discussing ideas for future clinical and research collaborations with their team to pursue during my postdoctoral fellowship. While in Cape Town, I am also spending time at Stellenbosch University and Tygerberg Hospital in the departments of psychiatry, infectious disease, and the department of medicine to become familiar with ongoing research projects and initiatives across these departments.  

One of the projects that my team in Behavioral Medicine at MGH has been planning with faculty in psychiatry at UCT is a randomized clinical trial (RCT) to examine the effectiveness of cognitive behavioral therapy (CBT) for improving depression and ART adherence in the South African setting. In this study, CBT will be implemented by nurses working in HIV clinics in the local townships, for instance in Khayelitsha. Khayelitsha is an impoverished settlement just east of Cape Town where an estimated 500,000 people reside. Recent estimates of the HIV prevalence in this area are approximately 20%. Further, rates of depression are also very high in these areas�among individuals with HIV, it has been estimated that rates of depression reach up to about 40%. There is a huge need for treatments for depression that can be integrated into HIV care in this context.

Khayelitsha

 

A manual for improving HIV medication adherence in HIV clinics in Khayelitsha that was developed by UCT faculty and our behavioral medicine director, Dr. Safren, which incorporates modifications for this setting.

There has been some preliminary work conducted by our team and the UCT faculty to adapt existing adherence interventions such as Life-Steps and CBT for depression for this setting. The resulting intervention culturally tailored for this setting, called �Ziphamandla�, translates as �to be empowered� in Xhosa. Xhosa, by the way, is one of the 11 official languages spoken in South Africa, and one of the most common spoken in the local townships such as Khayelitsha. Interestingly Xhosa has the unique feature of �click� consonants � the word Xhosa, pronounced �Kosa� also begins with a click. 

The CBT Ziphamandla intervention has been implemented thus far by two Xhosa-speaking nurses, one of whom was a psychiatric nurse, the other without previous mental health training. 14 individuals have been recruited from two of the busiest clinics in Khayelitsha, the Ubuntu and Michael Mapongwana ART clinics. The Ubuntu ART clinic was the first clinic in South Africa to offer ART and has approximately 7,000 HIV-positive patients registered in their database, the majority of whom are currently on ART. Initial results evaluating Ziphamandla seem very promising for improving depression, ART adherence, and overall functioning. The lead psychologist conducting this work, Dr. Lena Andersen, and I spent a lot of time during the visit discussing plans to disseminating the findings to the scientific community. The future RCT to compare this intervention with a control comparison condition in a larger sample will be an important future direction of this work and was an important priority for discussion throughout meetings with UCT faculty.

While in Cape Town I have also spent time at Stellenbosch University and Tygerberg Hospital to meet with faculty across different departments, including the Children�s Infectious Diseases Clinical Research Unit (KID-CRU), the psychiatry department, and the department of medicine.

During meetings at KID-CRU, although my clinical and research interests to date have largely focused on adults, we had interesting discussions regarding maternal psychosocial factors that may influence adherence and outcomes among infants and children living with HIV, as well as an emerging concern � psychosocial struggles among adolescents who are now living into adolescence and young adulthood following ART initiation from birth. 

KID-CRU, an impressive clinical research unit with its own pharmacy and laboratory, the site of numerous ongoing clinical trials focusing on improving HIV and TB outcomes among infants and children

This theme again came up while visiting the psychiatry department, where we discussed more in depth the types of psychosocial struggles among HIV-infected adolescents who have been taking ART since birth, and more specifically how factors such as substance use and impulsivity may affect adherence. It was also interesting to learn more about the structure of the psychiatry department at Stellenbosch and the different psychiatric clinical settings in the area (although I unfortunately could not visit the actual department...)

Finally, the meetings in the department of medicine were also very productive. We discussed the importance of integrating behavioral HIV research with other chronic conditions, importantly TB in this setting. We also discussed the lack of psychiatric epidemiological research to date on substance abuse among HIV-infected individuals in South Africa and ways in which initial quantitative research could lend itself to future intervention developmental efforts in an area. It is this area�the intersection of substance use, depression, and HIV self-care behaviors in both the South African and Zimbabwean context�that I hope to continue to pursue both clinically and in research.

I am extremely thankful for the opportunity to meet with faculty at UCT, Stellenbosch, and Tygerberg Hospital during this visit, for the hospitality of our gracious hosts in Zimbabwe, the support of Dr. Conall O�Cleirigh throughout the trip, as well as the mentorship in my global psychiatry fellowship from Drs. Steve Safren, Dave Henderson, and Greg Fricchione. I am very appreciative of the support from the COE travel award to enable these opportunities, particularly to be able to visit Zimbabwe for the first time. This was a fantastic experience for both clinical and research training, and I am already looking forward to the next visit to continue developing this line of clinical research and building  relationships with these clinical research teams in both Harare and Cape Town.

Early morning hike in the clouds up Table Mountain! Beautiful view of Cape Town.

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