Swine Flu in India – Are we prepared?

This is festival time in India. The festivities for Ganesh chaturthi and Eid barely over, this weekend is the culmination of Vijaydashami, celebrated across India in various forms. Whether it is Dussehra, Dasara, Dashahara, Navaratri or Durgotdsav, the common theme is victory of good over evil. Large crowds gather every day in temples and puja pandals across India.

In times of a flu outbreak, this is a public health nightmare. This year’s Ravana is the microscopic influenza A H1N1 (2009) virus. Will the arrows of public health preparedness be able to slay this new age Ravana? This unlikely in India, if you listen to what experts have to say.

I wrote earlier about the 3.1% mortality among swine flu cases in India. The latest Ministry of Health and Family Welfare (MoHFW) release is for September 24, 2009; it reports 8979 cases and 277 deaths – 3.08% mortality.

Prof. T. Jacob John, unarguably India’s most prominent public health scientist, thinks this high mortality could be due to a selection bias – those with more severe illness are being tested. So, what has been India’s testing policy? A larger question is how has India dealt with this outbreak from a public health perspective.

An editorial in the August issue of the Indian Journal of Medical Research (IJMR) written by Prof. Jacob John and Prof. Jayaprakash Muliyil, provides a very frank and analytical assessment. It also provides sagacious advice to the Government on what it should and should not be doing.

The editorial can be read at http://www.icmr.nic.in/ijmr/2009/august/editorial1.pdf (I am grateful to the authors and the Editor, IJMR for their permission to post this link).

They say, and I quote – “At the request of the World Health Organization (WHO), many countries including India had made a detailed Pandemic Preparedness and Response Plan (PPRP). Many experts believed that India would, for the first time in our history, be well prepared to face an epidemic.-------- The events that took place in June, July and up to mid-August (as we write this) are still fresh in our memory. The expectation that India would face the pandemic with confidence and competence gradually gave way to disappointment and dismay. While the virus is reaching many places and spreading among the population, as anticipated, India does not have a public health infrastructure that could put into practice the PPRP”.

Prof. Jacob John agreed with my call in an earlier post and adds – “Science must guide policy. Policy must drive public health. So public health interventions must be evidence-based”.

Those who matter at the MoHFW and Indian Council of Medical Research will do well to read this editorial (which is in their own journal), and to ensure that policy is driven by science and not the other way around.

A Vaccine for AIDS

The human immunodeficiency virus (HIV), which causes AIDS, has been a difficult target for vaccine developers.

Vaccines are substances that mimic a pathogen to raise immunity in the host (human), which disables (neutralizes) and clears the pathogen from the body in the event of a natural infection.

Two types of immune responses are required for complete protection. These include humoral responses in which antibodies develop to neutralize extracellular pathogens, and cellular responses in which special cytotoxic cells are recruited to kill host cells that have become infected. An ideal mix of the two types of responses are required, and this mix is different for different pathogens.

The problem in the HIV field has been a poor understanding of the correlates of protection. In other words, we don't understand the quality and quantity of humoral and cellular responses that are required to prevent HIV infection. The problem is compounded by the extremely variable nature of HIV, which enables it to evade host immunity.

September 2009 has been a good month for HIV/AIDS vaccine efforts.

On Sept 3, a paper published in the journal Science, by a consortium of scientists led by the International AIDS Vaccine Initiative reported the discovery of two neutralizing antibodies, which target a potential Achilles heel on the virus surface. The discovery was the result of a global effort to search for antibodies in people who naturally control HIV infection. This is likely to provide important clues for engineering better vaccines. 

Good news was released today from a vaccine trial conducted jointly by the US Military HIV Research Program and the Thai Ministry of Public Health. This trial initiated in 2003 was a Phase III efficacy study of a prime-boost combination of two vaccine candidates - ALVAC, a bird pox virus carrying the HIV envelop protein (gp120) gene manufactured by Sanofi-Pasteur, and AIDSVAX, a recombinant form of gp120, manufactured by VaxGen (now Global Solutions for Infectious Diseases). Both of these candidate vaccines were earlier tested individually and found to have no efficacy.

The results released today showed a 31% efficacy for a prime-boost approach using these two vaccine candidates. Though the efficacy is not impressive, this is the first time a candidate AIDS vaccine has shown any level of protection in humans.

More details on the antibody discovery and the vaccine trial are available from the following sources:
International AIDS Vaccine Initiative: http//www.iavi.org
US Military HIV Research Program: http://www.hivresearch.org/
Science magazine:  http://www.sciencemag.org/cgi/rapidpdf/1178746

Swine Flu in India

The last situation update from WHO puts the number of positive cases worldwide at over 296,471 with at least 3486 deaths (http://www.who.int/csr/don/2009_09_18/en/index.html).

India's Ministry of Health and Family Welfare (MoHFW) puts out daily updates on the swine flu situation in the country (http://mohfw.nic.in/press_releases_on_swine_flu.htm). The updates started on August 1, 2009, by which time there were already 534 positive cases but no deaths. The first death, a 14-year old schoolgirl from Pune, was reported on August 3, 2009. Since that time, the number of positive cases have gone up steadily. As I write this, the last MoHFW update from September 21, 2009 reports that samples from 35,148 persons have been tested across the country, 8153 (23 .1%) have been found positive and 257 persons have died as a result of this infection.

The mortality rate in India stands at 3.1%, compared to a global average of 1.1%. What is the reason for this higher mortality in India? We don't know as there is no epidemiological analysis available. The reasons could be
(a) virological - increased virulence of the virus circulating here,
(b) host genetics - maybe Indians are genetically predisposed to get more severe disease
(c) environment -  poor healthcare infrastructure, late reporting of cases, selection bias with only severe cases being tested, etc.
It could also be an interesting mixture of all of the above.

The point is - unless we look at these issues systematically, we will not know.

I have made a graph on the situation in India based on MoHFW updates. The plot shows positive cases and deaths every 5 days from the start of updates (Aug 1, 2009) for the first 50 days of reporting.

 

It is quite clear from the graph that the outbreak in India is growing at a steady rate. Since early in the outbreak, the number of cases have gone up  at the same rate. The pink line in the graph has a constant slope. Curiously, the death curve shows a hint of biphasic nature to it. The death rate seems to be picking up lately. After running almost parallel with the positive cases curve for some time, the death curve has now intersected it.  Will it continue its upward spiral? In the absence of any analysis or models, only time will tell.

India has done well in gearing up resources to put testing in place. Scientists and technicians involved in testing for swine flu have done an admirable job. They have used all the resources at their command to test quickly and have adhered to quality.

But this is only half the job done. We should be analyzing this outbreak. The Indian Council of Medical Research (ICMR; http://www.icmr.nic.in/), whose mandate is medical research, should be driving this. We have a National Institute of Epidemiology, an ICMR institute in Chennai (http://www.icmr.nic.in/pinstitute/nie.htm). What are those guys doing? What are the public health experts at the  Public Health Foundation of India (http://www.phfi.org/) doing? The PHFI website has H1N1 flu advice (http://www.phfi.org/h1n1flu/index.html), but no analysis.

It is the same case with virological analysis. No genomic data is available on the virus circulating in India. The Influenza Virus Resource uploads genomic data in the public domain on a daily basis. See http://www.ncbi.nlm.nih.gov/genomes/FLU/SwineFlu.html. There is no data in the public domain from India. And it is truly shameful.

Is the virus in India showing genomic signatures of increased virulence? How many mutations will it take to make it highly virulent? Are we beginning to see the H274Y mutation in the NA protein, which is reported to be associated with Oseltamivir (Tamiflu) resistance? WE DON'T KNOW.

Should we not have science drive policy? Where is the science? It is time for ICMR, PHFI, Ministry of Health, Ministry of Science and the scientific and biomedical research community at large to ask these questions.

In India, our flu season is just beginning. Wake up.

Swine Flu - a triumph for science

Influenza pandemics happen about three times in a century. At least this is what 20th century history teaches us. There was the big Spanish Flu of 1918 (which did'nt really start from Spain), which infected an estimated third of the human population at that time and killed 40 to 50 million people. Then, there were the Asian Flu of 1957 and the Hong Kong Flu of 1968, each killing an estimated 1 million persons each.

Historically we were due for another big one. Is this the one? The swine flu (again a misnomer) started in Mexico around March of this year and has gone around the world, prompting WHO to raise its alert to Level 6, the first time in over 30 years. As of September 6, 2009, this disease has infected over 277,000 persons and killed at least 3200 (see http://www.who.int/csr/don/2009_09_11/en/index.html). If you believe that in infectious diseases you only see the tip of the iceberg, there are many more infections and deaths that have gone unrecorded. And we are just getting into the flu season in the Northern hemisphere.

So far this virus appears to be mild. It has killed about 1% of infected people, many of whom had underlying problems such as asthma, diabetes, hypertension and obesity. Yes, obesity! Thats a new one positively identified for this virus. But will it remain mild? No one knows. History tells us otherwise.

The 'Spanish flu' started as a mild infection in the summer of 1918, spread rapidly and the virus got a lot of chance to mutate. By November of 1918, the flu season in the Northern hemisphere, it became highly virulent and killed with disdain. We are into a similar situation with this one. It has already gone around the world, including Australia and South America (Southern hemisphere) in their flu season, and is getting a lot of chance to transmit and mutate. Health agencies are already preparing for the 'second wave'. See
http://www.who.int/csr/disease/swineflu/notes/h1n1_second_wave_20090828/en/index.html

Are we then sitting ducks? Or pigs to be more appropriate for this one! Not really. Health systems are much better prepared to handle these emergencies today than they were 90 years ago. The agent for Spanish flu took over 11 years to identify. The 'swine flu' virus was identified in days.

This virus, technically called Influenza A H1N1 (2009), is a triple reassortant. Scientists have traced its 8 different gene segments to influenza viruses that have circulated in humans, birds and pigs (see: Garten et al, Science vol 325, pages 197-201; July 10, 2009). The cartoon below illustrates the lineage of different gene segments in this new virus.
The surface proteins of the virus - the hemeagglutinin (H1) and the neuraminidase (N1), are both of swine origin. This makes the virus new to the human population, not recognized by our immune system. This is obvious from the efficient manner in which it is transmitting between humans.

Every adversity has a lesson. The lesson here is how investments in biomedical science are paying up in unexpected ways. It took just days to identify this virus and weeks to come up with its origins. This is truly the power of molecular biology, built up over years with the Human Genome Project as a very visible high point. Many have criticized that megaproject, but consider that it enabled the development of technology, which is making all this possible. When SARS came around in 2003, the sequencing of its genome was also undertaken in facilities set up for the HGP. Chinese scientists sequenced the SARS virus genome in a facility built to sequence the rice genome! That is a great off-target effect and a lesson for science funders and planners.

Every day dozens of swine flu sequences are being uploaded in public databases (http://www.ncbi.nlm.nih.gov/genomes/FLU/SwineFlu.html). Many scientific journals, normally driven by commercial interests, have made swine flu papers "open access". This uninhibited access to knowledge and the power of internet is bringing the technical prowess of big science closer to where it matters - the hot zone.

Are we really making use of this knowledge in my hot zone - India? Stay tuned.

Ten days in Turkey - Part 10

Time to go home

Time to say goodbye to this lovely city. We spent the morning having a lazy breakfast, soaking the last views of Sultanahmet Camii from our hotel’s terrace.

As I reflect back on this trip, it could not have turned out any better. We had cherished this trip for a long time. Over almost two decades my interaction with Turkish students who trained with me in Delhi has been a pleasant one. We have become friends for life. Their warmth is genuine and that comes from the warmth you feel everywhere in this beautiful country. Our hosts, their extended families (the network of cousins), the staff at Ararat Hotel, the masseurs at the hamam, the shopkeepers at the Bazaar, the Turkish professor and his students at the conference, were all warm and interesting in many ways. The sights notwithstanding, it is they who made this trip memorable.

The writer Elif Shafak, whose novel The Bastard of Istanbul is both widely read and despised for insulting Turkishness, writes – “Like a pendulum, Istanbul swings obstinately between cosmopolitanism and nationalism, memory and amnesia — between a weighty past we can never fully shed, much as we like to try, and a hopeful future we can only run after but never quite grab hold of. Istanbul is the stepchild of the modern, secular Turkish Republic. But it still embodies remnants of a multicultural imperial legacy that don't quite match the founding myths of a supposedly homogeneous nation-state”.

There is so much common between Turks and Indians in their approach to life, their hospitality and the huzun they feel by not being in control of things. The muslims of India have historical attachments to Turkey with the Khilafat movement and its leaders being an integral part of our own struggle for independence. It was especially memorable for me as a muslim to see important religious relics at the Topkapi Palace, which one only has only read about. Being a muslim capital for over 700 years and never to have been conquered by the army of a different faith, the Islamic monuments and treasures are especially well preserved here. This is unlike Delhi, which was probably richer than Istanbul at the peak of the Mughal Empire, but was subsequently plundered by the British rulers.

Turkey, I hope you stay that way, even when you are part of the European Community. You aspire to be European, but you are more Asian in your approach to life, your values, your hospitality and your huzun.

Thank you Turkey. Thank you Bursa, Konya, Istanbul and all the lovely people we met in the last ten days. I hope to be back another day. Inshallah.

Ten days in Turkey - Part 9

The Bosphorus, Spice Bazaar and Hamam

Every great city has a river. In Istanbul, it is the Bosphorus, Bogaziçi to the Istanbullus. No visit is complete without a boat ride up and down the Bosphorus. We boarded a cruise boat at the Eminönü docks, paying 5 YTL per person for a two-hour cruise. It was a two-level boat that could easily accommodate about 300 people. As the boat leaves the dock one sees fantastic views of the city skyline dominated by architectural delights on the various hills that are part of Istanbul. There is the Yeni Camii next to the docks, the Suleimaniye Camii, the Galata Tower, the Topkapi Palace and various other mosques.

Travelling up the Bosphorus from the Golden Horn towards the Black Sea, the Asian part of Istanbul is on the right shore and the European part on the left shore. From the panoramic views, one cannot help notice the European bank to be dominated with the most important historical monuments of Istanbul. The Asian bank appears largely residential with Ottoman houses dominating the hills and fancy (and very expensive villas) along the river. Orhan Pamuk’s description of the Bosphorus in his “Istanbul: Memories of a City” comes alive. The Bosphorus yalis (Ottoman houses) Pamuk describes from his childhood are gone, but one can occasionally spot an odd one, half burnt, standing by itself, waiting to be torn down and replaced by an expensive villa.

A tower with smaller buildings around it stands in the water. This is the Kiz Kulesi also called Leander’s Tower. Originally built in 4th century BC and used by Greeks to regulate Bosphorus traffic, the tower was rebuilt by Sultan Mehmed II and then again in 1716 by the Grand Vizier Ibrahim Pasha. As the Ottomans consolidated their Empire the tower lost its defensive function and was used as a lighthouse. Legend has it that a fortuneteller predicted a princess to die of snakebite. The hapless girl was sent to this tower away from land to save her; the snake however made its way to the girl in a basket of fruits brought on by the locals. Historical records however reveal other uses for this tower.

The boat goes under the first bridge that connects the Asian and European sides of Istanbul. From here on, one building clearly dominates the Asian bank of the Bosphorus. This is the Çiragan Palace, now the Çiragan Hotel. This wooden palace of Fatima Sultan, wife of the Grand Vizier Ibrahim Pasha, was named Çiragan due to its night parties. Later it became a summer resort for the sultans. The main structure came up in the mid-19th century during the rule of Sultan Abdulaziz. This palace had a troubled history of imprisonments, rescue efforts and murders, but also served as a meeting place for the Ottoman Parliament. In 1910, at the time of the Turkish Revolution, the palace was burnt down to its bare walls and was reconstructed as a hotel in 1980.

As the boat approaches the second bridge across the Bosphorus, it starts turning back. The sun is low and colors the Bosphorus silver-grey. At this point the Rumeli Hisari (Rumelian or European Fortress) dominates the view. Sultan Mehmed II built this fortress in 1452 while preparing for the final assault on Constantinople. Built at the narrowest point on the Bosphorus, its purpose was to prevent the entry of Byzantine ships. With canons placed on the fortress walls, the channel was completely closed to the passage of ships. After the conquest of Constantinople, the fortress served no military purpose and has been used over the years as a prison and now as a museum.

Riding back, the European part of Istanbul that is on our right. At the suburb of Ortaköy the view is dominated by the small but beautiful Ortaköy Camii. Built by Sultan Abdulmecit in 1853, this mosque in Baroque style has wide and high windows to bring in the changing lights of the Bosphorus. The Istanbul skyline dominated by the hills and mosques comes in view again as we come to the end of a wonderful excursion over the Bosphorus. A trip to Istanbul is indeed incomplete without seeing the city views from this lovely channel connecting the Golden Horn to the Black Sea.

Across from the ferry docks in Eminönü stands the Yeni Camii (New Mosque). Only in Istanbul you have a 450-year old mosque called the New Mosque! Next to it is the Spice Bazaar. Good-natured shopkeepers recognized us as Indians and greet us with names of Indian movie stars. Indian movies are quite popular in Turkey and are dubbed in Turkish. I would really like to see how they dub Bollywood songs in Turkish. It was fun. We bought black olives, olive paste, and loads of lokum (Turkish delight), a form of gooey candy filled with nuts. This market is filled with interesting stuff such as tea in all flavours and “natural Turkish viagra”. Whether the stuff works is anyone’s guess.

After an early and lazy supper and on my son's insistence, we decided to visit a Turkish hamam. Public baths (or hamams) are an inseparable part of the Middle Eastern and Mediterranean culture, many still in operation across this region. Unfortunately, many public baths, especially those in the West, have gained notoriety in this AIDS-sensitized world. We were told that Turkey is different and going to the hamam as a family is still a tradition here.

The Çemberlitas Hamam is Istanbul’s oldest and best. Based on a 16th century design of the master architect Sinan, this hamam has been in continuous operation for the last 145 years. It has separate sections for men and women, is pricey at 36 YTL per head for a 45-minute session, but comes highly recommended. We changed into wrapping cloth and were led into the public central room that was hot and humid. We lay there on the central marble slab and sweated for the next 20 minutes. The sinuses clear up and all the aches and pains disappear. The massage had not begun yet. A good natured and burly masseur started working and for the next 15 minutes it was pure bliss. The first part was a scrubbing with a coarse mitten that is meant to loosen the dirt and get rid of dead skin. This is followed by a soapy massage and a thorough wash down. Later we were wrapped in thick towels and asked to rest in our cubicle for the next 30 minutes. A glass of freshly squeezed orange juice to end the experience and you already feel like a new person for whom no challenge is too great.

For once, I was glad I listened to my son.

Ten days in Turkey - Part 8

Walking in Istanbul

We walked through the Sultanahmet and Beyazit districts to the Istanbul University campus. This took us through streets bustling with activity, shoppers and tourists alike. This area is a good example of how the ancient and the modern flourish next to each other in Istanbul.

We went past the Sebil (water kiosk) and Turbé (Tomb) of Sultan Mahmud II, a mid-19th century monument. The mausoleum has a plain, octagonal design, displaying the impact that western architecture had started making on Ottoman buildings. The tomb is noteworthy for its window railings that are elegant examples of iron embroidery.

Along the way are shops and craftsmen selling calligraphy on metal, pottery and tiles, as also enclosures where one could enjoy çay and nargillé (water pipe, hubble-bubble or huqqa). There are eating places of all kinds from McDonald’s to traditional Turkish fare such as Gözlemé and Baklava. We were to come back to the Gözlemé restaurant for an interesting meal the following day.

We went past the Çemberlitas Hamam, walked along the outer perimeter of the Grand Bazaar to finally land up in a large open plaza, the Beyazit Square, with the Istanbul University Gate on one side and the Beyazit Mosque on the other, both imposing structures in their own right.

Entered through an impressive gate done in Imperial style are the large gardens and buildings that make up the main campus of Istanbul University. Completed in 1866 during the reign of Sultan Abdulaziz, the main building originally housed the Ministry of War. This was the first building in Istanbul built in the Beaux Arts style with a central courtyard covered with a glass ceiling. In 1924 this building was given over to Darülfünun (House of Sciences) and in 1933 it became Istanbul University. Within the gardens stands the Beyazit Tower built in 1828 during the reign of Sultan Mahmud II as a watchtower for fires. Today, in addition to that, this 85 metre high tower is also used to collect meteorological data.

The Beyazit mosque was built in 1501-1505 on orders of Sultan Bayezid II, who succeeded Sultan Mehmet II to the throne in 1481. Known for his piety and administration, he provided stability to the Ottoman Empire and a platform for subsequent rulers to patronize arts and architecture. The Beyazit mosque is in a complex that also includes a public kitchen, a primary school, hospice, a medresse, a hamam and a caravanserai. The design is similar to other Ottoman mosques of that period, with a prominent sadirvan (ablution foundation) in the middle of a large courtyard. Stonework, woodwork and stained glasses inside this mosque are of high artistic value. On the Kiblah (direction of Mecca) side of the mosque are the tombs of Sultan Bayezid II and his daughter.

The Sahaflar Çarsisi (Book market) stands adjacent to the Beyazit mosque. Entered through an arched stone doorway, the market is a collection of shops around a small park with chinar trees and a bust on a pedestal (I forget who this is). All kinds of books are available in this market, from antique Persian texts to the Complete Idiot’s Guide to Windows. Many shops sell Turkish miniatures, mostly at exorbitant prices claiming these to be originals. I wonder how so many originals could have survived over the centuries. We bought a book on Turkish cooking, hoping to occasionally relive the tastes of Turkey.

I learnt later this was also a good place to shop for Istanbul classics such as Melling’s watercolors of Bosphorus views and the writings of Tapinar and Yahya Kemal on life in mid-20th century Istanbul. Thats for another day.

From the Book market we entered the Grand Bazaar or the Kapaliçarsi. Built originally by Sultan Mehmet II in 1461 and then rebuilt after being completely destroyed in the 1894 earthquake, this is an Istanbul landmark. The covered bazaar is spread over 30 hectares and consists of 61 streets and three main sections. It houses dealers in antiques, carpets, garments, leather, etc with each street dedicated to one profession.

Just walking through the Grand Bazaar is quite an experience. Bargain your heart out and you will land a good deal.