Leptospirosis Hits Puerto Rico in the Aftermath of Hurricane Maria

As expected, the news of rising numbers of leptospirosis cases are trickling in from Puerto Rico. Since Hurricane Maria hit Puerto Rico, there have been areas which have experienced over 30 inches of rain, which, subsequently, led to flooding. As has been often observed, following the exposure to potentially contaminated water, the reported number of leptospirosis cases has been on the rise. Leptospirosis is a water borne zoonosis, with humans being unwitting targets in its transmission cycle.

Leptospirosis Transmission Cycle: Image Credits Georgia Gwinnet College Wiki
Leptospirosis Transmission Cycle: Image Credits Georgia Gwinnet College Wiki

This week, a news outlet has reported that there have been two confirmed fatalities from leptospirosis. The news article further elaborates:

“This bacteria, like any other bacteria, can kill you,” Deseda said.

The island typically sees between 63 and 95 cases per year, she said. Health officials had expected that there would be a jump after the hurricane.

“It’s neither an epidemic nor a confirmed outbreak,” Public Affairs Secretary Ramon Rosario Cortes said at a news conference Sunday. “But obviously, we are making all the announcements as though it were a health emergency.”

Although it has not assumed epidemic or outbreak proportions yet, the problem with leptospirosis is that this is a largely mild disease. That means that this is one of the conditions in which the actual magnitude of the issue is much larger than what falls within the clinically visible spectrum. In epidemiology, this is often hailed as (or depending on your viewpoint, trivialized as) the iceberg phenomenon.]

Iceberg Phenomenon (Image Credits: Community Medicine Blog)
The Iceberg Phenomenon Image Credits: Community Medicine Blog

Although there is limited evidence to give an exact accounting of the asymptomatic:symptomatic infection ratio for leptospirosis in outbreak settings, an oft-cited paper states that less than 30% of seropositive individuals, studied in Nicaragua, reported a febrile illness in the two months prior to the testing. The suggestion of this paper, that asymptomatic leptospiral infection is common in endemic situations, is further backed up by the conclusions presented in the Laboratory Manual on Leptospirosis (2007), published by the Indian Council of Medical Research, Regional Medical Research Center at Port Blair, Andaman and the South East Asia Regional Office of the WHO. The manual states:

In endemic areas, the incidence of asymptomatic infection could also be very high. A survey conducted in Seychelles (17) showed 9% point prevalence of asymptomatic leptospiral infection as proved by positive Polymerase Chain Reaction Test (PCR). In a study conducted in the North Andaman, 27% of the 396 persons followed up serologically had evidence of leptospiral infection during the follow up period of 12 weeks in the postmonsoon season (22). [Refer to document for cited reference; link]

There has been some accumulating evidence on what factors might potentially modulate the emergence of leptospirosis. As is often (or should I say always?) the case with zoonotic infections, the disease manifests especially well when there is a constellation of “favorable” factors present. A review attempted to graphically present the related risks in a Venn diagram, as below:

Factors contributing to leptospirosis. Development of leptospirosis depends on three types of factors (epidemiology, host, and pathogen) and their interactions. Epidemiologic factors include sanitation, housing, rainfall, and whether flooding occurs. Incidence is linked to income level, occupation, and travel, representing epidemiologic factors linked to specific hosts. Hosts vary in susceptibility depending on age, genetic factors (e.g., HLA-DQ6), skin integrity, and whether protective clothing (e.g., gloves and boots) are worn. The ways in which the host and leptospires interact determine the route, exposure, and dose of the pathogen. Leptospiral pathogens differ in their ability to cause disease, a reflection of their virulence, motility, and ability to survive in the host, a reflection (at least in part) of complement resistance. The types of reservoir hosts determine the types of pathogens present in a particular epidemiologic setting
Factors contributing to leptospirosis. 

Development of leptospirosis depends on three types of factors (epidemiology, host, and pathogen) and their interactions. Epidemiologic factors include sanitation, housing, rainfall, and whether flooding occurs. Incidence is linked to income level, occupation, and travel, representing epidemiologic factors linked to specific hosts. Hosts vary in susceptibility depending on age, genetic factors (e.g., HLA-DQ6), skin integrity, and whether protective clothing (e.g., gloves and boots) are worn. The ways in which the host and leptospires interact determine the route, exposure, and dose of the pathogen. Leptospiral pathogens differ in their ability to cause disease, a reflection of their virulence, motility, and ability to survive in the host, a reflection (at least in part) of complement resistance. The types of reservoir hosts determine the types of pathogens present in a particular epidemiologic setting.


Public Health Response to Leptospirosis

The following excerpt from the ““WHO recommended standards and strategies for surveillance, prevention and control of communicable diseases” are applicable for the management of potential outbreaks of leptospirosis.

Control activities

Case management

  • Early treatment with antibiotics. Severe cases usually treated with high doses of IV benzylpenicillin (30 mg/kg up to 1.2 g IV 6-hourly for 5-7 days). Less severe cases treated orally with antibiotics such as doxycycline (2 mg/kg up to 100 mg 12-hourly for 5-7 days), tetracycline, ampicillin or amoxicillin.
  • Third-generation cephalosporins, such as ceftriaxone and cefotaxime, and quinolone antibiotics may also be
    effective. Jarisch-Herxheimer reactions may occur after the start of antimicrobial therapy.
  • Monitoring and supportive care as appropriate, e.g. dialysis, mechanical ventilation.

Prevention

The large number of serovars and of infection sources and the wide difference in transmission conditions make
leptospirosis an unlikely candidate for national eradication. Preventive measures should be based on knowledge of
those groups at higher risk of infection and of local epidemiological factors; they include:

  • Identifying and controlling the source of infection (e.g. open sewers, contaminated wells).
  • Control of feral reservoirs is often not feasible but control measures can be highly effective in small, defined animal populations (dogs, certified cattle herds) Selective rodent control may be important.
  • Interrupting transmission, thereby preventing infection or disease in the human host: ƒ
    • wearing protective clothes and equipment;
    • disinfecting contaminated surfaces such as stable and abattoir floors;
    • marking areas with increased risk exposure (warning signs).
  • Preventing infection or disease in human hosts:
    • antibiotic prophylaxis of exposed persons in areas of high exposures may be effective, e.g. soldiers (doxycyclin 200mg in one weekly dose);
    • raising awareness of the disease and its of modes of transmission.

Epidemics

Conditions under which epidemics may occur

  • Conditions leading to an increase of contaminated surface water or soil, such as rain, floods and disasters
    increase the risk of leptospirosis and may lead to epidemics. During periods of drought both humans and animal reservoirs may be attracted to spare water places, hence increasing the risk of infection.
  • Social and recreational activities that expose persons to a contaminated environment.

Management of epidemics

In a suspected outbreak, attempts to diagnose leptospirosis must be encouraged to enable prompt treatment. For
outbreaks in remote or areas with poor access, local use of screening tests to detect antibody is helpful. When an
outbreak of leptospirosis is suspected or identified, and if it has been possible to identify the serovar concerned, the
source must be identified and appropriate environmental measures implemented, with public information to people at risk (including clinicians and health care workers and health authorities).

Drug-resistance monitoring

No reports of resistance for common antibiotics (see Case management above) and no guidelines for monitoring.
Testing of antibiotic resistance in individual clinical cases is not useful since it requires considerable time.

Performance indicators for control activities

  • Number of new cases per 100 000 population over time.
  • Seropositivity in selected populations.

The Diagnostic Dilemma of Leptospirosis

The challenge of reaching a diagnostic conclusion with a suspected case of leptospirosis is no less daunting than the public health activity of controlling an outbreak of this disease. Aside from the fact that it is not always on the diagnostic radar of clinicians, especially if they are not hyper-vigilant (which can sometimes come off as over-diagnostics or defensive medicine) or are not aware of the relevant exposure history, the complex immune response also plays a part in the diagnostic prevarication that often may accompany leptospirosis in areas where it is not always on the first list of differential diagnoses. In India, we were taught a “truism” which works well for identifying patients potentially exposed to a higher degree of risk of leptospirosis: “It is a disease of ‘rats, rains and rice’!”

This helpful schematic, from a review on Leptospirosis, can shed some light on the diagnostic approaches to managing leptospirosis:

Biphasic nature of leptospirosis and relevant investigations at different stages of disease. Specimens 1 and 2 for serology are acute-phase specimens, 3 is a convalescent-phase sample which may facilitate detection of a delayed immune response, and 4 and 5 are follow-up samples which can provide epidemiological information, such as the presumptive infecting serogroup. Adapted from Turner LH (1969). Leptospirosis. Br Med J i:231–235. Copyright © American Society for Microbiology, (Clin Microbiol Rev 2001, 14 (2):296–326. doi:10.1128/CMR.14.2.296-326.2001)
Biphasic nature of leptospirosis and relevant investigations at different stages of disease. 

Specimens 1 and 2 for serology are acute-phase specimens, 3 is a convalescent-phase sample which may facilitate detection of a delayed immune response, and 4 and 5 are follow-up samples which can provide epidemiological information, such as the presumptive infecting serogroup. Adapted from Turner LH (1969). Leptospirosis. Br Med J i:231–235. Copyright © American Society for Microbiology, (Clin Microbiol Rev 2001, 14 (2):296–326. doi:10.1128/CMR.14.2.296-326.2001)


Leptospirosis in India

India has had its own share of misfortunes with outbreaks of leptospirosis, with case in point being outbreaks in Mumbai and Chennai after massive rains led to a deluge. The National Centers for Disease Control, in collaboration with the Country Office for WHO, came up with a comprehensive document to address the public health challenge of leptospirosis outbreaks: Guidelines for the Prevention and Control of Leptospirosis. One interesting factor which has been addressed in these guidelines is the use of chemoprophylaxis for potentially exposed individuals. The document states:

15.8 Chemoprophylaxis

During the peak transmission season Doxycycline 200 mg, once a week, may be given to agricultural workers (eg. paddy field workers, canal cleaning workers in endemic areas) from where clustering of cases has been reported. The chemoprophylaxis should not be extended for more than six weeks.

There is some room to potentially study the beneficial impact of this strategy, and balance it against the potential adverse effects of basically exposing a large number of people to a mass drug administration strategy. As always, my personal interest is always inclined towards understanding the potential for the emergence of antimicrobial resistance, not only in Leptospires, but also other pathogens for which Doxycycline is a viable therapeutic alternative, which may get caught up in the crossfire – but not be entirely eliminated, thus helping to select for the resistant strains.

Antibiotic Resistance: Image Credits Beatrice the Biologist
Antibiotic Resistance: Image Credits Beatrice the Biologist

Hepatitis Outbreak in Syrian IDP Camp Follows Cholera Case Detection

In a matter of hours since I wrote about the diagnosis of a child suffering from cholera in the camp for housing the displaced population from Homs, I received yet another ProMED missive, informing us about the diagnosis of a hepatitis outbreak in the same settings. In fact, in addition to the information, there is a request for more information, especially data on the serologic diagnosis of these patients. The ProMED alert, translated by moderators, stands as below:

Viral hepatitis has started to spread among tens of displaced people in Zogra camp near Jarabulus city (125 km or 78 miles north of Aleppo) at the Syrian-Turkish border, which accommodates people displaced from Homs.

A medical source told Smart News on [Thu 19 Oct 2017] that jaundice or viral hepatitis has begun to spread among the displaced people aged 10 to 40 years in the camp. Around 100 cases of the disease have been identified in addition to almost the same number of suspected cases. It is expected that the cause of infection is water pollution, potential contamination of the distributed food or vegetables, and not washing them properly.

The source warned of the spread of infection among a larger number of people if preventive measures are not taken through awareness campaigns and maintenance of sewage networks as soon as possible.

The 10 200 persons living in the camp have previously complained of lack of food and health assistance and lack of water and electricity.


Now, this is not surprising at all, given that the risk of one water borne infection, especially in a conflict setting, is likely to increase the threat of other water borne infections, especially ones following the fecal-oral transmission pathway. Although the post does seek more information on the serology of the patients, one would not be too misplaced if they were to hazard a guess that the likely culprit was Hepatitis E, especially if a large proportion of the sickened population were adults. Hepatitis A is an omnipresent pathogen, especially in settings with inadequate sanitation barrier and constrains on water (both quality and quantity). Consequently, most people acquire the infection in their childhood and bring along the immune response alongwith them. The other worry with Hepatitis E is that although it is usually self-limiting, much like Hepatitis A, in one situation it can precipitate disasters – in pregnant women. Mortality rates in the ~30% are not unforeseen, especially if the diagnosis has been delayed.

 

Given the disorder which is expected in refugee camps, and the burgeoning numbers of water borne infections starting to crop up, one does feel like this is the beginning of a bad nightmare. With minimal infrastructure and sociopolitical stability available, it is likely that such an outbreak could prove difficult to contain. Immediate reassurance of water quality and quantity, and focusing on breaking the fecal-oral transmission cycle are, therefore, of vital importance.

It remains to be seen how this situation proceeds.

Cholera Case in Syrian Refugee Camp: Ominous Signals

According to a report disseminated by the ProMED mail service, a case of cholera has been detected in a refugee camp housing displaced people from Homs. The translated report reads as below:

The 1st case of cholera has been recorded in Zogra camp near Jarabulus city (125 km or 78 mi north of Aleppo) at the Syrian-Turkish border, which accommodates people displaced from Homs. A medical source told Smart News on [Thu 19 Oct 2017] that cholera symptoms have been identified in a 4-month-old girl who had a severe form of rice water diarrhea, accompanied by dehydration and hypotension.

The cause of the cholera outbreak is possibly related to polluted water sources in the camp and the exposed sewage system that provides a source for flies to transmit the disease. The source pointed out that they have communicated with the Directorate of Health, which promised to take appropriate action. The source warned of the spread of infection among a larger number of people if preventive measures are not taken through awareness campaigns and maintenance of sewage networks as soon as possible.

The 10 200 persons living in Zogra camp have previously complained of lack of food and health assistance and lack of water and electricity in the camp.

As the experience from Yemen has adequately demonstrated, a broken healthcare system, in conflict situations, with risks of water contamination and inadequate food and water supply provides the perfect storm for cholera to manifest as explosive outbreaks.

Image Credits: AA

The Global Task Force for Cholera Control highlights the following for cholera control:


Control

Among people developing symptoms, 80% of episodes are of mild or moderate severity. The remaining 10%-20% of cases develop severe watery diarrhoea with signs of dehydration. Once an outbreak is detected, the usual intervention strategy aims to reduce mortality – ideally below 1% – by ensuring access to treatment and controlling the spread of disease. To achieve this, all partners involved should be properly coordinated and those in charge of water and sanitation must be included in the response strategy. Recommended control methods, including standardized case management, have proven effective in reducing the case-fatality rate.

The main tools for cholera control are:

  • proper and timely case management in cholera treatment centres;
  • specific training for proper case management, including avoidance of nosocomial infections;
  • sufficient pre-positioned medical supplies for case management (e.g. diarrhoeal disease kits);
  • improved access to water, effective sanitation, proper waste management and vector control;
  • enhanced hygiene and food safety practices;
  • improved communication and public information.

WHO recommendations to unaffected neighbouring countries

Countries neighbouring an area affected by cholera should implement the following measures:

  • improve preparedness to rapidly respond to an outbreak, should cholera spread accross borders, and limit its consequences;
  • improve surveillance to obtain better data for risk assessment and early detection of outbreaks, including establishing an active surveillance system.

However, the following measures should be avoided, as they have been proven ineffective, costly and counter-productive:

  • routine treatment of a community with antibiotics, or mass chemoprophylaxis, has no effect on the spread of cholera, can have adverse effects by increasing antimicrobial resistance and provides a false sense of security;
  • restrictions in travel and trade between countries or between different regions of a country;
  • set up a cordon sanitaire at borders, a measure that diverts resources, hampers good cooperation spirit between institutions and countries instead of uniting efforts.

Image Credits: Oxfam on Medium
Drawing on the Yemen experience, and recent experience from conflict-ridden areas of South Sudan, using a single-dose based approach with oral cholera vaccines potentially presents a strategy to contain potential explosive outbreaks. On the bright side, the early detection of the case could help to staunch the potential cascade of cases that could follow. The appropriate actions being taken need to be established on an emergency basis so that the situation does not spiral out of control.
A girl fills a container with water from a public tap in the old city of Sanaa, Yemen (AP Photo/Hani Mohammed) Image Credits: Center for International Governance Innovation
The worry is that once an outbreak of cholera is in full swing, too much of effort and resources get redirected to case detection and management, and prevention of mortality, and little is left over to dedicate to preventive actions, especially to break the transmission cycle, which means not only interrupting transmission of infections, but also ensuring safe water provision across the board, which is, even at the best of times, a challenging affair.

Clinical Research in Times of Ebola… and other Epidemics

As the news trickles in about the raging cholera outbreak in Yemen, and an emerging outbreak is being dealt with urgently in North-Eastern Nigeria, we are more frequently being confronted with the uncomfortable question of leveraging these situations to conduct clinical research activities. The National Academies of Science, Engineering and Medicine (NASEM) have come out with a report dealing with exactly this quandary. This report, aptly titled, “Integrating Clinical Research into Epidemic Response: The Ebola Experience”, deals with this ethically challenging issue. In the blurb to this report, the authors succinctly hint at the importance of this publication:

The 2014 Ebola epidemic in western Africa was the longest and deadliest Ebola outbreak in history, resulting in 28,616 cases and 11,310 deaths. In the midst of the rapidly spreading, highly dangerous contagious disease—with no Ebola-specific vaccines or therapeutics available to help curb the epidemic—the international community implemented clinical trials on investigational agents, not yet studied in humans for safety or efficacy. Within that context, the Office of the Assistant Secretary for Preparedness and Response, the National Institute of Allergy and Infectious Disease, and the U.S. Food and Drug Administration, supported the National Academies of Sciences, Engineering, and Medicine to convene a committee to analyze the clinical trials that were conducted during the epidemic and consider the many scientific, ethical and practical issues related to the conduct of research in similar contexts. The resulting report, Integrating Clinical Research into Epidemic Response: The Ebola Experience, assesses the value of the trials and makes recommendations about how the conduct of trials could be improved in the context of a future international emerging or re-emerging infectious disease event.

The NASEM have further outlined a set of recommendations based on their Ebola experience. The highlights of these include:

RECOMMENDATION 1:
Support the development of sustainable health systems and research capacities—Inter-epidemic

RECOMMENDATION 2
A. Develop memoranda of understanding to facilitate data collection and sharing—Inter-epidemic
B. Provide resources to enable data collection and sharing—Epidemic

RECOMMENDATION 3
Facilitate capacity for rapid ethics reviews and legal agreements—Inter-epidemic

RECOMMENDATION 4
Ensure that capacity-strengthening efforts bene t the local population—Epidemic

RECOMMENDATION 5
Enable the incorporation of research into national health systems—Inter-epidemic

RECOMMENDATION 6
A. Prioritize community engagement in research and response—Epidemic
B. Fund training and research into community engagement and communication for research and response—Inter-epidemic

RECOMMENDATION 7
A. Coordinate international efforts in research and development for infectious disease pathogens—Inter-epidemic
B. Establish and implement a cooperative international clinical research agenda—Epidemic