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Lana

Cryptococcal Meningitis

Introduction
Cryptococcus neoformans is an encapsulated yeast. Infection with the encapsulated yeast Cryptococcus neoformans a subacute or chronic infection which may affect the lungs or the skin but most commonly manifest as meningitis, especially in immunocompromised. Cryptococcosis represents a major life-threatening fungal infection in patients with severe HIV infection and individuals with suppressed immunity those receiving organ transplant, reticuloendothelial malignancy, corticosteroid treatment, or sarcoidosis.

Signs and symptoms
The presentation in cryptococcosis varies with the site of infection and the patient’s immune status. Signs and symptoms of pulmonary cryptococcosis in immunocompetent patients are as follows:
•    Cough (54%)
•    Cough with the production of scant mucoid sputum (32%)
•    Pleuritic chest pain (46%)
•    Low-grade fever, dyspnea, weight loss, and malaise (less common)

HIV-infected patients with pulmonary cryptococcosis may present with the following:
•    Fever (84%)
•    Cough (63%)
•    Dyspnea (50%)
•    Headache (41%)
•    Weight loss (47%)

Other possible findings in pulmonary infection are as follows:
•    Pleuritic pain
•    Hemoptysis
•    Rales or pleural rub
•    Acute respiratory distress syndrome (ARDS)

HIV-infected patients may have minimal or nonspecific symptoms. Common symptoms are as follows:
•    Headache
•    Confusion
•    Lethargy
•    Obtundation
•    Coma
•    Normal or mildly elevated temperature
•    Nausea and vomiting (with increased intracranial pressure)
•    Fever and stiff neck (with an aggressive inflammatory response; less common)
•    Blurred vision, photophobia, and diplopia
•    Hearing defects, seizures, ataxia, aphasia, and choreoathetoid movements
 
After lung and CNS infection, the next most commonly involved organs in disseminated cryptococcosis include the skin, the prostate, and the medullary cavity of bones. Cutaneous manifestations (10-15% of cases) are as follows:
•    Papules, pustules, nodules, ulcers, or draining sinuses
•    Umbilicated papules in patients with AIDS
•    Cellulitis with necrotizing vasculitis in organ transplant recipients

Other less common forms of cryptococcosis include the following:
•    Optic neuritis or endophthalmitis
•    Myocarditis
•    Chorioretinitis
•    Hepatitis
•    Peritonitis
•    Renal abscess
•    Myositis
•    Adrenal involvement

Diagnosis
The workup in patients with suspected cryptococcosis includes the following:
•    Cutaneous lesions: Biopsy with fungal stains and cultures
•    Blood: Fungal culture, cryptococcal serology, and cryptococcal antigen testing
•    Cerebrospinal fluid: India ink smear, fungal culture, and cryptococcal antigen testing
•    Urine and sputum cultures, even if renal or pulmonary disease is not clinically evident
•    In AIDS patients with cryptococcal pneumonia, culture of bronchoalveolar lavage washings

With possible CNS cryptococcosis, especially in patients who present with focal neurologic deficits or a history compatible with slowly progressive meningitis, obtaining a CT or MRI scan of the brain prior to performing a lumbar puncture.

With pulmonary cryptococcosis, radiographic findings in patients who are asymptomatic and immunocompetent may include the following:
•    Patchy pneumonitis
•    Granulomas ranging from 2-7 cm
•    Miliary disease similar to that in tuberculosis
 
Treatment
Pulmonary cryptococcosis resolves without specific therapy in most immunocompetent patients. Antifungal therapy is necessary for the following:
•    Pulmonary cryptococcosis in immunosuppressed hosts
•    CNS cryptococcosis
•    Disseminated nonpulmonary non-CNS cryptococcosis
 
Treatment for cryptococcal meningitis in patients with AIDS is as follows:
•    Amphotericin B, 0.7-1 mg/kg/day for 2 weeks, with or without
•    Flucytosine, 100 mg/kg/day in 4 divided doses for 2 weeks
•    Flucytosine speeds clearance of viable yeast from CSF but is potentially toxic, especially in patients with renal dysfunction
•    After 2 weeks, fluconazole at 400 mg/day for a minimum of 8-10 weeks
Alternative initial therapies include the following:
•    A lipid formulation of amphotericin B, 4-6 mg/kg/day for 3 weeks
•    Fluconazole, 400-800 mg/day plus flucytosine for patients unable to tolerate amphotericin B

Guidelines published in 2000 recommended maintenance therapy with fluconazole at 200 mg/day for life.[1] Guidelines published in 2002 supported discontinuation of suppressive therapy if CD4 counts remained greater than 200 cells/µL but reinstitution if the CD4 counts fall to fewer than 200 cells/µL.[2]

Management of intracranial pressure in cryptococcal meningitis is as follows:
•    Monitor CSF pressure during the initial phase of therapy
•    If the opening pressure exceeds 250 mm H 2 O, remove CSF to reduce the closing pressure to below 200 mm H 2 O or at least 50% of the elevated opening pressure

In patients without AIDS, treatment of cryptococcal meningitis is as follows:
•    Amphotericin B (0.7-1 mg/kg/day) alone for 6-10 weeks or in combination with flucytosine (100 mg/kg/day in 4 divided doses) for 2 weeks, followed by fluconazole for a minimum of 10 weeks
•    Base therapy duration on CSF examination results
•    Consider weekly CSF examination until culture conversion is documented and cultures remain negative for 4 weeks
•    CSF protein abnormalities may persist for years despite successful therapy; thus, an elevated CSF protein as the only residual abnormality should not dictate prolonging therapy
Pulmonary cryptococcosis can be treated with observation only, if the following criteria are met:
•    CSF chemistry parameters are normal
•    CSF culture, India ink preparation, and serology results are negative
•    Urine culture results are negative
•    The pulmonary lesion is small and stable or shrinking
•    The patient has no predisposing conditions for disseminated disease

Antifungal treatment for cryptococcal pulmonary disease is as follows:
•    Mild-to-moderate disease: Fluconazole for 6-12 months, itraconazole for 6-12 months, or amphotericin B
Severe disease: Amphotericin B (0.7-1 mg/kg/day) plus flucytosine (100 mg/kg/day) for 6-10 weeks, or for 2 weeks followed by fluconazole at 400 mg/kg/day for at least 10 weeks, possibly followed by further consolidation therapy for 6-12 months.

Summary
Cryptococcal meningitis is a common opportunistic infection in AIDS patients. Cases also occur in patients with other forms of immunosupression and in apparently immunocompetent individuals. Mortality from HIV-associated cryptococcal meningitis remains high (10–30%), even in developed countries, because of the inadequacy of current antifungal drugs and the complication of raised intracranial pressure. In cohorts of HIV-infected patients from sub-Saharan Africa, cryptococcosis has accounted for 13–44% of all deaths. Optimal current therapy is with amphotericin B 0.7–1 mg/kg/day plus flucytosine 100 mg/kg/day for 2 weeks, followed by fluconazole 400 mg/day for 8 weeks and 200 mg/day thereafter.

References
•    1. [Guideline] Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis. 2000 Apr. 30(4):710-8.
•    2. [Guideline] Kaplan JE, Masur H, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep. 2002 Jun 14. 51:1-52.

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Lana

Measles Infection And Challenges

INTRODUCTION

Measles virus, a paramyxovirus is one of the main causes of death in children in developing countries and responsible for some deaths in industrialized nations. Infection resorts to immunosuppression, making the host more susceptible to secondary infections with a range of viral and bacterial pathogens and causing most measles associated (Carter et al, 2007).

Measles is an acute highly viral infectious disease. Before vaccines, infection was nearly universal during childhood. It has no known animal reservoir and no asymptomatic carrier state has been recorded (Roy P et al, 2015).

Measles is still a common and fatal disease especially in developing countries. It is primarily transmitted through large respiratory droplets. It is highly infectious, with greater than 90% secondary attack rates among susceptible persons (CDC, 2015). It infects nearly 30 million children per year worldwide. Complications related to pneumonia, diarrhea and malnutrition usually cause death (Orenstein et al, 2004).

WHO estimates that of the approximately two- thirds of the global burden of death due to measles, almost 1,36,000 (range: 98,000 to 1,80,000) occurred in the South East Asian Region in 2007, with most of in India. India had 47% of estimated global measles mortality in 2010 (Simon et al, 2012).


THE MEASLES DISEASE

Pathogenesis:

Infection is very contagious and usually through aerosol route. Initially, the Virus replicates in the respiratory tract, then spreads to lymphoid tissues. Viremia and spread to a variety of epithelial sites follows. About 1-2 weeks after infection disease symptoms develop.

(Hunt M, 2009).
  
 
Figure 1: The pathogenesis of measles.  


Diagnosis:

i.Clinical picture
History of exposure and upper respiratory tract symptoms, Koplik's spots and rash.

ii.Confirmatory tests
Disease is confirmed with RT-PCR serodiagnosis, isolation. Serology diagnosis by IgG is simpler than isolation but two samples are needed (one 10-21 days post rash) so it takes longer. An IgM test is now available.

Epidemiology:

Almost all individuals infected are symptomatic. Only one serotype exists. A single natural infection gives life-long protection. Inhalation is the main route of infection. It is highly contagious – the maximum period of contagiousness is 2-3 days before the onset of rash (Hunt M, 2009).

PROBLEMS ASSOCIATED WITH MEASLES INFECTION

A high fever is usually the first sign of infection with measles, which begins after incubation period which is about 10 to 12 days after exposure to the virus, and lasts for about 4 to 7 days. A runny nose with cough, conjunctivitis, and koplik can develop in the initial stage. After several days, a rash appears, often on the face and upper neck, averagely, the rash occurs 14 days after infection (in a range of 7 to 18 days). Over about 3 days, the rash spreads; it eventually gets to the hands and feet. It lasts for 5 to 6 days, and then fades (Roy P et al, 2015).

Most measles-related deaths are as a resort of associated complications. Complications are more common in children under the age of 5, or adults over the age of 20. The severe complications are blindness, severe diarrhea and resulting dehydration, ear infections, and severe respiratory infections such as pneumonia. Measles could be severe among poorly nourished young children, especially those with insufficient vitamin A, or the immune-compromised (WHO measles factsheet, 2015).

In a very small proportion, the virus establishes in the brain and, after a long period of incubation, causes a degenerative pattern of changes in brain function, this includes loss of higher brain activity, death is inevitable. Two related but different diseases result from neural infection, Measles Inclusion Body Encephalitis (MIBE) and Sub-acute Sclerosing Pan Encephalitis (SSPE).

MIBE occurs in approximately 1 in 2000 cases of infection, a chronic progressive encephalitis which occurs in young adults and children and is associated with a persistent measles virus infection. MIBE can be fatal with the survival time after diagnosis being an average of 3 years. It is usually a seen in immunocompromised patients and is associated with early primary infection usually before two years of age.

SSPE a slowly progressive neurological degenerative disease, occurs in approximately 1 in 100,000 cases. It is associated with a long term persistent measles virus infection that leads to death many years after the first infection (Dimmock et al, 2015).

AVAILABLE CONTROL MEASURES

A live attenuated virus vaccine (grown in chicken embryo fibroblast culture) is currently recommended to be given to children at twelve to fifteen months, Younger children do not show a strong immune response to the vaccine.

A Second dose is given at about four to six years of age. Thus, reducing the number of persons who are susceptible due to failure of primary vaccine. Vaccination gives long term immunity and the vaccine does not spread the virus.

Immune serum globulin can be used for at risk patients (less than 1 year old, or with impaired cellular immunity) during an outbreak (Hunt M, 2009).

Measles virus has not changed over its known history of about fifty years, the same level of protection is still reached by the original vaccines. The polio and measles viruses are stable when compared with HIV-1 and the influenza virus (Dimmock et al, 2007).

Although the vaccine can cause fatal giant cell pneumonia  in those with severely compromised cell-mediated immunity (Hunt M., 2009).

CHALLENGES FACED WITH GLOBAL AMBITION OF COMPLETELY ELIMINATING MEASLES

The feasibility of measles eradication has been proven by the Region of the Americas, where elimination of measles and interruption of transmission has been achieved and sustained since 2002 (WHO Global Eradication of Measles, 2015). Despite the success in global measles control, the progress in reduction of the numbers of measles cases and deaths became stagnant between 2008 and 2010. This is was mostly due to prolonged measles outbreaks in Africa and Europe and the high burden of the disease in India. The number of measles cases in western European countries, rose from 7,499 in 2009 to over 30,000 in 2010 and 2011, this contributed to an increase the number of reported cases globally. During the same period, twenty-eight countries in sub-Saharan Africa were affected in a widespread resurgence (CDC, Eliminating measles, Rubella and CRS worldwide, 2015).

The eradication of measles is faced with so many challenges, some of the key challenges include:

(1)  Maternal antibody Fast rate of waning
A large number of children are left unprotected before the first dose because of the fast rate of waning of these maternal antibodies (Adu, 2008).

(2)  Injectable nature of vaccine
There are problems with vaccine administration. Unlike the polio vaccine, the measles vaccine is administered with the injection, so it is not easy to administer. A large number of workforce are to be trained for vaccine administration. A very good solution to this problem would be the may be use of aerosol technique which, this can also be used by field workers. The acceptability of the vaccine may be improved through this method, since it would not require the use of injections (Roy P et al, 2015).

(3)  Adverse reaction and reversion to virulent strain
The chances of adverse reactions to the live vaccine need to be addressed. Maintaining proper cold chain during storage and transportation of vaccine should also be considered (Roy P et al, 2015).

(4)  Other competing priorities
The availability of qualified staff and funds are affected by competition from other health programs.There are competing priorities like streamlining of newer vaccines, polio eradication and other health initiatives (Roy P et al, 2015).

(5)  Population displacement and Migration
Population displacement and migration are challenges a measles eradication initiative would also face. Presently, there are large displaced populations in urban areas. Current eradication programs may face greater challenges than earlier programs as a result of exponential increase in trans- migration (United Nations Population Fund, 2015).

(6)  Political instability
In several countries particularly Somalia and Afghanistan, Sierra Leone, part of Pakistan, Congo, Sudan, Ethiopia and Liberia political instability and armed conflicts cause vaccination to be logistically unpredictable and difficult. In addition, Nigerian internal politics in the boycott of the 2003 immunization, were ramifications from the arena of international politics (Okonko et al, 2009).

(7)  Terrorism and War
The main measles- endemic countries are at war, and the world spends more on arms than ever before. Both real and perceived terrorism makes the situation more complex. As a resort, reaching high rates of vaccination coverage in areas affected by conflict will be very dangerous and difficult (Roy P et al, 2015).

(8)  Low vaccination rates and Surveillance
It is essential to maintain excellent vaccination coverage with high quality surveillance. Overcoming this, will be critical in dealing with importations of measles virus, so long as the measles virus is still endemic in other parts of the world (Andrus, 2011).

(9)  Poor maintenance of high population immunity
Maintaining a high population immunity with excellent coverage and laboratory networking that is efficient for high- quality surveillance would deal with the problem of the importation of measles virus into countries where it has been eliminated (Ministry of Health and Family Welfare, 2004).

(10) The changing epidemiology of measles
The increased transmission of measles among adolescents and adults as a result of the changing epidemiology of measles should also be considered (Roy P et al, 2015).

CONCLUSION

To eradicate measles, research has shown the need to have homogeneous population immunity of ≥93% (WHO Global Immunization Vision and Strategy, 2005). Elimination of measles requires immunization coverage of at least 96% of children aged less than one year and also the prevention of accumulation in the immunity gap (Roy P et al, 2015).

Three criteria are biologically important for the feasibility of the eradication of a disease, measles meets all:

(a) humans are the only reservoir;

(b) existence of accurate diagnostic tests

(c) an practical and effective intervention is available at an affordable cost.

It can be concluded, that measles eradication is a very challenging but feasible target. Exponential increase in commitment and resources is an essential requirements, if the measles eradication initiative should be pursued. To achieve measles eradication, all the regions and countries of the world will have to work together.

REFERENCES

1. Adu FD (2008). That Our Children Will Not Die. An Inaugural Lecture delivered at the
University of Ibadan, on Thursday 11th December. Ibadan University Press p. .34

2. Andrus JK, de Quadros CA, Solórzano CC, Periago MR, Henderson DA. Measles and
rubella eradication in the Americas. Vaccine 2011; 29(S4): 91-6.

3. Carter JB, Saunders VA. Virology Principles and Applications. 2007.

4. Centers for Disease Control and Prevention. Measles: Pink Book. Available at:
http://www.cdc.gov/vaccines/pubs/pinkbook/ downloads/meas.pdf. Last accessed on: 9 Feb, 2019.

5. Dimmock NJ, Easton AJ, Leppard KN. Introduction to Modern Virology. Sixth edition 2007.

6. Global eradication of measles. Report by the Secretariat. Sixty third World Health Assembly.
March 2010. Available at: http://apps.who.int/gb/ebwha/pdf_files/wha6 3/a63_18-en.pdf. Last accessed on: 9 Feb, 2019.

7. Hunt Margaret. Measles (Rubeola), Mumps, Rubella (German Measles) and Human
parvovirus B19. Medical Microbiology, PAMB 650/720. 2009.

8. Ministry of Health and Family Welfare, Government of India. Measles Mortality Reduction
India Strategic Plan 2005-2010, New Delhi.

9. Okonko IO, Nkang AO, Udeze AO, Adedeji AO, Ejembi J, Onoja BA, Ogun AA, Garba KN.
Global Eradication of measles: A highly contagious disease – what went wrong in Africa? JCAB 2009: 3(8) 119-140.

10. Orenstein WA, Perry RT, Halsey NA. The Clinical Significance of Measles: A Review. J
Infect Dis 2004; 189(Suppl 1): 4-16.

11. Roy P, Priyanka, Geol MK, Rasania SK. Measles Eradication: Issues, strategies and
challenges. JCD 2015: Article 10.

12. World Health Organization. GIVS: Global Immunization Vision and Strategy: 2006- 2015.
Geneva: WHO, 2005. Document WHO/IVB/05.05.p. 8.

13. World Health Organisation. Measles Factsheet. Available at http://www.who.int/mediacentre/factsheets/fs286/en/ . Accessed on 9 Feb, 2019.