ID

The Forgotten Influenza of 1918: When a Strong Immune System Becomes a Weakness

September 23, 2009

influenza19181Emily Breidbart

Faculty peer reviewed

As the threat of the swine flu surfaced in early 2009, doctors and the media referenced the influenza of 1918. Also known as the Spanish flu, this pandemic spread to nearly every part of the world and killed more humans than any other disease in a similar period in known history. According to an epidemiological study done in 2002, this unusually virulent strain of influenza A, subtype H1N1, is said to have killed approximately 50 million people worldwide.[1] At least 700,000 of the dead were Americans.[2]

The crowding and migrations of the First World War may have created the Spanish influenza and certainly helped its rapid spread. It is estimated that for every American soldier who died in battle in World War I, 1.02 died of disease.[2] Soldiers and other healthy young adults were hit hardest by the pandemic. According to the Bureau of Census, in the year 1918, while 1076 males died from the flu between ages 85-89 (3.9 per 1000), 39,958 males aged 25-29 died (146.6 per 1000).[2] What made adults in their twenties and thirties, people in the prime of life, so much more susceptible?

Several theories attempting to explain the virulence of this particular strain of influenza were offered during and after the pandemic. In the 1920s, the symbiosis theory suggested that the Spanish influenza was really a disease of two organisms that worked together to create a uniquely deadly disease.[2]Another long-held theory prominent in the 1920s was proposed by Richard Pfeiffer, one of the century’s giants of bacteriology. He believed that influenza was caused by rod-shaped bacteria, which he named Bacillus influenza, now known as Haemophilus influenzae. Studies of post-mortem victims were inconsistent, but this lack of evidence was blamed on the fact that the bacteria were extremely hard to culture. Moreover, the theory was hard to dismiss when there were no other likely agents found. It took until 1931 for this theory to be disproved. Scientists at the Rockefeller Institute found the cause of influenza in swine to be a virus which was later found to be directly descended from the 1918 killer.[1,3]

Another theory held that the virus was in constant mutation during the pandemic, thereby failing to create herd immunity. Other scientists claimed that the pandemic was really pneumonia, since it was the complications of secondary bacterial infection that often led to death.[2]

Still, these hypotheses failed to answer why the virus seemed to dig its sharpest fangs into young adults. At first, this phenomenon was thought to have a simple explanation: older members of society had been around for the 1889-1890 influenza pandemic and had acquired lasting immunity that younger people did not have. But scientists have since discovered that immunity to influenza probably lasts months to a few years, certainly not decades. Moreover, the mortality rate should have been low for everyone over the age of 30, which it was not.[2]

The appearance of victims’ lungs at autopsy gave the first clues to this question. Pathologists saw devastation of the lungs caused by the usual lobar and bronchopneumonias, but they saw something different in the lungs of 20-40 year old victims who died quickly during the pandemic. A pathologist was quoted as saying “[there was] essentially toxic damage to alveolar walls and exudation of blood and fluid. Very little evidence of bacterial action could be found in some of the cases.”[1] Whereas in bacterial pneumonia the infection rages inside the alveoli, in these lungs, the spaces between the alveoli were also filled, brimming with debris of destroyed cells, white blood cells, immune modulators, and blood.[1]

Frank Macfarlane Burnet, who isolated a strain of influenza A in 1935, posited that the 1918 virus was a virulent strain with which few humans had ever had contact. He explained that a child’s immune system is still learning, but is usually able to match the infection with an immune response, eventually fighting off the infection. After about 40 years of age, the ability to produce extreme inflammation declines, making the body more susceptible to infection. In young adulthood, individuals have acquired immunity to common generalized infections and have the vigor to launch an intense localized inflammatory response.

Influenza infection typically spreads by attaching to epithelial cells. Within fifteen minutes of entering through the airways, the hemagglutinin spikes of the influenza virus bind with sialic acid receptors on epithelial cells. About ten hours after influenza invades a cell, the cell bursts open, releasing thousands of viruses. These viruses attack the immune system directly by inhibiting the release of interferon, usually the body’s first weapon in fighting a viral infection. The inflammatory response releases cytokines, which in large amounts can cause shock.[1]

Most influenza viruses are warded off by the immune system before they gain a solid foothold in the lungs, halting the virus in the upper respiratory tract. Scientists believe that what made the influenza of 1918 unique was the virus’s ability to make its way down the respiratory tract to the epithelial cells of the alveoli. Killer T-cells then became active. The capillaries surrounding the alveoli dilated and poured out fluid composed of white blood cells, antibodies, and cytokines. Cytokines and enzymes effaced the capillaries. More fluid poured into the lung. The cells lining the alveoli were damaged, and hyaline membranes formed. Surfactant production ceased. The body produced fibrous connective tissue, entangling the lung in debris, fibrin, and collagen. Burnet himself noted that “continued exudation of fluid in areas where blocking of smaller bronchi had occurred would produce eventually airless regions.” There was no space for oxygen exchange to occur. The body effectively drowned itself, and death quickly ensued.[1]

Burnet’s theory has historical evidence to back it up. The Black Death killed young adults more readily than children, the middle-aged, or the elderly.[2] The rapid, pathologically unique process of death in people in their 20s and 30s may have been what is known today as acute respiratory distress syndrome (ARDS). While ARDS cannot be blamed for all of the deaths of the Spanish flu, it can help explain the rapid deaths of young healthy people. An Army commission conducted autopsies and reviewed pathology reports of young soldiers who died in 1918 and 1919, and found signs of what would today be called ARDS in half of the cases.[1]

Still, most of the deaths from the influenza of 1918 were due to bacterial pneumonia, for which we now have antibiotics. Currently, it is resistance that is the dilemma. In some parts of the United States, 35% or more of pneumococcal infections are resistant to the antibiotic of choice.[1] ARDS has a poor prognosis: despite advances in understanding its physiopathology, mortality rates remain as high as 40-46%.4 Though it is difficult to imagine a disaster on the scale of the 1918 infuenza almost a century later, a pandemic is not improbable. Now, in the face of a possible threat, efforts should be directed at prevention, which may be our best tool.

Emily Breidbart is a 4th year medical student at NYU School of Medicine.

Faculty peer reviewed by Harold Horowitz MD, Professor, NYU Division of Infectious Diseases and Immunology

1. Barry JM. The Great Influenza. New York, NY: Penguin Group; 2004:154-397.
2. Crosby AM. America’s Forgotten Pandemic. New York, NY: Cambridge University Press;1989:203-223, 269-302.
3. Kolata G. Flu: The Story of the Great Influenza Pandemic of 1918 and the Search for the Virus that Caused It. New York, NY: Farrar, Straus, and Giroux; 1999:69-75.
4. de Hemptinne Z, Remmelink M, Brimioulle S, Salmon I, Vincent, JL. ARDS: a clinicopathological confrontation. Chest. 2009;135(4):944-949.

Can you offer a liver transplant to a patient with HIV?

August 28, 2009

120px-bellevue_hospital_ambulance2c_new_york_times2c_1895Faculty Peer Reviewed

Uzma Sarwar MD

Coincident with greater use of highly active antiretroviral therapy (HAART), chronic liver disease has become one of the leading causes of death amongst HIV patients. This reflects the high prevalence of chronic liver diseases in the HIV-infected; almost a third of HIV-seropositive patients are afflicted with liver disease, predominantly as a result of hepatitis B and/or hepatitis C co-infection. Given their increased life-span, many HIV-infected patients now progress to end-stage liver disease, where they used to succumb to the effects of HIV prior to death due to liver disease, in the pre-HAART era. Liver transplantation is commonly considered for treatment of end-stage liver disease among the HIV seronegative population, but the situation is not as clear-cut for patients infected with HIV.

In the past, HIV was considered an absolute contraindication to liver transplant due to the infecteds’ overall poor prognosis and their inability to continue immunosuppressive therapy post transplant. The winds have now shifted and liver transplantation is now considered possible in this population. However, only 26 centers in the United States consider HIV-positive patients for liver transplant. Preliminary reports on the safety and efficacy of transplant in HIV positive patients are encouraging, having revealed that carefully selecting HIV-infected patients to receive solid organ transplants results in low rejection rates, few opportunistic infections and survival rates comparable to non HIV-seropositive patients. An outcome study of nineteen HIV patients conducted in 2002 by Roland, et al. at UCSF is particularly salient. In this study, transplanted patients, whose baseline CD4 cell count was 280 and whose plasma viral load was between undetectable and 115,000, experienced a low graft rejection rate of 21% after 300 days post-transplant. Another retrospective analysis of 15 HIV-infected patients (baseline CD4 cell count >100 and plasma viral load between undetectable and 141,000) who underwent transplant from 1999 to 2006 at the University of Miami, showed similar survival rates when compared with 857 HIV-uninfected patients, after 38 months median follow-up. However the HIV patients did have a higher rate of infectious complications.It should be noted that these studies did not specifically examine patients who underwent liver transplantation, but all HIV patients receiving solid organ transplants. Therefore, it is necessary for studies to specifically examine outcomes of liver transplantation in the HIV-infected population. Further, studies comparing long-term survival between transplanted HIV-infected and uninfected patients have yet to be reported.

In addition to the traditional criteria used for transplant eligibility, HIV patients have  stricter inclusion criteria for consideration and enrollment. Some of the prominent criteria that have been utilized in previous studies are included  below.

Inclusion Criteria:
Life expectancy greater than 5 years
CD4 cell count greater than 200 for over 6 months pre-transplant
Adherence to stable HAART regimen
Absence of any AIDS defining illness
Plasma viral load less than 50 copies/ml

Exclusion Criteria:
Presence of any cancer diagnosis
Any untreated chronic illness (included tuberculosis)
Greater than 3 classes of viral resistance
Persistent HIV viremia
Any non-compliance with HAART

To conclude, with careful and stringent selection criteria, HIV-infected patients may be considered for liver transplantation. They appear to have similar short-term survival post-transplant as do HIV-uninfected patients, although more studies are needed to evaluate their long-term prognosis.

Dr. Sarwar is a third year internal medicine resident at NYU Medical Center.

Reviewed by Michael Poles MD, Associate Editor, Clinical Correlations, Assistant Professor of Medicine, NYU Division of Gastroenterology 

References
1. Kozei, margaretJ, Peters, Marion G, Viral Hepatitis in HIV infection, NEJM 2007; 356:1445-54
2. Sulkowski MS et al, Rapid fibrosis progression among HIV/Hep C virus co-infected adults, AIDS 2007;16:2209-16
3. Merchante N et al, Survival and prognostic factors of HIV infected patients with HCV related end stage liver disease, AIDS 2006;20:49-57
4. Hadler, SC, Judson, FN, O’Malley PM et al, Outcome of hepatitis B virus infection in homosexual men and its relation to prior HIV infection
5. Thio et al, HIV-1, HBV and risk of liver related mortality in the Multicenter Cohort study. Lancet 2002;360:1921-6
6. Roland et al, Solid organ transplantation in HIV infected patients in potent anti-retroviral therapy era. Topics in HIV medicine;12:73-6
7. Schreibman Ian et al, Outcomes after orthotropic liver transplantation in fifteen HIV infected patients. Transplantation 2007; 84:697-704
8. Powderly, William, Antiretroviral therapy in patients with hepatitis and HIV: weighing the risks and benefits, CID 2004;38:109-113
9. Vennarecci,G et al, Transplantation in HIV positive patients. Transplantation Proceedings 2007;39:1936-38
10. Sanchez-Conde M, Berenguer, J, Miralles, P et al, Liver biopsy findings for HIV infected patients with chronic hepatitis C and persistently normal levels of alanine aminotransferases, Clin Infect Dis 2006; 43:640-4
11. Uptodate.com
12. Harrison’s Manual of Internal Medicine, 16th edition

Why is Syphilis Still Sensitive to Penicillin?

July 30, 2009

382px-syphilis_is_a_dangerous_disease.pngSam Rougas MD

Faculty Peer Reviewed

It seems that every week a new article in a major newspaper is reporting what most infectious disease physicians have been preaching for several years. Antibiotic resistance is rapidly spreading. Infections such as Methicillin Resistant Staphylococcal Aureus, Extremely Drug Resistant Tuberculosis, and Vancomycin Resistant Enterococcus have journeyed from the intensive care units to the locker rooms of the National Football League. That being said, some bacteria have strangely and until recently inexplicably behaved. Syphilis, a disease caused by the spirochete Treponema Pallidum, though first reported in Europe around the 15th century has likely been in North America since the dawn of mankind. Its rapid spread in Europe began shortly after Christopher Columbus returned from the new world[1] and remained unabated until it was first noted that Penicillin (PCN) could cure the disease[2]. However, since that time, syphilis, once the great pox, is now at the bottom of most differentials. How is it then, that one of our oldest diseases remains sensitive to our first antibiotic?Penicillin resistance to staphylococcal species was reported as early as 1946 and multiple cases were noted worldwide before the turn of the decade[3]. Literally within ten years of the existence of PCN there was resistance among staph species; however, after 50 years, PCN resistant syphilis is a worthy of a case report. In practically every case, the infection was cured with increasing the dose or duration of therapy or with another beta-lactam antibiotic[4,5]. One tempting explanation is that spirochetes are incapable of developing PCN resistance; however, that is not true. Brachyspira Pilosicoli, in intestinal spirochete has shown PCN resistance[6]. A second thought is that Syphilis is incapable of developing antibiotic resistance at all, though this too has not been shown to be true. Case reports of azithromycin resistance in T. Pallidum became increasingly common at the beginning of this century. Gene sequencing of these species mapped out the mutation leading to the macrolide resistant phenotype[7]. Obviously the mechanism of action of a macrolide antibiotic is different from a beta lactam as is the resistance profile. However, it does show that syphilis is capable of developing resistance to at least one class of antibiotic.

The classic teaching is that beta lactam antibiotics function at the level of the cell wall via binding to penicillin binding proteins (PBPs). Once bound, the beta lactams are able to interfere with the production of specific peptidoglycans critical for cell wall structure. Once these peptides are eliminated the cell wall ruptures and the bacteria dies. Resistance occurs when bacteria either via an innate mutation or via DNA exchange acquire the ability to produce beta lactamase, an enzyme cabable of cleaving the antibiotic rendering it useless. In syphilis the mechanism of action is thought to be the same, but resistance has never developed. This may be a direct consequence of one of the more recently discovered PBPs called Tp47[8]. Tp47 functions as both a PBP and a beta lactamase. However, it may paradoxically be responsible for the persistence of PCN sensitivity in syphilis. The binding of the beta lactam component of PCN to Tp47 results in hydrolysis of the beta-lactam bond of the antibiotic. However, in the process of this reaction several byproducts are created. The thought is that these byproducts have a higher affinity for Tp47 than the beta lactam itself[9]. Thus as a consequence of PCN being broken down, products are released which make it more difficult for the beta-lactamase to bind the antibiotic.

While this is one current theory behind the exquisite sensitivity of syphilis to PCN, it is clearly not cause for celebration. Cases of syphilis are increasing world-wide10 as the medical community has been unable to eradicate this disease. As the number of cases increase, so too does the potential for antibiotic resistance. Theoretically a mutation in Tp47 may alter the protective byproducts upon which the sensitivity of syphilis to PCN depends. Such a mutation would likely result in the end of the gravy train that has been the treatment of syphilis.

 
1. Rose M. Origins of Syphilis. Archeology 1997; Volume 50 Number 1
2. Mahoney J, Arnold R, Harris A. Penicillin treatment of early syphilis; a preliminary report. Vener Dis Inform 1943; 24:355-357
3. Shanson DC, Review Article: Antibiotic-resistant staphylococcus aureus. Journal of Hospital Infection (1981) 2: 11-36
4. Cnossen W, Niekus H, Nielsen et al. Ceftriaxone treatment of penicillin resistant neurosyphilis in alcoholic patients. J. Neurol. Neurosurg. Psychiatry 1995; 59; 194-195
5. Stockli H, Current aspects of neurosyphilis: therapy resistant cases with high-dosage penicillin? Schweiz Rundsch Med Prax. 1992 Dec 1; 81(49):1473-80
6. Mortimer-Jones S, Phillips N, Ram Naresh T et al. Penicllin resistance in the intestinal spirochaete Brachyspira pilosicoli associated with OXA-136 and OXA-137, two new variants of the class D Beta-Lacatmase OXA-63. Journal of Medical Microbiology 2006; 57 1122-1128
7. Katz K, Klausner J. Current Opinion in Infectious Disease 2008, 21:83-91
8. Deka R, Machius M, Norgard M et al. Crystal Structure of the 47-kDa Lipoprotein of Treponemal Pallidum Reveals a Novel Pencillin-Binding Protein. The Journal of Biological Chemistry 2002. 277:44: 41857-41864
9. Cha J, Ishiwata A, Mobashery S. A Novel B-Lactamase Activity from a Penicllin-binding Protein of Treponema pallidum and Why Syphilis Is Still Treatable With Penicllin. The Journal of Biological Chemistry 2004. 279: 15: 14917-14921
10. Gerbose A, Rawley J, Heymann D, et al. Global prevalence and incidence estimates of selected curable STDs. Sex Transm Infections 1998; 74: 512-516

Faculty Peer Reviewed with commentary by Meagan O’brien MD, NYU Division of Infectious Diseases and Immunology 

While it is true that Treponema Pallidum remains highly susceptible to Penicillin and has developed resistance to Azithromycin through an A–>G mutation at position 2058 of the 23S rRNA gene of T. pallidum, which confers resistance by precluding macrolide binding to the bacterial 50S ribosomal subunit, of which 23S rRNA is a structural component, the mechanisms of retained Penicillin sensitivity are not fully understood[7]. The discovery of Tp47 as a dual PBP and Beta-lactamase is interesting and important, but more studies would be needed to attribute this mechanism to the persistence of Treponema Pallidum sensitivity to Penicillin. Luckily, we do not have many clinical isolates to test this theorized mechanism. One key clinical point to remember is that eradication of the infection depends not only on the invading organism, but also upon the host defense system. In our HIV+ immunocompromized patient population, we routinely are concerned about treatment failure in syphilis infection due not to penicillin drug resistance but to dysfunctional host responses. A body of evidence now exists supporting the recommendation that if an HIV+ patient has a CD4 T-cell count ≤350 cell/uL and a blood RPR titer ≥ 1:32 with latent syphilis or syphilis of unknown duration, a lumbar puncture should be performed to rule out neurosyphilis, and if positive, that intravenous penicillin should be given instead of IM Benzathine Penicillin[11-14]. Additionally, after treating late or latent syphilis, a fall in RPR titer by 1:4 needs to be observed over 12 months or the patient should be evaluated for treatment failure or neurosyphilis, with the understanding that the CNS may be a more privelidged site for Treponema survival in the face of IM Benzathine Pencillin.

11. Marra, C.M., C.L. Maxwell, S.L. Smith, et al., Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis, 2004. 189(3): p. 369-76.

12. Marra, C.M., C.L. Maxwell, L. Tantalo, et al., Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis, 2004. 38(7): p. 1001-6.

13. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA. Lumbar puncture in HIV-infected patients with syphilis and no neurologic symptoms.
Clin Infect Dis. 2009 Mar 15;48(6):816-21.

14. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS. 2008 Jun 19;22(10):1145-51.

A Primer on H1N1

July 15, 2009

Liana Barkan MD

Faculty Peer Reviewed 

So much mystery and confusion, and yet so few answers, surround the current H1N1 Pandemic. From where did it come? How did it evolve to have genes from avian, human, and swine flu viruses? How does a virus that normally requires direct contact with the source animal develop the ability to sustain human-to-human transmission? What determines its mechanism of pathogenicity? Before we can attempt to answer these questions we need to review the basic pathophysiology of the influenza virus and its transmission.

The influenza virus belongs to the family of Orthomyxoviridae viruses, in which influenza types A and B belong to one genus and type C belongs to another. Antigenic characteristics of the nucleoprotein antigens and the matrix antigens determine the designation. Influenza viruses are also subdivided based on the properties of two types of surface glycoproteins projecting from the lipid envelope, known as the hemagglutinin (H) and neuraminidase (N) antigens (see Figure-1). Hemagglutinin binds to host cell receptors and neuraminidase subsequently degrades the cell receptor. Following viral replication, neuraminidase may also play a roll in releasing the viral progeny from the infected cell.

Influenza virus normally causes a predominant respiratory illness accompanied by non-specific constitutional symptoms, such as fevers, chills, headache, myalgias, and general malaise. Antibodies we form against the hemagglutinin antigen confer immunity to the influenza virus, whereas our antibodies against neuraminidase limit viral spread and severity of infection. However, despite vaccination efforts, the influenza A virus persists in the population. This is likely due to the reassortment of its eight single-stranded RNA segments during an infection and particularly in situations in which a cell becomes infected with more than one type of influenza A virus.[1] In addition to reassortment, antigenic mutations in the hemagglutinin and neuraminidase proteins lead to either antigenic shifts (major variations) or antigenic drifts (minor variations) that are responsible for some of the more severe outbreaks and pandemics seen since the early 1900’s.1

Figure 1

 swine

In an article published in May 2009 in the New England Journal of Medicine, Shinde et al. suggest that pigs might act as mixing vessels for the triple reassortment of avian, swine, and human influenza viruses and may have caused sporadic cases of infection in humans as early as the late 1990s, well before the current Swine Flu Epidemic.[2] In fact, a swine influenza virus causing febrile respiratory illness in pigs is well known to be enzootic to pigs in North America.[2] The sporadic cases in humans occurred in high-risk individuals working in direct contact with pig herds and to a much lesser extent those in contact with the people who worked with pigs. However, until the recent outbreak that started in Mexico, little evidence existed for sustained human-to-human transmission of swine influenza virus.

Transmission of the influenza virus usually occurs via aerosols generated during a cough or a sneeze, but can also occur through other types of personal contact, and even possibly through intermediary objects, such as door knobs, desks, tables, or phones. In the article cited above, Shinde et al. found evidence for only limited human-to-human transmission of swine influenza virus. Of the 11 human cases with documented triple reassortment swine influenza, five had had direct contact with a pig; three had been within six feet of a pig; one had been in the near vicinity; one had had contact with someone with a suspected case of swine influenza; and one had had no known contact with a pig. In contrast, one novel aspect of the current pandemic is that the majority of cases have not been linked to exposure to pigs and instead appear to demonstrate sustained human-to-human transmission.

In comparison to previous outbreaks, this current virus also demonstrates much more dramatically efficient transmission among people as evidenced by its rapid and prolific spread. According to a recent CDC update, although the current virus was originally referred to as “swine flu” due to genetic similarity to the enzootic influenza virus occurring in pigs, further study has shown that the new virus is actually very different. Swine flu typically only affects people in direct contact with pigs, whereas the human influenza virus spreads predominately from person to person. The new current virus has been called a “quadruple reassortment” virus because it contains swine genes from both Europe and Asia, avian genes, and human genes.[3] Shinde et al. revealed that in 10 of the 11 isolated influenza viruses in their study, five of the eight single-stranded RNA gene segments were of North American swine origin, two were of North American avian origin, and one was of human origin. Work is still being done to further classify the genomic sequences in the current outbreak and may help us better understand why the mode of transmission and its sustainability of the current virus appear to be so different from previous strains.

Unfortunately at this time, there are still more questions than answers, but the take home message remains the same: cover your mouth when you cough or sneeze, wash your hands frequently with antibacterial soaps or alcohol based cleansers, avoid close contact with sick people, and stay home if you are sick.

As of July 12 2009 at 11:00 AM ET, the CDC reports 37,246 confirmed and probable cases and 211 deaths in the United States. 3 WHO reports 94512 Cases with 429 deaths worldwide. [4]

Dr. Barkan is a 3rd year resident in internal medicine at NYU Medical Center.

Reviewed by Howard Leaf, MD, Assistant Professor, NYU Division of Infectious Diseases and Immunology 

References:

1. Fauci AS, et. al, Harrison’s Principles of Internal Medicine, 14th ed, McGraw-Hill, 1998, pp 1112-1116
2. Shinde V, et al. “Triple-Reassortant Swine Influenza A (H1) in Humans in the United States, 2005-2009, NEJM.org, May 7th, 2009
3. http://www.cdc.gov/h1n1flu/qa.htm.
4. http://www.who.int/csr/don/2009_07_06/en/index.html

How Should You Approach a Patient Co-infected with HIV and Hepatitis C?

June 11, 2009

120px-bellevue_hospital_ambulance2c_new_york_times2c_1895Uzma Sarwar MD

Faculty Peer Reviewed

With advancement in therapy, life expectancy has significantly increased among HIV-infected patients, and patients are now more likely to succumb to chronic disease processes. At present, approximately one third of deaths in HIV patients are related to liver disease, which has become the leading cause of death amongst HIV patients. The risk of death from liver disease in HIV patients is inversely related to their CD4 count. Infection with hepatitis C virus (HCV) accounts for the bulk of this burden, reflecting the fact that it shares a route of transmission with HIV,  intravenous drug use, with lower rates of transmission via the sexual route and with vertical transmission. However, it should be noted that the risk of sexual and vertical transmission of HCV are increased in patients infected with HIV. The prevalence of HCV among HIV infected patients can range from 30-80%, varying by geographic region and route of transmission.

In addition to being directly hepatotoxic, HCV also may indirectly cause liver damage by increasing the hepatotoxicity of anti-retroviral therapy. A prospective cohort study of 184 HIV/HCV co-infected patients identified concomitant alcohol use, increasing age, HCV genotype 3 and CD4<200 as risk factors associated with faster progression. Additional reports have identified an increased incidence of hepatocellular carcinoma amongst HIV/HCV co-infected patients.

Before considering treatment for HIV-HCV co-infected patients, infection should be confirmed by quantifying HCV RNA levels in patients with positive serologies against HCV. Additional tests should include liver function tests and CD4 cell counts. For these patients clinicians should have a lower threshold for performing a liver biopsy even if the labwork does not identify a transaminitis, as HIV-HCV co-infected patients can have a progression of disease irrespective of laboratory abnormalities.  Histology will help in determining the progression of disease in these patients and help guide management. If there is minimal damage noted on liver biopsy, treatment may be deferred with a liver biopsy repeated in three years. Signs of activity or fibrosis on biopsy should prompt consideration of treatment. However it is still a matter of debate whether to treat HIV or HCV first. Although there are no clear guidelines for therapy, the consensus is that treatment for HCV should be considered first if the patient has a stable CD4 count greater than 300cells/mm. If the patient has more advanced HIV disease, HAART should be instituted first before treatment for HCV to increase likelihood of successful HCV response.

Once the decision has been made to proceed with treatment, subcutaneous pegylated interferon(IFN) and oral ribavarin is typically used. Several clinical trials have shown that pegylated IFN therapy is superior to the standard IFN and can be dosed weekly, rather than thrice weekly. Therapy is typically continued for forty eight weeks, though it may be shortened to 24 weeks in those infected with genotypes 2 or 3. Regardless, the sustained virologic response (SVR), defined as the attainment of an undetectable HCV plasma viral load six months after cessation of therapy, is significantly lower among the HIV co-infected patients compared to HCV mono-infected individuals.
The risk of adverse side effects with this therapy is high and includes flu-like symptoms, weight loss, anemia, thrombocytopnenia, an increase in mitochondrial toxicity in patients receiving nucleoside analogues and, lastly, opportunistic infections.

 Dr. Sarwar is a third year internal medicine resident at NYU Medical Center.

Reviewed by Michael Poles MD, Associate Editor, Clinical Correlations, Assistant Professor of Medicine, NYU Division of Gastroenterology 

 
References
1. Kozei, M, Peters, Marion G. Viral Hepatitis in HIV infection. NEJM 2007; 356; 14:1445-54
2. Sulkowski M, Mehta, S, Torbenson, M, Higgins, Y, Brinkley, S, deOca, R, Moore, R, Afdhal, N, Thomas, D.Rapid fibrosis progression among HIV/Hepatitis C virus co-infected adults, AIDS 2007;21(16):2209-16
3. Merchante N, Giron-Gonzalez, J, Torre, C, Julian, G, Jose, A, Ana, R, Josefa, CL, Pilar, L, Fernando, MS, Carmen, MJ, Pineda, J Survival and prognostic factors of HIV infected patients with HCV related end stage liver disease, AIDS 2006;20 (1):49-57
4. Sanchez-Conde M, Berenguer, J, Miralles, P, Alvarez, F, Carlos Lopez, J, Cosin J, Pilar, C, Ramirez, M, Gutierrez, I, Alvarez, E. Liver biopsy findings for HIV infected patients with chronic hepatitis C and persistently normal levels of alanine aminotransferases, Clin Infect Dis 2006 Sep 1; 43(5):640-4
5. Thio, CL, Seaberg, EC, Skolasky, R, Phair, J, Visscher, B, Munoz, A, Thomas, DL. HIV-1, hepatitis B virus and risk of liver related mortality in the Multicenter Cohort study. Lancet 2002 Dec 14; 360 (9349):1921-6
6. Roland, ME, Perspective:Solid organ transplantation in HIV infected patients in potent anti-retroviral therapy era. Topics in HIV medicine; 12(3):73-6
7. Schreibman, I, Gaynor, J, Jayaweera, D, Pyrsopoulos, N, Weppler, D, Tzakis, A, Schiff, E, Regev, A.Outcomes after orthotropic liver transplantation in fifteen HIV infected patients. Transplantation 2007; 84(6):697-704
8. Powderly, William. Antiretroviral therapy in patients with Hepatitis and HIV: weighing risks and benefits, CID 2004; 38(Suppl2):109-113
9. Vennarecci, G, Ettore, G, Antonini, R, Santoro, L, Perracchio, G, Visco, G, Santoro, E. Liver Transplantation in HIV positive patients. Transplantation Proceedings 2007; 39:1936-38
10. Hadler, SC, Judson, FN, O’Malley PM, Altman, N, Penley, K, Buchbinder, S, Schable, C, Coleman, PJ, Ostrow, DN, Francis, DP. Outcome of hepatitis B virus infection in homosexual men and its relation to prior HIV infection. J Infect Dis. 1991 Mar; 163(3):454-9
11. Wilcox, CM. Evaluation of the HIV infected patient with hepatobilliary complaints. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2008.
12. McGovern, BH. Management and treatment of hepatitis C in the HIV infected patient. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2008
13. Kasper, D, Braunwald, E, Hauser, S, Longo, D, Jameson, JL, Fauci, A. Harrison’s Principles of Internal Medicine. Seventeenth ed. McGraw Hill medical publishing division; 2008

Breaking News: Swine Flu Reaches New York

April 26, 2009

pigEunice Kang, MD

The Centers for Disease Control (CDC) has confirmed eight cases of swine influenza A (A/H1N1) virus infection in New York City, in addition to a dozen cases caused by the same strain scattered throughout California, Texas, Ohio, and Kansas. The eight confirmed cases in New York are in students who just returned from a trip to Mexico, where officials began reporting three separate outbreaks of influenza-like illness beginning March 18th. According to the New York Times there have been 81 deaths and approximately 1,300 illnesses caused by the swine flu in Mexico, the apparent epicenter of the outbreak, prompting President Felipe Calderón to announce that the government would “take all the necessary measures to deal with this epidemic.” While the swine influenza virus has been confirmed in only 20 of the 81 deaths in Mexico, many of the affected were adults who were previously healthy, an epidemiologic trait that distinguishes the swine flu virus from other flu viruses of prior pandemics.
Swine influenza virus, like other animal flu viruses, usually causes a respiratory illness confined to the animal population that serves as its source. The swine flu virus can be spread to humans who are in close contact with pig populations. Modes of human-to-human transmission are similar to those of seasonal flu viruses. Collecting a respiratory specimen and sending it to the CDC can confirm a suspected diagnosis of swine flu.
The virus that has been isolated in Mexico and the US is being described as a new subtype of A/H1N1 not previously detected in pigs or humans. While the cases in the United States have been mild with only one requiring hospitalization, the CDC earlier today declared a public health emergency over concern of a potential swine flu pandemic. Symptoms of swine flu are similar to those of seasonal flu and include fever, malaise, lethargy, cough, anorexia, and in many cases nausea, vomiting, and diarrhea. Prevention of transmission is also similar to seasonal flu. The CDC is recommending oseltamivir (Tamiflu) and zanamavir (Relenza) as treatments for the current swine flu strain given findings of resistance to amantadine and rimantadine.
The New York City Department of Health and Mental Hygiene is currently recommending routine treatment of severe flu-like illness in people associated with the Queens high school (St. Francis Preparatory School) that is at the center of the New York outbreak. Otherwise, treatment of mild cases of flu-like symptoms, in both persons affiliated with the school and the general population, should be given to individuals who are susceptible to severe illness due to an underlying condition. For updated information on the swine flu outbreak as it evolves go to http://www.cdc.gov/swineflu/whatsnew.htm.

Eunice Kang is a Third Year Internal Medicine Resident at NYU Medical Center 

Picture Courtesy Wikimedia Commons

BREAKING NEWS: Another Nut that You’d Rather Not…

March 31, 2009

397px-ars_pistachio.jpgFDA ALERTS CONSUMERS TO RECALL OF PISTACHIO PRODUCTS

Commentary by Rebecca Hall MD, PGY-1

Growing concerns over Salmonella  contamination of pistachio products sold by Setton Pistachio of Terra Bella Inc in California have lead the manufacturer to voluntarily recall about a million pounds of its pistachio containing products. 1  The recall involves bulk lots o f roasted shelled pistachios and roasted inshell pistachios shipped on or after September 1st 2008. 2 Because pistachios are a component of numerous other products including many baked goods and nut mixes, many additional products may be affected and could be recalled in the near future.Already, nut containing products from Kroger, the “Georgia Nut Company” and  “Back to Nature Foods Company” have been recalled.

Multiple strains of Salmonella have been implicated.  Thus far, several illnesses in consumers which may be related to pistachio consumption have been reported but it has not yet been verified whether these illnesses have been caused by the Salmonella strains found on the implicated pistachio products.   Salmonellosis most often occurs in those most susceptible to food borne illness including the elderly, infants, and those with compromised immune systems.  Twelve to seventy two hours after exposure, persons infected with Salmonella may experience as diarrhea, fever, abdominal cramps.  It occasionally causes life-threatening diarrhea.3

Diagnosis is based on isolation of Salmonellae from stool cultures which takes a minimum of 48-72 hours. 4  However, given the lack of a rapid diagnostic test, symptomatic patients should be treated empirically with fluids and electrolyte replacement.  For mild to moderate illness, antibiotic treatment is not recommended for immunocompetent children over 12 months of age and adults.4  However, treatment with a fluroquinolone, TMP-SMX, or amoxicillin should be considered in immunocompetent patients with severe diarrhea (>9 stools/day), a high fever, or those patients requiring hospitalization.4

References

1.U.S. Food and Drug Administration, “Pistachio Product Recalls: Salmonella“. http://www.fda.gov/pistachios/ Updated 3/31/09.

2.U.S. Food and Drug Administration, “Recall- Firm Press Release, Setton Pistachio of Terra Bella” http://www.fda.gov/oc/po/firmrecalls/setton03_09.html

3. CDC, Division of Foodborne, Bacterial and Mycotic Diseases.  “Salmonellosis.” http://www.cdc.gov/nczved/dfbmd/disease_listing/salmonellosis_gi.html  

4. “Approach to the patient with nontyphoidal Salmonella in a stool culture”  Uptodate.com, accessed 3/31/09.

Salmonella Update

March 21, 2009

salmonella_typhimurium.jpgCommentary by Sherley Abraham MD, PGY-3

The CDC reports there have been 666 cases and 9 deaths associated with Salmonella Typhimurium infections. The outbreak began September 1st, 2008 and has spread across 45 states, including 30 cases in New York. The source has been traced back to peanut butter and peanut paste made at the production company in Blakely, Georgia which is owned and operated by the Peanut Corporation of America. There is a nationwide product recall which can be found on the FDA website or by calling the CDC at 1-800-CDC-INFO. Of note, national brands of jarred peanut butter are not on this recall list. The list does include many snack items and prepackaged foods with peanut butter or peanut paste and includes some pet foods.

Investigations of the Georgia peanut company revealed that Salmonella had been isolated in the internal sampling program at least a dozen times but no actions were taken to remedy the problem. The New York Times reports that the company had health violations since 2006 with numerous citations for substandard cleanliness. In light of these investigations, the Peanut Corporation has voluntarily recalled all products processed since 2007. The Corporation states it cannot provide additional recall information to consumers as it is undergoing bankruptcy proceedings.

Consumers are urged to adhere to the recall list. Salmonella infection usually presents with fever and gastrointestinal symptoms within hours to days of exposure, and lasts days, and up to one week. The illness may be self-limiting or require supportive hydration. In certain populations, such as the very young or very old, or those who are immunocompromised, there is higher risk of systemic infection, which can be fatal if not treated promptly with antibiotics. There are also connections between Salmonella infection and development of reactive arthritis in Reiter’s syndrome and osteomyelitis in patients with sickle cell.

In a NEJM perspective article, Dr. Maki states that foodborne disease causes 350,000 hospitalizations and 5000 deaths per year. In addition, there is a large problem of underreporting due to lack of diagnosis. It is estimated that in large salmonella outbreaks, there are 38 additional cases for every detected case. Prevention of such outbreaks would require expansion of the surveillance programs of the USDA and FDA, as well as better methods to rapidly detect enteropathogens and trace foods to their origin. Dr. Maki goes on further to call for the discontinuation of antibiotics in animal feeds which leads to microbial resistance, more hygienic food preparation, as well as routine irradiation of high risk foods.

References
CDC. Investigation Update: Outbreak of Salmonella Typhimurium Infections, 2008–2009. http://www.cdc.gov/salmonella/typhimurium/update.html

FDA. Peanut Product Recalls: Salmonella Typhimurium.
http://www.fda.gov/oc/opacom/hottopics/salmonellatyph.html

Rabin, RC. Peanut Plant Had History of Health Lapses. New York Times. 2009 Jan 27.
http://www.nytimes.com/2009/01/27/health/27peanuts.html?scp=7&sq=rabin%20salmonella&st=cse

Maki DG. Coming to Grips with Foodborne Infection — Peanut Butter, Peppers, and Nationwide Salmonella Outbreaks. N Engl J Med. 2009 Feb 11. Epub.
http://content.nejm.org/cgi/content/extract/NEJMp0806575v1

Mystery Quiz- The Answer

March 10, 2009

Posted by Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The answer to the mystery quiz is allergic bronchopulmonary aspergillosis (ABPA). The CXR shows right upper lobe opacities, two of which appear round (Image 3, arrow) and another tubular (Image 3, arrowhead), and a left upper lobe opacity which has the characteristics of subsegmental atelectasis (Image 3, double arrows). The CT scan, performed ten days after the CXR, shows central bronchiectasis of the RUL (Image 4, arrows); tubular branching shadows (Image 6, arrow) as well as ring shadows (Image 5 and 6, arrowhead) all of which represent ectatic airways filled with mucoid material. A left upper lobe ectatic airway with thickening of the bronchial wall is also present (Image 7, arrow). The left upper lobe subsegmental atelectasis seen on the initial CXR was not visible on the CT image, indicating clearing of mucoid impaction.

ABPA is seen in a small percentage of patients with asthma and represents a complex hypersensitivity reaction to aspergillus antigens colonizing the airways. The diagnosis is established when multiple clinical findings are present. These include frequently refractory asthma, eosinophilia, serum IgE reactive to aspergillus antigen, and very elevated total serum IgE levels (>1000 IU). Characteristic imaging shows central bronchiectasis and mucoid impaction (“finger in glove” shadows, Image 6, arrow) that result in subsegmental atelectasis, often in an upper lobe distribution. The atelectasis can appear migratory as one area clears and another becomes impacted. In addition to patients with asthma, ABPA is associated with cystic fibrosis in a small percentage of cases. Treatment consists of high dose glucocorticoids followed by a slow taper. Serum IgE levels decline but typically do not normalize and recurrences of disease are associated with increasing serum IgE levels. There is some evidence that the addition of itraconazole to glucocorticoids may be helpful. The addition of the antifungal agent may decrease the burden of aspergillus colonization and lead to less hypersensitivity. Left untreated, ABPA may progress to irreversible fibrosis.

Our patient was initially treated as an asthma exacerbation due to pneumonia. However, this initial diagnosis gave way to a final diagnosis of ABPA when the serum IgE level returned at 1365 IU (reference range 0-158), serum IgE specific for Aspergillus fumigatus was elevated and the CT imaging showed characteristic findings.

postimage3.JPGpost_image_4_ct.JPG

 

post_image_5_ct.JPGpost_image_6_ct.JPG

post_image_7_ct.JPG

 

Diseases 2.0: Sepsis

February 5, 2009

fluid11.jpgDiseases 2.0 – Bringing you the latest updates on disease pathophysiology and treatment

Commentary by Andrew McKinstry MD PGY-1

Faculty Peer Reviewed

For anyone who has stepped into an ICU, the septic patient is a familiar sight. Despite advances in research and management, including goal directed therapy and recombinant human activated protein C (Xigris), sepsis continues to be a major cause of mortality in the critical care setting, with an estimated 215,000 deaths annually, and costing roughly 16.7 billion dollars per year. Despite these staggering human and monetary costs, the nature of and mechanisms involved in sepsis remain either unknown or hotly contested. The continuing research into this problem is on the verge of producing a number of promising insights and interventions, from insights into the nature of the syndrome to new pharmaceutical solutions and systems-based interventions.

While sepsis is a well-documented syndrome, there is debate among sepsis researchers whether sepsis is actually a number of different processes with a common late-stage presentation. While this could seem a largely academic debate, a mechanistic understanding of sepsis would be important in determining biomarkers for use in early detection of the syndrome. Recently, procalcitonin emerged as a possible candidate for a sepsis biomarker. Studies as early as 1993 described procalcitonin as an infection variable, and a few studies early this decade showed higher levels of procalcitonin in septic states than other inflammatory states. Further investigation found that while is was another good indicator of systemic inflammation, calcitonin was not specific for sepsis to be useful as a diagnostic test. Research groups at Duke University and Henry Ford Hospital, at the University of Zurich and members of the SPEEDI trial in Copenhagen are now in the process of throwing a wide net in search of sepsis biomarkers using high-throughput protein screening.
The available armamentarium against sepsis is limited to recombinant human activated protein C (APC) which targets one of the dysregulated systems in sepsis, coagulation, and likely affects what is the major dysregulation of sepsis, inflammation. APC has been shown to improve all-cause mortality in severe sepsis, though is ineffective and potentially harmful in less severe sepsis due to a high complication risk. Looking down the pipeline, at least two other drugs that target the hypercoaguable state in sepsis are in late phase trials. Recombinant human soluble thrombomodulin and recombinant anti-thrombin are in trials for treatment of DIC in sepsis, with the hope that they might provide a similar improvement in mortality with fewer hemorrhagic complications associated with APC.

Current drug research in sepsis is primarily focused on correction of inflammatory dysfunction, and coagulation dysfunction. Earlier theories of sepsis categorized it as a purely hyperinflammatory state, and unsuccessful experimental therapies focused on broad reduction of inflammation systemically. Coritcosteroid treatment has been shown to be ineffective, and there was a mixed picture for the efficacy of monoclonal anti-TNF antibodies in sepsis. While there was a meta-analysis of trials using monoclonal anti-TNF antibodies in severe sepsis suggests some efficacy, none of the individual trials showed any significant improvement in outcome.

Current theories on mechanisms of sepsis postulate a complex, heterogenous dysfunction of inflammatory processes- a cytokine storm that can lead to a mixed hyper- and hypoinflammatory state. In animal models of bacterial sepsis, blockade of IL-22 resulted in improved bacterial clearance in the liver and kidneys with reduced kidney damage, a possible future therapy aimed at prevention of end-organ damage in sepsis. Similarly, in translational studies blocking function of IL-27, subjects showed an increase in survival- another potential target for future therapies. Hemodiafiltration using a membrane that filters cytokines shows some promise in treating the cytokine storm of sepsis- human trials have shown decreased markers of end-organ damage, though no survival benefit has yet been demonstrated. Statins, the wonder drugs that seem to have no end of new uses, also show some potential in treatment of sepsis. Prior statin use has been shown to decrease the rate of severe sepsis in hospitalized patients, and statin use in patients with multi-organ dysfunction have been shown to have improved survival.

The ability of relatively small amounts of lipopolysaccharide (LPS) from gram-negative bacteria to induce a septic-shock-like condition has long been known, but the discovery in the last decade of the receptor through which LPS induces a vasodilatory state, Toll-like Receptor 4 (TLR4), presented a promising drug-target. Eritorian is a TLR4 antagonist currently in Phase III trials for treatment of severe sepsis, and TAK-242, a small molecule cytokine inhibitor of TLR4 signaling, is also in late phase trials.

Last but not least, some of the most significant advances in treatment of sepsis have not come from new pharmaceutical interventions, but in improved delivery of care. Early goal-directed therapy was hugely successful in improving sepsis outcomes, but now researchers at the University of Pittsburgh are performing a head-to-head comparison between goal directed therapy (which requires a central venous line with all of its associated complications) to protocolized care (which does not require a central line) in the treatment of septic patients. Who knows, depending on the results of that study, maybe next year in the ICU, not every sepsis patient will need that central line that they have now.

Given the variety of research and the number of late-phase trials currently underway, the clinical approach to sepsis will likely have a number of significant changes in the next five years. Improved diagnostic tests will help ensure earlier interventions, improved protocols will improve the quality of interventions, and new pharmaceuticals will be available for treatment of both complications of sepsis and the dysfunctional inflammatory state of sepsis itself. Continued success in sepsis research may mean that at some point in the no-so-distant future, a sepsis diagnosis will be as simple as a blood test, and pharmaceutical treatment will be as straight forward as antibiotics and an inflammatory modulator. In the mean time, though, make sure those fluids are hanging.

Reviewed by Laura Evans MD, NYU Division of Pulmonary and Critical Care Medicine

Sources:

www.clinicaltrials.gov

Leaver, S. et al. Sepsis since the discovery of Toll-like receptors: Disease concepts and therapeutic opportunities. Critical Care Medicine. Vol 35, No. 5 2007. p1404-10

Leon, C et al. Discovery and Development of Toll-Like Receptor 4 (TLR4) Antagonists:
A New Paradigm for Treating Sepsis and Other Diseases. Pharmaceutical Research. Vol 25, No 8, August 2008. p1751-61.

Nakada, T et al. Continuous Hemodiafiltration with PMMA Hemofilter in theTreatment of Patients with Septic Shock. Molecular Medicine. 14(5-6) p 257-63.

Remick, D. Pathophysiology of Sepsis. The American Journal of Pathology, Vol. 170, No. 5, May 2007, p 1435-44.

Weber, G et al. Inhibition of Interleukin-22 Attenuates Bacterial Load and Organ
Failure during Acute Polymicrobial Sepsis. Infection and Immunity, Apr. 2007, p. 1690–97

Wirtz, S et al. Protection from lethal septic peritonitis by neutralizing the biological function
of interleukin 27. The Journal of Experimental Medicine. Voll 203, No 8, August 7, 2006. p 1875-81.

Should All Patients with Cellulitis Be Treated for Community-Acquired Methicillin-Resistant Staphylococcus Aureus?

January 22, 2009

120px-mrsa_sem_9994_lores.jpgCommentary by Melanie Maslow, MD, FACP, Associate Professor of Medicine, NYUSOM, Chief, Infectious Diseases, New York Harbor Healthcare System, NY

Faculty Peer Reviewed

Cellulitis is an acute spreading infection of the skin extending to the deep subcutaneous tissue characterized by pain, swelling, erythema and warmth. Cellulitis in the non-neutropenic patient, in the absence of bite wounds, salt or fresh water exposure, and coexisting ulcers is usually caused by Gram-positive pathogens, the most common being the beta-hemolytic streptococci and S .aureus, including methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) strains. Empiric therapy for management of cellulitis has traditionally included antibiotics with activity against beta-hemolytic streptococci and MSSA such as penicillinase-resistant penicillins or first generation cephalosporins, unless the patient was known to have a previous MRSA infection or in cases of severe systemic toxicity.

Over the past decade there has been a steady rise in the incidence of community-acquired methicillin-resistant S. aureus (CA-MRSA). A recent study [1] documented a nearly three-fold increase in the incidence of skin and soft tissue infections (SSTIs) presenting to Emergency Departments in this country concurrent with the emergence of CA-MRSA. A study published in 2006 from the Grady Health System found that 72% of community-acquired S. aureus skin and STI were caused by MRSA [2].

The USA 300 clone of CA-MRSA predominates in this country and differs from hospital acquired MRSA in several important ways. CA-MRSA is found in patients without the traditional risk factors for MRSA, is usually more susceptible to different antibiotic classes, has a unique chromosomal cassette containing a smaller resistance gene thought to result in more efficient transmission, and usually contains a virulence factor, Panton-Valentine leukocidin (PVL) [3]. PVL produces cytotoxins, causing tissue necrosis and leukocyte destruction, which can result in serious infections such as necrotizing fasciitis and pyomyositis. However, most CA-MRSA associated infections are purulent or pustular skin lesions and SSTIs.
Outbreaks of CA-MRSA have been documented in inmates of correctional facilities, athletes, military personnel, intravenous drug abusers, homosexual men, homeless persons, in healthy children, and in specific populations including Alaskan Natives, Native Americans and Pacific Islanders. The current epidemic extends to populations not traditionally infected with MRSA such patients with diabetes, HIV-infection, ESRD on hemodialysis, those receiving prior antibiotics, and in recently hospitalized and/or nursing home patients [3]. A recent prospective study of patients hospitalized with MRSA found that there were no clinical or epidemiological risk factors that could reliably distinguish between community-acquired MRSA and MSSA [4].

Given the increasing incidence of CA-MRSA SSTIs and the inability to reliably identify CA-MRSA, alternative regimens have been recommended for the treatment of suspected and/or confirmed CA-MRSA infection. In the outpatient setting, these include sulfamethoxazole-trimethoprim, clindamycin, doxycycline, and linezolid. Clindamycin has the potential advantage of also decreasing production of staphylococcal toxins, but increasing resistance to clindamycin has been documented and the microbiology lab should test for inducible resistance using the double-disk D-test. Increasing resistance to doxycycline in CA-MRSA has also been reported [5]. For hospitalized patients, recommended parenteral agents for the treatment of suspected CA-MRSA cellulitis include vancomycin, linezolid, daptomycin and tigecycline. Although vancomycin remains the gold standard, increasing resistance to vancomycin has been documented and strains with heteroresistance to vancomycin may also develop resistance to daptomycin. Linezolid, like clindamycin, has the ability to impair toxin production in more serious SSTI and limited resistance to linezolid has been documented to date [5]. Several promising investigational agents include dalbavancin and telavancin (lipoglycopeptides), oritavacin (a semisynthetic glycopeptides), and ceftobiprole, a broad-spectrum third generation cephalosporin [6].

Given the current epidemic of CA-MRSA skin and soft tissue infections and the inability to distinguish MRSA from MSSA by risk factors and/or clinical presentation, the clinician should initiate treatment for MRSA with one of the recommended oral or parenteral antibiotics. It is also important to attempt confirmation of the etiologic agent of cellulitis, which is not usually done secondary to the low yield of cultures. All abscesses and pustules should be aspirated and sent for culture. Bullae should be unroofed and the base swabbed and sent for culture. Establishing the susceptibility of S. aureus isolates in even a small proportion of patients will enable the provider to switch to a narrower spectrum agent if CA-MRSA is ruled out, decreasing the resistance pressure that is driving this current epidemic.

 

Reviewed by Howard Leaf MD, Assistant Professor, NYU Division of Infectious Diseases and Immunology

References:

1. Pallin DJ, Egan DJ et al. Increased US Emergency Department Visits for Skin and Soft Tissue Infections, and Changes in Antibiotic Choices During the Emergence of Community-Associated Methicillin-Resistant Staphylococcus aureus. Ann Emerg Med 2008;51(3):291-298
2. King MD, Humphrey, BJ et al. Emergence of Community-Acquired Methicillin-Resistant Staphylococcus aureus USA 300 clone as the Predominant Cause of Skin and Soft-Tissue Infections. Ann Intern Med 2006;144(5):309-317
3. Weber, JT. Community-Associated Methicillin-Resistant Staphylococcus aureus. Clin Infect Dis 2005;41:(suppl 4):S269-279.
4. Miller, LG, Perdreau-Remington, F. et al. Clinical and Epidemiologic Characteristics Cannot Distinguish Community-Associated Methicillin-Resistant Staphylococcus aureus from Methicillin-Susceptible Staphylococcus aureus Infection: A Prospective Investigation. Clin Infect Dis 2007;44:471-82.
5. Moellering, Robert C. Jr. Current Treatment Options for Community-Acquired Methicillin-Resistant Staphylococcus aureus Infection. Clin Infect Dis 2008;46:1032-7.
6. Stryjewski, ME and Chambers, HF. Skin and Soft-Tissue Infections Caused by Community-Acquired Methicillin-Resistant Staphylococcus aureus. Clin Infect Dis 2008:46(Suppl 5);S368-377.

Image courtesy of Wikimedia Commons

Grand Rounds: “Combating the Poverty Associated Tropical Diseases”

December 3, 2008

Bellevue Amphitheater

 

Commentary by Alpana Marwaha MD PGY-3

Please also see the clinical vignette presented before last week’s grand rounds.

This week, the Department of Medicine Grand Rounds was presented by Dr. Peter Hotez MD, PhD and chair of the Department of Microbiology and Tropical Medicine at GW Medical Center. The talk was entitled, “Combating The Poverty Associated Tropical Diseases.”

 

There are a staggering 1.4 Billion people living at wages below $ 1.25 per day known as the “The Bottom Billion.” The prevalent Neglected Tropical Diseases (NTDs) affecting these “bottom billion” include Ascariasis, Trichuriasis, Hookworm, Schistosomiasis, Lymphatic Filariasis, Trachoma, Onchocerciasis. While Filariasis can cause disabilities such as disfigurement and loss of limb use, millions of villagers are rendered blind by Trachoma. These diseases also reduce agricultural productivity, have a huge social stigma attached to them and increase maternal morbidity and mortality. Furthermore, they impact child growth and development as children often tend to have the highest worm burden. Thus these diseases that are bred by poverty go on to promote poverty, forming a vicious cycle. When studies calculated DALY’s lost due to these conditions, NTDs stood head to head with Ischemic Heart Diseases at 56 million. Facts like these have made policy makers realize the actual threat and extent of these tropical diseases.

Understanding this, Dr. Hotez went on to explain what has been done to treat and prevent these diseases so far. Initially, this was with preventive chemotherapy and through mass drug administration. Prevalence studies have revealed that people in endemic areas are often poly-parasitized. Thus a solution called the Rapid Impact Package (RIP) was designed and it includes four medications aimed at treating the 7 most common tropical diseases at an affordable price of 50 cents per package. Using these solutions, the United Nations formed a Global Network for Neglected Tropical Diseases Control (GNNTDC) which seeks to coordinate the efforts of seven organizations that fight NTDs. Dr. Hotez has been a motivational force in organizing this movement.

However there were setbacks to the project. Metanalyses showed drug failure of mebendazole to eradicate Hookworm infection, either due to reinfection or through drug resistance (as the hookworm only requires a single point mutation). Therefore, a new initiative was undertaken by Dr. Hotez. He is the Principal Scientist of the Human Hookworm Vaccine Initiative (HHVI), a public-private partnership sponsored by the Sabin Vaccine Institute with major funding from the Bill and Melinda Gates Foundation providing an $18 million hookworm vaccine grant. The Human Hookworm Vaccine will be bivalent, consisting of 2 antigens. One will help the immune system target larval stage hookworm parasites while the other will target adult hookworm (Anti-APR-1). The hookworm larval antigen ASP-2 (ancylostoma secreted protein-2) is identified as the protective antigen linked to reduced risk of heavy hookworm infection. Currently, the vaccine is in Phase 1 clinical trials in Brazil. The HHVI also plan to come up with multivalent Anti-Helminthic vaccine in the future. Lastly, Dr. Hotez talked about the prevalence of tropical diseases in the Unites States, given the increasing migrant population. NTD in the US include trichomoniasis, cysticercosis and even cases of dengue.

In summary, we realize the huge global burden of NTDs, need to control them through chemoprophylaxis and the need for development of innovative and cost effective strategies like the HHVI.