ID

Mystery Quiz- The Answer

November 13, 2010

Dana Clutter, MD

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

Faculty peer reviewed

The answer to the mystery quiz is bacillary angiomatosis (BA). BA is a disease that most frequently affects individuals infected with the human immunodeficiency virus (HIV) and typically presents with multiple cutaneous papules and nodules. Visceral manifestations also occur and can involve the bone, lungs, lymph nodes, spleen, liver (termed peliosis hepatis) and the central nervous system.(1) Since the relatively recent first description of the disease in 1983, the two causative organisms, Bartonella quintana and Bartonella henselae, have been identified. The main risk factors for B. henselae infection are contact with flea-infested cats and cat scratches, while those for B. quintana are lice infestation and homelessness. Erythromycin or doxycycline are the first line treatments.(2)

There are multiple clinical forms of cutaneous lesions in bacillary angiomatosis including dermal and subcutaneous nodules. The more common dermal form, present in 60% of patients, is characterized by multiple erythematous nodules/plaques that may be quite friable. An epithelial collarette may develop around some of these lesions. The subcutaneous form, present in approximately 50% of patients, features nodules which are often tender beneath skin that may be normal in color, dusky, or inflamed.(1)

Because it is frequently difficult to distinguish BA from other diseases, particularly Kaposi’s sarcoma (KS) and pyogenic granuloma, by clinical means alone, a biopsy is usually performed to establish the diagnosis. Histologically, biopsies of cutaneous lesions demonstrate lobular proliferation of small blood vessels lined by large endothelial cells. An infiltrate of scattered neutrophils is another important clue to the diagnosis. There may be an epithelial collarette and varying amounts of edema. A silver stain can help to visualize clumps of Bartonella bacteria.(1) A serologic test for Bartonella is available; however, up to 25% of culture-positive patients with advanced acquired immunodeficiency syndrome (AIDS) never develop anti-Bartonella antibodies.(1)

The differential diagnosis of BA includes other vascular lesions, such as pyogenic granulomas and angiomas, and given that the patient has advanced HIV/AIDS, it is particularly important to include KS and atypical mycobacterial infections.

In this case, there are several clinical clues to the diagnosis of BA. The facial lesion demonstrates a typical erythematous nodule surrounded by a collarette which is present in both BA and pyogenic granuloma, but not KS. The lesion is friable, which is characteristic of BA, where a firmer texture is expected in KS.(3) The lesion on the forearm represents a subcutaneous lesion, a finding common in BA and KS and rarely in pyogenic granuloma. Although these three diseases can affect immunocompetent patients, BA and KS have a strong predilection for patients with advanced AIDS. Thus, our patient with a CD4+ T-cell count of 1 cell/cmm has an increased risk of both diseases. Although insufficient sample remained for silver staining, pathology was most consistent with BA. The dramatic response to erythromycin pictured below in both the facial and forearm lesions also strongly supports the diagnosis of BA (Images 1 and 2).

Dr. Clutter is a first year resident at NYU Langone Medical Center.

Faculty Peer Reviewed by Jennifer Stein, MD, Assistant Professor in the Department of Dermatology, NYU Langone Medical Center.

1. Cotell S, Noskin G. Bacillary angiomatosis: clinical and histologic features, diagnosis and treatment. Arch Intern Med. 1994 Mar; 154: 524-528.

2. Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. MMWR 2009; 58(No. RR-4):1-203.

3. Wong R. Bacillary angiomatosis and other Bartonella species infections. Semin Cutan Med Surg. 1997 Sep; 16(3): 188-199.

How do you Manage the Adult with Perinatally Acquired Hepatitis B?

October 22, 2010

Nathaniel Rosso Smilowitz, MD

Faculty Peer Reviewed

Hepatitis B virus is a DNA hepadnavirus affecting 1.25 million people in the United States and nearly 400 million worldwide.  The virus is transmitted perinatally, sexually, and percutaneously, and is endemic in many countries in South East Asia, Central Asia, and Africa.  When exposure occurs early in life, the likelihood of chronic infection is high; up to 90% of cases of vertical transmission result in the persistence of the viral envelope protein, the hepatitis B surface antigen (HBsAg), in the serum, indicative of chronic infection.[1],[2] Over time, chronic hepatitis is associated with a risk of progression to cirrhosis, liver failure, and hepatocellular carcinoma that is proportional to levels of viral replication.[3] Screening for serum HBsAg should be performed in patients with abnormal liver transaminases and those with risk factors, including immigration from Asia or Africa, high-risk sexual intercourse, IV drug use, occupational exposure, and blood transfusions.

Once an asymptomatic patient has been identified as being chronically-infected with HBV, the physician should check liver transminase values every 3 to 6 months, which serve as a surrogate to the presence of ongoing liver damage.  Viral replication should be assessed every 6-12 months by performing a quantitative viral DNA PCR-based assay, and by screening for HBeAg, a soluble nucleocapsid protein, as well as for anti-HBe antibodies. The distinction between viral activity and liver damage is important for management.  When HBV is acquired perinatally, immunologic tolerance is manifest, characterized by an absent cellular immune response to viral proteins and by high viral replication without significant liver injury.  Later in life, an immune-reactive phase occurs whereby the host immune response recognizes the foreign viral proteins and attacks HBV-infected hepatocytes, resulting in elevated aminotransferases and histologic liver damage. Most patients are infected with wild-type HBV virus that expresses the HBeAg, and they typically experience high levels of viral replication. Some will undergo spontaneous or treatment-related seroconversion to HBeAg negative, at which point they are considered to have inactive disease.  This seroconversion is associated with a reduction in HBV replication and clinical improvement.[4] Thus, in asymptomatic patients newly diagnosed with HBV, treatment should be postponed for three to six months to determine whether spontaneous seroconversion will occur, except in rare instances of fulminant hepatic failure.  Other individuals are infected with HBV with a “pre-core” mutation that results in lack of, or severely reduced production of HBeAg.  These patients have a serologic pattern of HBeAg negativity and HBeAB positivity, but they are still in danger of progressive liver injury, despite lower levels of viral replication.  Furthermore, since patients with HBeAg-negative disease already have HBeAB positivity, they lack a clear treatment-induced endpoint of HBeAg seroconversion that can signify inactive disease.

The goal of treatment in chronic hepatitis B is to achieve a sustained reduction in levels of HBV replication that can limit liver disease and improve clinical outcomes.  However, indications for initiation of antiviral therapy are complex.  In the immune-tolerant stage of disease, treatment of patients with high HBV DNA levels (≥20,000 IU per mL) and normal serum ALTs, is unlikely to result in a meaningful biochemical or serologic response and is not recommended.  Instead, close monitoring of serial ALTs can identify progression to active liver disease at which time treatment may be considered.  For patients older than 40 years or with elevated ALTs less than twice the upper limit of normal, physicians may consider a liver biopsy to help dictate management, though this is controversial.  Prompt initiation of treatment is indicated for patients with more than 3-6 months of HBeAg-positive immune-reactive infection (HBV DNA levels ≥20,000 IU per mL and serum ALT more than twice the upper limit of normal).[5] These patients are most likely to achieve durable responses to therapy, and without antiviral treatment, progression to fibrosis occurs in 25% of patients within 1 year.[6] Similarly, patients with HBeAg-negative chronic hepatitis with ALT elevated above two times the upper limit of normal and HBV levels of ≥20,000 IU are eligible for initiation of treatment.  For HBeAg-negative chronic hepatitis B with lower ALTs (between one and two times the upper limit of normal) and HBV DNA ≥2,000 IU, antiviral treatment is not routinely recommended.  In this situation, liver biopsy can be considered to guide management.  Finally, patients with HBeAg-negative disease, DNA levels less than 2,000 IU, and ALTs less than twice the upper limit of normal do not require treatment.v

There are now seven antiviral drugs licensed for use in the United States, including interferon alfa, pegylated interferon alfa-2a, and the oral nucleoside and nucleotide analogs lamivudine, adefovir, entecavir, telbivudine, and tenofovir.vi Interferon therapy and the newer oral nucleotide analogs have comparable rates of HBsAg seroconversion at 1 year, although interferon therapy is associated with a substantial side effect profile.[7] Viral resistance to oral drug therapy also poses a continuing challenge to Hepatitis B treatment; currently entecavir and tenofovir are the preferred first line oral therapies, with less utility for lamivudine and telbivudine. Ultimately, the decision to start oral antivirals or a fixed 48-week schedule of injectable interferon therapy is dictated by patient and physician preference. Regardless of treatment modality, clinical endpoints of treatment are typically seroconversion to HBeAg-negative infection (or more rarely, HBsAg-negative disease), reductions in HBV DNA levels, normalization of serum ALT, and improvement in grade and stage of fibrosis on liver biopsy.v

In conclusion, the criteria for initiation of antiviral therapy in adults presenting with perinatally acquired Hepatitis B are complex, and begin with evaluation of viral replication and liver damage.  Patients ineligible for antiviral therapy need periodic evaluation (with liver function and viral replication studies) to identify the earliest possible opportunity for therapeutic intervention.

Dr. Smilowitz is a recent medical student graduate of NYU School of Medicine

Peer reviewed by Michael Poles, MD, GI Section Editor, Clinical Correlations

Image of Philippe Maupas (hepatitis B vaccine discoverer) courtesy of Wikimedia Commons.

References:

1. Cooke GS, Main J, Thursz MR. Treatment for hepatitis B.  BMJ. 2010 Jan 5;340:b5429.  http://www.bmj.com/content/340/bmj.b5429.extract

2. Gay NJ, Hesketh LM, Osborne KP, Farrington CP, Morgan-Capner P, Miller E. The prevalence of hepatitis B infection in adults in England and Wales.  Epidemiol Infect. 1999 Feb;122(1):133-8.  http://www.ncbi.nlm.nih.gov/pubmed/10098796

3. Iloeje UH, Yang HI, Jen CL, Su J, Wang LY, You SL, Chen CJ; Risk and predictors of mortality associated with chronic hepatitis B infection.  Clin Gastroenterol Hepatol. 2007 Aug;5(8):921-31.  http://www.ncbi.nlm.nih.gov/pubmed/17678844

4. Lok AS, Lai CL, Wu PC, Leung EK, Lam TS.  Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection.  Gastroenterology. 1987 Jun;92(6):1839-43.  http://www.ncbi.nlm.nih.gov/pubmed/3569757

5. Lok AS, McMahon BJ.  Chronic hepatitis B.  Hepatology. 2007 Feb;45(2):507-39

6. Dienstag JL.  Hepatitis B virus infection.  N Engl J Med. 2008 Oct 2;359(14):1486-500.  http://www.ncbi.nlm.nih.gov/pubmed/18832247

7. Gish RG, Lok AS, Chang TT, de Man RA, Gadano A, Sollano J, Han KH, Chao YC, Lee SD, Harris M, Yang J, Colonno R, Brett-Smith H.  Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B.  Gastroenterology. 2007 Nov;133(5):1437-44.  http://www.ncbi.nlm.nih.gov/pubmed/17983800

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

October 14, 2010

Please enjoy a post from the Clinical Correlations Archives, first posted 1/22/09

Commentary 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

Circumcision as Primary Protection?

October 8, 2010

Emily Taylor, MD

Faculty Peer Reviewed

The earliest documented evidence of circumcision is in artwork from the Sixth Dynasty in Egypt (2345-2181 BC) found in a wall relief from Saqqara in Lower Egypt. Circumcised North Americans were described by Columbus upon arrival to the continent; circumcision was practiced by Australian aboriginals, native South Americans, and Pacific Islanders. It is unknown if circumcision was common amongst some earlier ancestor of all these peoples, or if it evolved independently in societies that lived in dry, sandy areas, where sand could get under the foreskin and lead to balanitis and urethritis. Throughout history, circumcision was often performed due to its perceived medical benefits, from curing excessive masturbation to decreasing rates of infection, but the practice fell out of favor in the last century within the medical community as there was insufficient data to support these claims. Today, reasons for circumcision often stem from religious beliefs or social customs, but now there is some compelling data showing that circumcision may be beneficial to one’s health.

Sub-Saharan Africa remains the region most heavily affected by HIV. In 2008, it accounted for 67% of HIV infections worldwide, 68% of new HIV infections among adults and 91% of new HIV infections among children. The region also accounted for 72% of the world’s AIDS-related deaths. A link between circumcision rates and HIV prevalence in heterosexual men in Africa was first hypothesized in the late 1980s, when researchers studying risk factors for HIV infection in 422 men who visited commercial sex workers found that men who were not circumcised had an 8.2 fold increased risk of seroconversion compared with circumcised men.[3] Additional studies found similar (though not as striking) trends, and a meta-analysis showed an adjusted relative risk of 0.42. In further support of their theory, a cohort study of Ugandan discordant couples in which the female was HIV infected and the male partner was initially HIV seronegative, 37 of 134 uncircumcised men while none of 50 circumcised men became seropositive after approximately 2 years of follow-up. [11] When one looks at a map of AIDS prevalence in the 1990s, one can see a distinct area of overlap: The areas of high prevalence (also known as the “AIDS belt”) coincide with areas where circumcision rates are lower than other parts of Africa. The researchers looked into a variety of confounders such as prostitution, IVDU and homosexuality and were still able to show association.

“Orange Farm” was the first randomized, controlled, blindly evaluated trial to look at male circumcision as an intervention to prevent acquiring HIV.  The primary objective of the trial was to determine the impact that male circumcision would have on the acquisition of HIV by young men. A total of 3274 uncircumcised men, aged 18 to 24, were randomized to a control or an intervention group with follow-up visits at months 3, 12 and 21.  Circumcision was offered to the intervention group immediately and to the control group at the end of the study. The trial was stopped at the interim analysis (mean follow-up: 18.1 months), when analysis showed a risk ratio of 0.42 with 20 HIV infections in the intervention group and 49 infections in the control group, signifying an approximate protection rate of 60% with the intervention of male circumcision. [1] Subsequent trials in Kisumu, Kenya and Rakai, Uganda showed risk ratios of 0.41 and 0.50 respectively; these trials were also stopped during their interim analysis. [2, 5] The pooled analysis shows that in a two year period, in order to prevent one HIV infection, approximately 72 circumcisions will have to be performed. [7]

As a means to explain the results of all three trials, one must consider the following: The presence of penile foreskin makes for a larger total surface area over which the HIV virus can invade, and the area under the foreskin is warm and moist which is a favorable environment for pathogen survival and replication. With a foreskin in place, there is a longer drying time after sexual contact, which increases life expectancy of HIV on the penis after sexual activity. The inner surface of the foreskin is not keratinized, making it prone to micro tears during sex. Of more probable importance, there are a larger number of target cells for HIV in the foreskin in comparison to keratinized penile skin (nine times the number of target cells; including Langerhaans cells, CD4+ T cells, and macrophages). [8]  It is important to note that a retrospective study looking at the control group of men who seroconverted in the Rakai study, at the two year mark when the control groups were also circumcised, found that the men who seroconverted had on average possessed larger foreskin areas than the members of the study who remained HIV negative. [6]

The current recommendations regarding male circumcision are still under discussion, but there now exists mounting data to support male circumcision as primary protection against female-to-male acquisition of HIV during vaginal intercourse. UNAIDS/WHO met in 2007 to discuss the trials, and recommended that it is important to stress the fact that male circumcision will never provide complete protection from HIV, but that it may be a good adjunct to condom use in areas where heterosexual HIV transmission rates are high and men are not commonly circumcised.  [12]

Researchers also looked at male-to-female transmission of HIV, but the results were not conclusive. 922 uncircumcised, HIV-infected, asymptomatic men aged 15-49 with CD4 counts 350 or more were enrolled in an unblinded, randomized controlled trial in Rakai District in Uganda. The intervention group was circumcised immediately, and HIV-uninfected female partners of these men were concurrently enrolled. 18% of women in the intervention group and 12% in the control group became infected but the results were deemed statistically insignificant. There was a subanalysis, not specified in the protocol, which looked at HIV transmission rates in couples who had had early resumption of sexual relations after circumcision prior to complete healing.  Five out of eighteen women in the intervention group who had early resumption of sex became HIV positive (27.8%) with a rate ratio of 3.5 (p value 0.038), and in the intervention group who waited until after healing to resume sexual activity, 6 out of 63 women became HIV positive.  Of the control group composed of uncircumcised HIV-infected men with uninfected female partners, 5 out of 63 women seroconverted.[10]  Needless to say, it stands to reason that early resumption of sexual activity would increase male to female transmission in the setting of continued penile wound healing. HIV-positive men undergoing circumcision should receive extensive counseling regarding the increased risk of infection they pose to their partners during the period of healing. Studies looking at the spread of other sexually transmitted infections in circumcised versus uncircumcised men are as yet inconclusive. [9]

This data might not be applicable to the US where the population and its sexual practices differ from those in sub-Saharan Africa. According to the CDC, which compiles data from the 34 states that have confidential name-based HIV infection reporting, male-to-male sexual activity accounted for 62% of all reported sexually transmitted cases of HIV in 2007. Of the reported cases of heterosexual transmission, approximately 65% were male to female; meaning that about 13% of HIV transmission in the US was female to male heterosexual transmission.  The studies reviewed in this article look only at female to male transmission in populations with low rates of circumcision. The fact that these trials may not affect policy in the US, is likely the reason why there has been limited local publicity surrounding the data. Despite the lack of local news coverage, these studies are of enormous importance as widespread implementation of circumcision in countries with low prevalence of male circumcision and high rates of heterosexual transmission should help to curb the spread of HIV.

Dr. Taylor is an Attending Physician, Dept. of Medicine, NYU Langone Trinity Center

Peer reviewed by Melanie Maslow,  MD,  Section Editor, Infectious Diseases, Clinical Correlations

References:

1.  Auver B et al. Randomized, Controlled Intervention Trial of Male Circumcision for Reduction of HIV Infection Risk: The ARNS 1265 Trial. PLoS Medicine 2005; 2: 1112-21.

2.  Bailey RC et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet 2007; 369: 643-56.  http://www.ncbi.nlm.nih.gov/pubmed/17321310

3.  Cameron DW,et al. Female to male transmission of human immunodeficiency virus type 1: risk factors for seroconversion in men. Lancet 1989; 2: 403-7.  http://www.ncbi.nlm.nih.gov/pubmed/2569597

4.  Drain PK et al. Male circumcision, religion, and infectious diseases: an ecologic analysis of 118 developing countries. BMC Infectious Diseases 2006; 6: 172.  http://www.biomedcentral.com/1471-2334/6/172

5.  Gray RH et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet 2007; 369: 657-65.

6.  Kigozi G et al. Foreskin surface area and HIV acquisition in Rakai, Uganda (size matters). AIDS 2009; 23: 2209-13.

7.  Mills E et al. Male circumcision for the prevention of heterosexually acquired HIV infection: a meta-analysis of randomized trials involving 11 050 men. HIV Medicine 2008; 9: 332-5.  http://www.ncbi.nlm.nih.gov/pubmed/18705758

8.  Szabo R et al. How does male circumcision protect against HIV infection? BMJ 2000; 320: 1592-4

9.  Tobian AAR et al. Male Circumcision for the Prevention of HSV-2  and HPV infections and Syphilis. NEJM 2009; 360: 1298-309.  http://www.nejm.org/doi/full/10.1056/NEJMoa0802556

10.  Wawer MJ et al. Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: a randomised controlled trial. The Lancet 2009; 374: 229-37.  http://www.hivinsite.org/InSite?page=jl-56-03

11.  Weiss HA et al. Male circumcision and risk of HIV infection in sub-Saharan Africa: A systematic review and meta-analysis. AIDS 2000; 14: 2361-70.  http://www.circs.org/library/weiss/index.html

12.  WHO/UNAIDS. WHO and UNAIDS announce recommendations from expert meeting on male circumcision for HIV prevention. http://data.unaids.org/pub/PressRelease/ 207/20070328_pr_mc_recommendations_en.pdf

The Challenge of Measles Control

September 15, 2010

By Taher Modarressi

Faculty Peer Reviewed

Measles remains one of the leading causes of preventable child mortality worldwide, despite the development of an effective vaccine in the 1960s. Even as late as the early 1990s, measles continued to infect tens of millions of people and claimed over a million lives each year (51]. Although mortality dropped by 78% from 2000 to 2008 due to aggressive control initiatives, the disease is still responsible for 164,000 deaths annually [12, 72]. Morbidity and mortality is mostly due to measles-associated pneumonia [13, 59], middle-ear infection [13, 30, 59], corneal inflammation and ulceration (27, 28, 46, 64), diarrhea [19, 35, 61, 70] and, rarely, subacute sclerosing panencephalitis [36, 37, 77].

Currently, the disease accounts for 3-4% of all deaths worldwide in children under the age of five, over half of which occur in sub-Saharan Africa [5, 74]. This region and the South-East Asia region are the two areas that are most struggling with measles control [75]. In addition to the widespread conflicts, enormous populations and persistent impoverishment that have debilitated immunization campaigns in these two regions, effective global measles control and elimination must also overcome a number of challenges posed by technical aspects of the vaccine, the clinical course of the disease and recent social issues.

Technical challenges of the measles vaccine include heat- and light-sensitivity [1, 3, 79]. Measles vaccines are stable for two years at 2-8°C and for one month at 25-30°C [1]. Above 37°C (98.6°F), however, the vaccine is inactivated within one hour. Unfortunately, nearly every country struggling with measles control is located in the tropics and regularly experiences temperatures much higher than 37°C [75], thus necessitating continuation of the cold chain for mobile vaccination units.

However, the main technical challenge of measles control programs is deciding the timing of the first dose. Infants are protected by passive maternal antibodies until 6-9 months after birth, during which time immunization is not possible [62]. If the vaccine is administered too early, it is ineffective and leads to a large percentage of susceptible individuals. If the vaccine is administered too late, there is a chance of widespread outbreaks occurring in the window of time between loss of maternal antibody and vaccination. Countries usually plan their first dose in respect to the status of the disease in the region. If measles incidence is high, the first dose is given at 9 months or sometimes as early as 6 months [20, 25]. If measles incidence is low, the first dose is administered between 12 to 15 months of age [15, 56]. Such is the case in the United States [14, 49], where measles vaccine is required in every state for grade school and/or college entry requirements [55]. A second dose of vaccine is administered to cover the 3-5% who fail to develop immunity after the first dose [48, 60], a minority which has played a very significant role in measles outbreaks [48]. While in the United States this dose is given between 4-6 years of age [14], countries with high measles prevalence can administer the second dose as early as one month after the first dose [11].

Several important challenges exist today that were either largely or wholly absent in past decades. First is the increased frequency and ease of regional and global travel. Primarily, this factor amplifies the spread of measles within susceptible areas. Areas in developing countries where measles is locally extinct are not free of the burden of the virus since importation of the disease can quickly reestablish indigenous transmission and trigger outbreaks [26].

Additionally, countries that have entirely eliminated measles are required to continuously maintain high vaccination coverage in their populations. Recent outbreaks in Western Europe [2, 38, 40, 63], Canada [7, 45] and the United States [9, 16, 57, 78], including 2008 and 2009 outbreaks in Brooklyn [34, 80], are a testament to this obligation. While measles vaccine has always been recommended for Americans travelling abroad [58], a large outbreak in South Africa, host of the 2010 World Cup, has underscored the importance of immunization to measles [8, 10].

In addition to these challenges, coverage in industrialized countries is not as simple as it may seem. In 1998, a study seemed to suggest a link between MMR vaccine and both autism and inflammatory bowel disease [71]. Coverage rates fell dramatically in the United Kingdom (where the study was conducted) from highs of near 90% in 1994 to <80% by the end of 1998 [39]. Levels remained as low as 79% until 2004 [47], much lower than the 95% necessary for effective herd immunity [31, 76]. Declines in coverage were also reported in various regions in the United States and Western Europe.

Despite countless studies showing no correlation and reports from the World Health Organization, the Centers for Disease Control and Prevention, the National Institutes of Health and the United Kingdom’s National Health Service to the same effect [17, 53, 54, 73], the shaken confidence has yet to fully recover. As of 2009, coverage rates in the United Kingdom stood at 82-84% in children under the age of two and 75% in children under the age of five [4, 47]. Activist groups against the MMR vaccine are persistent even though the author of the study has been accused of fixing his data [22] and charged with professional misconduct [24], as he had been paid £400,000 before the 1998 study by a legal group trying to sue vaccine companies for the alleged ill effects of the MMR vaccine [23]. In 2004, 10 of the original 13 authors issued a retraction of their interpretations presented in the article [50].

Recently, the General Medical Council of the United Kingdom condemned the manner in which the study was undertaken as dishonest, irresponsible and misleading [21, 33, 69], and The Lancet, which originally published the work, issued a full retraction of the paper [67]. On May 24, 2010, the author was formally stricken off the medical register in the United Kingdom [6, 32, 68].

Apart from these challenges, attempts at measles control must also deal with issues specific to the measles virus. Most candidates for control and elimination are compared to smallpox and the successful global smallpox eradication campaign. The measles virus has several biological characteristics that are advantageous to attempts at control. Like smallpox (and polio), there is no animal reservoir for the measles virus. The presence of animal reservoirs, which exist in diseases such as malaria, rabies, cholera and influenza, make eradication very difficult, as eradication would necessitate pathogen elimination from the animal reservoir as well. The lack of an animal reservoir means that all efforts can be aimed at disease transmission between humans.

Also like smallpox, a measles infection confers life-long immunity. The lack of reinfection results in a smaller population of susceptible individuals and therefore both slower and more limited transmission. Finally, molecular and structural constraints restrict mutation of the measles virion’s surface epitopes, allowing for continuous use of the current vaccines for many decades [29]. This is in stark contrast to viruses like influenza whose vaccines must be updated yearly due to high levels of surface molecular alterations [66]. As RNA viruses, both measles and influenza have high rates of genetic mutation, but only measles is limited structurally.

Other factors related to the clinical course of a measles infection, however, make the disease difficult to control. First, measles is highly contagious. The R0 value of the virus, which measures the average number of secondary infections resulting from a single primary case in a completely naïve (susceptible) population, is 12-18. In contrast, polio and smallpox both have values of 5-7. This infectivity can also be analyzed in terms of household members that will contract the disease from a single infected individual. In the case of measles, this figure is 75% [18, 43]; similar studies for smallpox have yielded figures between 19-36% [41, 44, 65]. In addition to increased numbers of cases, higher household incidence has been correlated to higher mortality [52], presumably because familial resources are overwhelmed in trying to care for the infected family members.

One of the benefits of the clinical course of smallpox infection is that the infectivity of the individual begins when the rash appears. In contrast, individuals infected by measles are most contagious three days before the appearance of rash [59]. This characteristic of measles contributes partly to its high R0 value and also to its high household infectivity rate. Those infected by smallpox, on the other hand, can be quickly targeted by quarantine and care before the disease is transmitted. In the smallpox eradication campaigns in central Africa, researchers observed that infected individuals would retreat to their villages and stay home when the rash appeared, limiting contact of the individual to the household and therefore yielding a lower R­­0 than expected [42]. Measles presents a more intricate challenge.

Therefore, while global measles elimination is theoretically possible, it will be significantly more difficult than the successful example of smallpox eradication. Key differences between the diseases biologically and clinically, as well as technical challenges specific to the measles vaccine, virtually ensure that the disease will continue to take a global toll for years to come. It is essential to appreciate the obstacles to measles control if this burden is to be further reduced.

Taher Modarressi is a second year medical student at NYU School of Medicine

Peer reviewed by Melanie Maslow, Infectious Diseases, Section Editor, Clinical Correlations

Image courtesy of Wikimedia Commons.

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Antimicrobial Therapy Geared at Pseudomonas aeruginosa for Bronchiectasis

April 7, 2010

psuedomonasDiana Hubulashvili, Pharm.D.

Edited by Tania Ahuja, Pharm.D., BCPS

Faculty peer reviewed

Bronchiectasis is an uncommon condition that is characterized by irreversible dilation of the bronchi. Chronic pulmonary infections and airway inflammation cause bronchial damage through destruction of the muscular and elastic layer of the bronchial wall leading to bronchiectasis. Bronchiectasis is associated with serious pulmonary infections, inflammation, chronic cough, and increased sputum production secondary to pooling in the dilated tubules. On physical exam patients can present with rhonchi, crackles, wheezing, or clubbing. High-resolution CT scanning of the chest is considered the gold standard for diagnosis. 1,2,3,4

The goals of therapy include improving symptoms of cough and mucociliary clearance, enhancing bronchodilation, preventing progression of further airway damage, and reducing the number of exacerbations. There is limited data on the treatment of idiopathic bronchiectasis, however prolonged antimicrobial therapy is often warranted to prevent worsening infections. Antimicrobial therapy should be initiated in patients experiencing an acute exacerbation after sputum cultures are obtained to better help guide therapy.  In a study by O’Donnel et al, patients with bronchiectasis were considered to have an acute exacerbation if they had 4 or more of the following symptoms: change in sputum production, increased dyspnea, increased cough, fever (>38 ºC), increased wheezing, fatigue or malaise, reduced pulmonary function, evidence of radiographic or auscultatory changes.5

Antimicrobial therapy should target the following common pathogens depending on the patient specific risk factors: Haemophilus influenza, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. 1-3. Patients with cystic fibrosis, severe chronic obstructive pulmonary disease or recent antibiotic use are at greater risk for P. aeruginosa.4,6  Other patient populations at risk for P. aeruginosa include: immunocompromised patients such as those on chronic oral steroids or with malignancy, asplenic patients,  patients with renal or liver disease and chronic heart failure.7 In cystic fibrosis (CF), P. aeruginosa infections  have shown to cause deterioration of pulmonary function, respiratory failure, and death. P. aeruginosa usually becomes a chronic infection and is rarely eradicated, despite the use of intravenous antibiotic therapy. There is little data in non-CF patients on the long term outcomes when treating             P. aeruginosa.

Once a patient with bronchiectasis is thought to have an acute exacerbation, sputum cultures should be obtained prior to antimicrobial therapy.  Once sputum microbiology results are available de-escalation of antimicrobial therapy is essential to prevent future resistance.1 Fluoroquinolones such as ciprofloxacin or levofloxacin are reasonable outpatient antibiotics in patients with severe symptoms for 7-14 days. 1,2,4,8,9  However it is essential to evaluate a patient’s prior antimicrobial therapy and culture and sensitivity data in order to prevent inappropriate treatment or future resistance.  Prior fluoroquinolone use is a risk factor for subsequent infection with quinolone-resistant extended spectrum beta lactamase (ESBL)-producing organisms, and there is also a potential connection with colonization or infection with methicillin-resistant Staphylococcus aureus (MRSA).10

Inhalation antimicrobial therapy, such as inhaled tobramycin can also be considered for the management of an acute exacerbation.  However, inhalation therapy often results in prolonged duration of therapy leading to resistance and unwarranted side effects such as wheezing.  In addition, although treatment in non-CF patients with inhaled tobramycin has been reported to decrease pseudomonas density; there is no improvement in quality of life, decreased need for additional antibiotics, or improvement in pulmonary function. 11-14 A study by Barker et al, looked at the use of tobramycin solution 300mg for inhalation in 37 non-CF bronchiectasis for 6 weeks and showed to have significant improvement in medical condition (62% vs. 38% in placebo) and 35% eradication of P. aeruginosa compared to none in placebo. Tobramycin resistance developed in 11% of patients treated with tobramycin and 3% of patients treated with placebo. The mean change in FEV1 did not vary between the two groups and patients in the tobramycin group experienced significant side effects such as cough, dyspnea, wheezing, and noncardiac chest pain, limiting their compliance.15 Finally, Bilton et al, looked at tobramycin inhalation solution added to oral ciprofloxacin therapy for the treatment of acute exacerbation of bronchiectasis due to P.aeruginosa. The combination group showed an improved microbiological outcome but patients experienced increased frequency of wheezing. 12

In patients that are hospitalized with more severe symptoms and risk factors for resistant organisms, treatment with intravenous antimicrobials is often warranted.  It is important to use antimicrobials with activity against P. aeruginosa and be cognizant of the fact that most of these patients may have been treated as an outpatient with a fluoroquinolone leading to the selection of drug-resistant organisms and the unwanted development of colonization with a multidrug-resistant organism.  Antipseudomonal beta lactams, carbapenems, or aminoglycosides may be considered as treatment options for acute exacerbations in these patients.16,7

Tsang et al, studied the efficacy of oral levofloxacin as compared to intravenous ceftazidime for 10 days in 35 patients for the empiric treatment of acute exacerbations of bronchiectasis. There was no significant difference between the two groups and both groups had improvement in sputum volume, sputum purulence score, dyspnea, and cough score.8 Rayner et al, assessed the safety and efficacy of long term ciprofloxacin, defined as treatment for 90 days in the management of severe bronchiectasis in 10 patients.  Ciprofloxacin was well tolerated and patients had a significant improvement in the number of exacerbations and symptoms, however antimicrobial resistance developed in 2 out of 10 patients to P. aeruginosa.9

Fluoroquinolone resistance to P. aeruginosa is an emerging concern today and it is therefore crucial to be sensitive to the resistance patterns within your institution and geographical area.  At NYU Langone Medical Center, only 63% of non-ICU P. aeruginosa isolates were found susceptible to ciprofloxacin and only 51% of ICU isolates were susceptible in 2008. Consequently, careful antimicrobial selection is warranted in hospitalized patients who require coverage against P. aeruginosa to prevent treatment failure. When a non-CF patient experiences an acute exacerbation, empiric treatment for P. aeruginosa should be initiated only if the patient meets specific risk factors for P. aeruginosa. If empiric treatment for P. aeruginosa is determined to be appropriate, it is imperative that clinicians become familiar with their local institution’s P. aeruginosa susceptibility patterns and choose antimicrobials with greater than 50-60% susceptibility to prevent treatment failure.  In addition, this will help prevent the selection of drug-resistant organisms, infections with multidrug-resistant organisms, or super-infections like Clostridium difficile.

Commentary by Neal Steigbigel MD, Professor, NYU Division of Infectious Diseases/Immunology

In considering this well-written article on the treatment of brochiectasis complicated by infection with Pseuodomonas aeruginosa, consider the as yet unproven potential role of macrolides, especially azithromycin, used for several months, in patients with chronic lung disease/bronchiectasis, especially if they are heavily colonized with P.aeruginosa.

The suggestion originally comes from older studies in Japan demonstrating the major benefits of macrolides, originally demonstrated with erythromycin, in patients in that country with “diffuse panbronchiolitis” (a potentially fatal lung condition in some individuals esp in Japan, possibly of genetic origin). That finding led Japanese scientists to their discoveries of the multiple potent anti-inflammatory effects of the macrolides and later to the demonstration of potent effects of macrolides in down-regulating some P. aeruginosa virulence factors, including adhesins for host cells. Those effects are demonstrated even though the macrolides have no traditional antibiotic (killing or growth inhibiting effects) on that organism. More recently several studies in patients with cystic fibrosis (CF), who are often heavily colonized with that organism, have demonstrated significant improvements in pulmonary function when they are treated for months with azithromycin. Azithromycin is now subject to great interest in treatment of COPD; a large NIH-sponsored controlled trial is now underway. These aspects of the macrolides with literature citations can be found in the most recently revised chapter on the macrolides by Sumathi Sivapalasingam and me in latest edition of “Principles and Practice of Infectious Diseases” ed by Mandell, Bennett and Dolin, Churchill-Livingstone-Elsevier, 2010 (actually already available this year).

References

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2. Barker AF. Bronchiectasis. NEJM 2002;346(18):1383-93.

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8. Tsang KW, Chan W-M, Ho P-L, et al. A comparative study on the efficacy of levofloxacin and ceftazidime in acute exacerbations of bronchiectasis. Eur Respir J 1999; 14:1206-1209

9. Rayner CF, Tillotson G, Cole PJ, et al. Efficacy and safety of long-term ciprofloxacin in the management of severe bronchiectasis. J Antimicrob Chemother 1994;34:149-156

 10. Paterson DL.  “Collateral Damage” from Cephalosporin or Quinolone Antibiotic Therapy.  Clin Infect Dis 2004; 38(Suppl 4): S341-5.

11. Drobnic ME et al. Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infections with Pseudomonas aeruginosa. Ann Pharmacotherapy 2005;39:39-44

12. Rubin BK, Eng M. Aerosolized Antiobiotics for Non-Cystic Fibrosis Bronchiectasis. J of Aer Med and Pulm Drug Deliv 2008;21:71-76

13. Bilton D, Henig N, Morrissey B, Gotfried M. Addition of Inhaled Tobramycin to Ciprofloxacin for Acute Exacerbations of Pseudomonas aeruginosa Infections in Adult Bronchiectasis. Chest 2006;130:1503-1510

14. Scheinberg P, Shore E. A pilot study of the efficacy and safety of tobramycin solution for inhalation in patients with severe bronchiectasis. Chest 2005;127:1420-1426

15. Barker AF, Couch L, Fiel SB, et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med 2000; 162:481-485

16. Murray MP et al.  Assessing response to treatment of exacerbation of bronchiectasis in adults. Eur Respir J 2009:33:312-317

  

How Easily is Tuberculosis Spread?

March 31, 2010

tbMolly Cason

Faculty peer reviewed

In a city of over 8 million people, New York City has an annual tuberculosis case rate of 11.4 per 100,000 people, which is more than twice the national average.[1]  Seventy-one percent of these cases occur in people who were born outside the United States.1 As a student, I had a patient (Y) who was being evaluated for active tuberculosis because he is a household contact of a person (X) known to have active multi-drug resistant tuberculosis. I wondered what his chances were of infection.  If he has the infection and is asymptomatic, is he contagious to others? 

Tuberculosis is spread by the cough of an infected person when droplet nuclei travel to the lungs.[2]  A single bacillus may cause infection.2  Bacteriological evidence of disease by smear analysis or culture is the gold standard for diagnosis.  Patients with tuberculosis are classified as smear-positive, culture-positive, or culture-negative.  Smear-positive is the most infectious, but half of tuberculosis cases are smear-negative.[3]  The difference in transmission is found in the number of organisms in the sputum.  In smear-positive persons, there are 106 to 109 acid-fast bacilli per milliliter of sputum, while there are fewer in the sputum of a smear-negative person.3  Because tuberculosis is spread by airborne droplets, many factors affect transmission, including the nature of the exposure, the ventilation of the environment, and the duration and intensity of exposure.3

 Historical epidemiological studies have compared the tuberculin positivity rates of known contacts of an index case to the positivity rates of the local community.  In general, the rate of tuberculin positivity among household contacts of smear-positive patients ranges from 30 to 50% above the community rates.3 Young children appear to be the most susceptible.2  The tuberculin positivity rate among household contacts of smear-negative patients is only about 5% above the community rate; however, a recent study revealed that 17% of new cases of tuberculin positivity were acquired from smear-negative patients.3,[4]

Studies by Loudon and Roberts showed increased rates of transmission among contacts exposed to coughing and singing versus talking.[5] They found that coughing and singing produced a greater quantity of droplets present after 30 minutes.  In a boarding school outbreak, a higher rate of infection was seen in kids who were in a choir group with the index case as compared to kids who were exposed in other settings.[6]  Ventilation also appears to play a factor in transmission of disease.  A study aboard the naval ship USS Byrd showed higher conversion rates in sleeping compartments that shared recirculation of contaminated air in a closed ventilatory circuit.  Other nearby compartments that did not share ventilation with the index case had lower rates of transmission.[7]  

Another study involving children who were exposed to tuberculosis from their school bus driver showed a difference in conversion rates based on duration of exposure.[8] Of the children who rode the bus less than 10 minutes per day, 22% were found to be tuberculin positive in comparison to 57% of children riding greater than 40 minutes per day.  Similar studies of hospital cases have shown an increased rate of tuberculin positivity in patients who have longer exposure to a roommate with tuberculosis.3  The rate of tuberculin positivity increased with the number of days spent sharing a hospital room.  Additionally, the effects of the intensity of exposure have been shown in community studies of casual versus close contacts of a smear-positive patient.3  Casual contacts were noted to have the lowest rates of tuberculin positivity, while spouses were shown to have greater rates than other family members. 

Although many variables play a role in the transmission of tuberculosis, the strongest predictor of contagiousness appears to be the smear status of the host.  The index case, X, is smear- negative after several weeks of treatment.  The household contact, patient Y, has an unknown tuberculin and smear status.  Patient Y has cohabitated with patient X for over one year.  Studies of close contacts of smear-positive patients indicate that up to 50% become tuberculin positive.  This can vary greatly with patient’s degree of closeness with patient X, the amount of ventilation, coughing, and type of bacteria.   However, patient Y had a negative chest x-ray and is symptom-free.  Although bacteriological evidence is the gold standard for diagnosing tuberculosis, a South African study showed that chest x-ray is a very sensitive alternative to smear and culture for screening for tuberculosis.[9] Based on the patient’s lack of symptoms and negative chest x-ray, patient Y is unlikely to have smear- or culture-positive tuberculosis necessitating infectious precautions.  If he has been infected with tuberculosis, he is at low risk for transmitting tuberculosis in the community. 

Molly Cason is a 4th year medical student at NYU Medical Center.

Faculty peer reviewed by Dr. Joel Ernst


[1] TB Annual Summary: 2007. New York: New York City Department of Health and Mental Hygiene, 2008.

[2] Musher DM.  Medical Progress: How contagious are common respiratory tract infections?  New Engl J Med. 2003; 348(13):1256-1266.

[3] Sepkowitz KA.  How Contagious is tuberculosis?  Clin Infect Dis. 1996;23(5):954-962.

[4] Behr MA, Warren SA, Salamon H, et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet. 1999;353(9151):444-449.

[5] Loudon RG, Roberts RM. Singing and the dissemination of tuberculosis. Am Rev Respir Dis. 1968;98(2):297-300.

[6] Bates JH, Potts WE, Lewis M.  Epidemiology of primary tuberculosis in an industrial school. N Engl J Med. 1965;272:714-717.

[7] Houk VN. Spread of tuberculosis via recirculated air in a naval vessel: the Byrd study. Ann NY Acad Sci. 1980;353:10-24.

[8] Rogers EF. Epidemiology of an outbreak of tuberculosis among school children. Public Health Rep. 1962;77:401-409.

[9] den Boon S, White NW, van Lill SW, et al.  An evaluation of symptoms and chest radiographic screening in tuberculosis prevalence surveys.  Int J Tuberc Lung Dis.  2006;10(8):876-882.

What Should We Know About Bedbugs?

February 18, 2010

Jia Huang

Faculty peer reviewed

A 46 year-old Asian female presented with recurrent pruritic erythematous papules in a partially linear pattern over her forearms, face, and trunk. Each papule measured about 3/4 inch in diameter. The eruption first appeared two to three weeks ago and simultaneously appeared over these areas. She denies using any new skin products or taking any new medication. Travel history is positive for a recent trip to Los Angeles. Bedbugs were suspected and the patient was prescribed oral diphenhydramine and topical fluocinonide. She returned one week later, despite healing of the old lesions. A few more papules have appeared over her forearms.

Cimex lectularius, commonly known as the bedbug, had been a pest of yesteryear, until recently. Reports of bedbug infestation in hotels began to emerge at the turn of the millennium.[1] Soon after, bedbugs spread like wildfire across major cities in the country, infesting apartments, private houses, college dormitories, nursing homes, and even hospitals.[2] New York City was no exception; in 2008, the city’s 311 hotline received almost 10,000 bedbug complaints, a 34% increase from the year before. [3] New York has a bedbug epidemic, and there is no relief in sight.

Host reactions to bedbug bites are widely variable. Most people do not have a reaction; others may develop pruritic erythematous papules,[4] or local urticaria with wheals or welts. Bullous skin lesions and systemic anaphylactic reactions have also been reported but are rare.[5] The lesions may be evident upon awakening or may appear a day or two later. They are the result of host hypersensitivity against foreign antigens in bedbug saliva; [5]the bite itself is harmless. The lesions are usually pruritic, and they can become superinfected after intense scratching. Secondary skin lesions such as cellulitis or folliculitis may also develop.[5] The diagnosis is not always clear, especially without a suggestive history. The eruption has been mistaken for scabies, allergic contact dermatitis, dermatitis herpetiformis, and even chicken pox. [7,8] Lesions in a linear or clustered pattern should raise the suspicion of bedbug bites, although other insect bites can present in similar manner. A detailed history exploring possible sources of exposure is helpful. The most common lesions are pruritic papules,[5] which spontaneously regress over one to two weeks, but often leave behind the telltale sign of postinflammatory hyperpigmentation.

Treatment provides symptomatic relief only. The most commonly used agents are oral antihistamines and topical medium-strength corticosteroids. Severe reactions such as bullous skin lesions may require oral corticosteroids.[7] Those with secondary infections should be treated with topical or oral antibiotics. Systemic or anaphylactic reactions to bedbug bites are treated with intramuscular epinephrine, oral antihistamines, and corticosteroids.[5] Insect repellents containing N,N-diethyl-meta-toluamide (DEET), and oil of lemon eucalyptus may help ward off some attacks.[5] Although the majority of patients improve with symptomatic treatment, a complete cure from bedbug bites requires total extermination of the pest from the household.

There is no evidence that bed bugs serve as vectors for infectious agents. Research has shown that hepatitis B viral DNA (HBV DNA) and surface antigen (HBsAg) can persist for weeks in bedbugs,[5] although there is no evidence of viral replication in the insect. HBV DNA has also been found in bedbug excrement, which raises concern about transmission of HBV via deposition of infected waste matter after feeding. However, an epidemiologic study found bedbugs an unlikely factor in the spread of hepatitis B in a Gambian pediatric population. Human immunodeficiency virus (HIV) is also detected in bedbugs after experimental feeding; again, the virus does not replicate in the insect, and the bedbug’s ability to transmit HIV has not been demonstrated under experimental conditions.[5]

C. lectularius are flightless nocturnal insects that solely feed on the blood of humans, other mammals, bats, and birds. Adult insects average about 5 mm in length. They are flat, oval and reddish brown, but may become elongated, engorged, and dark red after a blood meal. Bedbugs feed on their reclining hosts at night. [11]They are attracted to their hosts by warmth, carbon dioxide, and kairomones within a 1.5-meter radius.6 Each blood meal takes about 10 minutes,[11] after which they quickly flee from the hosts and return to their hiding places, which can be any nook or cranny in and around the bed. Bedbug harborages have been found in furniture, mattresses, and box springs, as well as behind loose wallpaper, headboards, floorboards, and even electric outlets and picture frames.11 Because bedbugs hide during the day, initial signs of infestation may not be visible to the victim. The insects are better caught when surprised by a flashlight at night. 2,7 Bedbugs also leave dark specks of waste matter on bed linen.[7,11]

Extermination of bedbugs is extremely difficult. Complete eradication requires meticulous and multiple applications of insecticide. A major concern is resistance to pyrethroids, the most commonly used agents. Organophosphate and carbamate insecticides are effective, but their use indoors is banned for safety reasons.[2] Non-insecticide means of control may be used. Bedbugs are killed at temperatures above 45C (113F);11 bedding and clothes should be washed and dried at the hottest settings. Other means to control the infestation include encasing the mattress and boxspring, routinely using the vacuum cleaner, chalking the baseboard, and covering all crevices in the floor.[5] Techniques to contain bedbugs may fail because the insects are resilient; they may live up to one year without a blood meal. For some, hiring a professional exterminator and discarding the affected furniture are expensive but inevitable last resorts.

Because bedbug extermination is so difficult, prevention is key. People should refrain from reusing second-hand furniture and mattresses, which may be infested.[2] Bedbugs can latch onto luggage during travel; travelers should vacuum and clean their suitcases thoroughly after returning from their trips.[11] Although bedbug infestations are not associated with unsanitary conditions, households should eliminate clutter, which offers places for bedbugs to establish harborages. People with a bedbug problem should seek help right away. Bedbug infestation is associated with considerable psychological distress in most victims. Many feel shame and may be reluctant to speak up for fear of eviction from their apartments or ostracism by their peers. This worsens the situation and may promote the spread of bedbugs to neighboring rooms or apartments.

Bedbugs are a growing public health issue. Although there is no evidence that they can transmit infectious diseases, they cause considerable physical discomfort and psychological anguish. As bedbug infestations become more prevalent, the medical community needs to be vigilant about this problem. Bedbug infestation should be a part of the differential diagnosis for patients who present with recurrent pruritic skin eruptions. Because healthcare providers are often the first persons from whom bedbug victims seek help, they are instrumental in providing education, reassurance, and treatment.

Jia Huang is a 3rd year medical student at NYU Medical Center.

Peer reviewed by Miriam Pomeranz MD

[1] Bedbugs checking in at the best hotels. New York Times. July 26, 2001: F5.

[2] Potter MF, Romero A, Haynes KF. Battling bed bugs in the USA. In: Proceedings of the Sixth International Conference on Urban Pests. Robinson WH, Bajomi D, eds. http://www.icup.org.uk/reports%5CICUP859.pdf. Accessed on August 26, 2009

 

[3] Lisberg A. New York bedbug complaints increase 34% in a year. Daily News. February 17, 2009. http://www.nydailynews.com/ny_local/2009/02/17/2009-02-17_new_york_bedbug_complaints_increase_34_i.html. Accessed on August 26, 2009.

 

[4] Stucki A, Ludwig R. Images in clinical medicine: bedbug bites. N Engl J Med. 2008;359(10):1047.

 

[5] Goddard J, deShazo R. Bed bugs (Cimex lectularius) and clinical consequences of their bites. JAMA. 2009;301(13):1358-1366.

 

[6] Reinhardt K, Siva-Jothy MT. Biology of the bed bugs (Cimcidae). Annu Rev Entomol. 2007;52:351-374.

 

[7] Ter Poorten MC, Prose NS. The return of the common bedbug. Pediatr Dermatol. 2005;22(3):183-187.

 

[8] Cooper R. Bed bugs – still more questions than answers: a need for research and public awareness. Am Entomol. 2006;52(2):111-112.

 

[9] Silverman AL, Qu LH, Blow J, et al. Assessment of hepatitis B virus DNA and hepatitis C virus RNA in the common bedbug (Cimex lectularius L.) and kissing bug (Rodnius prolixus). Am J Gastroenterol. 2001;96:2194-2198.

 

[10] Mayans MV, Hall AJ, Inskip HM, et al. Do bedbugs transmit hepatitis B? Lancet. 1994;343(8900):761-763.

 

[11] Quarles W. Bed bugs bounce back. IPM Practitioner. 2007;29:1-8.

Zinc Cold Remedies: Are They Safe and Effective–Who Nose?

February 11, 2010

Bellevue 1Amanda Benkoff

Faculty peer reviewed

Each year doctors are presented with the dilemma of the common cold. Adults in the U.S. experience an average of 3 colds per year, and children up to 8-10, resulting in over 500 million colds annually.(1) Patients often visit the doctor with cold symptoms requesting antibiotics. Since the etiology of the common cold is viral, antibiotic therapy is ineffective and inappropriate, and only contributes to bacterial antibiotic resistance. More than 200 viruses can cause the common cold, including rhinoviruses, coronaviruses, adenoviruses, respiratory syncytial virus, and parainfluenza viruses.(2) Rhinovirus is the most common culprit.3 Although considered a self-limited benign illness, the common cold is not without complications, including otitis media, sinusitis, and exacerbations of reactive airway diseases.(3) Additionally, the economic impact is far-reaching due to related work absences. Thus, it is clear why patients implore doctors for treatment of this ailment. In more recent years the use of zinc cold remedies has become popular. The question is, are they safe and effective?

The idea of using zinc to control viral disease is not novel. In 1937 zinc sulfate was sprayed intranasally during the poliovirus epidemic in Canada. It was theorized that zinc ions formed a protective coating around olfactory nerves, thereby preventing virus absorption. Unfortunately, this intervention did not alter the attack rate.(4) In more recent years the use of zinc acetate/gluconate lozenges and zinc gluconate nasal spray has become widespread. The basis for therapeutic zinc use is founded on scientific observation over the years. Empirical virology has shown that zinc interferes with rhinoviral coat proteins, thereby preventing viral particle assembly and replication. Mechanistically, it was suggested that zinc ions formed complexes with viral coat proteins.5 Scientific observation has also demonstrated that zinc can alter immune system regulation. By studying the effects of zinc on plasma cytokines, it was determined that patients treated with zinc had reduced levels of intracellular adhesion molecule-1 (ICAM-1). Researchers proposed that zinc ions formed complexes with ICAM-1. This effect is significant because human rhinovirus 14 docks onto somatic cells using ICAM-1; thus, less ICAM-1 results in fewer infected cells.(3) Driessen et al. provided further empirical evidence regarding the immune-regulatory effects of zinc. They demonstrated that in patients with excess zinc, after immune challenge with bacterial endotoxin, there was upregulation of interferon gamma (increased T cell activation) and increased secretion of tumor necrosis factor-alpha and interleukin 1-beta (increased monocyte activation).(6) While much has been revealed regarding the therapeutic actions of zinc, more research is necessary to establish a concrete mechanism for zinc against the common cold.

Regarding the clinical efficacy of zinc, a number of studies have been performed, and the results are inconclusive. One structured review looked at 14 randomized controlled trials (RCTs) evaluating zinc lozenges and nasal sprays/gels. The review created 11 criteria to assess validity of experimental design, and found that only four studies were valid. Of the four studies, three found no therapeutic effect from zinc lozenges or nasal spray, and only one study reported benefit from zinc nasal gel, showing decreased symptom severity and duration with early treatment.(1) In contrast, a second review article looking at 7 double-blind RCTs using zinc gluconate lozenges showed an overall benefit, with decreased cold duration (1-3 days) and symptom severity. This study suggested that 13.3 mg of zinc (the lowest therapeutic dose) should be administered every two hours, with greater efficacy if treated within 24-48 hours of symptom onset. The review also showed astringent taste and nausea as common adverse reactions. Ultimately, it is difficult to judge the overall scientific efficacy of zinc against the common cold due to inconsistent study results. There are many reasons behind this variability, including poor study design (small sample size, artificially-induced vs. natural infection), poor follow-up, sub-therapeutic dosing, and use of additives (mannitol, citric acid, or sorbitol), which have been purported to decrease efficacy by binding to zinc ions.(7)

As for the question of safety, we can again look to 1937 and the use of prophylactic zinc sulfate. Of the 5000 children treated, approximately 10-13% were found to be anosmic months later.(4) This result was further corroborated by an animal study in 1978. Harding et al. showed that mice treated with intranasal zinc sulfate experienced immediate and total anosmia. Up to 80% of the mice were anosmic for 6 weeks, and some still showed changes at 1 year.(4) This result has since been reproduced by McBride et al. in 2003. This study showed that intranasal zinc sulfate produces total disruption of connections from the olfactory epithelium to the olfactory bulb. However, this anosmia was brief, and most mice recovered in 5-30 days.(8)

Of more significance is the safety profile for intranasal zinc gluconate, the key ingredient in nasal sprays/gels, such as Zicam. One study coined the term “zinc-induced anosmia syndrome,” characterized by burning and anosmia. It described a series of patients, all of whom reported sniffing deeply with gel application, followed by anosmia within hours. They reported some degree of recovery over time.(9) Another case series showed that olfaction impairment persisted for up to 2 years, and proposed that the anosmia was potentially permanent. It was hypothesized that zinc cations acted to block the nonspecific cation channel necessary for olfactory receptor cell depolarization, and subsequent transduction of odors to the olfactory bulb. Recent animal studies show that odor detection in mice is affected only at doses ~100 times greater than a single application of Zicam, and even at massive doses the anosmia resolved over time.(10) Despite this, Zicam nasal sprays/gels have been associated with anosmia or hyposmia in over 300 consumers. In June 2009, the FDA discontinued Zicam nasal products, and alerted the public to the possibility of permanent anosmia. This is of particular concern in children, who may not report decreased olfaction and are at increased risk for repeated exposure.(11) The advisory did not concern oral zinc tablets and lozenges.

In conclusion, the evidence for the efficacy of zinc cold remedies remains questionable, and the treatment is not without risk. More valid scientific studies with enhanced methodology are necessary to find conclusive results. The search for effective cold therapies must continue.

Amanda Benkoff is a 4th year student at NYU Medical School.

Peer reviewed by Dr. Robert Holzman, Professor of Medicine, NYU Medical Center

References

1. Caruso TJ, Prober CG, Gwaltney, JM Jr. Treatment of naturally acquired common colds with zinc: a structured review. Clin Infect Dis. 2007;45(5):569-574.
2. Mossad SB, Macknin ML, Medendorp SV, Mason P. Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study. Ann Intern Med. 1996;125(2):81-88.
3. Prasad AS, Beck FW, Bao B, Snell D, Fitzgerald JT. Duration and severity of symptoms and levels of plasma interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, and adhesion molecules in patients with common cold treated with zinc acetate. J Infect Dis. 2008;197(6):795-802.
4. Jafek BW, Linschoten MR, Murrow BW. Anosmia after intranasal zinc gluconate use. Am J Rhinol. 2004;18(3):137-141.
5. Hirt M, Nobel S, Barron E. Zinc nasal gel for the treatment of common cold symptoms: a double-blind, placebo-controlled trial. Ear Nose Throat J. 2000;79(10):778-780, 782.
6. Driessen C, Hirv K, Kirchner H, Rink L. Zinc regulates cytokine induction by superantigens and lipopolysaccharide. Immunology. 1995;84:272-277.
7. Marshall, S. Zinc gluconate and the common cold, review of randomized controlled trials. Can Fam Physician. 1998;44:1037-1042.
8. McBride K, Slotnick B, Margolis FL. Does intranasal application of zinc sulfate produce anosmia in the mouse? An olfactometric and anatomical study. Chem Senses. 2003;28(8):659-670.
9. Alexander TH, Davidson TM. Intranasal zinc and anosmia: the zinc-induced anosmia syndrome. Laryngoscope. 2006;116(2):217-220.
10. Slotnick B, Sanguino A, Husband S, Marquino G, Silberberg A. Olfaction and olfactory epithelium in mice treated with zinc gluconate. Laryngoscope. 2007;117(4):743-749.
11. U.S. Department of Health and Human Services. FDA: Loss of sense of smell with intranasal cold remedies containing zinc. http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm166059.htm. Accessed September 21, 2009.

Oldies but Goodies: How should you approach a low titer +RPR?

February 5, 2010

Please enjoy a post from the Clinical Correlations Archives, first posted November 28, 2006…

45 year old male with a history of Hepatitis B ( Hep B Surf Ag + but Hep B E Ab+ and E Ag – and DNA viral load was not sent) and syphilis treated in the past. He has RPRs in the past that were 1:1 for years and then negative x 2 a year apart, the last being over two years ago. He had labs drawn last week and had an RPR of 1:4. He does report high-risk unsafe sexual activity (with female prostitutes) over the past two years. He does not recall seeing a chancre and his exam was negative. He has not tested for HIV.

Questions:

1. Would you retreat?

2. Would you retreat if the RPR was 1:2? (should we consider reinfection?)

Commentary By Neal Steigbigel M.D., Professor of Medicine (Infectious Diseases/Immunology)

The RPR antibody (a non-treponemal or reaginic antibody) titer of 1:4 may be associated with:

1) reinfection syphilis (immunity brought about by previous syphilis infection is incomplete)

2) may represent a biological false positve when the titer is less than 1:8 in that this is a reagin antibody which is not specific for syphilis and and can be elevated non-specifically by conditions (particularly liver diseases, especially cirrhosis or HIV infection) that produce non-specific polyclonal increases in various antibodies.

3) persistent mild elevation from his former episode of syphilis, although the fact that it became negative prior to this last determination is somewahat against that possibility.

The patient should have a specific treponemal test performed (such as the MHA-TP test) which is specific for Treponemal infection and usually persists as positive for life. If the latter is positive in this patient that means that he has had syphilis in the past, but 1,2, and 3 above are still the possibilities which cannot be entirely resolved. That is, the patient may have late latent syphilis and if the MHA is positive and there is not documentation that he has been treated for late latent syphilis since his last sexual exposures, I would treat with benzathine penicillin G 2.4 million units im weekly for 3 weeks in the absence of a penicillin allergy. The RPR titer usually becomes negative two years after treatment. If it does not, then again the posibilities are persistent infection, reinfection or false-positive test (most likely the latter).

What would you do if the titer bounced up to 1:2 from 0?

If it fluctuates at low titer (<1:8) after the treatment that is suggested and without signs of disease I would not retreat.

What would you do in a person whose titer never falls below 1:4 and then jumps to 1:16?

That would be unlikely, but would suggest true infection requiring retreatment if the MHA was positive.

Some gleanings from the meeting of the Infectious Diseases Society of America (IDSA) in Philadelphia, October 29-November 1. 2009

January 6, 2010

idsa_logoNeal H. Steigbigel, M.D.

The recent IDSA meeting reviewed many important and interesting findings.  Topics spanned a wide array of subjects, many of which are of importance and interest to all physicians.  These subjects included:

  • HIV/AID- increasing support for starting HAART earlier
  • Influenza-details regarding pathogenesis, epidemiology, clinical presentation and treatment for the H1N1 2009 Influenza pandemic infections
  • Updates regarding  pyogenic bacterial meningitis and Group A streptococcus necrotizing fasciitis
  • Management information regarding the all too common hospital-associated multiple drug resistant gram-negative bacillary infections (especially, P. aeruginosa and Acinetobacter species infections)
  • New information on the pharmacology of the polymyxins
  • Information on some new antibiotics for methicillin resistant staph aureus (MRSA) and gram-negative bacterial infections and new assessments of some older antibiotics (vancomycin/daptomycin) that we have been increasingly using
  • New information on the diagnosis and management of C. difficile infections.

This high quality meeting has many simultaneous sessions and therefore one individual cannot cover all that is presented.  Much of the material covered is information that has been available before in publications or discussions, but at the meeting such information is often placed in a more appropriate context with superb critical evaluation.

Attached is a collection of my notes and an occasional editorial comment for the interested reader.  Although my notes cannot do justice to each particular piece, I hope to give the reader a flavor of the emerging trends and ideas in the world of infectious disease.  Enjoy…

Dr. Steigbigel’s notes from IDSA 2009

Dr. Steigbigel is a Professor in the NYU Department of Medicine, Division of Infectious Diseases and Immunology

It’s Lyme Season: How Should You Manage the Tick-bitten Patient?

October 14, 2009

ticJoshua Allen-Dicker

Faculty peer reviewed

A healthy 42-year old patient presents to your office after a day of hiking with his family in Upstate New York. This morning in the shower he found a “big black tick” on his right leg. He is currently asymptomatic and wants to know what his risk of Lyme disease is.

For New York City physicians, the end of summer and beginning of fall herald a spike in cases of Lyme Disease. Each year in the United States, over 19,000 patients are diagnosed with Lyme Disease; 93% of cases occur in just 10 states, among them New York, and its neighbors, Connecticut and New Jersey.(1) When there are four hundred New York City residents presenting with this illness every year, what’s a physician to do when patients are worried that they are about to become a statistic? (2) In the following article, we discuss the diagnostic and therapeutic approaches to a patient who reports being bitten by a tick.

Transmission
Lyme disease is a tick-borne illness caused by the spirochete Borrelia burgdorferi. It is transmitted to humans by the bite of several species of tick from the genus Ixodes. These ticks go through several stages in their life cycle: egg, larva, nymph, and adult. Borrelia is usually carried by those parasites in the nymph stage, inhabiting the lumen of the insect’s gut. Once a blood meal enters the gut, Borrelia reproduces and migrates to the salivary glands of the insect, where it can be transmitted to a new host. This process creates a time lag in between the tick attachment to the host and the transmission of Lyme disease. Prospective studies of patients bitten by Ixodes confirm the clinical significance of this incubation: Lyme disease is rarely transmitted from tick to human host without at least 72 hours of feeding.(3,4)

Proper removal technique
A successful tick removal will completely remove all tick body parts without releasing infectious material and/or inducing the tick to salivate. While multiple methods of tick removal have been documented in the literature, including several commercial products, the most commonly recommended method is via manual extraction.(5,6) Using blunt forceps, the tick should be grasped as close to the skin as possible and pulled up without crushing any tick body parts. Following the successful removal, the surrounding skin should be thoroughly disinfected.

Possibility of Prophylaxis
While many patients will likely request antibiotics following a tick bite, recent guidelines from the Infectious Diseases Society of America recommend prophylaxis as an option only for certain patients.(7) Patients can be given doxycycline if all of the following criteria are met:

(1) The tick must be identified as a member of the Ixodes genus. Nymphal Ixodes ticks are tiny and round without spots. A good chart for differentiating the common North American ticks can be found at the CDC’s Division of Vector-Borne Infectious Diseases at http://www.cdc.gov/ncidod/dvbid/lyme/ld_blackleggedTick.htm.
(2) The tick is estimated to have been attached for at least 36 hours. This can be calculated based either on the most likely time of exposure or clinician evaluation of the level of tick engorgement.
(3) Infection occurred in area with a high level of Borrelia infection of the ticks (>20%). This can be assumed for most areas in New York, New Jersey, and Connecticut.
(4) The patient presents within 72 hours of removing the tick.
(5) Doxycycline is not otherwise contraindicated, as in the case of pregnant women and children under 8 years of age.
For patients who do not meet the above requirements, a watchful waiting strategy is recommended. The patient should be instructed to regularly inspect the site of the bite for 30 days and alert the physician of any changes in their health.

Signs of Infection
Less than four percent of patients who are bitten by ticks develop signs of Lyme disease.(4) Given the severity of undiagnosed late stage disease, timely identification of infected patients is vital.  The targetoid rash, erythema migrans, occurs at the site of microbe entry and is characteristic of an early localized response to infection with Borrelia.(8)  Diagnosis of Lyme disease can be made based on the presence of erythema migrans. Antibiotic therapy should be started immediately. A small portion of Lyme disease patients will develop early disseminated disease without ever documenting signs of the characteristic rash.(8) It is important to be vigilant regarding the onset of acute neurologic (cranial neuropathy, peripheral neuropathy or meningitis) or cardiac (myocarditis or atrioventricular block) symptoms. In both cases, the diagnosis of Lyme disease can be made purely based on clinical symptoms. Serologic testing should not be part of a first-line diagnostic work-up.

Treatment
The literature supports the use of doxycycline, amoxicillin, or cefuroxime for early local infections.(7) Of these three, doxycycline is often used because of its coverage of a potential co-infecting microbe, Anaplasma phagocytophilum, which causes human granulocytic anaplasmosis. In the case of early disseminated disease, 14 days of intravenous therapy with ceftriaxone and cefotaxime is recommended.vii If the patient presents with symptomatic heart disease, hospitalization for cardiac monitoring may be required.

Case Conclusion
An attached but unengorged tick is found on the right thigh of your hiking patient and removed intact appropriately with blunt forceps. Given that the tick was likely attached for less than 24 hours, the patient does not require prophylaxis. He is educated about tick safety and sent home with instructions to report the appearance of a rash or any changes in his health.

Joshua Allen-Dicker is a 4th year medical student at NYU School of Medicine.

Faculty peer reviewed by Harold Horowitz MD, Professor of Medicine (Infectious Diseases and Immunology)

1) Bacon. MR, Kugeler, KJ, Mead PS. Surveillance for Lyme Disease: United States, 1992-2006. MMWR. 2008;57(SS10):1-9.
2) Lyme Disease. Bureau of Communicable Diseases New York City Department of Health and Mental Hygiene. http://www.nyc.gov/html/doh/html/cd/cdlym.shtml. Accessed July 27, 2009.
3) Sood SK; Salzman MB; Johnson BJ et al. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis 1997 Apr;175(4):996-9.
4) Nadelman RB, Nowakowski J, Fish D et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med 2001 Jul 12;345(2):79-84.
5) Oteo JA, Martinez de Artola V, Gomez-Cadinanos R, et al. Evaluation of methods of tick removal in human ixodidiasis. Rev Clin Esp 1996;196:584-7.
6) Gammons, M and Salam, G. Tick Removal. Am Fam Physician 2002;66:643-5.
7) Wormser GP et al. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089-1134.
8 ) Steere, AC, Sikand, VK. The presenting manifestations of Lyme disease and the outcomes of treatment. N Engl J Med 2003; 348:2472.