Category Archives: Rare Diseases

Parkland Morning Report: Pulmonary Mucormycosis

This week at Parkland, Dr. Thomas Rose presented an interesting case of pulmonary mucormycosis in a 19-year old presenting in DKA.  Fortunately, through quick identification and appropriate management, the patient is back at home and continuing to improve 6 months after her initial presentation! Continue reading Parkland Morning Report: Pulmonary Mucormycosis

Listeria Hysteria

In the last few days, your favorite ice cream (BLUE BELL!) and your favorite hummus (SABRA!) have been recalled due to concerns for contamination with Listeria. Time to get a handle on the situation by learning the basics of this food-borne pathogen.

Introduction

  • Listeria monocytogenes is a gram-positive foodborne pathogen that is ubiquitously found in diverse environments such as soil, water, various food products, animals, and humans
  • The bacteria are readily inactivated at pasteurization temperature, the main source of infection represents contaminated raw food that is subjected to minimal further processing, such as soft cheeses, vegetables, and postprocessed contaminated milk products (ICE CREAM!)
  • Ingestion of food contaminated with monocytogenes is the usual mode of transmission leading to listeriosis.
  • Characterized by bacteremia and meningoencephalitis in individuals with impaired cell-mediated immunity
  • Represents one of the most deadly bacterial infections due to its high mean mortality rate of 20%–30%, despite early antibiotic treatment.
  • In contrast to the severe invasive disease recent outbreaks demonstrated that infection of healthy individuals with monocytogenes often leads to the development of a febrile gastroenteritis.
  • The organisms are well adapted to the conditions in the gastrointestinal tract; the finding that the bacteria are able to colonize and persist in the gallbladder suggests the occurrence of long-term and chronic infections and demonstrates the ability of pathogenic Listeria to survive within the various microenvironments of the gastrointestinal tract.
  • Facultative intracellular organism:Listeria

 

Clinical Syndromes

  • The diverse clinical manifestations of infection with monocytogenes reflect its ability to cross three tight barriers in the human host.
    • Following ingestion, monocytogenes crosses the intestinal barrier by invading the intestinal epithelium, thereby gaining access to internal organs.
    • During severe infections, crossing the blood–brain barrier results in infection of the meninges and the brain, and in pregnant women, crossing the fetoplacental barrier leads to infection of the fetus.
  • Invasive Clinical Syndromes:
    • Bacteremia: most common manifestation in immunocompromised patients – similar to other forms of bacteremia, including fever, myalgias, sepsis, etc. May have a prodrome of diarrhea and nausea. The observed symptoms like fever as well as occasionally bloody diarrhea and bacteremia further support the hypothesis that diarrhea results from direct invasion of monocytogenes to the intestinal mucosal epithelium.
    • Meningoencephalitis: more common in neonates and adults over 60 years of age. Listeria has a predilection for the brainstem and meninges. Flu-like prodrome possible. Can present with altered mentation, muscle contractions, personality changes, seizures, and other typical signs of meningitis. Brain abscess can occur in up to 10% of patients. Would expect a lymphocytosis on CSF analysis.
    • Pregnancy: highest risk of infection is during the third trimester, associated with depressed cell-mediated immunity. Often manifests with an acute febrile illness, myalgias, arthralgias, headache, and backache. Can result in stillbirth or neonatal death.
    • Infective Endocarditis
  • Non-invasive Clinical Syndrome:
    • Febrile Gastroenteritis: Incubation period is typically short (6 hours to 10 days). Common symptoms observed in the effected patients included fever, watery diarrhea, nausea, headache, and pain in joints and muscles. No testing is recommended unless the patient is in a specific high-risk group (i.e. pregnant, immunocompromised, neonates).

Diagnosis

  • Culture: from CSF, blood, or other body fluids; grows on Muller-Hinton agar with sheep blood . Can see small zone of hemolysis underneath the colony.
  • Antibody testing has not proven useful

 

Management

  • Bacteremia
    • 1st line: ampicillin ≥ 6 g/d IV plus gentamicin (if patient > 50 y, chronic disease, cardiovascular or respiratory compromise) x 14 total days up to 6 weeks if endocarditis.
    • 2nd line: erythromycin 4 g/d, or TMP/SMX 200–320 mg, or vancomycin 1 g tid x 14 total days.
  • Acute Meningitis
    • 1st line: ampicillin ≥ 6 g/d IV plus gentamicin (if patient > 50 y, chronic disease, cardiovascular or respiratory compromise) x 21 total days (4-6 weeks if brain abscess)
    • 2nd line: Second-line: TMP/SMX 200–320 mg x 21 total days (4-6 weeks if brain abscess)
  • Bacteremia in pregnancy
    • 1st line: ampicillin ≥ 6 g/d IV x 7–14 total days; if fetus survives, consider longer treatment
    • 2nd line: erythromycin 4 g/d IV x 7–14 total days; if fetus survives, consider longer treatment
  • Gastroenteritis: supportive care

 

 

 

-Markus Schuppler and Martin J. Loessner, “The Opportunistic Pathogen Listeria monocytogenes: Pathogenicity and Interaction with the Mucosal Immune System,” International Journal of Inflammation, vol. 2010, Article ID 704321, 12 pages, 2010.

Nature Reviews Microbiology4, 423-434(June 2006)

-Rev Obstet Gynecol. 2008 Fall; 1(4): 179–185.

Idiopathic Pulmonary Fibrosis – a Review

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive irreversible fibrotic lung disease of unknown cause. The prognosis is dismal with a median survival of 3-5 years, worse than most cancers. The disease is localized solely in the lungs, occurs only in adults and is associated with a radiological and/or pathological pattern called usual interstitial pneumonia (UIP). The diagnosis demands the exclusion of other types of interstitial pneumonias, the exclusion of any known cause of fibrosis such as occupational or environmental diseases, medication or connective tissue diseases. New anti-fibrotic treatment can inhibit the development of IPF and prolong survival; early and correct diagnosis is thus paramount.

Classification

In recent years, new international definitions, classifications, guidelines and treatment possibilities have developed in interstitial lung disease (ILD) and specifically in IPF. The term ILD covers more than 200 distinct entities. The first pathologic classification was described in the 1960ies, and in the following 20-30 years no clear distinction was made between the inflammatory and fibrotic ILDs which led to an exaggerated optimism of the effect of steroid treatment. In the 1990s, it was discovered that not all ILDs were steroid sensitive; this led to a new pathological classification and new guidelines in 2000 and 2002 in which the distinction between the different types of ILD were specified for the first time.

The first guideline specifically for IPF was published in 2011 and provided a new definition of the disease based on the exclusion of all known causes for ILD and the identification of specific combinations of radiological and histological patterns of UIP. Thus, a surgical lung biopsy was no longer necessary for making a confident diagnosis in patients with a definite UIP pattern on a high resolution computed tomography (HRCT). In 2013, the most recent multidisciplinary classification of ILD was published in which, for the first time, it was acknowledged that not all patients can be sub-typed and the term “unclassifiable ILD” was introduced. Nevertheless, idiopathic pulmonary fibrosis remains the most common of the idiopathic interstitial pneumonias.

Epidemiology

Studies on the prevalence and incidence of IPF are sparse and the results depend on the research method used (questionnaire, national registries, health care databases etc.) and on the definition of IPF. A new Danish retrospective study found a prevalence of IPF of 1.3 cases/ 100,000 inhabitants. The prevalence in other studies varies between 0.5-27.9/100,000 and the incidence between 0.22-8.8/100,000.

The incidence of IPF seems to have increased in recent years, probably due to improved and faster diagnostic procedures. Most general practitioners perform a spirometry and can distinguish between obstructive or restrictive functional impairment; moreover, access to CT/HRCT examinations has become easier and faster. Furthermore, the demographic development points towards an ageing population.

Symptoms

IPF is rarely diagnosed before the age of fifty and incidence increases with age and the mean age at diagnosis is 67 years. Approximately 75% of the patients are males and 2/3 are smokers or former smokers.

Typical symptoms of IPF are progressive dry cough and dyspnea, typically deteriorating over months. Some patients have symptoms for many years before they contact a physician or are referred for investigations. In the beginning, symptoms are normally experienced in relation to exercise, but later even the slightest movement can result in severe dyspnea, cough and desaturation. Weight loss is not typical, but may be seen in the terminal phase of the disease when the respiratory work load increases. In these cases, cancer should always be excluded. Some patients have recurrent “airway infections” prior to diagnosis often characterized by increased dyspnea, cough and phlegm, and crackles at lung auscultation, but without fever or significantly raised C-reactive protein. Antibiotic therapy rarely improves symptoms and should probably be interpreted as minor acute exacerbations of IPF.

When pulmonary function becomes severely reduced, chronic respiratory insufficiency usually develops with cyanosis, in the beginning at exercise, but later also at rest. Pulmonary hypertension may cause peripheral edemas, increased dyspnea, need of oxygen and decreasing diffusion capacity, which is a relatively common complication to severe IPF and a serious prognostic sign.

The clinical findings are often subtle or non-existing in the beginning of the disease, but may include basal velcro crackles and clubbing. These findings may precede the respiratory symptoms for several months. It is important to search for extrapulmonary manifestations of connective tissue disease, as this would exclude IPF but instead classify the lung disease as related to the rheumatologic disease. The differential diagnosis is important since prognosis and treatment of ILD related to connective tissue diseases are different from that of IPF.

Early Diagnosis

Early diagnosis of IPF has become highly relevant after the introduction of anti-fibrotic therapy in IPF. Medication inhibits disease progression, but do not improve the disease and therefore early diagnosis, referral and treatment is important.

Reduced ventilatory capacity in a patient with a dry cough and exertional dyspnea should lead to referral on suspicion of ILD. In some IPF patients, spirometry may be in the normal range even though the diffusion capacity is reduced. Decline in oxygen saturation of more than 4% at exercise is an easy marker of a reduced diffusion capacity.

The detection of drumstick fingers and/or hour glass nails read clubbing (Figure 2) and especially velcro crackles should lead to immediate referral to a pulmonary specialist. Radiographic signs of lung fibrosis should raise the suspicion of interstitial lung disease and prompt referral for further investigations. Due to the low incidence of IPF, screening programmes using CT or HRCT do not seem cost effective.

Diagnosis

IPF is seen only in adults and is limited to the lungs. The diagnosis requires a specific combination of a radiological and/or a histopathological UIP pattern, and other interstitial lung diseases, environmental and occupational reasons must be excluded. The diagnosis demands highly specialized knowledge of IPF and other interstitial lung diseases.

HRCT patterns are divided into definite UIP, possible UIP and non-UIP patterns depending on the presence and localization of honey combing, reticulation and traction bronchiectasis as well as the exclusion of other specified findings (nodules, air trapping, cysts, ground glass opacities etc.). Diagnosis of a definite or possible UIP pattern can be difficult and even among experienced radiologists with a special interest in ILD, inter-individual variation is large with kappa-values of 0.4-0.58. The histopathological patterns are divided into definite UIP, possible UIP, probable UIP and non UIP patterns, and the inter-individual variation between pathologists is also high.

Different combinations of these patterns determine a diagnosis of definite, possible or not IPF. If the HRCT shows a definite UIP pattern in the correct clinical setting, a surgical lung biopsy is not needed. On the other hand, if the HRCT shows a possible UIP pattern, a biopsy is per definition required to make a confident diagnosis.

The most common differential diagnosis is chronic hypersensitivity pneumonitis and fibrotic non-specific interstitial pneumonitis (NSIP).

International guidelines recommend that the diagnosis is based on a multidisciplinary approach with the participation of pulmonologists, radiologists and pathologists.

Investigations

A detailed history with the specific aim of identifying or excluding any specific cause of ILD is paramount for the diagnosis. It is important to obtain a systematic occupational history, to identify extrapulmonary manifestations of connective tissue diseases, housing, pets and other animals, pharmacological treatment, previous chemotherapy, radiation therapy etc.

X-ray of thorax is typically the first radiological investigation performed but is only a rough screening method. Bilateral basal fibrosis is a classic sign, but the identification of specific patterns such as UIP requires a HRCT. In some interstitial lung diseases, i.e. sub-acute hypersensitivity pneumonitis, the X-ray of thorax may be normal in spite of severely reduced diffusion capacity and widespread ground glass opacities on HRCT.

HRCT is the most important investigation and if performed optimally, it provides a detailed picture of the lung parenchyma. The performance and description of HRCTs requires a specialized radiologist.

Pulmonary function test shows restriction by measuring the dynamic volumes (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC), the static lung volumes (total lung capacity (TLC), residual volume (RV)) and the diffusion capacity. The dynamic lung volumes are typically normal or equally reduced with a normal or high FEV1/FVC ratio. The static lung volumes and the diffusion capacity are all typically reduced.

A standard 6-minute walk test is performed according to the ATS guidelines with the registration of the walking distance in 6 minutes, and the saturation before and after. The 6- minute walk test is a very sensitive marker for a reduced diffusion capacity, demonstrated by desaturation of more than 4%. It has to be kept in mind that desaturation is not specific for ILD. Patients with i.e. pneumonia or congestive heart failure can also show a reduced walking distance and pathological desaturation. Reduced walking distance and desaturation in IPF is a severe prognostic sign.

There are no specific serologic assays or blood tests in the diagnostics of IPF. Typically, routine blood tests include hematology, liver enzymes and renal parameters. Antibodies such as anti-CCP, IgM-RF, ANA, ACE and ANCA are used as a screening tool for connective tissue disease.

The presence of pulmonary hypertension increases the risk of bleeding complications to a lung biopsy and it is also a severe prognostic sign. Therefore, an echocardiography is a part of most IPF diagnostic investigations.

Bronchoscopy with bronchoalveolar lavage (BAL, instillation of minor amounts of sodium chloride and examination of the aspirate) is a part of the diagnostic procedure in many centers. The ATS/ERS statement has a weak recommendation against the performance of BAL but does not distinguish between patients with a definite or possible UIP pattern. The investigations seem justified in patients without a definite UIP pattern. The aspirate is examined for microbes and malignant cells, and often, a cytological differential count of the inflammatory cells is performed. In patients with IPF, neutrophil inflammation is typical, while other inflammatory patterns are seen in other types of ILD such as eosinophils > 25% in eosinophilic pneumonia.

Transbronchial biopsies (TBB) can be performed if the HRTC shows diffuse inflammatory changes but is seldom helpful in fibrotic diseases such as IPF. New techniques such as cryobiopsies have been developed and seem to give larger biopsies with less crush artifacts and have the potential to identify a UIP pattern.

A surgical lung biopsy is most often performed by video-assisted thoracoscopic surgery (VATS) and has fewer complications than a thoracotomy. VATS is associated with risk of infection, bleeding, persisting air leakage, and neuralgic pain. The procedure-related mortality is 2-7% and is primarily caused by acute exacerbations in IPF. The mortality risk is increased in patients older than 65 years, in patients with a diffusion capacity below 40% of predicted, severe co-morbidities and in patients on supplementary oxygen or assisted ventilation. Therefore, patients referred for VATS should be carefully selected and also carefully informed of the aim and risks.

Treatment

During the last 10-15 years, an increasing number of randomised, placebo-controlled trials in IPF have been published, culminating in 2014 with the publication of three studies of which two were positive and showed a reduced disease progression of I.

Historically, the treatment of IPF has been immunosuppression with high-dose corticosteroids, azathioprin and cyclophosphamide. Before year 2000, a number of smaller, less well-designed studies found a beneficial effect of immunosuppressive treatment probably due to the study population not only being IPF but also patients with inflammatory ILD . In recent years, it has been realized that high-dose corticosteroids have no impact on the disease course of IPF but instead imply a high risk of side effects. The Panther study was a placebocontrolled study comparing the triple combination of N-acetylcysteine (NAC), azathioprin and corticosteroids to mono-therapy with NAC and placebo. The study showed that triple therapy resulted in more hospital admissions, more side effects and a decreased survival. Furthermore, mono-therapy with NAC did not influence the level of decline in FVC.

Pirfenidone is a new anti-fibrotic drug that has just been approved by the Food and Drug Administration (FDA). Pirfenidone has been approved in Japan for several years and in Europe since 2011. Pirfenidone inhibits several growths factors such as TGF-β and TNF-α inhibitors and inhibits the formation of collagen. Pirfenidone has been studied in several trials of which CAPACITY and ASCEND are the most recent. These trials have promoted the approval of the drug in USA and Europe. In the ASCEND study, 555 patients were randomized to pirfenidone 2403 mg daily or placebo. The primary endpoint was the change in FVC or death. There was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died in the pirfenidone group as compared to placebo. A pooled analysis of ASCEND and CAPACITY showed a significantly increased survival in the pirfenidone treated group. In Europe, pirfenidone is indicated for patients with mild to moderate IPF with a FVC > 50% and a diffusion capacity > 30%. Patients with severe IPF were not included in the trials, but in USA, FDA has approved pirfenidone for all patients. Pirfenidone side effects include nausea, reduced appetite, anorexia, reflux and weight loss, photosensitivity and hepatitis but rarely led to treatment discontinuation.

The INPULSUS trial was a 52 week, randomized double-blind trial that evaluated the efficacy and safety of the tyrosine kinase inhibitor Nintedanib (Orfev®). The primary end point was the annual rate of decline in FVC. A total of 1066 patients were randomized to Nintedanib 150 mg twice daily or placebo. The adjusted annual rate of change in FVC was −114.7 ml with Nintedanib versus −239.9 ml with placebo in INPULSIS-1 and −113.6 ml with nintedanib versus −207.3 ml with placebo in INPULSIS-2. The treatment effect is comparable to pirfenidone although the patients included were not completely comparable. So far, no studies have compared the two drugs. Nintedanib side effects were primarily diarrhoea (62%), but the drop-out rate in the study was acceptable at 5%. Nintedanib has been approved by the FDA and awaits approval in Europe in the spring of 2015.

Supplementary oxygen is indicated when hypoxemia is present at rest or when exertional desaturation is demonstrated. Cough can be treated with codeine or low dose corticosteroids. A single study has shown a beneficial effect of thalidomide on invalidating cough. In case of severe dyspnea, morphine treatment can be attempted. Many patients benefit from referral to palliative care programmes.

Lung transplantation should always be considered in IPF. The median survival after lung transplantation in IPF is 4.7 years.

Comorbidities

Most IPF patients have one or more co-morbidities. Arterial hypertension, ischemic heart disease, gastro-oesophageal reflux, pulmonary hypertension, depression, emphysema and cancer are among the most commonly reported co-morbidities. Although no evidence exists, IPF experts recommend screening, diagnosis and treatment of co-morbidities and believe that treatment improves the prognosis.

Prognosis

The prognosis of IPF is dismal with a median survival of 3-5 years, but there are phenotypes with different survival. Some patients remain stable for several years, some progress slowly, others experience a rapid decline over a few months. About 5% of the patients develop acute exacerbations. Acute exacerbations in IPF are associated with a very high mortality of 90-95%.

Severely reduced pulmonary function, hypoxemia, severe dyspnea, and severe fibrosis on HRCT at the time of diagnosis are all signs of a dismal prognosis. More than 10% reduction in FVC over six months, progressive reduction of diffusion capacity and increasing dyspnea are also poor prognostic signs.

No tests or biomarkers have been able to identify the phenotype of the individual patient. The GAP-index combines gender, age and physiology and divides the patients into three groups with a 3-year survival of 16%, 42% and 77%, respectively.

Conclusion

IPF is an irreversible, progressive fibrotic lung disease with a median survival of 3-5 years. The diagnosis should be made using a multidisciplinary approach with evaluation of the environmental and occupational exposure, pharmacologic treatment, co-morbidities, history, HRCT, cytology and. histopathology, if available. Diagnosis and treatment is a specialist task. Treatment includes anti-fibrotic treatment with the potential of slowing disease progression and prolonging survival. Other important components in the care of patients with IPF include supplementary oxygen, transplantation evaluation, and palliation such as rehabilitation, counseling and end-oflife decisions. Referral for specialist evaluation is necessary when velcro crackles, clubbing, restrictive pulmonary function or radiological signs of fibrosis are observed, as early identification of IPF is paramount for the timely initiation of anti-fibrotic treatment.

 

Bendstrup E, Hilberg O, Hyldgaard C (2015) Idiopathic Pulmonary Fibrosis – Diagnosis and Treatment. General Med 3:161. doi:10.4172/2327-5146.1000161

Neglected Tropical Diseases in Texas

Overview of the NTDs in Texas and the American South

The major NTDs in Texas and other areas of the American South are listed in Box 1. Among their common features is the observation that most of these conditions cause chronic disabilities, which disproportionately affect people living in extreme poverty [3], [5], [13][15]. Another key feature is that NTDs are important examples of health disparities mostly affecting people of color, particularly African American and Hispanic minorities, largely because of the poverty link [3], [5], [13][15].

 Neglected Tropical Diseases in Texas

Parasitic Infections

  • Chagas disease
  • Cutaneous leishmaniasis
  • Cysticercosis
  • Toxocariasis
  • Trichomoniasis

Bacterial and Viral Infections

  • Murine typhus
  • Tuberculosis in diabetes mellitus
  • Dengue
  • West Nile virus

Neglected Parasitic Infections

Among the parasitic infections, Chagas disease (American trypanosomiasis caused by Trypanosoma cruzi infection) received renewed attention in 2012 based on recently published estimates of large numbers of people infected in the Western Hemisphere, including the high prevalence rates among pregnant women and subsequent maternal-to-child transmission [16], [17]. Of note, the first reported case of mother-to-child transmission in the U.S. was announced on July 6, 2012 by the Centers for Disease Control and Prevention (CDC) [18]. The CDC estimates that 300,000 cases of Chagas disease are found in the U.S. [19], whereas other investigators have suggested that almost as many cases occur in Texas alone [20]. Several kissing bug vector species are widespread in Texas and capable of transmitting T. cruzi; a significant percentage of these vectors are polymerase-chain-reaction (PCR) positive for T. cruzi [19], [21]. In South Texas, a high percentage of dogs, which are natural hosts, are also infected with T. cruzi [22], and a risk map for humans acquiring Chagas disease in Texas has been developed [21]. However, the extent to which T. cruzi transmission to humans actually occurs in the state is unknown [14]. There is an urgent need to increase surveillance for human T. cruzi infection in the region, possibly through seroprevalence studies, as well as for studies that attempt to document the extent of autochthonous transmission and mother-to-child transmission. In this sense, we are still at the “tip of the iceberg” in terms of our understanding of the epidemiology of Chagas disease in Texas and elsewhere in the American South. An alternative metaphor is that we have only seen the “ears of the armadillo” (similar to the ears of the hippopotamus metaphor sometimes used for malaria in Africa), referring to the nine-banded armadillo (Dasypus novemcinctus), which is native to Texas (Figure 1).

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Information is also scant for several other key NTDs in Texas. As with Chagas disease, these NTDs appear to be widespread in different areas of the state, but supporting surveillance and transmission studies are either sporadic or missing. Cutaneous leishmaniasis (CL) is another vector-borne parasitic protozoan infection, caused by Leishmania spp. and transmitted by sand flies of the genus Lutzomyia. Human cases of autochthonous CL caused by Leishmania mexicana infection have been recognized in Texas, primarily in the south-central region, since 1903 [23]. In 2008, nine cases were reported in northern Texas, not far from the Dallas-Fort Worth area [24]. There are several important animal reservoirs of Leishmania spp. in the Americas. In Latin America, rodents serve as an important animal reservoir for L. mexicana, and the Southern Plains woodrat has been implicated in Texas [23] and elsewhere in the southern U.S. Widespread infection of foxhounds in the U.S. with visceralizing L. infantum is also of concern, but the true extent of veterinary and human transmission in Texas and the rest of the U.S. is largely unknown [25]. A recent modeling study suggests that the range of reservoirs and sand fly vectors for CL is likely to expand deeper into the U.S., possibly in association with climate change [26], and thus, a northward expansion of CL infection in humans is conceivable.

Among the helminthic infections, neurocysticercosis (NCC) is now a major cause of epilepsy in Texas [27]. Most of the recent cases of NCC are believed to have been imported through immigration from Latin America [27], but autochthonous transmission still remains a possibility. Toxocariasis (Toxocara canis and Toxocara cati infection) is widespread in the American South, particularly among African American and Hispanic minority populations [28]. A covert form of this NTD has been linked to asthma and developmental delays [29], but the prevalence of toxocariasis in Texas and its potential contribution to chronic sequelae in the state have not been accurately determined.

Neglected Viral and Bacterial Infections

West Nile virus (WNV) infection, a mosquito-transmitted arbovirus infection, emerged in Houston, Texas in 2002 [30], where it occurs more commonly among people living in proximity to bayous lined with vegetation and other bodies of stagnant or slow-moving water [31]. Texas experienced a historic peak in WNV cases in 2012 affecting several areas of the state [32]. Like other vector-borne NTDs, WNV infection has been linked to poverty and its associated conditions [13], [33], [34]. A study in Houston in 2004 found that 7% of homeless people were positive for WNV infection, and that seroprevalence rose to 17% for those who did not seek shelter at night [34]. Risk factors for severe disease from WNV infection include hypertension, diabetes, and alcohol and substance abuse [35][39], which are all chronic morbidities that often go untreated in marginalized populations. In Texas and elsewhere, WNV infection was recently identified as an emerging etiologic agent of chronic renal disease and kidney failure [40].

Dengue emerged in South Texas in 1980, with additional outbreaks recognized in 1999 and 2005, and where conditions related to poverty also represent major risk factors for infection [41], [42]. Studies to determine the prevalence of dengue virus infection among residents of city-pairs on the U.S.-Mexico border have shown much higher rates of acute and past infection in Texas than would have been anticipated based on how infrequently the disease is recognized and reported [41][43]. In 2004 and 2005, recently contracted dengue virus infections were found among an estimated 2–4% of the residents of Brownsville, Texas, compared to 7–32% of residents of Matamoros, Mexico, with part of the difference having been ascribed to socioeconomic factors [41], [42]. The under-recognition of an ongoing dengue outbreak in the U.S. was recently highlighted in Key West, Florida [44], [45] and emphasizes the need for better surveillance and education of clinicians about NTDs in the U.S. Severe dengue has occurred in the continental U.S. and is always a concern where frequent dengue virus infections occur. Preliminary studies indicate that dengue may have already emerged in Houston (unpublished data). International air travel increases the risk for importation of dengue virus and possible outbreaks [46], an especially salient factor given Houston’s role as a major international air travel hub and the presence of the mosquito vector.

Among the major bacterial infections, murine typhus (Rickettsia typhi infection, transmitted by cat fleas) is emerging in South Texas [47]. An important evolving scenario lies at the interface of infectious diseases and the pandemic of chronic disease. Substantial evidence documents type 2 diabetes as the most important major risk factor for tuberculosis (TB) along the Texas border with Mexico [48], [49], increasing the risk of active TB three-fold. Similar observations have now been made in TB high burden countries across the globe [50]. Altered gene expression in the host and altered immune responses to several other pathogens in diabetes have been identified [51][54]. Studies conducted in South Texas were instrumental in uncovering the relationship between TB and diabetes such that additional studies in Texas might help in determining if similar relationships exist for other neglected diseases. The interaction between TB and type 2 diabetes illustrates how a neglected disease may interface with a chronic noncommunicable disease (CNCD). Some data suggest that the NTDs themselves manifest much like the CNCDs with respect to their chronic morbidities [55], and may certainly account for a hidden burden of CNCD-related morbidity [56].

 

Andrus J, Bottazzi ME, Chow J, Goraleski KA, Fisher-Hoch SP, et al. (2013) Ears of the Armadillo: Global Health Research and Neglected Diseases in Texas. PLoS Negl Trop Dis 7(6): e2021. doi:10.1371/journal.pntd.0002021

Atrial Myxoma

General Information
  • Most common primary cardiac neoplasm
  • Prevalence of cardiac tumors at autopsy ranges from 0.001% to 0.3%
  • Thought to originate from entrapped entrapped embryonic foregut
  • Histologically, composed of scattered cells within a mucopolysaccharide stroma
  • Produce VEGF, which contributes to the induction of angiogenesis and the early stages of tumor growth
  • On a macroscopic level, typical myxomas are pedunculated and gelatinous in consistency; the surface may be smooth, villous, or friable.
  • 35 percent of myxomas are friable or villous, and these tend to present with emboli.
Clinical Manifestations
  • Symptoms:
    • Due to obstruction of blood flow, valvular regurgitation, impaired contractility
    • Can see dyspnea, orthopnea, paroxysmal nocturnal dyspnea, pulmonary edema, cough, hemoptysis, edema, and fatigue
    • Direct invasion of myocardium can cause arrhythmias, heart block, or pericardial effusion with or without tamponade
    • Left atrial tumors may release tumor fragments or thrombi into the systemic circulation, leading to embolization in multiple vascular territories
    • May be worse in certain body positions, due to motion of the tumor within the atrium
  • Signs:
    • On physical examination, a characteristic “tumor plop” may be heard early in diastole.
    • Constitutional symptoms (e.g., fever, weight loss) are seen in around 30 percent of patients.
    • Laboratory abnormalities (e.g., anemia and elevations in the ESR or CRP) are present in 35 percent, usually those with systemic symptoms].

 

Diagnostic Evaluation 
  • Echocardiography
    • Images both the myocardium and the cardiac chambers can usually identify the presence of a mass
    • In addition, echocardiography may provide information about any obstruction to the circulation, as well as the likelihood that the tumor could be a source of emboli
    • TTE is sufficient, but TEE may be better. The superior diagnostic utility of TEE is due to the proximity of the esophagus to the heart, the lack of intervening lung and bone, and the ability to use high-frequency imaging transducers that afford superior spatial resolution.
  • Cardiac MRI and Computerized Tomography
    • MRI is preferred. In addition to furnishing detailed anatomic images, the T1- and T2-weighted sequences reflect the chemical microenvironment within a tumor, thereby offering clues as to the type of tumor that is present.
    • However, CT scanning is still useful when MRI is not immediately available or is contraindicated.
  • PET scan
    • Useful in identifying cardiac involvement in patients with metastatic tumors, atrial myxoma or lipomatous septal hypertrophy.
  • Transvenous biopsy
    • Limited data is available on the risks and benefits of transvenous biopsy of suspected cardiac tumors.
    • Because myxomas may embolize, transvenous biopsy is not generally warranted if the appearance is typical on noninvasive imaging.
    • Biopsy is considered reasonable for other cardiac tumors if potential benefits are deemed sufficient to outweigh potential risks.

 

Treatment and Prognosis

 

  • Once a presumptive diagnosis of myxoma has been made on imaging studies, prompt resection is required because of the risk of embolization or cardiovascular complications, including sudden death.
  • The results of surgical resection are generally very good, with most series reporting an operative mortality rate under 5 percent.
  • Postoperative recovery is generally rapid.
  • Atrial arrhythmias or atrioventricular conduction abnormalities were present postoperatively in about 25% of patients
  • Approximately 5% risk for recurrence, suggesting the need for careful follow-up

Adapted from: Cohen et al. Atrial Myxoma: A Case Presentation and Review.Cardiology Research. 3 (1), 2012, 41-44. CC BY-SA 4.0

 

“Remember when we tested for porphyria by…”

This week at Weissler Conference we talked about how acute porphyria used to be diagnosed many years ago – exposing urine to ultraviolet radiation (the sun!) and the color becoming purple-pink. This was even mentioned in the TV show, Scrubs, when JD accidentally diagnoses a patient with acute porphyria by this method in the episode “My Dumb Luck” (thanks to Punag for the reference). The diagnosis is now established in a patient who presents with neurovisceral symptoms (abdominal pain, nausea, vomiting, constipation, neuropathies) with a substantial elevation in urinary porphobilinogen.  Measurements of fecal, serum, urine porphyrins and and erythrocyte porphobilinogen deaminase (PBGD) will help distinguish the type of acute porphyria. Check out the review article below from Blood to learn more about porphyrias!

The porphyrias: advances in diagnosis and treatment.

(image courtesy of http://scrubs.wikia.com/wiki/My_Dumb_Luck)

Thrombotic Thrombocytopenic Purpura (TTP)

General Information

TTP is a rare hematologic emergency in which various organs, mainly the brain and kidneys, are affected by ischemic damage due to platelet aggregation. Advances in our understanding of the molecular pathology led to the recognition of three different diseases: typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS); atypical HUS (aHUS), associated with genetic or acquired disorders of regulatory components of the complement system; and TTP that results from a deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor.  TTP may be congenital or acquired as a result of HIV, connective tissue disorder, cancers, drugs like quinine, mitomycin C, cyclosporine, oral contraceptives, and ticlopidine or it may be idiopathic. 


Clinical Manifestations (i.e. the PENTAD!)

It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fever, neurological abnormalities, and renal dysfunction; however, this pentad is not necessary for diagnosis. Only thrombocytopenia and MAHA without another clinically apparent etiology (e.g., disseminated intravascular coagulation, malignant hypertension, severe preeclampsia, sepsis, systemic malignancy, etc.) are required to suspect the diagnosis of TTP and to initiate therapy. MAHA is defined as nonimmune hemolysis (i.e., negative direct antiglobulin test) with prominent red cell fragmentation (schistocytes) observed on the peripheral blood smear.


Pathogenesis

The pathogenesis may be autoimmune in nature since autoantibodies against ADAMTS13 (acronym for a Disintegrin and a Metalloproteinase with Thrombospondin-1 Motifs, 13th member of the family), which cleaves von Willebrand Factor (vWF), are typically present in most cases of idiopathic TTP. These antibodies cause the absence of ADAMTS 13 protease activity and the persistence of vWF. Subsequently the procoagulation tendency dominates and causes the systemic abnormalities. 

In STEC-HUS, the toxin triggers endothelial complement deposition through the upregulation of P-selectin and possibly interferes with the activity of complement regulatory molecules. 

In aHUS, mutations in the genes coding for complement components predispose to hyperactivation of the alternative pathway of complement. 


Management

The mainstay of treatment for patients with TTP is plasma exchange (PE) in conjunction with steroids. The mortality rate of TTP prior to the use of PE was approximately 90 percent and is currently 20 percent or less in patients treated with PE. PE reverses the platelet consumption responsible for the thrombus formation and symptoms in TTP.

Rituximab is a monoclonal antibody directed against CD20 which is specific to B lymphocytes. It depletes the production of antibodies from these lymphocytes and thus has been used for antibodies-mediated diseases including TTP. Observational studies have suggested good outcomes in some settings. Rituximab should be considered in the management of TTP along with PE and well-designed prospective studies are needed to evaluate its role in TTP.

Importantly, evidence is emerging that pharmacological targeting of complement with the anti-C5 monoclonal antibody eculizumab can effectively treat not only aHUS for which it is indicated, but also STEC-HUS and TTP in some circumstances.


N. Abdel Karim, S. Haider, C. Siegrist, et al., “Approach to Management of Thrombotic Thrombocytopenic Purpura at University of Cincinnati,” Advances in Hematology, vol. 2013, Article ID 195746, 4 pages, 2013. doi:10.1155/2013/195746

Noris, M., Mescia, F., Remuzzi, G.
STEC-HUS, atypical HUS and TTP are all diseases of complement activation
(2012) Nature Reviews Nephrology, 8 (11), pp. 622-633.

Neuro-Behcet Disease

General Information

  • Excluding headaches, neurological complications of Behçet syndrome (neuro-Behçet syndrome) occur in less than 12% of cases, often a few years after the onset of the other systemic features.

Clinical Manifestations and Diagnosis

  • In parenchymal disease, meningoencephalitis occurs, with a mixed inflammatory cell infiltrate leading to necrosis and apoptotic neuronal loss. Inflammatory infiltration, rather than fibrinoid necrosis, is seen around small vessels.
    • The brainstem and mid-brain are the most commonly affected areas, but spinal cord lesions and cerebral involvement may also occur and, occasionally, neuro-Behçet syndrome presents as a pseudotumour cerebri.
    • Brainstem involvement usually presents subacutely, with headache, cranial neuropathies or cerebellar or corticospinal tract dysfunction.
    • Sensorineural hearing loss can occur, resulting in sudden deafness, balance disturbances and dizziness.
    • The characteristic MRI lesion in parenchymal neuro-Behçet syndrome is a unilateral upper brainstem lesion extending into the thalamus and basal ganglia.
    • Analysis of cerebrospinal fluid shows a neutrophilic (in early disease) or lymphocytic (in late disease) pleocytosis, but usually no oligoclonal bands.
  • Neurovascular disease accounts for approximately 20% of cases of neuro-Behçet syndrome and symptoms include dural sinus thrombosis, intracranial aneurysm and extracranial aneurysm and/or dissection.
    • The clinical findings are usually limited to those of intracranial hypertension (that is, headache, vomiting, altered levels of consciousness and papilloedema).
    • Intracranial hypertension may be present without MRI abnormalities and should be managed in the same way as idiopathic benign intracranial hypertension.
    • Aneurysms of the cerebral, vertebral and carotid arteries can also occur.

Management

  • Headaches are often under-treated. An effort should be made to classify the type of headache and, in the case of migraine, agents such as pizotifen and β­blockers should be offered.
  • Parenchymal disease:
    • Initial Management: treated with high-dose steroids in the first instance, along with initiation of a DMARD, usually azathioprine.
      • Methotrexate, mycophenolate, cyclophosphamide, tacrolimus and IFN-­α are probably effective, although evidence is lacking.
      • Cyclosporin is potentially neurotoxic and should not be used for patients with a history of CNS disease.
    • The alternative therapeutic option for severe and aggressive disease is the early use of a biologic agent (i.e. anti-TNF therapy, like infliximab)
  • Neurovascular disease:
    • Cerebral vascular thrombosis and aneurysms also require aggressive immunosuppression.
    • Anti-coagulation for venous thrombosis needs to be assessed on a case-by-case basis.

Ambrose, N. L. & Haskard, D. O. Nat. Rev. Rheumatol. 9, 79–89 (2013); published online 25 September 2012; doi:10.1038/nrrheum.2012.156

Behçet’s Disease

General Information

  • Behçet’s disease (BD) is a chronic, relapsing, multisystemic vasculitis characterized by mucocutaneous lesions, as well as articular, vascular, ocular and central nervous system manifestations.
  • BD is most often reported in populations along the Silk Road, with highest prevalence reported in Turkey at >1/1,000, versus 1/10,000 in Japan. European cases are more often described in Mediterranean countries.

Clinical Manifestations

  • Onset most commonly occurs in adults, but pediatric cases have been reported.
  • Relapsing episodes of round oral aphthae with sharp erythematous and elevated borders (1-3 cm diameter) may be accompanied by genital aphthae (>50%); cutaneous features may include pseudo-folliculitis and erythema nodosum.
  • Ocular disorders (posterior uveitis, retinal vasculitis) occur in over 50% of BD patients.
  • Arthralgia and/or arthritis are frequent (45%) and can occur as an initial symptom.
  • Vasculitis in BD is more frequent in the venous system where thromboses in femoro-iliac, superior and inferior vena cava and cerebral territories may occur. Rarer arterial thromboses and aneurysms primarily affect the pulmonary vessels.
  • Sporadic neurological manifestations (neuro-BD) are frequent (>20%), often occuring 1-10 years after intial symptoms, and may include headache, pyramidal signs with hemiparesis, behavioral changes and sphincter dysfunction.
  • Aphthoid and/or ulcerative lesions may affect the whole digestive tract but mainly the ileo-cecum and ascending colon, potentially leading to hemorrhages and perforations.

Etiology

  • Of unknown origin, genetic predisposition in BD may allow certain infectious (in particular Streptococcus sanguis) and/or environmental insults to trigger symptoms involving sporadic inflammatory attacks reminiscent of auto-inflammatory disorders due to cross reactions with oral mucosa antigens.
  • HLAB5101 antigen is associated to BD in 50-70% of patients and aberrant cytokine levels (eg- IL-6, TNF-a, IL-8, IL-12, IL-17 and IL-21) have been implicated in the pathogenesis of BD.

Diagnosis

  • International classification criteria, as defined by clinical presentation, are sensitive and specific.
  • The presence of recurrent oral aphthae, at least 3 times over 12 months, is mandatory, in combination with two of the following:
    • Recurrent genital ulceration
    • Eye lesions
    • Skin lesions
    • Pathergy
  • In neuro-BD, lumbar puncture is mandatory and MRI may reveal inflammatory lesions in the cerebral trunk, brainstem and hemispheric areas.

Differential

  • Depending upon manifestations, infectious uveitis, relapsing polychondritis, sarcoidosis, antiphospholipid syndrome, Takayasu arteritis, Crohn disease or multiple sclerosis may be considered.

Management

  • Anti-inflammatory steroids are the basis of treatment, however, corticodependance and relapses may occur upon discontinuation.
  • Concurrent administration of immunosuppresive drugs (e.g. azathioprine, cyclophosphamide, methotrexate), are also prescribed but their action is delayed.
  • Infliximab and alpha-interferon (2a or 2b) are efficient, particularly in severe uveitis, and antiagregant or anticoagulation treatments are used in the case of vascular involvement.
  • Colchicine relieves mucocutaneous symptoms. Efficacy is dependent upon rapid initiation and patient compliance.

Prognosis

  • In the absence of treatment, the prognosis is severe due to ocular involvement leading potentially to blindness, the risk of lethal arterial rupture and neurological symptoms potentially causing encephalopathy that may lead to a loss of autonomy.
  • Intensive ophthalmological care coupled with immunosuppressive treatment has been shown to reduce morbidity greatly..

Orphanet: an online rare disease and orphan drug data base. Copyright, INSERM 1997. Available on http://www.orpha.net.Accessed (3.13.15).

Idiopathic Pulmonary Fibrosis

This morning, Dr. Zea Borak presented an interesting talk on idiopathic pulmonary fibrosis  at Grand Rounds. Perfect time for a quick primer on this rare condition!

General Information

Idiopathic pulmonary fibrosis (IPF) is a nonneoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known cause. IPF is a rare disease that affects approximately 5 million people worldwide. The prevalence is estimated to be slightly higher in men (1/5000) than in women (1/7700).

Clinical Manifestations 

The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathlessness and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease and classic signs of right heart failure may be present.

Etiology 

The etiology is not yet completely understood. Environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock).

Diagnosis 

IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that have been published in guidelines endorsed by several professional societies.

Differential Diagnosis 

includes other idiopathic interstitial pneumonias, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures.

Management 

Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medications. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. However, IPF is typically progressive and leads to significant disability.

Prognosis 

The median survival is 2 to 5 years from the time of diagnosis.

Orphanet: an online rare disease and orphan drug data base. Copyright, INSERM 1997. Available on http://www.orpha.net. Accessed (3.13.15).