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Infection

Primary Care Corner with Geoffrey Modest MD: Malaria Prophylaxis Twice a Week With Atovaquone-proguanil?

7 Oct, 16 | by EBM

By Dr. Geoffrey Modest

Overall, the results are pretty miserable for medication adherence to malaria prophylaxis in long-term travelers to malaria-infested areas. A recent article found that twice-a-week prophylaxis with atovaquone – proguanil (Malarone) was very effective (see doi: 10.1093/jtm/taw064).

Details:

  • An observational study was conducted in two sites in West Africa: the jungle in Angola and a medical station in Equatorial Guinea.
  • Angola: 14 male expatriates, median age 24, working in the jungles of Angola for 16 months. During the first six months, all refused malaria prophylaxis, and eight developed malaria, 2 with severe cases. They then accepted twice weekly AP (atovaquone-proguanil), given through directly-observed therapy.
  • Equatorial Guinea: 108 medical staff and families (50% male, age range 1.5 to 71 with 28 < 12 years old, mean stay 19.5 months. 49 declined malaria prophylaxis, 40 received mefloquine, in 19 heard about the Angola experience and decided to take twice-weekly AP.
  • Overall, 122 people were included in the study. 63 did not take prophylaxis, 40 took mefloquine, and 33 took AP twice-weekly.

Results:

  • No prophylaxis: 16 cases of malaria: 11.7 per thousand person-months (1368 months at risk)
  • Mefloquine: two cases per 1000 person-months (983 months at risk)
  • AP twice-weekly: zero cases per 391 person-months (391 months at risk)
  • Either treatment was associated with a 20-fold decreased odds of malaria infection compared to no prophylaxis, OR = 0.05 (0.006 – 0.42), p= 0.006.

Commentary:

  • Malaria in general, and falciparum in particular, is a huge international problem, with ramifications for travelers:
    • 97 countries have continuing risk of malaria transmission. These countries are visited by more than 125 million international travelers per year
    • At least 10,000 cases of travel-associated malaria occur annually, mostly in those who did not take malaria chemoprophylaxis.
    • Malaria is still the leading cause of hospitalization in ill-returning febrile travelers
    • Malaria remains the leading cause of death from infectious diseases among travelers
    • Travel to sub-Saharan Africa has both a heavy burden of Plasmodium falciparum, as well as most deaths from malaria.
    • There are three approved options for malaria chemoprophylaxis in sub-Saharan Africa: mefloquine weekly, doxycycline daily, and AP daily.
  • Travelers spending more than a few weeks in a malarial zone often do not take prophylaxis. It was quite striking in this study that the 45% of the participants not taking prophylaxis were in fact medical personnel.
  • Although not formally studied, AP has the potential for long-term of prophylaxis given the long half-life of atovaquone of 50 to 84 hours, though proguanil is only 14 to 20 hours, with some suggestive data that weekly dosing may be adequate.
  • AP is in some ways the most appealing regimen, given its very low side effect profile vs. mefloquine or doxycycline, but is quite expensive. The weekly costs are approximately:  AP daily $50, mefloquine once a week $10, doxycycline daily $18.
  • This was not a large randomized controlled trial, but the numbers are quite impressive. I think at this point it is wise to recommend the standard approved treatments, but given the high likelihood for non-adherence, I personally will offer the option (as a second-tier option) of the twice-a-week AP therapy for those who are reluctant to take AP daily because of either cost (which then becomes $14/week and comparable to the other options), or concerns about effectiveness, or other concerns about taking daily medications.

Primary Care Corner with Geoffrey Modest MD: Zika and Neurologic Problems in Brazil

1 Aug, 16 | by EBM

By Dr. Geoffrey Modest

STAT (see statnew.com) has frequent updates on Zika, noting the following:

  • Puerto Rico reported the biggest weekly rise in Zika cases yet, with 1,336 new cases for the week ending June 30, including 533 pregnant women diagnosed with the virus
  • Two patients who were infected with the Zika virus have developed severe thrombocytopenia
  • Brazilian researchers have observed a sharp increase in cases of Guillain-Barré syndrome

For this last point, there was a recent release of an article in Neurology (see doi:10.1212/WNL.0000000000003024) from Brazilian neurologists who started a study group in Rio to further understand the Zika-related neurologic disorders (Guillain-Barré syndrome –GBS, meningoencephalitis, transverse myelitis), finding that in the period Dec 5, 2015 to <arch 18, 2016, there were:

  • 20 confirmed cases of GBS (there had previously been 15 case in 24 months prior to Zika: so average GBS cases increased from 0.67/month to 5.4/month)
  • 17 were associated with a viral prodrome consistent with Zika (pruritic rash, fever, arthralgias).
  • But there is an issue with associating all cases with Zika, since Zika is so prevalent there and 80% of cases are asymptomatic, making the causal link difficult especially in those without a clear prodrome
  • They have also seen Zika-related AMAN (acute motor axonal neuropathy), acute motor sensory polyneuropathy, acute inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, and Miller Fisher variant along with encephalitis, transverse myelitis and acute disseminated encephalomyelitis following a Zika prodrome.
  • The neurological associations are not limited to Brazil’s outbreak/variant: there were cases of Zika-related GBS and AMAN in French Polynesia, which is genetically distinct from Brazil.
  • Also a couple of recent new transmissions: from an infected woman to her male sexual partner, and a possible case of a domestic worker getting infected.

Primary Care Corner with Geoffrey Modest MD: Zika Virus Testing

26 May, 16 | by EBM

By Dr. Geoffrey Modest

Zika virus testing: the CDC just published new guidance for testing for the Zika virus (see http://www.cdc.gov/mmwr/volumes/65/wr/mm6518e1.htm?s_cid=mm6518e1_w ):

  • Use real-time reverse transcription-polymerase chain reaction (rRT-PCR) on urine if <14 days after the onset of symptoms in patients with suspected Zika virus disease
  • Use rRT-PCR test on urine and on serum if <7 days after symptom onset
  • Any positive test result provides evidence of Zika infection

Basis of recommendations (details in http://www.cdc.gov/mmwr/volumes/65/wr/mm6518e2.htm?s_cid=mm6518e2_w )

  • rRT-PCR is a rapid test and is highly specific
  • In most patients, the Zika virus RNA is not detected in the serum after the first week of illness
  • Recent report found the rRT-PCR to be positive in the urine for at least 2 weeks after onset of symptoms (in Florida study, from as early as 1st day of symptoms till as late as 20 days later)
  • The Florida study also found that of 66 cases, 61 (92%) had positive urine and 31 (47%) positive blood testing.
  • Within the first 5 days of symptoms, of 55 patients, 52(95%) had a positive urine test and 31 (56%) had a positive blood test
  • >5 days after symptoms, 9 (82%) had positive urine and none had positive serum
  • Of the 53 who had testing at multiple sites: 92% had positive urine, 81% positive saliva, and 51% positive serum

So, urine testing is by far the most sensitive overall, but there are occasional cases of Zika positive only on blood testing.

No change in recommendations on who to test (see http://www.cdc.gov/zika/pdfs/denvchikvzikv-testing-algorithm.pdf ):

  • Persons with 2 or more of: rash, fever, arthalgias or conjunctivitis during or within 2 weeks of return from an area with Zika virus activity, or with a link to a Zika virus infected traveler (sexual partner, household contact, etc.)
  • For CDC guidance for women of reproductive age with possible Zika virus exposure, see http://www.cdc.gov/mmwr/volumes/65/wr/mm6512e2.htm

For recent review on Zika: see http://blogs.bmj.com/ebm/2016/04/27/primary-care-corner-with-geoffrey-modest-md-zika-virus-review/

Primary Care Corner with Geoffrey Modest MD: Zika Virus Review

27 Apr, 16 | by EBM

By Dr. Geoffrey Modest

There was a good review of the Zika virus from the CDC in a recent issue of NEJM (see DOI: 10.1056/NEJMra1602113​).

Details:

  • Epidemiology: flavivirus, discovered in 1947 in Zika rainforest in Uganda, transmitted by Aedes africanus mosquit​o, with seroprevalence of 6.1% back then (i.e., lots of human transmission), and with documented wide geographic distribution in Africa and Southeast Asia. Though only rare reports of cases of human illness over the next 57 years
  • 2007: Outbreak in Micronesia (State of Yap) with 5000 infections in population of 6700
  • 2013-4: Big outbreak in French Polynesia involving 32,000 people. Some cases of Guillan-Barre. Other outbreaks in Pacific Islands, not much more in Southeast Asia
  • 2015: outbreak in Brazil, then widely spread with up to 1.3 million suspected cases, with >4300 cases of microcephaly (now officially caused by the Zika virus, per the CDC – i.e., not from insecticides, herbicides, etc.)
  • By March 2016, spread to at least 33 countries and territories in the Americas. The strains of Zika in the Americas is of the Asian genotype, similar to the outbreaks in Yap, French Polynesia, though overall Zika virus has conserved its genetic structure very well over time [which is good in terms of diagnostic testing, development of vaccines, and understanding expected symptoms/sequelae]
  • Transmission: many different Aedes mosquitoes likely involved in nonhuman transmission in nonhuman animals in Africa; A. aegypti and (to lesser extent) A. albopictus, have been involved in nearly all human cases. (? If A. hensilli and A. polynesiensis were involved in Yap)
  • egypti likely to be the bad actor overall: it feeds primarily on humans, often bites multiple people in a single blood meal, has an almost imperceptible bite, and lives in close proximity to humans.
  • Both A. egypti and A. albopictus bite primarily during the daytime, and are widely spread throughout the tropical and subtropical world. A. albopictus is more widely distributed in the eastern US and Hawaii
  • But it seems that A. albopictus does not cause much problem so far, with dengue or Zika, except in Hawaii, which has had some dengue outbreaks.
  • Though Zika has been identified in malaria mosquito vectors, they seem to have low potential for transmission for Zika
  • Non-mosquito transmission– pretty definitely: mother-to-fetus (found in amniotic fluid in fetuses with cerebral abnormalities, found in brain tissue), but in the very few cases of peripartum transmission, not a significant problem; sexual transmission: in one case occurred before the onset of symptoms. Virus identified in sperm up to 62 days after onset of symptoms. Though blood transfusion transmission not reported, it is likely given this happens with other similar flaviviruses. Zika virus has been recovered in breast milk
  • Clinical presentation: unclear incubation period, but likely <1 week (if similar to other flaviviruses). In a volunteer, febrile illness after 82 hours of subcutaneous inoculation, viremia only when symptomatic. In Yap, about 20% of people become symptomatic: macular/pruritic rash (90%), short-term fever (65%), arthralgia/arthritis (65%), conjunctivitis (55%), myalgias (48%), headache (45%), retro-orbital pain (39%), edema (19%), vomiting (10%). Also, hematospermia, dull hearing, swelling of hands/ankles, subcutaneous bleeding. In French Polynesia Guillan-Barre was found in 38 people of 28,000 who sought medical care. Also meningoencephalitis and acute myelitis. In terms of fetal outcomes, much is inferred from other infections (CMV, rubella). Most prominent effects in first trimester infections, though there is evidence that microcephaly can occur with infection late in second trimester or early third. Recent data does suggest that most infections associated with microcephaly occur between 7-13 weeks of gestation. In Brazil, fetal abnormalities were detected by ultrasound in 29% of women infected with Zika (though, note: ultrasound is not a very sensitive method to detect microcephaly). Fetal loss/death has been found in infections from 6-32 weeks gestation. Ocular anomalies in 35%
  • Diagnosis: detection of viral nucleic acid in the blood is definitive, but that may be transient (mostly up to 1 week), though viral RNA has been detected in serum of pregnant women with infected fetus 10 weeks after infection. The virus-specific IgM antibody develops at the end of the first week, but may reflect cross-reaction with other flaviviruses (e.g. dengue, yellow fever). Plaque-reduction neutralization testing provides more specific Zika virus assessment.
  • Prevention: use of mosquito repellent, permethrin treating of clothing, bed nets, window screens help.

 

Primary Care Corner with Geoffrey Modest MD: TMP/SMX For Uncomplicated Skin Abscesses

10 Mar, 16 | by EBM

By Dr. Geoffrey Modest

NEJM just a published a study looking at trimethoprim-sulfamethoxazole (TMP/SMX) vs placebo in patients with uncomplicated skin abscesses (see N Engl J Med 2016;374:823).

Details:

  • Study done in 5 US ERs, assessing TMP/SMX at dose of 320mg/1600mg (i.e., two DS tablets) twice daily (n=630) for 7 days vs placebo (n=617). Patients had to have the abscess for at least 1 week, and it had to be at least 2cm in diameter, including the induration.
  • Mean age 35; 58% male; 4.0 days of symptoms; 18% with fever; 11% diabetic; 4% with chronic skin conditions; site: 13% head/neck, 21% trunk/abdomen/back, 21% groin/buttocks, 23% arms/hands, 21% legs/feet; mean abscess size 2.5 cm x 2.0 cm x 5cm deep; erythema 7.0×5.0cm; wound culture: 45% MRSA, 16% methicillin-sensitive S. aureus, 12% coagulase-negative staph, 5% strep)
  • Main outcome was clinical cure 7-14 days after the end of the treatment period

Results:

  • Of those who took at least 1 dose of med, 64.7% were 100% adherent, and an additional 17.2% took 76-99% of the meds.
  • ​Modified intention-to-treat population (took at least one dose of med): clinical cure in 80.5% on TMP/SMX vs 73.6% on placebo (difference 6.9 percentage points (2.1-11.7, p=0.005)
  • Per-protocol population (took at least 75% of doses during first 5 days and had in-person test-of-cure): clinical cure in 92.9% on TMP/SMXvs 85.7% on placebo (difference 7.2 percentage points (3.2-11.2, p<0.001)
  • 7-14 days after treatment period, TMP/SMX also associated with lower rates of:
    • Subsequent surgical drainage (3.4% vs 8.6%, difference of -5.2 percentage points (-8.2 to -2.2)
    • ​Skin infections at new sites (3.1% vs 10.3%, difference of -7.2 percentage points (-10.4 to -4.1)
    • Infections in household members (1.7% vs 4.1%, difference of -2.4 percentage points (-4.6 to -0.2)
    • No difference in invasive infections (0.4% in each group)
  • Extended follow-up at 42-56 days: an invasive infection occurred in 1 patient in the TMP/SMX arm, “unrelated to the original abscess”
  • Adverse events: overall similar rates, most considered mild. Most common were GI (42.7% vs 36.1%); no cases of c. diff-diarrhea.

So, this study raises a few issues:

  • Historically, the primary treatment for cutaneous abscesses had been incision and drainage (I&D). Smaller studies have shown no benefit of antibiotics. The concern here is that >80% of abscesses are cured with I&D alone (as in the current study), so there needs to be a pretty large study to show efficacy of antibiotics in the remaining patients. Also, there is some question in the literature as to whether the situation now is different in the era of MRSA, that antibiotics may play a greater role in treatment of abscesses. To show this, there would need to be an even larger study to see if MRSA needs different treatment. But, from a primary care perspective, we do not know the organism at the time of presentation and need to treat empirically anyway, and this study is therefore applicable/useful.
  • Of course, TMP/SMX is not benign: it can be associated with c. diff infections, renal/electrolyte problems, hepatotoxicity, drug interactions, and other life-threatening reactions (g. Stevens-Johnson syndrome in about 3/100K people, or erythema multiforme). Overall, adverse reactions are on the order of 5%, though higher in those with HIV, esp if more severely immunocompromised. And there is the development of resistant organisms and microbiome changes (though, interestingly, a VA study did not find significant increases in antibiotic resistance in the post- vs pre- MRSA period, after which much more TMP/SMX has been prescribed — see Antimicrob Agents Chemother. 2012; 56 (11): 5655)
  • Still not so clear what the correct dose should be: there are data that a single DS pill bid achieves adequate serum levels for MRSA, and that is what I have been prescribing (the guidelines I’ve seen recommend 1-2 tabs bid, g. NEJM 2014; 370: 1039), though the current study was extra cautious and used the 2 tablet bid regimen
  • So, this study does raise the issue of routinely using TMP/SMX for abscesses in people with uncomplicated skin infections. As with many clinical issues, the right path for an individual patient is not so clear. The positives of treating are the higher cure rate by 7%, but also the pretty significant 5% decrease in need for subsequent surgical drainage and the 7% decrease in skin infections in new sites. The negatives are the immediate adverse effects of TMP/SMX, about 5% but including some rare fatal reactions, the potential for drug resistance (though not so much in above cited study) and perhaps longish term microbiomeMy bias is that I would lean more strongly to using antibiotics in a few instances:  in immunocompromised person (including diabetes)​, in some sites more than others (e.g., face/neck and groin area — anecdotally, I did have a patient many years ago with a groin abscess, and put on anti-staph antibiotics, but developed a fatal case of necrotizing fasciitis, so I do treat groin infections much more aggressively/broadly, covering anaerobes as well), and in a really mean looking, large (?not sure how to quantitate) abscess, especially if large surrounding area of cellulitis/induration or systemic symptoms (fevers, etc.). I think the conclusion is that there needs to be a discussion with the patient and a collaborative decision, reviewing risks/benefits.

For prior blog on using bleach baths for recurrent infections, see http://blogs.bmj.com/ebm/2014/04/02/primary-care-corner-with-geoffrey-modest-md-bleach-baths-to-decrease-recurrent-skin-infections/

the recommendations are for 1/4 cup of bleach in 1/4 bathtub (13 gallons of water), though will add the caveat, per Dr. Richard Bird, that it is not uncommon for people to add a lot more bleach or into only small amounts of water, and that they can get an associated cough or precipitate asthma (toxic reaction to the bleach/chlorine). Also can get rashes.​

Primary Care Corner with Geoffrey Modest MD: Zika Guidelines/Updates from CDC

18 Feb, 16 | by EBM

By Dr. Geoffrey Modest

A brief update on a few developments with Zika virus:

The CDC came out with new recommendations on reducing sexual transmission of Zika (see http://www.cdc.gov/mmwr/volumes/65/wr/mm6505e1er.htm​ ).

  • There are a few cases of very-likely sexual transmission of Zika: one mentioned in prior blog: http://blogs.bmj.com/ebm/2016/01/29/primary-care-corner-with-geoffrey-modest-md-zika-virus/ ), and a recent one in Texas.
  • There was a report of a replication-competent Zika virus isolated from a Tahitian man at least 2 weeks and up to 10 weeks after Zika illness onset (the virus might persist in semen after it is no longer detectable in blood). He reported no sexual contacts
  • There are not a lot more data: i.e., we do not know the actual length of time that replication-competent Zika virus​ is present in semen; we do not know if men with asymptomatic disease (which seems to happen in 80% of infections) have the virus in their semen, and if so then for how long; or if the virus is of sufficient quantity to be transmissable; if condoms are in fact completely protective (not the case in all viruses, e.g. HSV); if men can develop Zika (symptomatic or asymptomatic) from infected women; how robust and longstanding is immunity after an initial infection?
  • So the recommendations regarding sexual transmission and ways to prevent it are largely guess-work, erring to being overly cautious, and are likely to be modified as our understanding increases. The current recommendations:
    • Men with pregnant partners: if the man resided in or traveled to an area with Zika, either abstain from sexual activity or consistently and correctly use condoms. This includes vaginal, oral or anal sex. Pregnant women should mention this to their obstetric providers and should consider Zika virus testing even if they are asymptomatic (see http://www.cdc.gov/mmwr/volumes/65/wr/mm6505e2.htm for updated guidelines).Since we do not know how long viable virus is present in semen, the CDC does not say when it is okay to resume unprotected sex.
    • ​Men with nonpregnant sex partners: if the man resided in or traveled to an area with Zika, he ​”might consider abstaining from sexual activity or using condoms consistently and correctly during sex” (again, not sure for how long). At this point testing men for the purpose of assessing risk is not recommended (we need to know a lot more about the incidence, consistency, and duration of viral shedding in semen).

Also, there are news reports of Zika transmission by blood donation, and virus detection in saliva and urine. Again, unclear if these are important means of viral spread. We need lots more information. But it is interesting that this virus has been around since first identified in 1947. This is not new (though it would be good to know for sure if the virus has mutated): why is there so little information? Because of inadequate surveillance in rural Africa? Because perhaps the virus has been around for a lot longer than that and there was a lot of immunity already there? Or it infects little kids who are then immune and not able to acquire a new infection when pregnant later? And the new outbreaks in Brazil and elsewhere reflect the rapid spread in a nonimmune community replete with lots of mosquito vectors and enough infected people coming from Africa or other more endemic areas?

A couple of other points. My guess (assuming this is the same virus as in 1947) is that Zika was prevalent then, infected kids, was not such a serious infection, and created long-term immunity. Again, this is highly speculative, but on my searching around, there were no reported cases of microcephaly in Africa (suggesting that pregnant women were not susceptible to the virus, which suggests that they were infected as kids and that they had longish term immunity). And I am concerned that there may well be nonhuman reservoirs which help the virus spread (both given the rapidity and extent of the current outbreaks, and a finding in the rain forest in Nicaragua that 40 howler monkeys were found dead with no evidence of trauma or other clear cause). The sort-of-good-news is that Zika is similar enough to other flaviviruses that it is likely that we can develop a vaccine pretty rapidly (i.e., 1.5 years vs 3-4 years).

As of 2/11/16: Western Hemisphere countries with confirmed local transmission: Chile, Brazil, Colombia, Suriname, El Salvador, Mexico, Panama, Venezuela, Honduras, French Guiana, Martinique, Puerto Rico, Bolivia, Saint Martin, Haiti, Barbados, U.S. Virgin Islands, Dominican Republic, Nicaragua, Jamaica, Costa Rica, United States

Dr. Paul Sax, a prolific ID specialist from the Brigham and Women’s Hospital in Boston, has a blog with 12 questions about Zika and his answers. The direct URL to his blog does not seem to be working, so I will take the liberty of pasting his questions/responses:

  1. I’m pregnant or know someone who’s pregnant. Can I/she travel to — [insert country close to one of the countries that has Zika transmission,but is not currently listed]?  Yes … but … with a caveat. It’s a highly dynamic situation, and just like dengue and chikungunya, Zika is likely to be reported in many of these adjacent countries soon (especially in the Caribbean). Not only that, incidence frequently rises quickly in countries after they first report the disease. So why not change those travel plans if possible?
  2. I’m pregnant or know someone who’s pregnant. Can I/she travel to Florida (or Alabama or Mississippi or Louisiana or Texas or Hawaii)?   There has been no mosquito-borne Zika transmission in the USA yet, though likely there will be sporadic cases soon. But just like dengue and chikungunya, it seems that a widespread outbreak is unlikely — we have more resources for mosquito control, and way more air conditioning.
  3. How long after returning from [insert Zika country here] can someone safely get pregnant? After all, since 80% of people who get it are asymptomatic, how does one know if Zika infection even occurred?  We don’t know the precise duration of viremia for Zika, or whether the duration of viremia correlates with symptoms. (My gut feeling is that it will, but who knows.) Estimates are that viremia clears on average in about a week. So right now it seems prudent to wait at least a couple of weeks after returning before trying to get pregnant, maybe a month to be on the safe side.
  4. A guy travelled to [insert Zika location here]. How long after travel should he wait before having sex with his pregnant partner?We don’t know how long Zika virus remains in semen after infection, nor (again) whether this duration correlates with symptomatic infection (again, my guess is that it does). Since Zika acquisition during pregnancy is what we’re trying to avoid, these guidelinesrecommend abstinence or condom use during the pregnancy, which makes sense to me. Now what about the more common scenario, partner isn’t pregnant? Next question, please.
  5. A guy travelled to [insert Zika location here]. How long after travel should he wait before having sex with his non-pregnant partner? The guidelines linked in the previous question state that these couples “might consider abstaining from sexual activity or using condoms consistently and correctly during sex,” but no duration for this “safe sex” practice is given. Note the use of the word, “might” — this is CDC parlance for, “Look, we’re not going to tell you that doing nothing is totally safe, but we don’t feel that strongly about this recommendation.” (Check out the rabies guidelines for plenty of “mights” in this mode.) After all, Zika infection is pretty mild, and there have only been 2 documented sexual transmissions. In fact, one could argue that if other forms of contraception are being used, that transmitting the infection would have a benefit — namely, immunity for a future pregnancy. For worried folks, I’ve been saying they “might” as well wait a month. For unworried folks, I’m not saying anything. Importantly, there is no evidence that prior infection with Zika will have a negative impact on future pregnancies, once the infection clears.
  6. Can’t the woman who wants to get pregnant — or even the guy with the pregnant partner — just get a Zika blood test when they return from a Zika country/region, and find out if they were infected? That would make us all less anxious.  Not yet. Zika testing is now done mostly through CDC (someone from Florida told me they had local access to testing), and there isn’t the capacity to test everyone. This is why testing is now recommended only for pregnant women who were in Zika transmission areas. Initially it was recommended only for women with symptoms; this was broadened last week to include allpregnant women, even those without symptoms. And remember, the test isn’t so great — there is extensive cross-reactivity with dengue and prior Yellow fever vaccination. So while it would be ideal to have a widely available, rapid, and accurate Zika test, our current test misses on all these marks. I suspect (hope) this will improve shortly.
  7. I read a vaccine is in the works. When will it be available?Vaccines take years to develop, and many, many millions of dollars. While some have stated that it should be technically feasible to produce a Zika vaccine, that doesn’t mean it will work in humans, or even that if one does work, that it will be marketed. So put this one on the way back burner (unless you’re a vaccine researcher).
  8. The virus was discovered decades ago. Why hasn’t the link to microcephaly been reported before?  A couple of theories, not mutually exclusive: 1) It is likely that in areas where Zika is already established, initial infections predominantly occur during the pre-childbearing years, which induces immunity. 2) The incidence of an infection is often highest after infections enter a community for the first time, as the pathogen encounters a large pool of susceptible hosts. In areas with established infection, the combination of some regional immunity and lower incidence means that fewer women acquire the infection during pregnancy — making it much harder to identify an association.
  9. I read that some countries with Zika transmission are recommending that women delay pregnancy — isn’t the virus still going to be around for years to come, maybe indefinitely? They can’t be expected to delay having babies indefinitely. This is a controversial recommendation, and indeed the WHO does not endorse it. However, it makes some sense, largely for the reasons cited in the previous question — the delay could allow immunity-inducing infection to occur in some non-pregnant women of childbearing age. Even if this doesn’t happen, the incidence of infection should be sharply lower once a substantial fraction of the population has been infected.
  10. How do we know that Zika even causes microcephaly? I’m a skeptic.It’s true that we don’t know definitively that Zika causes microcephaly. And it’s highly likely that reporting bias has to at least some degree increased the number of cases, especially in Brazil. But the number of cases reported in Zika-transmission countries is many fold higher than usual, beyond what public health officials would consider solely the result of reporting bias — read this excellent piece in the New York Times, which conveys vividly what was happening as the epidemic accelerated. Lending further support to the connection, researchers have isolated the virus from babies with microcephalyand there are now reports that French Polynesia may well have had an increase in CNS abnormalities in babies around the time that their Zika outbreak occurred in 2014. Finally, one needs to consider the source of the travel advice — our CDC is very cautious about issuing such travel warnings (substantial geopolitical and economic consequences), and would not make this recommendation unless the evidence were very strong.
  11. How about Zika and the Guillain-Barré syndrome syndrome?Though there have been reports of Guillain-Barré syndrome after Zika virus infection, whether Zika causes this neurologic syndrome is not conclusively established — more research is needed here, though again the anecdotal data are suggestive. There are, of course, other infections linked to Guillain-Barré, most notably campylobacter, so the association is plausible.
  12. I hear the virus can be transmitted not just by Aedes aegypti, but also the much more widespread Aedes albopictus. Isn’t it just a matter of time before this virus is charging through the United States like it is through Central and South America?  With the important upfront caveat that prognostications on disease spread are notoriously iffy, experts in vector-borne illnesses do not think that this scenario is likely — related to the lower “efficiency” of viral transmission from Aedes albopictus,and the experiences to date with dengue and chikungunya. But sure, there will always be worst-case scenarios — and noisy champions of these views who get lots of attention

Primary Care Corner with Geoffrey Modest MD: Zika Virus

29 Jan, 16 | by EBM

By Dr. Geoffrey Modest

The Zika virus has made the headlines of late. Some details:

  • Zika virus is a mosquito-born flavivirus, mostly transmitted by Aedes aegypti mosquitoes (which also seem proficient in transmitting dengue, chikungunya and yellow fever viruses)
  • Zika infections have been documented through intrauterine as well as intrapartum transmission from a viremic mother. RNA from the virus is also detected in breast milk though transmission has not been documented by breastfeeding
  • 80% of people are asymptomatic with the virusAedes_Albopictus
  • When symptomatic, there are usually only mild symptoms, with acute onset of fever, maculopapular rash, arthralgia, nonpurulent conjunctivitis. Lasting several days to 1 week. Fatalities are rare. But Guillan-Barre has been reported [note: there is a background incidence of Guillan-Barre. Not clear that the association with the Zika virus is causal, though a few cases have been found in Zika-infected individuals]
  • In Brazil outbreak, Zika RNA has been identified in brain tissue, placenta and amniotic fluid
  • Though there has been a dramatic increase in the numbers of infants with microcephaly or intracracial calcifications, it is unclear how many are associated with Zika
  • Testing: there are PCR tests for the viral RNA, and both IgM ELISA and PRNT (plaque reduction neutralization test) testing for antibodies.There can be cross-reacting antibodies causing false positives, but the PRNT is more specific to Zika. Contact the State Dept of Public Health for info
  • Since unclear which test is most reliable, CDC recommends both PCR and one of the antibody tests. All testing is done by the CDC or state labs.
  • PCR testing should be within 2 days of birth. Also CSF, if obtained for other studies, and maternal serum

Zika virus has been found largely in Africa and Southeast Asia in the past. In May 2015, the WHO reported lots in the Western Hemisphere, including travelers to the US (though no active transmission found so far). But almost all of Central and South America has active cases, including Puerto Rico, Mexico, and pretty much everywhere else except Costa Rica, Argentina, Chile, Uruguay. Also active transmission reported in Cape Verde (see www.CDC.gov/travel for virus/travel updates)

See http://www.cdc.gov/mmwr/volumes/65/wr/mm6503e3er.htm for the CDC guidelines on evaluation and testing of infants with possible congenital Zika infection. In brief:

  • Follow closely new mothers who were potentially exposed to Zika during pregnancy based on travel or residence in areas with Zika transmission
  • Review fetal ultrasounds and maternal testing for Zika
  • Test infants for the virus, if
    • Infant with microcephaly or intracranial calcifications
    • Infants born to mothers with positive or inconclusive test results for Zika virus
    • Also, Zika virus is a nationally notifiable condition
  • Infants with positive or inconclusive Zika tests: they should have ophthalmologic exam including retinal exam, within the first month of life, given reports of abnormal eye findings in those with possible congenital Zika. And repeat hearing screen at 6 months
  • Still look for other possible etiologies of microcephaly or intracranial calcifications if these findings present, and treat appropriately (including consultation with dysmorphologist, a new term to me…., as well as routine testing for syphilis, toxo, rubella, cmv, lymphocytic choriomeningitis virus infection, hsv) [even with appropriate training and interest, I’m not sure I would like the word “dysmorphologist” to be attached to my name]
  • In infants without any findings at birth but born to a Zika-positive mother, test the infant for Zika infection, and if possible infection, do routine exam with comprehensive neuro exam, check for hepatosplenomegaly and rashes, cranial ultrasound (unless normal in 3rd trimester check).
  • Only mothers who report symptoms suggestive of Zika within 2 weeks in an area with ongoing Zika virus transmission should get Zika testing. Then if positive or inconclusive, test the infant.
  • Management of Zika: nothing specific, no vaccines. Mothers should be encouraged to breastfeed, with apparent benefits outweighing potential risks
  • Prevention: just avoid mosquitoes

The CDC recommends that “all pregnant women consider postponing travel to areas where Zika virus transmission is ongoing”, and if she goes there, avoid mosquitoes (remember that this mosquito, unlike the dawn/dusk types that transmit malaria, is more around in the daytime. So, use lots of anti-mosquito protection — though I’m not sure that is so great for the infant, the CDC recommends DEET, picaridin and IR3535 as more likely to be safe)

The NY Times reported on possible risk of Zika sexual transmission. See http://www.nytimes.com/2016/01/26/health/two-cases-suggest-zika-virus-could-be-spread-through-sex.html . Basically, there is a “theoretical risk” of sexual transmission per the CDC.  A Tahitian man was exposed to the Zika virus in 2013, and a high level of virus was found in his semen and in his urine. Another was a malaria researcher in 2008, who was collecting mosquitoes for a malaria study in Senegal. He developed rash, fatigue, headaches, bloodshot eyes, and genital pain/likely hematospermia late in the illness. Tests for malaria, dengue and yellow fever were negative. After his return to the US, his wife who had remained in the US, developed several of these symptoms. Frozen serum from both the researcher and wife were subsequently positive for Zika virus, and no other family members were positive, suggesting sexual transmission.​

So, the clear concern here is yet another emerging infectious disease with potential dire consequences to those infected, unclear if there will be new and threatening modes of transmission, and lack of current vaccine or treatment. But overshadowing much of this is the effects of climate change. It turns out that even small degrees of warming lead to major changes in the territory for mosquitoes. New cases of dengue, for example, have migrated north to the US (sporadic new cases reported in Hawaii and Florida), though the range of the vector mosquito has spread considerably into the southern US

Primary Care Corner with Geoffrey Modest MD: Sleep Deprivation and Colds

11 Sep, 15 | by EBM

By Dr. Geoffrey Modest

There have been several articles finding an association between short sleep duration and various infectious diseases. The current study was a better-documented clinical trial supporting this (see SLEEP 2015;38(9):1353–1359). Details:

  • 164 healthy adults (94 men and 70 women, mean age 30) volunteered for the study
  • These volunteers were monitored for 7 consecutive days for their sleep duration and continuity, both by subjective questionnaires and by wrist actigraphy (which correlates well with polysomnography, the gold standard)
  • Then they were given nasal drops containing rhinovirus 39 and subsequently monitored for 5 days in a quarantined hotel. A “clinical cold” was defined if they were both infected and met the illness criteria (objective measures of mucous production and nasal congestion)

Results:

  • 124 of 164 participants (75.6%) were infected with rhinovirus (antibody measurements before and 28d after viral exposure, and daily nas
    al rhinovirus cultures)
  • 48 (29.3% of them) developed a clinical cold
  • Objective sleep duration (by actigraphy) was associated with an increased likelihood of developing a clinical cold, with odds ratios of developing a cold, as compared to those sleeping >7hrs per night:
    • <5 hrs/night had OR=4.50 (1.08-18.69)
    • <5-6 hrs/night had OR=4.24 (1.08-16.71)
    • 6-7 hrs/night had a nonsignificant  OR=1.66 (0.40-6.95)
  • These results were independent of prechallenge antibody levels, demographics (e.g. SES, education), season of the year, BMI, various psychological variables (e.g. perceived stress), and health practices (e.g. smoking, physical activity, alcohol)
  • Sleep continuity was not associated with developing a cold
  • Sleep duration was not related to getting the infection, just in getting sick

sleep

I bring up this study for a few reasons:

  • This study fits in with the very large literature on stress and diseaseover the past many decades, showing that both acute and chronic stressors, both physical and mental, can create huge changes in both hormones (essentially all hormones are affected), and in immunologic function (esp T cell and natural killer NK cell function), perhaps largely through the effects of the cortisol increases from the stressors. Of note, at least in several studies which directly looked at this: the issue is not so much the intensity of the stressor, but how the stressor is perceived by the person; and the physiologic effect of the stressor (including cortisol levels) is moderated by the degree of social support that the person has (not surprising that there are mediators to the effect of stress on individuals, since people exposed to the same physical or mental stressor often have different physiological reactions to it).
  • It brings up the limitations of the “germ theory”. Perhaps the main conclusion (to me) of this study is that infectious diseases (at least the vast majority of them) reflect a complex interplay between the characteristics of the bug and the host response to that bug. It is not just the presence of an external stimulus, but its interaction with the human organism.  Not everyone exposed to an organism gets infected (in this study 75.6% actually got infected, though this was not related to decreased sleep) and not everyone who gets infected develops disease (in this study 29.3% got a cold, which was related). In addition, not assessed in this study, there is great variability in the disease severity in those who get the disease, perhaps related to the individual’s immunologic response that is partly determined by the social environment. One summary article noted that even relatively acute sleep deprivation (less than one week) is associated with increases in cortisol, decreases in TSH, increases in prolactin, increases in growth hormone, and  increases in ghrelin/decreases in leptin, which might cause the munchies found with sleep deprivation (see http://www.medscape.org/viewarticle/502825, as well as the whole issue of the journal Brain, Behavior, and Immunity, volume 18, 2004 devoted to the hormonal/immunological effects of sleep deprivation​). Other studies have found sleep deprivation related to increases in inflammatory markers (e.g. C-reactive protein), down regulation of T cell production of interleukin-2, overall decreased proliferative capacity of T cells in vitro, and decreases in NK cells. Of interest, there seems to be a bidirectional association between sleep deficiency and inflammation, with studies finding that cognitive behavioral therapy for older adults with insomnia leads to decreased levels of systemic inflammation (Sleep. 2014; 37: 1543-52).
  • And, as the graph below showed, overall we are getting less sleep over the past 50 years.
  • The presumed association between disease and social conditions, by the way, has been articulated for a long time. For example, Virchow in 1879 wrote: “Don’t crowd diseases (epidemics) point everywhere to deficiencies of society?”​

Primary Care Corner with Geoffrey Modest MD: Pertussis vaccine — not quite up to snuff

19 Mar, 15 | by EBM

By: Dr. Geoffrey Modest

I’ve commented in a few blogs about the resurgence of pertussis, despite immunizing adults with the Tdap. I thought it might be useful to elaborate — there have been a few insights into what seems to be happening.

–In the bad old days, pertussis infection was pretty rampant in the US

–With the development of the whole inactivated  pertussis vaccine in the 1940s, the number of cases plummeted from 157/100K to 1/100K in 1973.

–There have been gradual increases in pertussis since 1982, attributed to the fact that immunity from pertussis is not life-long, as for example, it is with measles. In 2012 there were 42,000 cases in the US. Some of this is undoubtedly ascertainment bias: for example, a study of adolescents/adults with prolonged cough actually looked at it and found that 13-20% had b. Pertussis infection (see Clin Microbiol Rev 2005; 18: 326). Also, newer studies are using PCR and finding much more b. pertussis overall than previously.

–Because of adverse effects (esp high fevers, with about 1 in 330 kids getting temperatures > 105 deg, and about 1/2 getting temps >100.4 —  by the way, these were treatable with acetaminophen, and we used to suggest giving the kid acetaminophen prior to the vaccine, which used to prevent many of the complications), an acellular vaccine was developed in the 1990s based on pieces of the b. pertussis bacterium, renaming the old DPT as DTaP, and was used exclusively in kids (the “a” was for acellular).

–However, it became clear that the immunogenicity of the acellular pertussis component was not as strong as the older inactivated pertussis vaccine (see, for example, NEJM 2012; 367: 785). A California study looked at kids who received their fifth/final dose of DTaP from 2006-2011, a time-span which included the large pertussis outbreak in 2010. They looked at 277 kids who developed pertussis (PCR positive) vs 3318 PCR-negative controls and determined when they received their last DTaP vaccine, finding that those who developed PCR-positive pertussis were more likely to receive their DTaP earlier, with an odds of acquiring pertussis increasing 42% per year (see NEJM 2012; 367: 1012).

–As pertussis infections became more common, the CDC  recommended adults be vaccinated with the acellular vaccine (Tdap) once, though we are now experiencing pertussis outbreaks in adults within a few years after this vaccine was administered (making the suggestion of one vaccine in one’s adult life a tad suspect).

–Infant baboons were infected with b. pertussis bacteria at age 7 months, with 2 groups having been vaccinated before (with either acellular or whole-cell pertussis vaccines at ages 2, 4,and 6 months), a group naive to infection and unvaccinated, and another group who had prior infection. Results: colonization of the nasopharynx was no different in those who were unvaccinated and naive to infection and those immunized with the acellular vaccine (there was a gradual decrease in colonization after 14 days, cleared by 30 days). There was dramatically less colonization in those given whole-cell vaccine (almost all cleared by 14 days). And there was no colonization in those previously infected. Those with nasopharyngeal colonization after acellular vaccine were able to transmit pertussis infection to naive animals.

Also, they found that the actual immunologic T-cell response of those given the whole-cell vaccine was the same as seen in baboons who had natural infection, whereas the acellular vaccine produced a significantly different immunologic response (see doi/10.1073/pnas.1314688110).

–So, let’s see: we have a serious infection which does not create life-long immunity, an old vaccine that really worked well but had too many adverse effects, a new vaccine which not only does not elicit the same immunologic response as the natural infection but seems to work only transiently and probably does not do much to affect colonization or potential transmission….. About time to develop a more effective pertussis vaccine????

Primary Care Corner with Geoffrey Modest MD: Choosing wisely — infectious disease society recommendations

3 Mar, 15 | by EBM

By: Dr. Geoffrey Modest

Will pass along the infectious disease society “choosing-wisely” recommendations for decreasing antibiotic use. Although none of these are new or surprising, data suggest that antibiotics are still being prescribed for these conditions unwisely….  (see here)

  1. Don’t treat asymptomatic bacteruria with antibiotics. (except pregnant patients, those undergoing invasive urological surgery including prostate surgery, or those within 1 year of kidney or kidney pancreas transplant)
  2. Avoid antibiotics for upper respiratory infections. most are viral. But one should treat group A strep and pertussis
  3. Don’t use antibiotics for stasis dermatitis of lower extremities. Use leg elevation and compression. [in my experience, this can be a difficult call: stasis dermatitis can really look like cellulitis with bright red, well-demarcated erythema, though with less induration than cellulitis. And i would add that topical steroids do work quickly with stasis dermatitis]
  4. Don’t test for clostridium difficile infection in the absence of diarrhea. Except if ileus from c. difficile is suspected. In general​, c. diff carriage should not be treated so shouldn’t be looked for
  5. Don’t use prophylactic antibiotics for treatment of mitral valve prolapse as a means to prevent endocarditis.

So, just a reminder.

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