Puzzles: My Favorite Part of the Job

Today I was consulted on a complicated patient with an unexplained elevation of the WBC count. In most cases, there is a standard approach to figuring out what is triggering this immune response. It involves searching for sources of infection such as a pneumonia, urinary tract infection, skin infection, or abscess as well as non-infectious causes too.

However, in some cases it is not an easy task.

Today's patient had received a kidney transplant 10 years ago. Transplantation of an organ necessitates severely suppressing the immune system in order to allow the foreign organ to avoid rejection by the immune system. However, immunosuppression renders the patient vulnerable to infections--ordinary and unusual--and often presents particularly challenging puzzles to the infectious disease physician, something we all relish.

My patient was not only immunosuppressed with an elevated WBC count, he also had a cancerous mass on his wrist, likely another consequence of his immunosuppression. The disabled immune system of a transplant patient is not only impaired in its ability to fight infections, but also in its ability conduct tumor surveillance. As such, cancers are not infrequent in transplant patients. 

To add to the complexity, the patient was found to have a nodule in his lung. In an ordinary patient, a nodule is usually an incidental finding. But, in a transplant patient a nodule can be the result of myriad big and bad things including unusual bacterial, viral,  mycobacterial, or fungal infections as well as cancer. In a transplant patient, the cause of nodules must always be run down lest it cause severe illness (see this excellent review written by my colleagues whom I once trained under).

Pittsburgh, led by the father of transplantation Dr. Thomas Starzl (for whom our transplant center and a street is named), became a city renown for its pioneering work in organ transplantation. Dr. Starzl's memoirs are aptly entitled The Puzzle People. The title refers to the notion of transplant patients as being amalgamations of various puzzle pieces (i.e. transplanted organs) but I also like to think of transplant patients as presenting vexing and intellectually stimulating puzzles to physicians who are forced to think and think again before a solution becomes apparent--an intellectual exercise like no other.

Cerberus visits Pittsburgh: A CRE Like No Other

In most discussions of antimicrobial resistance, the menace of carbapenemase-producing Enterobacteriaceae (CRE) is mentioned. This family of bacteria,  which includes E.coli and Klebsiella species, often cause hospital-acquired infections and are extremely difficult--if not impossible to treat.

The carbapenem class of drugs are, in many ways, the last line of resort and include the drugs: imipenem-cilastatin, meropenem, ertapenem, and doripenem. CRE employ one of 3 enzymes to inactivate this class of drugs:

1. KPC: the most common mechanism in the US
2. NDM-1: reported multiple times in the US and also linked to medical tourism in India
3. OXA-48: only reported twice in the US

A team from the University of Pittsburgh led by Yohei Doi--who I am honored to have been a co-fellow with--recently reported Klebsiella pneumoniae isolated from a patient in Pittsburgh that produces both OXA-48 and NDM-1. The isolate also possessed mutations that conferred high level aminoglycoside resistance.

The patient was a woman initially hospitalized in India for a neurologic condition who was subsequently transferred to Pittsburgh for further care. Once in Pittsburgh, she bounced between the hospital and long term acute care facilities-- a common theme amongst patients who harbor pathogens such as this one. Fortunately, this pathogen was merely colonizing the patient's urinary system and not causing an overt infection meriting treatment.

This case highlights the fact that bacteria, who have dominated the earth for billions of years, are genetically very plastic and can possess several modes of resistance due to selection pressure from antibiotics, uptake of plasmids from other bacteria, or other reasons. Also, the fact that this patient had been hospitalized in India should serve to remind clinicians of the high prevalence of these resistant isolates in other countries (see this excellent review on medical tourism for more information). 

Getting to the Brain by Hijacking miRNA: The EEE story

The mechanism by which Eastern Equine Encephalitis (EEE), a deadly mosquito-borne viral disease with a 50% mortality rate, causes its characteristic illness is the subject of a pathbreaking article in Nature by authors from Pitt's Center for Vaccine Research. 

The paper is focused on the role of miRNAs and their interaction with viral RNA. miRNAs are small pieces of RNA that cells use to regulate the expression of genes. miRNAs have not been thought to have a role in controlling viral genes. In the case of EEE, however, William Klimstra and colleagues found an miRNA that binds to the virus, blunting its ability to infect specific cells of the immune system and, consequently, stops the triggering of an immune response.

This suppression of host immune defenses by exploiting--or hijacking, as the authors put it--host miRNAs allows the virus to reek havoc in the central nervous system causing the signs and symptoms of encephalitis.

Furthermore, the viral sequences that bind the miRNA serve a dual purpose, enhancing replication in the mosquito vector.

The elegance and ingenuity of this viral mechanism is truly fascinating and it will be important to determine if other viruses use similar mechanisms.

Hantavirus: Our Very Own Special Pathogen

That most exotic diseases occur outside the US relegates infectious disease physicians to treating scores of patients with MRSA; diabetic foot infections; pneumonia; urinary tract infections; and the occasional zebra.

One domestic disease that packs all of the punch of its more well known foreign brothers-in-arms, however, is the rodent-associated hantavirus.

Hantavirus Pulmonary Syndrome (HPS) first came to wide notice after a headline-grabbing outbreak occurred in the Navajo-inhabited Four Corners region of the western US in 1993 (see the book Of Mice, Men, and Microbes for a great overview). Since that time, sporadic cases have occurred including an outbreak last year at Yosemite National Park.

A recent paper authored by CDC officials details 20 years of hantavirus infections in the US. Some important points include that a total of 624 cases occurred since 1993 and 96% of cases occurred west of the Mississippi River.

The aspect of hantavirus that I find most fascinating is the association of outbreaks with high amounts of rainfall. When high levels of rainfall occur, such as during an El Niño, rodent populations surge because of the abundance of food available. Such rodent population surges make contact with humans much more common and, consequently, human cases of hantavirus occur. In fact, this correlation was known in Navajo medical traditions long before recent outbreaks.

Though rare, it is important to consider HPS in patients with unexplained pulmonary edema and fever, especially if hemoconcentration is present and the patient is relatively young.

Raw Milk: A Return to the Primitive?

It’s unfortunate that in the 21st Century the American Academy of Pediatrics has to release a policy statement regarding the danger of consuming raw milk. Over 100 years ago, Louis Pasteur discovered that heating wine could prevent it from souring by killing the bacteria responsible. The process was named pasteurization in honor of Pasteur (but the use of heat to preserve food stuffs had been practiced before). It seems that the ongoing fad of raw milk consumption represents a return to the primitive.

During my critical care fellowship, I took care of a patient who consumed raw milk who developed Campylobacter gastroenteritis and subsequent paralysis secondary to Guillan-Barre Syndrome. Though the patient knowingly consumed the raw milk, he subsequently filed a lawsuit labeling the product he consumed “defective”.

To me, the consumption of raw milk represents a dangerous return to a pre-industrial practice that needlessly increases risk. Though I believe it is each adult’s right to consume this—by definition and design—defective product, I find it highly questionable.