Internal Medicine

Given the patient's presentation with lethargy, headache, confusion, fever, and neck stiffness, along with cerebrospinal fluid (CSF) analysis showing a lymphocytic pleocytosis, a viral encephalitis is strongly suggested. Additionally, the patient lives in Connecticut and is an avid gardener, which increases her exposure to tick-borne diseases.

Powassan virus is a tick-borne flavivirus that can cause encephalitis and is transmitted by the same ticks that spread Lyme disease (Ixodes scapularis). This is particularly relevant given her geographic location in Connecticut, where Powassan virus is endemic.

**Anaplasmosis (A) ** and **Babesiosis

(B) ** are also tick-borne diseases, but they typically present with different symptoms and blood abnormalities, such as leukopenia and thrombocytopenia (anaplasmosis) or hemolytic anemia (babesiosis), neither of which are described in this patient.

**Lyme disease (C) ** can cause neuroborreliosis, but it is less likely given the negative serology for Borrelia burgdorferi.

Thus, the most likely diagnosis is:

**D. Powassan virus infection**

Key Points:

• Clinical Presentation: Swelling and tenderness in multiple joints, rash on lower extremities, and elevated inflammatory markers.

• Risk Factors: Multiple sexual partners and substance use.

• Laboratory Findings: Elevated leukocyte count, neutrophilia, elevated ESR, and CRP.

Neisseria gonorrhoeae is known to cause disseminated infections, presenting with symptoms such as tenosynovitis, dermatitis, and polyarthralgia, which matches the patient's symptoms.

4

The gold standard therapy for non-perforated appendicitis is surgical excision, which can be done laparoscopically or by open procedure. (Nonperforated appendicitis is defined as acute appendicitis that presents without clinical or radiographic signs of perforation, specifically inflammatory mass or abscess). The surgical approach has many advantages e.g., confirms the diagnosis, identifies any perforation or peritonitis that was missed on imaging, and avoids the possibility of recurrent appendicitis.

The attitude towards medical management is changing for children, and this is affecting management of adults.

There is extensive literature on the use of medical therapy after CT confirmed appendicitis. 90% respond to medical management and 10% require rescue surgery, often due to persistent pain. However, 10-30% of patients have recurrent appendicitis, sometimes within two weeks of stopping antibiotics, but sometimes occurring as long as a year later. Thus, medical therapy can be an effective measure for non-perforated appendicitis in low risk patients.

High risk patients would include the elderly, the immunosuppressed, or patients with substantial comorbidities, although the exact definition of these groups in this context can be vague.

A perforated appendix always requires antibiotics and drainage. There are multiple factors that determine whether drainage should be surgical or by interventional radiology, and whether the surgery should be immediate, should follow a period of IV antimicrobial therapy or whether non-operative management (i.e., no removal of the appendix following the initial drainage) is appropriate.

You should know that medical therapy is a reasonable option for non-perforated appendicitis, understanding that CT with contrast often fails to recognize perforations, and that recurrent appendicitis is common following medical management.  

This patient has migratory arthritis which might make one think of disseminated gonorrhea since you are given gratuitous information about her sexual history. The key to this question is the hilar adenopathy and the skin lesions which are nodules rather than the petechial or pustular lesions typical of disseminated gonorrhea. Gonococcemia may be accompanied by arthritis which is not symmetrical and not associated with hilar adenopathy or erythema nodosum.

Lofgren’s Syndrome, a form of sarcoidosis, is characterized by the triad of hilar adenopathy, erythema nodosum and arthritis, typically of the lower extremities.

Rheumatic fever causes a migratory polyarthritis following streptococcal pharyngitis but is not associated with hilar adenopathy.

Dengue viral infection causes joint pain (and is sometimes called “break-bone fever” for that reason) and is endemic to Puerto Rico but does not cause erythema nodosum or hilar adenopathy.

Primary tuberculosis can cause hilar adenopathy without pulmonary infiltrate and erythema nodosum but not the bilateral arthritis seen here.

The most common cause of acute ascending neuromuscular paralysis is Guillain-Barré. The disease is symmetrical and slowly progressive from most distal to proximal. Lack of reflexes and dysautonomia are characteristic. There is no specific diagnostic test although the CSF often shows an elevated protein but normal cell counts (albuminocytologic dissociation).

Campylobacter is the most common and well-established infection associated with subsequent development of Guillain-Barré syndrome. Other infections that have been linked with this disease include HIV, CMV, and influenza. Zika virus infection has also been reported to cause Guillain-Barré syndrome. The presumptive mechanism of infection-related Guillain Barre syndrome is production of an antibody that cross-reacts with host peripheral nerve components because of shared epitopes (i.e., molecular mimicry).

An increased incidence of Guillain-Barré followed influenza immunization for swine flu in 1976-77. Subsequent studies have not confirmed an association between influenza vaccine and Guillain-Barre syndrome. Quinolones may produce a variety of neuropsychiatric side effects, but not Guillain-Barré.

The incubation period for Q Fever (Coxiella burnettii) is usually 14-22 days (range 9-39 days) while Legionella is shorter (2-10 days). Listeria and Brucella don’t cause pneumonia typically, so they don’t fit although Brucella has an incubation period similar to Q fever. The cluster and incubation period do not fit pneumococcal disease.

Humans acquire Q Fever pneumonia due to Coxiella burnetii by inhaling infected aerosols from animals, particularly cattle, goats and sheep, but also cats, dogs, and rabbits. In infected animals, high concentrations of Coxiella are found in the placenta, so aerosols at the time of parturition are often the source of human infection. The incubation period is about 3 weeks. Simultaneous pneumonia and hepatitis should always raise the possibility of Q fever. Thrombocytopenia and a temperature-pulse disparity are common.

The above scenario is based on a well-known outbreak published many years ago that question writers might remember!

Common source outbreaks of pneumococcal pneumonia are rare and usually seen with severe crowding as in jail settings.

Legionella can cause pneumonia, hepatitis, and a temperature-pulse disparity, but the incubation period here is too long and most patients with Legionnaire’s have leukocytosis.

@Everyone

@Everyone

These EKGs show the following patterns:

A) A-V Block

B) Atrial Fibrillation

C) Ventricular Fibrillation

D) Sinus tachycardia

When the infectious process of endocarditis spreads beyond the valve leaflets, mycotic aneurysm of the sinus of Valsalva may form, which can rupture into the interventricular septum and injure the AV node, leading to complete heart block.

Although mycotic aneurysms of the sinus of Valsalva can involve other coronary cusps, rupture into the septum most often results from aneurysms in the noncoronary cusp.

Transesophageal echocardiogram is the most reliable imaging technique to detect aneurysms of the sinus of Valsalva. Surgical repair of a ruptured mycotic aneurysm, usually with aortic valve replacement, can be lifesaving.

Neisseria meningitidis is transmitted person-to-person by respiratory particles, which travel about 3 feet before dropping from the air by the force of gravity or being diluted by the surrounding air. N. meningitidis is a common cause of bacterial meningitis, and therefore, patients with suspected bacterial meningitis are placed on droplet precautions -- personal mask when within 6 feet of the patient.

After 24 hours of effective antimicrobial therapy, patients with meningitis due to Neisseria meningitidis are no longer contagious and hence, in this case in which the patient had been treated for >24 hours, isolation precautions were no longer indicated. @Everyone

Microscopic urine analysis

This physician has obviously had potential exposures since her last PPD. Epidemiologically, she could have been infected with M. tuberculosis by one of her clients at the shelter.

There two major issues here: 1) is the patient really latently infected; 2) is a rifapentine containing preventive regimen the best option for this patient? The use of directly observed therapy (DOT) is also an issue, but is more controversial.

Tuberculosis skin tests are read at 48-72 hours; so, a 48-hour interval is acceptable. Tests may be repeated in 1-3 weeks if initially negative, to look for the "booster" phenomenon (an amnesic response), but this test is already positive and therefore does not need re-testing. Treating an individual for a positive PPD skin test is done based on the likelihood that the test represents latent tuberculosis infection.

If present, latent tuberculosis has about a 2-5% of reactivating during the individual's lifetime. The likelihood of a positive test representing latent disease is based on the amount of induration and pre-test probability of infection. In this case - a physician with plausible patient exposure -10 or more mm of induration would be considered a positive reaction.

Then the question is the appropriate preventive regimen; 6 months of isoniazid, unless there is concern for drug resistance based on exposure history, will reduce the risk of reactivation of tuberculosis by more than 90%.

Three months of daily isoniazid plus rifampin, or 12 weeks of once-weekly isoniazid plus rifapentine, or 4 months of daily rifampin are listed as preferred regimens in current US guidelines. However, and especially for this patient, rifapentine and rifampin have numerous drug interactions (warfarin, certain antidepressants, certain antihypertensives, oral contraceptives, methadone, etc.) and would be a poor choice for someone relying on warfarin for anticoagulation in the setting of a mechanical heart valve.

In some hospitals, when prior BCG vaccination is likely, employees would be screened with an interferon-gamma release assay. The Quantiferon assays and T-SPOT assay have encountered problems of false positives in hospital screening in the United States, but the same could be said of tuberculin skin tests.

ANSWER: C

This patient's chest radiograph is consistent with a large right pneumothorax and complete lung collapse. In addition, there is a leftward mediastinal shift that raises the concern for a tension pneumothorax. The most appropriate next step in management would be placement of a chest tube.

The chest radiograph is notöconsistent with pneumonia, so antibiotics would not be appropriate.

While a pulmonary embolus and non-ST-elevation myocardial infarction could have a similar presentation, the abnormal chest radiograph points to the most likely diagnosis, and a heparin infusion would not be indicated. Cardiac catheterization is not the most appropriate next step in the management of a

pneumothorax because the focus should be on stabilizing the lung condition and ensuring proper healing before considering invasive procedures.

This patient has a cerebrospinal fluid (CSF) shunt infection. Staphylococci are the most likely infecting agents (55-95% of cases), with most caused by coagulase-negative staphylococci. The most common clinical symptoms are headache, nausea, lethargy and altered mental status; fever is reported in 14-92% of cases.

Numerous methods of treating CSF shunt infections have been reported, but no randomized, prospective trials have been performed. The principles of antimicrobial therapy are generally the same as for acute bacterial meningitis. Direct instillation of antimicrobial agents into the ventricles (i.e., through an external ventriculostomy or shunt reservoir) is occasionally needed for difficult to eradicate infections, but the indications for intraventricular administration are not well-defined.

Attempts to treat Staph epidermidis CSF shunt infections with use of systemic antimicrobial agents alone (given by the intravenous and/or intraventricular route) rarely have been successful.

Combining removal of shunt hardware with immediate shunt replacement and intravenous antimicrobial therapy cures approximately 65-75% of patients.

Antimicrobial use with removal of all components of the shunt along with some component of external drainage appears to be the most effective treatment, with treatment success usually >85%. @Everyone

Can we do multiple options?

Currently, the only recommended treatment regimen for pharyngeal gonorrhea is ceftriaxone 500 mg intramuscularly. No other regimen is recommended by the CDC. All patients treated for pharyngeal gonorrhea must have a test of cure nucleic acid amplification test (NAAT) of the pharynx performed one to two weeks after treatment. If antimicrobial resistance is suspected, a pharyngeal sample for culture and antimicrobial susceptibility testing  should also be sent. @Everyone

Guillain-Barre is the most common cause of acute neuromuscular paralysis in the world. Many cases follow an obvious antecedent infection and many such infections have been described. One of the most common of these, if not the most common, is gastroenteritis due to Campylobacter jejuni. Other precipitating infections include cytomegalovirus, Epstein-Barr virus, HIV, and Zika virus. The presumptive mechanism for this syndrome is that the antecedent infection evokes an autoimmune response that cross-reacts with peripheral nerve components because of shared epitopes (i.e., molecular mimicry), resulting in an acute ascending demyelinating polyneuropathy. This immune response is directed against the myelin or the axon of peripheral nerves.

Shigella produces febrile diarrhea and may be associated with seizures but not a Guillain-Barre like illness.

Clostridium botulinum is a very rare cause of GI symptoms other than constipation as part of infant botulism; botulism is a descending paralytic illness.

HSV causes meningitis or encephalitis but is not associated with a Guillain-Barré- like syndrome. Enteroviruses can cause diarrhea and aseptic meningitis but not Guillain-Barré syndrome, although there is mounting evidence that enterovirus D68 is associated with acute flaccid paralysis in children.

@Everyone

Strongyloidiasis is common in Southeast Asia, where she had worked, and in many other parts of the world. Infection is acquired by exposing skin to larvae in fecally contaminated water. Infection may be asymptomatic, and because the roundworm may complete its life cycle within the human host, infection may persist for years to decades.

Steroids may result in dissemination of worms that leave the GI tract carrying along with them GI flora. This may result in Gram-negative rod bacteremia, and less commonly bacteremia due to other gut organisms including Streptococcus gallolyticus or Enterococcus. Meningitis due to these bowel organisms may occur either due to direct bacteremia or larval invasion of the CNS.

S. gallolyticus bacteremia and endocarditis may be associated with underlying bowel disease including colon cancer, and colonoscopy should be considered in patients with S. gallolyticus bacteremia. However, this patient’s young age and the onset with corticosteroids make strongyloidiasis more likely.

CSF leak is a high risk factor for bacterial meningitis, but most cases are due to pneumococci or viridans streptococci; S. gallolyticus would be very unlikely.

Common variable hypogammaglobulinemia is typically associated with a history of recurrent respiratory tract infections, a history absent in this case.

Accidental ingestion of dog fleas may result in human infection with the dog tapeworm, Dipylidium caninum, but meningitis is not seen.

@Everyone

This patient’s illness is most consistent with a diagnosis of Behçet’s Disease, a multisystem inflammatory disease characterized by recurrent painful aphthous oral ulcers, recurrent painful genital ulcers, and eye or skin lesions. Pathergy, development of a red papule or pustule more than one-half centimeter in diameter is often seen one to two days after skin trauma, such as a needle stick. Behçet’s is particularly prevalent in persons of Asian or Eastern Mediterranean descent. Aseptic meningitis, as in this patient, may also occur, as can GI symptoms.

Colchicine has long been the drug of choice for Behçet’s Disease, although is best studied for mucocutaneous disease. Other agents that have been used for treatment include dapsone, corticosteroids, thalidomide, and immunosuppressive agents. Anakinra has been used in refractory cases.

This patient has a classic mononucleosis syndrome. About 90% of mononucleosis like illnesses in adolescents and young adults are due to Epstein-Barr virus, and the peak age for EBV mononucleosis in the United States is 16 to 17 years of age. The Monospot test, a rapid agglutinin test for heterophile antibody, is highly specific but not highly sensitive.

The important point is: The false negative rates are highest during the beginning of clinical symptoms (25 percent are falsely negative in the first week; 5 to 10 percent in the second week, 5 percent in the third week).

Measurement of EBV-specific antibodies is usually not necessary since the majority of patients are heterophile positive. However, testing for EBV-specific antibodies can confirm the diagnosis if the heterophile test is negative and there is a need for a definitive diagnosis. IgM and IgG antibodies directed against viral capsid antigen (VCA) have high (>95%) sensitivity and specificity for the diagnosis of mononucleosis.

Ten percent of mononucleosis syndromes are due to other agents including HIV, CMV (sore throat less likely), toxoplasmosis (no sore throat), HHV-6 and HHV-7.

For strep pharyngitis there should be no splenomegaly and no severe fatigue.

This halo sign is very suggestive (but not diagnostic) of aspergillosis or, less commonly, mucormycosis. Aspergillus species can form a “halo sign” (central dense consolidation surrounded by ground glass infiltrate) seen in Figure A below because they invade and thrombose blood vessels. The nodule is fungus and infarcted lung; the halo is due to hemorrhage into the alveoli. Halo signs occur early in infection and last only a few days. The other diseases listed would be unusual causes of a halo sign in a neutropenic patient.

This patient has classic HAND (HIV-associated neurocognitive disease) with mild ventricular enlargement and periventricular enhancement. The triad of cognitive loss (memory, concentration, and executive function), behavioral issues (apathy) and motor abnormalities (tremor) are typical. This patient has HIV encephalopathy. HHV 8 does not cause encephalopathy.

HHV 6 has occasionally been associated with an acute or subacute encephalopathy, but this is uncommon.

JC encephalitis, also known as Progressive Multifocal leukoencephalopathy, usually manifests with multiple focal white matter lesions. A CSF JC PCR would confirm this diagnosis if the clinical history and MRI were compatible.

With negative serum RPR, CNS syphilis is not likely in a patient of this age. The negative CSF VDRL does not, however, rule out neurosyphilis.

The treatment of choice for HIV encephalopathy is antiretroviral therapy (ART).

The patient’s painful skin lesions, neutrophilic infiltrate and fever are most compatible with Sweet syndrome, one of the so-called neutrophilic dermatoses, often seen in patients with AML, myelodysplastic syndrome or other malignancies.

Appearance of skin lesions as the neutrophils return during G-CSF treatment is a common timing. Were the lesions fungal in origin, the fungal stains of the biopsy would have shown the fungi and culture of the biopsy would have been positive for Candida and or occasionally moulds (e.g., fusarium) at 48 hours. A short, tapering course of prednisone leads to rapid improvement in Sweet syndrome, though relapse can occur.

G-CSF does not cause skin lesions, though some have postulated a role in increasing the incidence of Sweet syndrome.

Herpes simplex hepatitis should be considered when there is marked transaminase elevations in a patient who is either pregnant or immunosuppressed. Onset is sudden with fever, abdominal pain and profound rises in aminotransferases. There are usually no active signs of herpes simplex in the oral mucosa, vagina or skin.

There may be a role for measuring blood HSV DNA level but diagnosis can also be made by in liver tissue collected by biopsy, or at transplantation or autopsy, or in this case, possibly from the skin vesicles.

The dramatic elevations of ALT and AST in this case are incompatible with the other diagnoses listed except hepatitis B but that disease is excluded by a negative HBsAg and negative blood HBV PCR.

Adenovirus can cause fulminant hepatitis in HSCT patients but is not offered as a choice here.

The principal concern in this patient is possible BK virus nephropathy.

Although quantitative PCR of plasma or urine has been advocated for diagnosis, the most reliable diagnostic measure is demonstration of the characteristic basophilic inclusions in renal tubular cells on renal biopsy. Seeing these tubular cells in urine cytology, “decoy cells” is too common to be diagnostic, though absence of these cells suggests against the diagnosis.

BK, a polyoma virus, cannot be cultured by routine measures and large quantities can be found by PCR of urine from immunosuppressed patients without nephropathy. Blood may be positive for BK virus but cannot distinguish between BK nephropathy and rejection, which would be treated differently (reduction versus intensification of immunosuppression).

JC virus causes progressive multifocal leukoencephalopathy, not nephropathy. 

Adenovirus would not be expected to cause azotemia in renal transplant recipients.

CMV is extremely unlikely while on prophylaxis and very rarely causes kidney injury.

ORF is a poxvirus (specifically a parapoxvirus) that causes painless lesions at inoculation sites about 14-21 days after inoculation and which ultimately resolve spontaneously over 4-8 weeks. It does not typically cause systemic symptoms or disseminate except in unusual cases in immunosuppressed hosts. There is no therapy.

The patient has a painless ulcerated nodule. The differential might include anthrax, leishmania, or Buruli ulcer: patients are not necessarily systemically ill with any of these entities (with cutaneous anthrax, however, systemic manifestations may develop). This woman had been in the United States for 5 years, making Leishmania and anthrax unlikely. Anthrax is seen primarily in the United States in bison, not domestic animals. Buruli ulcers, due to M. ulcerans, are acquired in Africa, not the United States.

Orf is common in herds of goats and sheep: contact with oral lesions of animals, or with milking them, can lead to this type of lesion. Presumably this woman had contact with an oral lesion in the sheep head and the virus was then inoculated into her skin by the minor trauma.

Similar cases can occur with goats, deer, or with elk. See the lesion in the goat oropharynx below.