Why might hydroxychloroquine and azithromycin be effective against the novel Coronavirus SARS-CoV-2/Covid-19?

Repurposing of older drugs such as chloroquine or hydroxychloroquine (HC) and more recently, azithromycin (AZ), has received much attention recently in the treatment of Covid-19. Both HC and AZ have immune modulating and antiviral activity that may potentially be effective in our fight against Covid-19.

Chloroquine/HC: Chloroquine is an old drug used for its antimalarial activity as well as for its immune modulation and anti-inflammatory properties. It is active in mice against a variety of viruses, including some enteroviruses, Zika virus, and influenza A H5N1 (1). Both chloroquine and HC are active in vitro against Covid-19, though HC appears to be more active (2).

Azithromycin: A macrolide often used for treatment of bacterial respiratory tract infections but also with anti-inflammatory and antiviral activity. Azithromycin has been shown to augment interferon response in rhinovirus-infected bronchial epithelial cells as well as in an experimental mouse model of asthma exacerbation (3,4). It also has activity against Zika virus (5). As recently as 2016, some authors opined that macrolides may be useful in pandemic influenza characterized by excessive inflammatory cytokine production because of their anti-inflammatory and interferon-boosting potential (6).

March 2020 French clinical trial: A small non-randomized clinical trial involving 36 confirmed Covid-19 patients (mean age 45 y) reported that HC (200 mg 3x/day x 10 days) was associated with rapid viral clearance from nasopharynx, often within 3-6 days (7). The effect was even more pronounced when AZ (500 mg 1st day, followed by 250 mg daily x 4 days) was added in 6 patients.

It’s worth emphasizing that most subjects in this study were either asymptomatic (17%) or had mild disease with upper respiratory tract infection symptoms only (61%). Pneumonia was diagnosed in only 6 patients.  A significant number of patients in the treatment arm also dropped out of the study, some due to ICU transfer.

Although such preliminary reports appear promising, the proof of the efficacy and safety of HC and/or AZ in the treatment of Covid-19 awaits larger properly designed clinical studies. Stay tuned!



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1. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Research 2020;177. 104762. https://www.ncbi.nlm.nih.gov/pubmed/32147496
2. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respirartory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020, March 9. https://www.ncbi.nlm.nih.gov/pubmed/32150618
3. Menzel M, Akbarshai H, Bjermer L, et al. Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD patients. Scientific Reports 2016;6:28698. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923851/
4. Menzel M, Akbarshai H, Uller L. Azithromycin exhibits interferon-inducing properties in an experimental mouse model of asthma exacerbation. Eur Resp J 2015;46:PA5095. https://erj.ersjournas.com/content/46/suppl_59/PA5095
5. Retallack H, Di Lullo E, Knopp AC, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Nat Acad Sci USA 2016;113:14408-13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167169/
6. Porter JD, Watson J, Roberts LR, et al. Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III-IFN-augmenting activity in airway epithelium. J Antimicrob Chemother 2016;71:2767-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031920/
7. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19:results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents—In Press 17 March 2020-DOI: 10.1016/j.ijantimicag.2020.105949 . https://www.sciencedirect.com/science/article/pii/S0924857920300996


Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why might hydroxychloroquine and azithromycin be effective against the novel Coronavirus SARS-CoV-2/Covid-19?

Should I consider acute acalculous cholecystitis in my elderly ambulatory patient admitted with right upper quadrant pain?

Short answer: Yes! Although we usually associate acute acalculous cholecystitis (AAC) with critically ill patients (eg, with sepsis, trauma, shock, major burns) in ICUs, AAC is not as rare as we might think in ambulatory patients. In fact, a 7 year study of AAC involving multiple centers reported that AAC among outpatients was increasing in prevalence and accounted for 77% of all cases (1)!

Although the pathophysiology of ACC is not fully understood, bile stasis and ischemia of the gallbladder either due to microvascular or macrovascular pathology have been implicated as potential causes (2). One study found that 72% of outpatients who developed ACC had atherosclerotic disease associated with hypertension, coronary, peripheral or cerebral vascular disease, diabetes or congestive heart failure (1). Interestingly, in contrast to calculous cholecystitis, “multiple arterial occlusions” have been observed on pathological examination of the gallbladder in at least some patients with ACC and accordingly a name change to “acute ischemic cholecystitis” has been proposed (3).

AAC can also complicate acute mesenteric ischemia and may herald critical ischemia and mesenteric infarction (3). The fact that cystic artery is a terminal branch artery probably doesn’t help and leaves the gallbladder more vulnerable to ischemia when arterial blood flow is compromised irrespective of the cause (4).

Of course, besides vascular ischemia there are numerous other causes of ACC, including infectious (eg, viral hepatitis, cytomegalovirus, Epstein-Barr virus, Salmonella, brucellosis, malaria, Rickettsia and enteroviruses), as well as many non-infectious causes such as vasculitides and, more recently, check-point inhibitor toxicity (1,5-8).

Bonus Pearl: Did you know that in contrast to cholecystitis associated with gallstones (where females and 4th and 5th decade age groups predominate), ACC in ambulatory patients is generally more common among males and older age groups (mean age 65 y) (1)?


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1. Savoca PE, Longo WE, Zucker KA, et al. The increasing prevalence of acalculous cholecystitis in outpatients: Result of a 7-year study. Ann Surg 1990;211: 433-37. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1358029/pdf/annsurg00170-0061.pdf
2. Huffman JL, Schenker S. Acute acalculous cholecystitis: A review. Clin Gastroenterol Hepatol 2010;8:15-22. https://www.cghjournal.org/article/S1542-3565(09)00880-5/pdf
3. Hakala T, Nuutinene PJO, Ruokonen ET, et al. Microangiopathy in acute acalculous cholecystitis Br J Surg 1997;84:1249-52. https://bjssjournals.onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2168.1997.02775.x?sid=nlm%3Apubmed
4. Melo R, Pedro LM, Silvestre L, et al. Acute acalculous cholecystitis as a rare manifestation of chronic mesenteric ischemia. A case report. Int J Surg Case Rep 2016;25:207-11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941110/
5. Aguilera-Alonso D, Median EVL, Del Rosal T, et al. Acalculous cholecystitis in a pediatric patient with Plasmodium falciparum infection: A case report and literature review. Ped Infect Dis J 2018;37: e43-e45. https://journals.lww.com/pidj/pages/articleviewer.aspx?year=2018&issue=02000&article=00020&type=Fulltext  
6. Kaya S, Eskazan AE, Ay N, et al. Acute acalculous cholecystitis due to viral hepatitis A. Case Rep Infect Dis 2013;Article ID 407182. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784234/pdf/CRIM.ID2013-407182.pdf
7. Simoes AS, Marinhas A, Coelho P, et al. Acalculous acute cholecystitis during the course of an enteroviral infection. BMJ Case Rep 2013;12. https://casereports.bmj.com/content/12/4/e228306
8. Abu-Sbeih H, Tran CN, Ge PS, et al. Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment. J ImmunoTherapy of Cancer 2019;7:118. https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0604-2



Should I consider acute acalculous cholecystitis in my elderly ambulatory patient admitted with right upper quadrant pain?

My previously healthy patient developed a viral illness with fever and headache few days after swimming in a community pool. Can swimming pools be a source of viral infection?

Yes! Swimming pools have been implicated in the transmission of a variety of pathogens,  including enteric viruses (eg, echovirus, coxackie virus, hepatitis A virus, norovirus) which account for nearly one-half of all swimming pool-related outbreaks.  Adenoviruses also account for a significant number of swimming pool outbreaks.1,2

The most commonly reported symptoms in swimming pool outbreaks have been gastroenteritis, respiratory symptoms and conjunctivitis. However, aseptic meningitis and hepatitis may also occur. 1

Because viruses cannot replicate in the environment outside of host tissues, their presence in swimming pool is the result of direct contamination by those in the water who may shed viruses through unintentional fecal release or through body fluids, such as saliva, mucus, or vomitus.  The finding of E. coli in 58% of pool water samples in 1 CDC study suggests the presence of stool as a primary source of infection.3

On average, each person has 0.14 grams (range 0.1 gram to 10 grams) of fecal material on their perianal surface that could rinse into the water if pre-swim shower with soap is omitted.4-5 Coupled with the potential for inadequate disinfection or chlorination of pool water, it is not surprising that swimming pools may serve as a source of infection.  

CDC recommends keeping feces and urine out of the water, checking the chlorine level and pH before getting into the water and not swallowing the water you swim in.3 

Bonus pearl: Did you know that pool water has also been associated with Cryptosporidium and Giardia and waterslides with E.coli-0157 outbreaks?

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  1. Bonadonna L, La Rosa G. A review and update on waterborne viral diseases associated with swimming pools. Int j Environ Res Public Health 2019;16, 166. Doi:10.3390/ijerph16020166. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352248/
  2. Keswick BH, Gebra CP, Goyal SM. Occurrence of enteroviruses in community swimming pools. Am J Public Health 1981;71:1026030. https://www.ncbi.nlm.nih.gov/pubmed/6267950
  3. CDC.Microbes in pool filter backwash as evidence of the need for improved swimmer hygiene—Metro-Atlanta, Georgia, 2012. MMWR 2013;62:385-88. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6219a3.htm
  4. Gerba CP. Assessment of enteric pathogen shedding by bathers during recreational activity and its impact on water quality. Quant Microbiol 2000; 2:55-68 https://arizona.pure.elsevier.com/en/publications/assessment-of-enteric-pathogen-shedding-by-bathers-during-recreat
  5. CDC. Model Aquatic Health Code. 8.0 Annexes: fecal/vomit/blood contamination response Annex (6.0 policies and management), 2008. https://www.cdc.gov/healthywater/pdf/swimming/pools/mahc/structure-content/mahc-fecal-vomit-blood-contamination-response-annex.pdf
  6. CDC. Surveillance of waterborne disease outbreaks and other health events associated with recreational water—United States, 2007-2008 and surveillance of waterborne disease outbreaks associated with drinking water—United States, 2007-2008. MMWR 2011;60. 1-76. https://www.ncbi.nlm.nih.gov/pubmed/21937976



My previously healthy patient developed a viral illness with fever and headache few days after swimming in a community pool. Can swimming pools be a source of viral infection?

My patient with acute onset headache, photophobia, and neck stiffness does not have CSF pleocytosis. Could she still have meningitis?

Although the clinical diagnosis of meningitis is often supported by the presence of abnormal number of WBCs in the CSF (AKA pleocytosis), meningitis may be present despite its absence.

Among viral causes of meningitis in adults, enteroviruses are associated with lower CSF WBC count compared to herpes simplex and varicella zoster, with some patients (~10%) having 0-2 WBC’s/mm31,2.  Of interest, among children, parechovirus (formerly echovirus 22 and 23) meningitis is characterized by normal CSF findings3.

Though uncommon, bacterial meningitis without CSF pleocytosis has been reported among non-neutropenic adults,  including Neisseria meningitidis, Streptococcus pneumoniae, Hemophilus influenzae, Listeria monocytogenes, E. coli, and Proteus mirabilis4A European study also reported normal CSF WBC in nearly 10% of patients with Lyme neuroborreliosis (including meningitis) caused primarily by Borrelia garinii5.

Cryptococcal meninigitis may also be associated with normal CSF profile in 25% of patients with HIV infection6.



  1. Ihekwaba UK, Kudesia G, McKendrick MW. Clinical features of viral meningitis in adult:significant differences in cerebrospinal fluid findings among herpes simplex virus, varicella zoster virus, and enterovirus infections. Clin Infect Dis 2008;47:783-9. https://www.ncbi.nlm.nih.gov/pubmed/18680414
  2. Dawood N, Desjobert E, Lumley J et al. Confirmed viral meningitis with normal CSF findings. BMJ Case Rep 2014. Doi:10.1136/bcr-2014-203733. http://casereports.bmj.com/content/2014/bcr-2014-203733.abstract
  3. Wolthers KC, Benschop KSM, Schinkel J, et al. Human parechovirus as an important viral cause of sepsis like illness and meningitis in young children. Clin Infect Dis 2008;47:358-63. https://www.ncbi.nlm.nih.gov/pubmed/18558876
  4. Hase R, Hosokawa N, Yaegashi M, et al. Bacterial meningitis in the absence of cerebrospinal fluid pleocytosis: A case report and review of the literature. Can J Infect Dis Med Microbiol 2014;25:249:51. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211346/pdf/idmm-25-249.pdf
  5. Ogrinc K, Lotric-Furlan S, Maraspin  V, et al. Suspected early Lyme neuroborreliosis in patients with erythema migrans. Clin Infect Dis 2013; 57:501-9. https://www.ncbi.nlm.nih.gov/pubmed?term=23667259
  6. Darras-Joly C, Chevret S, Wolff M, et al. Cryptococcus neoformans infection in France: epidemiologic features of and early prognostic parameters for 76 patients who were infected with human immunodeficiency virus. Clin Infect Dis 1996;23:369-76. https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/cid/23/2/10.1093/clinids/23.2.369/2/23-2-369.pdf?Expires=1501035620&Signature=FhHMHUHAMmT3rz4ld8QAMet-weu-BWgm5YR6nA4jjSGVGIeaVlMNPgeOkW2fniiel54HQhIs1Kkp3PpzT1glxhJeZvQiGXQCSOoF-jS1SK7S~kBb-oHs4qsIJzN0OJxNAXfoJi4bl7OeKaLTyIE3P8~slwH0BBi7RncSYVgVR4NkOnFpYgn27~wY7pDSUNWvzGFKoSeYGeM0TsAqna-QmXzodITB5bgr1mO6Q6OGUxCsqRwhr6xNb~4G93oqRcsO19gyUluCE0xYt0KbKWuQxJeh8AbtJkNrS08~XInMR50bQZOUb80j0~dtg9jRTGzXQaDllVByoX2Alr48hlhogw__&Key-Pair-Id=APKAIUCZBIA4LVPAVW3Q
My patient with acute onset headache, photophobia, and neck stiffness does not have CSF pleocytosis. Could she still have meningitis?